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  1. Spinal Muscular Atrophy (SMA)

    MedlinePlus

    ... Habits for TV, Video Games, and the Internet Spinal Muscular Atrophy (SMA) KidsHealth > For Parents > Spinal Muscular Atrophy (SMA) Print ... treatment for the disease's most troubling symptoms. About SMA Normally, healthy nerve cells in the brain called ...

  2. Spinal Muscular Atrophy (SMA)

    MedlinePlus

    ... children with SMA develop spinal deformities, such as scoliosis (sideways curvature of the spine) and kyphosis (front- ... Magnetic Resonance Imaging (MRI) Brain and Nervous System Scoliosis Contact Us Print Resources Send to a friend ...

  3. Types of SMA (Spinal Muscular Atrophy)

    MedlinePlus

    ... initially able to walk, but have increasingly limited mobility as they grow and eventually, many need to ... SMA Causes & Diagnosis What Diagnosis Means Research Our Strategy Latest Advances For Researchers Research Publications Spinraza Support & ...

  4. Genetic testing and risk assessment for spinal muscular atrophy (SMA).

    PubMed

    Ogino, Shuji; Wilson, Robert B

    2002-12-01

    Spinal muscular atrophy (SMA) is one of the most common autosomal recessive diseases, affecting approximately 1 in 10,000 live births, and with a carrier frequency of approximately 1 in 50. Because of gene deletion or conversion, SMN1 exon 7 is homozygously absent in approximately 94% of patients with clinically typical SMA. Approximately 30 small intragenic SMN1 mutations have also been described. These mutations are present in many of the approximately 6% of SMA patients who do not lack both copies of SMN1, whereas SMA of other patients without a homozygous absence of SMN1 is unrelated to SMN1. A commonly used polymerase chain reaction/restriction fragment length polymorphism (PCR-RFLP) assay can be used to detect a homozygous absence of SMN1 exon 7. SMN gene dosage analyses, which can determine the copy numbers of SMN1 and SMN2 (an SMN1 homolog and a modifier for SMA), have been developed for SMA carrier testing and to confirm that SMN1 is heterozygously absent in symptomatic individuals who do not lack both copies of SMN1. In conjunction with SMN gene dosage analysis, linkage analysis remains an important component of SMA genetic testing in certain circumstances. Genetic risk assessment is an essential and integral component of SMA genetic testing and impacts genetic counseling both before and after genetic testing is performed. Comprehensive SMA genetic testing, comprising PCR-RFLP assay, SMN gene dosage analysis, and linkage analysis, combined with appropriate genetic risk assessment and genetic counseling, offers the most complete evaluation of SMA patients and their families at this time. New technologies, such as haploid analysis techniques, may be widely available in the future.

  5. Columbia SMA Project: A Randomized, Control Trial of the Effects of Exercise on Motor Function and Strength in Patients With Spinal Muscular Atrophy (SMA)

    DTIC Science & Technology

    2011-06-01

    www.CQillmbiasma.org No. 1994 ?. 2 Musc::ular Dystrophy Assoc1at1on (hUAJ Clinic Spinal Muscular Atrophy Clinical (SMA) Research Center Nan<:y E. Strauss, M.D...3 ~ COLUMBIA UNIVERSIT~ 0 ~ Muscutar Dystrophy Association (MDA) Clinic \\WI M C Spinal Muscular Atrophy Clinical {SMA) - EDICAL ENTER Research...9lu mbi~_rlli:’U~t9 0000000000 p.1 Muscular Dystrophy Association (MDA) Clinic Spinal Muscular Atrophy Clinical (SMA) Research Center Nancy E

  6. SMA-MAP: a plasma protein panel for spinal muscular atrophy.

    PubMed

    Kobayashi, Dione T; Shi, Jing; Stephen, Laurie; Ballard, Karri L; Dewey, Ruth; Mapes, James; Chung, Brett; McCarthy, Kathleen; Swoboda, Kathryn J; Crawford, Thomas O; Li, Rebecca; Plasterer, Thomas; Joyce, Cynthia; Chung, Wendy K; Kaufmann, Petra; Darras, Basil T; Finkel, Richard S; Sproule, Douglas M; Martens, William B; McDermott, Michael P; De Vivo, Darryl C; Walker, Michael G; Chen, Karen S

    2013-01-01

    Spinal Muscular Atrophy (SMA) presents challenges in (i) monitoring disease activity and predicting progression, (ii) designing trials that allow rapid assessment of candidate therapies, and (iii) understanding molecular causes and consequences of the disease. Validated biomarkers of SMA motor and non-motor function would offer utility in addressing these challenges. Our objectives were (i) to discover additional markers from the Biomarkers for SMA (BforSMA) study using an immunoassay platform, and (ii) to validate the putative biomarkers in an independent cohort of SMA patients collected from a multi-site natural history study (NHS). BforSMA study plasma samples (N = 129) were analyzed by immunoassay to identify new analytes correlating to SMA motor function. These immunoassays included the strongest candidate biomarkers identified previously by chromatography. We selected 35 biomarkers to validate in an independent cohort SMA type 1, 2, and 3 samples (N = 158) from an SMA NHS. The putative biomarkers were tested for association to multiple motor scales and to pulmonary function, neurophysiology, strength, and quality of life measures. We implemented a Tobit model to predict SMA motor function scores. 12 of the 35 putative SMA biomarkers were significantly associated (p<0.05) with motor function, with a 13(th) analyte being nearly significant. Several other analytes associated with non-motor SMA outcome measures. From these 35 biomarkers, 27 analytes were selected for inclusion in a commercial panel (SMA-MAP) for association with motor and other functional measures. Discovery and validation using independent cohorts yielded a set of SMA biomarkers significantly associated with motor function and other measures of SMA disease activity. A commercial SMA-MAP biomarker panel was generated for further testing in other SMA collections and interventional trials. Future work includes evaluating the panel in other neuromuscular diseases, for pharmacodynamic

  7. SMA-MAP: A Plasma Protein Panel for Spinal Muscular Atrophy

    PubMed Central

    Kobayashi, Dione T.; Shi, Jing; Stephen, Laurie; Ballard, Karri L.; Dewey, Ruth; Mapes, James; Chung, Brett; McCarthy, Kathleen; Swoboda, Kathryn J.; Crawford, Thomas O.; Li, Rebecca; Plasterer, Thomas; Joyce, Cynthia; Chung, Wendy K.; Kaufmann, Petra; Darras, Basil T.; Finkel, Richard S.; Sproule, Douglas M.; Martens, William B.; McDermott, Michael P.; De Vivo, Darryl C.; Walker, Michael G.; Chen, Karen S.

    2013-01-01

    Objectives Spinal Muscular Atrophy (SMA) presents challenges in (i) monitoring disease activity and predicting progression, (ii) designing trials that allow rapid assessment of candidate therapies, and (iii) understanding molecular causes and consequences of the disease. Validated biomarkers of SMA motor and non-motor function would offer utility in addressing these challenges. Our objectives were (i) to discover additional markers from the Biomarkers for SMA (BforSMA) study using an immunoassay platform, and (ii) to validate the putative biomarkers in an independent cohort of SMA patients collected from a multi-site natural history study (NHS). Methods BforSMA study plasma samples (N = 129) were analyzed by immunoassay to identify new analytes correlating to SMA motor function. These immunoassays included the strongest candidate biomarkers identified previously by chromatography. We selected 35 biomarkers to validate in an independent cohort SMA type 1, 2, and 3 samples (N = 158) from an SMA NHS. The putative biomarkers were tested for association to multiple motor scales and to pulmonary function, neurophysiology, strength, and quality of life measures. We implemented a Tobit model to predict SMA motor function scores. Results 12 of the 35 putative SMA biomarkers were significantly associated (p<0.05) with motor function, with a 13th analyte being nearly significant. Several other analytes associated with non-motor SMA outcome measures. From these 35 biomarkers, 27 analytes were selected for inclusion in a commercial panel (SMA-MAP) for association with motor and other functional measures. Conclusions Discovery and validation using independent cohorts yielded a set of SMA biomarkers significantly associated with motor function and other measures of SMA disease activity. A commercial SMA-MAP biomarker panel was generated for further testing in other SMA collections and interventional trials. Future work includes evaluating the panel in other neuromuscular

  8. Spinal Muscular Atrophy

    MedlinePlus

    ... here Home » Disorders » Patient & Caregiver Education » Fact Sheets Spinal Muscular Atrophy Fact Sheet What is spinal muscular atrophy? What ... Where can I get more information? What is spinal muscular atrophy? Spinal muscular atrophy (SMA) is one of several ...

  9. Review of Spinal Muscular Atrophy (SMA) for Prenatal and Pediatric Genetic Counselors.

    PubMed

    Carré, Amanda; Empey, Candice

    2016-02-01

    Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular condition with degeneration of the anterior horn cells in the spinal column. Five SMA subtypes exist with classification dependent upon the motor milestones achieved. Study of the SMN1 (survival motor neuron) and SMN2 genes as well as the concepts of the "2 + 0" carriers, gene conversion, de novo mutations and intragenic mutations allow for a better understanding of SMA. Detailing the carrier and diagnostic testing options further deepens the genetic counselor's knowledge of SMA. A review of care guidelines and research options is included as this information gives a patient a well-rounded view of SMA. Although SMA is most commonly associated with the SMN1 gene, a number of spinal muscular atrophies not caused by genetic changes in this gene may be included as differential diagnoses until confirmatory testing can be completed. SMA is a complex condition requiring a detailed knowledge on the genetic counselor's part in order to explain the disorder to the patient with clarity thus facilitating increased communication and decision making guidance with the patient.

  10. [Prenatal diagnosis of spinal muscular atrophy (SMA) -- indications, restrictions, interpretation of results].

    PubMed

    Jedrzejowska, Maria; Zimowski, Janusz; Wiszniewski, Wojciech; Sielska, Danuta; Bal, Jerzy; Mazurczak, Tadeusz; Hausmanowa-Petrusewicz, Irena; Zaremba, Jacek

    2004-01-01

    Proximal spinal muscular atrophy of childhood and adolescence (SMA) is a genetic autosomal recessive disease. Caused in 96.5% by deletion in the SMN1 gene. Owing to the homogeneity of the molecular defect. Secondary prophylaxis can readily be offered to families at risk of SMA. Prenatal diagnosis of SMA was carried out in a group of 50 families. Which were divided into two subgroups: with high and relatively low genetic risk of SMA. In all, 55 prenatal tests were performed in the period 1998-2003. In the first group including 45 families at high genetic risk, 9 of the 50 tests were positive (18%). The diagnosis of SMA was tentative in 7 cases from this group and it was based only on the clinical picture (the affected children are not alive, therefore DNA samples are not available). Prenatal examination in 1 of these 7 families showed the SMA genotype. In the second subgroup including 5 families with relatively low genetic risk of SMA in none of the studies was there a biallelic deletion of exon 7 in the SMNI gene. Mainly parents of children with a severe form of SMA and having no healthy offspring asked for prenatal examination (73% of the families). Prenatal diagnosis could be offered to families even if the diagnosis of SMA was not genetically verified. The negative result should he then interpreted individually. Until the carrier test will not he introduced to routine procedures. prenatal diagnosis can be also offered to families at relatively low risk of SMA.

  11. Isolation of cDNA clones from within the spinal muscular atrophy (SMA) disease gene region

    SciTech Connect

    McLean, M.; Roy, N.; Tamai, K.

    1994-09-01

    Spinal muscular atrophy (SMA) is a recessive neuromuscular disease characterized by death of spinal cord {alpha} motor neurons, resulting in skeletal muscle atrophy. The critical SMA disease gene region on 5q13.1 contains families of microsatellite repeat sequences which exist at multiple subloci that are dispersed over a 100 to 200 kbp region. We have detected significant linkage disequilibrium between SMA type 1, the most severe form of the disorder, and two subloci of one such microsatellite, the CATT-1 family of microsatellites. Furthermore, a recombination event in a chromosome of an individual with SMA type 1 mapping between the members of two other extended microsatellite families, including CMS-1, has been observed. Combining this with previously reported recombinants refines the critical SMA region to approximately 300 kbp. P1 artificial chromosome (PAC), YAC and cosmid clones which possess both CMS-1 alleles which bracket this recombination event, as well as CATT-1 alleles showing linkage disequilibrium with SMA, have been used to probe cDNA libraries from human and other mammalian sources in search of genes within this interval; three of these cDNAs are currently being tested as candidates for the SMA gene.

  12. Revised Hammersmith Scale for spinal muscular atrophy: A SMA specific clinical outcome assessment tool.

    PubMed

    Ramsey, Danielle; Scoto, Mariacristina; Mayhew, Anna; Main, Marion; Mazzone, Elena S; Montes, Jacqueline; de Sanctis, Roberto; Dunaway Young, Sally; Salazar, Rachel; Glanzman, Allan M; Pasternak, Amy; Quigley, Janet; Mirek, Elizabeth; Duong, Tina; Gee, Richard; Civitello, Matthew; Tennekoon, Gihan; Pane, Marika; Pera, Maria Carmela; Bushby, Kate; Day, John; Darras, Basil T; De Vivo, Darryl; Finkel, Richard; Mercuri, Eugenio; Muntoni, Francesco

    2017-01-01

    Recent translational research developments in Spinal Muscular Atrophy (SMA), outcome measure design and demands from regulatory authorities require that clinical outcome assessments are 'fit for purpose'. An international collaboration (SMA REACH UK, Italian SMA Network and PNCRN USA) undertook an iterative process to address discontinuity in the recorded performance of the Hammersmith Functional Motor Scale Expanded and developed a revised functional scale using Rasch analysis, traditional psychometric techniques and the application of clinical sensibility via expert panels. Specifically, we intended to develop a psychometrically and clinically robust functional clinician rated outcome measure to assess physical abilities in weak SMA type 2 through to strong ambulant SMA type 3 patients. The final scale, the Revised Hammersmith Scale (RHS) for SMA, consisting of 36 items and two timed tests, was piloted in 138 patients with type 2 and 3 SMA in an observational cross-sectional multi-centre study across the three national networks. Rasch analysis demonstrated very good fit of all 36 items to the construct of motor performance, good reliability with a high Person Separation Index PSI 0.98, logical and hierarchical scoring in 27/36 items and excellent targeting with minimal ceiling. The RHS differentiated between clinically different groups: SMA type, World Health Organisation (WHO) categories, ambulatory status, and SMA type combined with ambulatory status (all p < 0.001). Construct and concurrent validity was also confirmed with a strong significant positive correlation with the WHO motor milestones rs = 0.860, p < 0.001. We conclude that the RHS is a psychometrically sound and versatile clinical outcome assessment to test the broad range of physical abilities of patients with type 2 and 3 SMA. Further longitudinal testing of the scale with regards change in scores over 6 and 12 months are required prior to its adoption in clinical trials.

  13. Revised Hammersmith Scale for spinal muscular atrophy: A SMA specific clinical outcome assessment tool

    PubMed Central

    Scoto, Mariacristina; Mayhew, Anna; Main, Marion; Mazzone, Elena S.; Montes, Jacqueline; de Sanctis, Roberto; Dunaway Young, Sally; Salazar, Rachel; Glanzman, Allan M.; Pasternak, Amy; Quigley, Janet; Mirek, Elizabeth; Duong, Tina; Gee, Richard; Civitello, Matthew; Tennekoon, Gihan; Pane, Marika; Pera, Maria Carmela; Bushby, Kate; Day, John; Darras, Basil T.; De Vivo, Darryl; Finkel, Richard; Mercuri, Eugenio; Muntoni, Francesco

    2017-01-01

    Recent translational research developments in Spinal Muscular Atrophy (SMA), outcome measure design and demands from regulatory authorities require that clinical outcome assessments are ‘fit for purpose’. An international collaboration (SMA REACH UK, Italian SMA Network and PNCRN USA) undertook an iterative process to address discontinuity in the recorded performance of the Hammersmith Functional Motor Scale Expanded and developed a revised functional scale using Rasch analysis, traditional psychometric techniques and the application of clinical sensibility via expert panels. Specifically, we intended to develop a psychometrically and clinically robust functional clinician rated outcome measure to assess physical abilities in weak SMA type 2 through to strong ambulant SMA type 3 patients. The final scale, the Revised Hammersmith Scale (RHS) for SMA, consisting of 36 items and two timed tests, was piloted in 138 patients with type 2 and 3 SMA in an observational cross-sectional multi-centre study across the three national networks. Rasch analysis demonstrated very good fit of all 36 items to the construct of motor performance, good reliability with a high Person Separation Index PSI 0.98, logical and hierarchical scoring in 27/36 items and excellent targeting with minimal ceiling. The RHS differentiated between clinically different groups: SMA type, World Health Organisation (WHO) categories, ambulatory status, and SMA type combined with ambulatory status (all p < 0.001). Construct and concurrent validity was also confirmed with a strong significant positive correlation with the WHO motor milestones rs = 0.860, p < 0.001. We conclude that the RHS is a psychometrically sound and versatile clinical outcome assessment to test the broad range of physical abilities of patients with type 2 and 3 SMA. Further longitudinal testing of the scale with regards change in scores over 6 and 12 months are required prior to its adoption in clinical trials. PMID:28222119

  14. Molecular, genetic and stem cell-mediated therapeutic strategies for spinal muscular atrophy (SMA).

    PubMed

    Zanetta, Chiara; Riboldi, Giulietta; Nizzardo, Monica; Simone, Chiara; Faravelli, Irene; Bresolin, Nereo; Comi, Giacomo P; Corti, Stefania

    2014-02-01

    Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease. It is the first genetic cause of infant mortality. It is caused by mutations in the survival motor neuron 1 (SMN1) gene, leading to the reduction of SMN protein. The most striking component is the loss of alpha motor neurons in the ventral horn of the spinal cord, resulting in progressive paralysis and eventually premature death. There is no current treatment other than supportive care, although the past decade has seen a striking advancement in understanding of both SMA genetics and molecular mechanisms. A variety of disease modifying interventions are rapidly bridging the translational gap from the laboratory to clinical trials. In this review, we would like to outline the most interesting therapeutic strategies that are currently developing, which are represented by molecular, gene and stem cell-mediated approaches for the treatment of SMA.

  15. Molecular, genetic and stem cell-mediated therapeutic strategies for spinal muscular atrophy (SMA)

    PubMed Central

    Zanetta, Chiara; Riboldi, Giulietta; Nizzardo, Monica; Simone, Chiara; Faravelli, Irene; Bresolin, Nereo; Comi, Giacomo P; Corti, Stefania

    2014-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease. It is the first genetic cause of infant mortality. It is caused by mutations in the survival motor neuron 1 (SMN1) gene, leading to the reduction of SMN protein. The most striking component is the loss of alpha motor neurons in the ventral horn of the spinal cord, resulting in progressive paralysis and eventually premature death. There is no current treatment other than supportive care, although the past decade has seen a striking advancement in understanding of both SMA genetics and molecular mechanisms. A variety of disease modifying interventions are rapidly bridging the translational gap from the laboratory to clinical trials. In this review, we would like to outline the most interesting therapeutic strategies that are currently developing, which are represented by molecular, gene and stem cell-mediated approaches for the treatment of SMA. PMID:24400925

  16. Plastin 3 Expression Does Not Modify Spinal Muscular Atrophy Severity in the ∆7 SMA Mouse

    PubMed Central

    Wang, Xueyong; Le, Thanh T.; Le, Hao T.; Beattie, Christine E.; Rich, Mark M.; Burghes, Arthur H. M.

    2015-01-01

    Spinal muscular atrophy is caused by loss of the SMN1 gene and retention of SMN2. The SMN2 copy number inversely correlates with phenotypic severity and is a modifier of disease outcome. The SMN2 gene essentially differs from SMN1 by a single nucleotide in exon 7 that modulates the incorporation of exon 7 into the final SMN transcript. The majority of the SMN2 transcripts lack exon 7 and this leads to a SMN protein that does not effectively oligomerize and is rapidly degraded. However the SMN2 gene does produce some full-length SMN and the SMN2 copy number along with how much full-length SMN the SMN2 gene makes correlates with severity of the SMA phenotype. However there are a number of discordant SMA siblings that have identical haplotypes and SMN2 copy number yet one has a milder form of SMA. It has been suggested that Plastin3 (PLS3) acts as a sex specific phenotypic modifier where increased expression of PLS3 modifies the SMA phenotype in females. To test the effect of PLS3 overexpression we have over expressed full-length PLS3 in SMA mice. To ensure no disruption of functionality or post-translational processing of PLS3 we did not place a tag on the protein. PLS3 protein was expressed under the Prion promoter as we have shown previously that SMN expression under this promoter can rescue SMA mice. High levels of PLS3 mRNA were expressed in motor neurons along with an increased level of PLS3 protein in total spinal cord, yet there was no significant beneficial effect on the phenotype of SMA mice. Specifically, neither survival nor the fundamental electrophysiological aspects of the neuromuscular junction were improved upon overexpression of PLS3 in neurons. PMID:26134627

  17. Plastin 3 Expression Does Not Modify Spinal Muscular Atrophy Severity in the ∆7 SMA Mouse.

    PubMed

    McGovern, Vicki L; Massoni-Laporte, Aurélie; Wang, Xueyong; Le, Thanh T; Le, Hao T; Beattie, Christine E; Rich, Mark M; Burghes, Arthur H M

    2015-01-01

    Spinal muscular atrophy is caused by loss of the SMN1 gene and retention of SMN2. The SMN2 copy number inversely correlates with phenotypic severity and is a modifier of disease outcome. The SMN2 gene essentially differs from SMN1 by a single nucleotide in exon 7 that modulates the incorporation of exon 7 into the final SMN transcript. The majority of the SMN2 transcripts lack exon 7 and this leads to a SMN protein that does not effectively oligomerize and is rapidly degraded. However the SMN2 gene does produce some full-length SMN and the SMN2 copy number along with how much full-length SMN the SMN2 gene makes correlates with severity of the SMA phenotype. However there are a number of discordant SMA siblings that have identical haplotypes and SMN2 copy number yet one has a milder form of SMA. It has been suggested that Plastin3 (PLS3) acts as a sex specific phenotypic modifier where increased expression of PLS3 modifies the SMA phenotype in females. To test the effect of PLS3 overexpression we have over expressed full-length PLS3 in SMA mice. To ensure no disruption of functionality or post-translational processing of PLS3 we did not place a tag on the protein. PLS3 protein was expressed under the Prion promoter as we have shown previously that SMN expression under this promoter can rescue SMA mice. High levels of PLS3 mRNA were expressed in motor neurons along with an increased level of PLS3 protein in total spinal cord, yet there was no significant beneficial effect on the phenotype of SMA mice. Specifically, neither survival nor the fundamental electrophysiological aspects of the neuromuscular junction were improved upon overexpression of PLS3 in neurons.

  18. Prenatal prediction of childhood-onset spinal muscular atrophy (SMA) in Turkish families.

    PubMed

    Savas, S; Eraslan, S; Kantarci, S; Karaman, B; Acarsoz, D; Tükel, T; Cogulu, O; Ozkinay, F; Basaran, S; Aydinli, K; Yuksel-Apak, M; Kirdar, B

    2002-08-01

    Childhood-onset spinal muscular atrophy (SMA) is one of the most common neurodegenerative genetic disorders. SMN1 is the SMA-determining gene deleted or mutated in the majority of SMA cases. There is no effective cure or treatment for this disease yet. Thus, the availability of prenatal testing is important. Here we report prenatal prediction for 68 fetuses in 63 Turkish SMA families using direct deletion analysis of the SMN1 gene by restriction digestion. The genotype of the index case was known in 40 families (Group A) but unknown in the remaining 23 families (Group B). A total of ten fetuses were predicted to be affected. Eight of these fetuses were derived from Group A and two of these fetuses were from Group B families. Two fetuses from the same family in Group A had the SMNhyb1 gene in addition to homozygous deletion of the NAIP gene. One fetus from Group A was homozygously deleted for only exon 8 of the SMN2 gene, and further analysis showed the presence of both the SMN1 and SMNhyb1 genes but not the SMN2 gene. In addition, one carrier with a homozygous deletion of only exon 8 of the SMN1 gene was detected to have a SMNhyb2 gene, which was also found in the fetus. To our knowledge, these are the first prenatal cases with SMNhyb genes. Follow-up studies demonstrated that the prenatal predictions and the phenotype of the fetuses correlated well in 33 type I pregnancies demonstrating that a careful molecular analysis of the SMN genes is very useful in predicting the phenotype of the fetus in families at risk for SMA. Copyright 2002 John Wiley & Sons, Ltd.

  19. Skeletal Muscle DNA Damage Precedes Spinal Motor Neuron DNA Damage in a Mouse Model of Spinal Muscular Atrophy (SMA)

    PubMed Central

    Fayzullina, Saniya; Martin, Lee J.

    2014-01-01

    Spinal Muscular Atrophy (SMA) is a hereditary childhood disease that causes paralysis by progressive degeneration of skeletal muscles and spinal motor neurons. SMA is associated with reduced levels of full-length Survival of Motor Neuron (SMN) protein, due to mutations in the Survival of Motor Neuron 1 gene. The mechanisms by which lack of SMN causes SMA pathology are not known, making it very difficult to develop effective therapies. We investigated whether DNA damage is a perinatal pathological event in SMA, and whether DNA damage and cell death first occur in skeletal muscle or spinal cord of SMA mice. We used a mouse model of severe SMA to ascertain the extent of cell death and DNA damage throughout the body of prenatal and newborn mice. SMA mice at birth (postnatal day 0) exhibited internucleosomal fragmentation in genomic DNA from hindlimb skeletal muscle, but not in genomic DNA from spinal cord. SMA mice at postnatal day 5, compared with littermate controls, exhibited increased apoptotic cell death profiles in skeletal muscle, by hematoxylin and eosin, terminal deoxynucleotidyl transferase dUTP nick end labeling, and electron microscopy. SMA mice had no increased cell death, no loss of choline acetyl transferase (ChAT)-positive motor neurons, and no overt pathology in the ventral horn of the spinal cord. At embryonic days 13 and 15.5, SMA mice did not exhibit statistically significant increases in cell death profiles in spinal cord or skeletal muscle. Motor neuron numbers in the ventral horn, as identified by ChAT immunoreactivity, were comparable in SMA mice and control littermates at embryonic day 15.5 and postnatal day 5. These observations demonstrate that in SMA, disease in skeletal muscle emerges before pathology in spinal cord, including loss of motor neurons. Overall, this work identifies DNA damage and cell death in skeletal muscle as therapeutic targets for SMA. PMID:24667816

  20. Skeletal muscle DNA damage precedes spinal motor neuron DNA damage in a mouse model of Spinal Muscular Atrophy (SMA).

    PubMed

    Fayzullina, Saniya; Martin, Lee J

    2014-01-01

    Spinal Muscular Atrophy (SMA) is a hereditary childhood disease that causes paralysis by progressive degeneration of skeletal muscles and spinal motor neurons. SMA is associated with reduced levels of full-length Survival of Motor Neuron (SMN) protein, due to mutations in the Survival of Motor Neuron 1 gene. The mechanisms by which lack of SMN causes SMA pathology are not known, making it very difficult to develop effective therapies. We investigated whether DNA damage is a perinatal pathological event in SMA, and whether DNA damage and cell death first occur in skeletal muscle or spinal cord of SMA mice. We used a mouse model of severe SMA to ascertain the extent of cell death and DNA damage throughout the body of prenatal and newborn mice. SMA mice at birth (postnatal day 0) exhibited internucleosomal fragmentation in genomic DNA from hindlimb skeletal muscle, but not in genomic DNA from spinal cord. SMA mice at postnatal day 5, compared with littermate controls, exhibited increased apoptotic cell death profiles in skeletal muscle, by hematoxylin and eosin, terminal deoxynucleotidyl transferase dUTP nick end labeling, and electron microscopy. SMA mice had no increased cell death, no loss of choline acetyl transferase (ChAT)-positive motor neurons, and no overt pathology in the ventral horn of the spinal cord. At embryonic days 13 and 15.5, SMA mice did not exhibit statistically significant increases in cell death profiles in spinal cord or skeletal muscle. Motor neuron numbers in the ventral horn, as identified by ChAT immunoreactivity, were comparable in SMA mice and control littermates at embryonic day 15.5 and postnatal day 5. These observations demonstrate that in SMA, disease in skeletal muscle emerges before pathology in spinal cord, including loss of motor neurons. Overall, this work identifies DNA damage and cell death in skeletal muscle as therapeutic targets for SMA.

  1. SMA-EUROPE workshop report: opportunities and challenges in developing clinical trials for spinal muscular atrophy in Europe

    PubMed Central

    2013-01-01

    Spinal muscular atrophy (SMA) is the most common lethal recessive disease in childhood, and there is currently no effective treatment to halt disease progression. The translation of scientific advances into effective therapies is hampered by major roadblocks in clinical trials, including the complex regulatory environment in Europe, variations in standards of care, patient ascertainment and enrolment, a narrow therapeutic window and a lack of biomarkers of efficacy. In this context, SMA-Europe organized its first international workshop in July 2012 in Rome, gathering 34 scientists, clinicians and representatives of patient organizations to establish recommendations for improving clinical trials for SMAa. PMID:23514578

  2. [Molecular Features of SMA-related Genes in Spinal Muscular Atrophy Patients of Han Nationality in Southwest China.

    PubMed

    Wang, Min-Jin; Wang, Jun; Bai, Meng-Ge; Zhou, Wen-Jing; Wu, Li-Juan; Tang, Si-Shi; Lu, Xiao-Jun; Ying, Bin-Wu

    2016-11-01

    To investigate the molecular features of spinal muscular atrophy (SMA) related genes in SMA patients of Han nationality of southwest of China. We collected 62 unrelated patients of SMA and 50 unrelated healthy individuals in this study.The copy numbers of survival motor neuron gene (SMN) and uronal-apoptosis inhibitory protein gene (NAIP) were measured by using multiplex ligation-dependent probe amplification (MLPA). Of 62 patients,the copy number of SMA1-4 were 30.65% (19/62),41.94%(26/62),16.13% (10/62),11.29% (7/62),respectively.The deletion of SMN1 exon 7 accounts for 98.38% (61/62).The deletion of SMN1 exon 8 accounts for 82.26% (51/62).Among SMA 1 patients,the homozygous deletion of NAIP exon 5 accounts for 68.42% (13/19) and heterzygous deletion accounts for 26.32% (5/19).Among SMA2-4patients,the homozygous deletion of NAIP exon 5 accounts for 13.95% (6/43) and heterzygous deletion accounts for 62.79% (27/43).Furthermore,68.42% (13/19) patients of SMA1have 1 copy and 2 copies of SMN2 gene,84.62% (22/26) patients of SMA 2 have more than 2 copies of SMN2 gene,90.00% (9/10) SMA3 and 85.71% (6/7) SMA4 have over 2 copies of SMN2 gene and even have 5 and 6 copy of SMN2 gene. The deletion of SMN1 gene is the main cause of SMA,and the change of SMN2 and NAIP copy number can affect the severity of SMA.

  3. Spinal muscular atrophy (SMA) after conception using gametes from anonymous donors: recommendations for the future.

    PubMed

    Callum, Pamela; Urbina, Maria Teresa; Falk, Rena E; Alvarez-Diaz, Jorge A; Benjamin, Isaac; Sims, Charles A

    2010-02-01

    To discuss the diagnosis of spinal muscular atrophy in a child conceived using donor gametes. None. None. Offspring of gamete donors. None. None. A child conceived using gametes from anonymous sperm and ova donors was diagnosed with spinal muscular atrophy type 1. Gamete donor facilities are not required to perform extensive genetic testing on their donors; however, the well-being of the children conceived through assisted reproductive technologies should be a primary objective of reproductive medicine. The risk for specific medical problems in donor offspring can be significantly reduced by incorporating carrier screening for common, severe disorders such as spinal muscular atrophy into donor screening practices. Future efforts should focus on communicating the limitations of genetic screening to donor gamete recipients and educating them about their reproductive options. Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  4. Biomarker for Spinal Muscular Atrophy: Expression of SMN in Peripheral Blood of SMA Patients and Healthy Controls

    PubMed Central

    Czech, Christian; Tang, Wakana; Bugawan, Teodorica; Mano, Calvin; Horn, Carsten; Iglesias, Victor Alejandro; Fröhner, Stefanie; Zaworski, Phillip G.; Paushkin, Sergey; Chen, Karen; Kremer, Thomas

    2015-01-01

    Spinal muscular atrophy is caused by a functional deletion of SMN1 on Chromosome 5, which leads to a progressive loss of motor function in affected patients. SMA patients have at least one copy of a similar gene, SMN2, which produces functional SMN protein, although in reduced quantities. The severity of SMA is variable, partially due to differences in SMN2 copy numbers. Here, we report the results of a biomarker study characterizing SMA patients of varying disease severity. SMN copy number, mRNA and Protein levels in whole blood of patients were measured and compared against a cohort of healthy controls. The results show differential regulation of expression of SMN2 in peripheral blood between patients and healthy subjects. PMID:26468953

  5. Evaluation of SMN Protein, Transcript, and Copy Number in the Biomarkers for Spinal Muscular Atrophy (BforSMA) Clinical Study

    PubMed Central

    Crawford, Thomas O.; Paushkin, Sergey V.; Kobayashi, Dione T.; Forrest, Suzanne J.; Joyce, Cynthia L.; Finkel, Richard S.; Kaufmann, Petra; Swoboda, Kathryn J.; Tiziano, Danilo; Lomastro, Rosa; Li, Rebecca H.; Trachtenberg, Felicia L.; Plasterer, Thomas; Chen, Karen S.

    2012-01-01

    Background The universal presence of a gene (SMN2) nearly identical to the mutated SMN1 gene responsible for Spinal Muscular Atrophy (SMA) has proved an enticing incentive to therapeutics development. Early disappointments from putative SMN-enhancing agent clinical trials have increased interest in improving the assessment of SMN expression in blood as an early “biomarker” of treatment effect. Methods A cross-sectional, single visit, multi-center design assessed SMN transcript and protein in 108 SMA and 22 age and gender-matched healthy control subjects, while motor function was assessed by the Modified Hammersmith Functional Motor Scale (MHFMS). Enrollment selectively targeted a broad range of SMA subjects that would permit maximum power to distinguish the relative influence of SMN2 copy number, SMA type, present motor function, and age. Results SMN2 copy number and levels of full-length SMN2 transcripts correlated with SMA type, and like SMN protein levels, were lower in SMA subjects compared to controls. No measure of SMN expression correlated strongly with MHFMS. A key finding is that SMN2 copy number, levels of transcript and protein showed no correlation with each other. Conclusion This is a prospective study that uses the most advanced techniques of SMN transcript and protein measurement in a large selectively-recruited cohort of individuals with SMA. There is a relationship between measures of SMN expression in blood and SMA type, but not a strong correlation to motor function as measured by the MHFMS. Low SMN transcript and protein levels in the SMA subjects relative to controls suggest that these measures of SMN in accessible tissues may be amenable to an “early look” for target engagement in clinical trials of putative SMN-enhancing agents. Full length SMN transcript abundance may provide insight into the molecular mechanism of phenotypic variation as a function of SMN2 copy number. Trial Registry Clinicaltrials.gov NCT00756821 PMID:22558076

  6. Spinal Muscular Atrophy

    MedlinePlus

    ... are most often affected. Complications include scoliosis and chronic shortening of muscles or tendons around joints. × Definition Spinal Muscular Atrophy (SMA) Types I, II, and III belong to a group of hereditary diseases that cause weakness and wasting of the voluntary muscles in the arms and ...

  7. Spinal Muscular Atrophy.

    PubMed

    Kolb, Stephen J; Kissel, John T

    2015-11-01

    Spinal muscular atrophy is an autosomal-recessive disorder characterized by degeneration of motor neurons in the spinal cord and caused by mutations in the survival motor neuron 1 gene, SMN1. The severity of SMA is variable. The SMN2 gene produces a fraction of the SMN messenger RNA (mRNA) transcript produced by the SMN1 gene. There is an inverse correlation between SMN2 gene copy number and clinical severity. Clinical management focuses on multidisciplinary care. Preclinical models of SMA have led to an explosion of SMA clinical trials that hold great promise of effective therapy in the future. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Candidate Proteins, Metabolites and Transcripts in the Biomarkers for Spinal Muscular Atrophy (BforSMA) Clinical Study

    PubMed Central

    Finkel, Richard S.; Crawford, Thomas O.; Swoboda, Kathryn J.; Kaufmann, Petra; Juhasz, Peter; Li, Xiaohong; Guo, Yu; Li, Rebecca H.; Trachtenberg, Felicia; Forrest, Suzanne J.; Kobayashi, Dione T.; Chen, Karen S.; Joyce, Cynthia L.; Plasterer, Thomas

    2012-01-01

    Background Spinal Muscular Atrophy (SMA) is a neurodegenerative motor neuron disorder resulting from a homozygous mutation of the survival of motor neuron 1 (SMN1) gene. The gene product, SMN protein, functions in RNA biosynthesis in all tissues. In humans, a nearly identical gene, SMN2, rescues an otherwise lethal phenotype by producing a small amount of full-length SMN protein. SMN2 copy number inversely correlates with disease severity. Identifying other novel biomarkers could inform clinical trial design and identify novel therapeutic targets. Objective: To identify novel candidate biomarkers associated with disease severity in SMA using unbiased proteomic, metabolomic and transcriptomic approaches. Materials and Methods: A cross-sectional single evaluation was performed in 108 children with genetically confirmed SMA, aged 2–12 years, manifesting a broad range of disease severity and selected to distinguish factors associated with SMA type and present functional ability independent of age. Blood and urine specimens from these and 22 age-matched healthy controls were interrogated using proteomic, metabolomic and transcriptomic discovery platforms. Analyte associations were evaluated against a primary measure of disease severity, the Modified Hammersmith Functional Motor Scale (MHFMS) and to a number of secondary clinical measures. Results A total of 200 candidate biomarkers correlate with MHFMS scores: 97 plasma proteins, 59 plasma metabolites (9 amino acids, 10 free fatty acids, 12 lipids and 28 GC/MS metabolites) and 44 urine metabolites. No transcripts correlated with MHFMS. Discussion In this cross-sectional study, “BforSMA” (Biomarkers for SMA), candidate protein and metabolite markers were identified. No transcript biomarker candidates were identified. Additional mining of this rich dataset may yield important insights into relevant SMA-related pathophysiology and biological network associations. Additional prospective studies are needed to confirm

  9. Social/economic costs and health-related quality of life in patients with spinal muscular atrophy (SMA) in Spain.

    PubMed

    López-Bastida, Julio; Peña-Longobardo, Luz María; Aranda-Reneo, Isaac; Tizzano, Eduardo; Sefton, Mark; Oliva-Moreno, Juan

    2017-08-18

    The aim of this study was to determine the economic burden and health-related quality of life (HRQOL) of patients with Spinal Muscular Atrophy (SMA) and their caregivers in Spain. This was a cross-sectional and retrospective study of patients diagnosed with SMA in Spain. We adopted a bottom up, prevalence approach design to study patients with SMA. The patient's caregivers completed an anonymous questionnaire regarding their socio-demographic characteristics, use of healthcare services and non-healthcare services. Costs were estimated from a societal perspective (including healthcare costs and non-healthcare costs), and health-related quality of life (HRQOL) was assessed using the EQ-5D questionnaire. The main caregivers also answered a questionnaire on their characteristics and on their HRQOL. A total of 81 caregivers of patients with different subtypes of SMA completed the questionnaire. Based on the reference unitary prices for 2014, the average annual costs per patient were € 33,721. Direct healthcare costs were € 10,882 (representing around 32.3% of the total cost) and the direct non-healthcare costs were € 22,839 (67.7% of the total cost). The mean EQ-5D social tariff score for patients was 0.16, and the mean score of the EQ-5D visual analogue scale was 54. The mean EQ-5D social tariff score for caregivers was 0.49 and their mean score on the EQ-5D visual analogue scale was 69. The results highlight the burden that SMA has in terms of costs and decreased HRQOL, not only for patients but also for their caregivers. In particular, the substantial social/economic burden is mostly attributable to the high direct non-healthcare costs.

  10. An essential SMN interacting protein (SIP1) is not involved in the phenotypic variability of spinal muscular atrophy (SMA).

    PubMed

    Helmken, C; Wetter, A; Rudnik-Schöneborn, S; Liehr, T; Zerres, K; Wirth, B

    2000-07-01

    The survival motor neuron (SMN) protein and the SMN interacting protein 1 (SIP1) are part of a 300 kD protein complex with a crucial role in snRNP biogenesis and pre-mRNA splicing. Both proteins are colocalised in nuclear structures called gems and in the cytoplasm. Approximately 96% of patients with autosomal recessive spinal muscular atrophy (SMA) show mutations in the SMN1 gene, while about 4% fail to show any mutation, despite a typical SMA phenotype. Additionally, sibs with identical 5q13 homologs and homozygous absence of SMN1 can show variable phenotypes which suggest that SMA is modified by other, yet unknown factors. Since both genes, SMN1 and SIP1, belong to the same pathway and are part of the same protein complex, it is obvious to ask whether mutations within SIP1 are responsible for both the phenotypic variability and the appearance of non-SMN mutated SMA patients. First, we identified the chromosomal location of SIP1 and assigned it to chromosomal region 14q13-q21 by fluorescence in situ hybridisation. No SMA related disorder has yet been assigned to this chromosomal region. Next, we determined the exon-intron structure of the SIP1 gene which encompasses 10 exons and identified five transcription isoforms. We sequenced either RT-PCR products or genomic DNA covering the complete coding region from 23 typical SMA patients who had failed to show any SMN1 mutation. No mutation and no polymorphism was found within SIP1. Additionally, we sequenced RT-PCR products or genomic fragments of the entire SIP1 coding region from 26 sibs of 11 SMA families with identical genotypes (delta7SMN/delta7SMN or delta7SMN/other mutation) but different phenotypes and again no mutation was found. Finally, we performed quantitative analysis of RT-PCR products from the same 26 sibs. No difference in expression level of the five isoforms among phenotypically variable sibs was observed. Based on these data, we suggest that neither the phenotypic variability nor the 5q

  11. Whole transcriptome sequencing in blood provides a diagnosis of spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME).

    PubMed

    Kernohan, Kristin D; Frésard, Laure; Zappala, Zachary; Hartley, Taila; Smith, Kevin S; Wagner, Justin; Xu, Hongbin; McBride, Arran; Bourque, Pierre R; Consortium, Care Rare Canada; Bennett, Steffany A L; Dyment, David A; Boycott, Kym M; Montgomery, Stephen B; Warman-Chardon, Jodi

    2017-03-02

    At least 15% of disease-causing mutations affect mRNA splicing. Many splicing mutations are missed in a clinical setting due to limitations of in silico prediction algorithms or their location in non-coding regions. Whole transcriptome sequencing is a promising new tool to identify these mutations; however, it will be a challenge to obtain disease relevant tissue for RNA. Here, we describe an individual with a sporadic atypical spinal muscular atrophy, in whom clinical DNA sequencing reported one pathogenic ASAH1 mutation (c.458A>G;p.Tyr153Cys). Transcriptome sequencing on patient leukocytes identified a highly significant and atypical ASAH1 isoform not explained by c.458A>G(p<10(-16) ). Subsequent Sanger-sequencing identified the splice mutation responsible for the isoform (c.504A>C;p.Lys168Asn) and provided a molecular diagnosis of autosomal recessive spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME). Our findings demonstrate the utility of RNA sequencing from blood to identify splice-impacting disease mutations for non-hematological conditions, providing a diagnosis for these otherwise unsolved patients. This article is protected by copyright. All rights reserved.

  12. Learning about Spinal Muscular Atrophy

    MedlinePlus

    ... Disorders 2003 News Release Fischbeck Group Learning About Spinal Muscular Atrophy What is spinal muscular atrophy? What are the ... Additional Resources for Spinal Muscular Atrophy What is spinal muscular atrophy? Spinal muscular atrophy is a group of inherited ...

  13. Spontaneous Breathing Pattern as Respiratory Functional Outcome in Children with Spinal Muscular Atrophy (SMA)

    PubMed Central

    LoMauro, A.; Aliverti, A.; Mastella, C.; Arnoldi, M. T.; Banfi, P.; Baranello, G.

    2016-01-01

    Introduction SMA is characterised by progressive motor and respiratory muscle weakness. We aimed to verify if in SMA children 1)each form is characterized by specific ventilatory and thoraco-abdominal pattern(VTAp) during quiet breathing(QB); 2)VTAp is affected by salbutamol therapy, currently suggested as standard treatment, or by the natural history(NH) of SMA; 3)the severity of global motor impairment linearly correlates with VTAp. Materials and methods VTAp was analysed on 32 SMA type I (SMA1,the most severe form), 51 type II (SMA2,the moderate), 8 type III (SMA3,the mildest) and 20 healthy (HC) using opto-electronic plethysmography. Spirometry, cough and motor function were measured in a subgroup of patients. Results In SMA1, a normal ventilation is obtained in supine position by rapid and shallow breathing with paradoxical ribcage motion. In SMA2, ventilation is within a normal range in seated position due to an increased respiratory rate(p<0.05) with reduced tidal volume(p<0.05) secondary to a poor contribution of pulmonary ribcage(%ΔVRC,P, p<0.001). Salbutamol therapy had no effect on VTAp during QB(p>0.05) while tachypnea occurred in type I NH. A linear correlation(p<0.001) was found between motor function scales and VTAp. Conclusion A negative or reduced %ΔVRC,P, indicative of ribcage muscle weakness, is a distinctive feature of SMA1 and SMA2 since infancy. Its quantitative assessment represents a non-invasive, non-volitional index that can be obtained in all children, even uncollaborative, and provides useful information on the action of ribcage muscles that are known to be affected by the disease.Low values of motor function scales indicate impairment of motor but also of respiratory function. PMID:27820869

  14. Physical therapy services received by individuals with spinal muscular atrophy (SMA).

    PubMed

    Dunaway, Sally; Montes, Jacqueline; McDermott, Michael P; Martens, William; Neisen, Annie; Glanzman, Allan M; Pasternak, Amy; Riley, Susan; Sproule, Douglas; Chiriboga, Claudia; Finkel, Richard; Tennekoon, Gihan; Darras, Basil; De Vivo, Darryl; Pandya, Shree

    2016-01-01

    The consensus statement for standard of care in SMA recommends multidisciplinary medical care including physical therapy (PT) services. To date there are no reports regarding the implementation of these recommendations and the type of care or services received by individuals with SMA. The purpose of this study is to describe the PT services received by individuals with SMA. Interviews were conducted with patients or their caregivers at the Pediatric Neuromuscular Clinical Research (PNCR) Network sites from October 2011 to September 2012. Questions included information about clinical status of the patient, sociodemographic profile of the patient or caregiver, and PT services received in the past year, including the setting, frequency, duration and type of PT, and therapies administered by caregivers. Eighty-six percent of 105 participants reported receiving PT services, some in multiple settings: 62% in the neuromuscular clinic, 38% at school, 34% at home, and 13% in an outpatient clinic. Greater frequency of PT services received was associated with younger age and inability to walk, but not SMA type. This is the first multicenter study documenting PT services received by patients with SMA. Further research is needed to better understand the impact of PT services on the natural history of SMA.

  15. A YAC contig of the region containing the spinal muscular atrophy gene (SMA): Identification of an unstable region

    SciTech Connect

    Carpten, J.D.; DiDonato, C.J.; Ingraham, S.E.

    1994-11-15

    The authors report a 3.0-Mb YAC contig of the region 5q11.2-q13.3, which is where the spinal muscular atrophy gene has been localized. Three total genomic YAC libraries were screened by the polymerase chain reaction (PCR), and 45 YACs were recovered. These YACs were characterized for sequence tag site (STS) content, and overlaps were confirmed by vectorette PCR. Of the 45 YACs, 20 were isolated with the polymorphic marker CATT-1, which demonstrates significant allelic association with the SMA gene and maps within the 850-kb interval defined by the markers D5S557 and D5S823. Haplotyping of these YACs and their mother cell line indicates that the majority of YACs from this region contain deletions. Furthermore, a 1.9-Mb CATT-1 YAC that was negative for MAP1B and D5S435 and nonchimeric by FISH analysis provides a minimum distance between MAP1B and D5S435. 30 refs., 2 figs., 3 tabs.

  16. An Evaluation of a Continuing Education Program for Family Caregivers of Ventilator-Dependent Children with Spinal Muscular Atrophy (SMA).

    PubMed

    Boroughs, Deborah S

    2017-04-29

    Until 25 years ago, there were limited options for long-term mechanical ventilation of children, and the majority of children were cared for in hospitals. However, with improving technology, the pediatric intensive care unit has moved from the hospital to a home setting, as children with increasingly complex healthcare needs are now often cared for by family members. One of the most complex care conditions involves ventilator and tracheostomy support. Advanced respiratory technologies that augment natural respiratory function prolong the lives of children with respiratory compromise; however, this care often comes with serious risks, including respiratory muscle impairment, respiratory failure, and chronic pulmonary disease. Both non-invasive assisted ventilation and assisted ventilation via tracheostomy can prolong survival into adulthood in many cases; however, mechanical ventilation in the home is a high-stakes, high risk intervention. Increasing complexity of care over time requires perpetual skill training of family caregivers that is delivered and supported by professional caregivers; yet, opportunities for additional training outside of the hospital rarely exist. Recent data has confirmed that repetitive caregiver education is essential for retention of memory and skills in adult learners. This study analyzes the use of continued education and training in the community for family caregivers of ventilator-dependent children diagnosed with spinal muscular atrophy (SMA).

  17. An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA).

    PubMed

    Wirth, B

    2000-01-01

    Spinal muscular atrophy (SMA) is characterized by degeneration of motor neurons in the spinal cord, causing progressive weakness of the limbs and trunk, followed by muscle atrophy. SMA is one of the most frequent autosomal recessive diseases, with a carrier frequency of 1 in 50 and the most common genetic cause of childhood mortality. The phenotype is extremely variable, and patients have been classified in type I-III SMA based on age at onset and clinical course. All three types of SMA are caused by mutations in the survival motor neuron gene (SMN1). There are two almost identical copies, SMN1 and SMN2, present on chromosome 5q13. Only homozygous absence of SMN1 is responsible for SMA, while homozygous absence of SMN2, found in about 5% of controls, has no clinical phenotype. Ninety-six percent of SMA patients display mutations in SMN1, while 4% are unlinked to 5q13. Of the 5q13-linked SMA patients, 96.4% show homozygous absence of SMN1 exons 7 and 8 or exon 7 only, whereas 3. 6% present a compound heterozygosity with a subtle mutation on one chromosome and a deletion/gene conversion on the other chromosome. Among the 23 different subtle mutations described so far, the Y272C missense mutation is the most frequent one, at 20%. Given this uniform mutation spectrum, direct molecular genetic testing is an easy and rapid analysis for most of the SMA patients. Direct testing of heterozygotes, while not trivial, is compromised by the presence of two SMN1 copies per chromosome in about 4% of individuals. The number of SMN2 copies modulates the SMA phenotype. Nevertheless, it should not be used for prediction of severity of the SMA. Copyright 2000 Wiley-Liss, Inc.

  18. Spinal muscular atrophies.

    PubMed

    Viollet, Louis; Melki, Judith

    2013-01-01

    Spinal muscular atrophies (SMA) are genetic disorders characterized by degeneration of lower motor neurons. The most frequent form is caused by mutations of the survival motor neuron 1 gene (SMN1). The identification of this gene greatly improved diagnostic testing and family-planning options of SMA families. SMN plays a key role in metabolism of RNA. However, the link between RNA metabolism and motor neuron degeneration remains unknown. A defect in mRNA processing likely generates either a loss of function of some critical RNA or abnormal transcripts with toxic property for motor neurons. Mutations of SMN in various organisms highlighted an essential role of SMN in motor axon and neuromuscular junction development or maintenance. The quality of life of patients has greatly improved over recent decades through the improvement of care and management of patients. In addition, major advances in translational research have been made in the field of SMA. Various therapeutic strategies have been successfully developed aiming at acting on SMN2, a partially functional copy of the SMN1 gene which remains present in patients. Drugs have been identified and some are already at preclinical stages. Identifying molecules involved in the SMA degenerative process should represent additional attractive targets for therapeutics in SMA. Copyright © 2013 Elsevier B.V. All rights reserved.

  19. Carrier screening for spinal muscular atrophy (SMA) in 107,611 pregnant women during the period 2005-2009: a prospective population-based cohort study.

    PubMed

    Su, Yi-Ning; Hung, Chia-Cheng; Lin, Shin-Yu; Chen, Fang-Yi; Chern, Jimmy P S; Tsai, Chris; Chang, Tai-Sheng; Yang, Chih-Chao; Li, Hung; Ho, Hong-Nerng; Lee, Chien-Nan

    2011-02-25

    Spinal muscular atrophy (SMA) is the most common neuromuscular autosomal recessive disorder. The American College of Medical Genetics has recently recommended routine carrier screening for SMA because of the high carrier frequency (1 in 25-50) as well as the severity of that genetic disease. Large studies are needed to determine the feasibility, benefits, and costs of such a program. This is a prospective population-based cohort study of 107,611 pregnant women from 25 counties in Taiwan conducted during the period January 2005 to June 2009. A three-stage screening program was used: (1) pregnant women were tested for SMA heterozygosity; (2) if the mother was determined to be heterozygous for SMA (carrier status), the paternal partner was then tested; (3) if both partners were SMA carriers, prenatal diagnostic testing was performed. During the study period, a total of 2,262 SMA carriers with one copy of the SMN1 gene were identified among the 107,611 pregnant women that were screened. The carrier rate was approximately 1 in 48 (2.10%). The negative predictive value of DHPLC coupled with MLPA was 99.87%. The combined method could detect approximately 94% of carriers because most of the cases resulted from a common single deletion event. In addition, 2,038 spouses were determined to be SMA carriers. Among those individuals, 47 couples were determined to be at high risk for having offspring with SMA. Prenatal diagnostic testing was performed in 43 pregnant women (91.49%) and SMA was diagnosed in 12 (27.91%) fetuses. The prevalence of SMA in our population was 1 in 8,968. The main benefit of SMA carrier screening is to reduce the burden associated with giving birth to an affected child. In this study, we determined the carrier frequency and genetic risk and provided carrier couples with genetic services, knowledge, and genetic counseling.

  20. Spinal muscular atrophy

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/000996.htm Spinal muscular atrophy To use the sharing features on this page, please enable JavaScript. Spinal muscular atrophy is a group of disorders of the motor ...

  1. Spinal muscular atrophy

    PubMed Central

    2011-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by degeneration of alpha motor neurons in the spinal cord, resulting in progressive proximal muscle weakness and paralysis. Estimated incidence is 1 in 6,000 to 1 in 10,000 live births and carrier frequency of 1/40-1/60. This disease is characterized by generalized muscle weakness and atrophy predominating in proximal limb muscles, and phenotype is classified into four grades of severity (SMA I, SMAII, SMAIII, SMA IV) based on age of onset and motor function achieved. This disease is caused by homozygous mutations of the survival motor neuron 1 (SMN1) gene, and the diagnostic test demonstrates in most patients the homozygous deletion of the SMN1 gene, generally showing the absence of SMN1 exon 7. The test achieves up to 95% sensitivity and nearly 100% specificity. Differential diagnosis should be considered with other neuromuscular disorders which are not associated with increased CK manifesting as infantile hypotonia or as limb girdle weakness starting later in life. Considering the high carrier frequency, carrier testing is requested by siblings of patients or of parents of SMA children and are aimed at gaining information that may help with reproductive planning. Individuals at risk should be tested first and, in case of testing positive, the partner should be then analyzed. It is recommended that in case of a request on carrier testing on siblings of an affected SMA infant, a detailed neurological examination should be done and consideration given doing the direct test to exclude SMA. Prenatal diagnosis should be offered to couples who have previously had a child affected with SMA (recurrence risk 25%). The role of follow-up coordination has to be managed by an expert in neuromuscular disorders and in SMA who is able to plan a multidisciplinary intervention that includes pulmonary, gastroenterology/nutrition, and orthopedic care. Prognosis depends on the phenotypic

  2. Spinal muscular atrophy.

    PubMed

    D'Amico, Adele; Mercuri, Eugenio; Tiziano, Francesco D; Bertini, Enrico

    2011-11-02

    Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by degeneration of alpha motor neurons in the spinal cord, resulting in progressive proximal muscle weakness and paralysis. Estimated incidence is 1 in 6,000 to 1 in 10,000 live births and carrier frequency of 1/40-1/60. This disease is characterized by generalized muscle weakness and atrophy predominating in proximal limb muscles, and phenotype is classified into four grades of severity (SMA I, SMAII, SMAIII, SMA IV) based on age of onset and motor function achieved. This disease is caused by homozygous mutations of the survival motor neuron 1 (SMN1) gene, and the diagnostic test demonstrates in most patients the homozygous deletion of the SMN1 gene, generally showing the absence of SMN1 exon 7. The test achieves up to 95% sensitivity and nearly 100% specificity. Differential diagnosis should be considered with other neuromuscular disorders which are not associated with increased CK manifesting as infantile hypotonia or as limb girdle weakness starting later in life. Considering the high carrier frequency, carrier testing is requested by siblings of patients or of parents of SMA children and are aimed at gaining information that may help with reproductive planning. Individuals at risk should be tested first and, in case of testing positive, the partner should be then analyzed. It is recommended that in case of a request on carrier testing on siblings of an affected SMA infant, a detailed neurological examination should be done and consideration given doing the direct test to exclude SMA. Prenatal diagnosis should be offered to couples who have previously had a child affected with SMA (recurrence risk 25%). The role of follow-up coordination has to be managed by an expert in neuromuscular disorders and in SMA who is able to plan a multidisciplinary intervention that includes pulmonary, gastroenterology/nutrition, and orthopedic care. Prognosis depends on the phenotypic

  3. Genetics Home Reference: spinal muscular atrophy with progressive myoclonic epilepsy

    MedlinePlus

    ... myoclonic epilepsy spinal muscular atrophy with progressive myoclonic epilepsy Enable Javascript to view the expand/collapse boxes. ... All Description Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is a neurological condition that causes ...

  4. Genetics Home Reference: spinal and bulbar muscular atrophy

    MedlinePlus

    ... MedlinePlus (2 links) Encyclopedia: Muscle Atrophy Health Topic: Spinal Muscular Atrophy Genetic and Rare Diseases Information Center (1 link) ... Patient Support and Advocacy Resources (5 links) Cure SMA Kennedy's Disease Association Muscular Dystrophy Association National Organization ...

  5. The Power of Human Protective Modifiers: PLS3 and CORO1C Unravel Impaired Endocytosis in Spinal Muscular Atrophy and Rescue SMA Phenotype.

    PubMed

    Hosseinibarkooie, Seyyedmohsen; Peters, Miriam; Torres-Benito, Laura; Rastetter, Raphael H; Hupperich, Kristina; Hoffmann, Andrea; Mendoza-Ferreira, Natalia; Kaczmarek, Anna; Janzen, Eva; Milbradt, Janine; Lamkemeyer, Tobias; Rigo, Frank; Bennett, C Frank; Guschlbauer, Christoph; Büschges, Ansgar; Hammerschmidt, Matthias; Riessland, Markus; Kye, Min Jeong; Clemen, Christoph S; Wirth, Brunhilde

    2016-09-01

    Homozygous loss of SMN1 causes spinal muscular atrophy (SMA), the most common and devastating childhood genetic motor-neuron disease. The copy gene SMN2 produces only ∼10% functional SMN protein, insufficient to counteract development of SMA. In contrast, the human genetic modifier plastin 3 (PLS3), an actin-binding and -bundling protein, fully protects against SMA in SMN1-deleted individuals carrying 3-4 SMN2 copies. Here, we demonstrate that the combinatorial effect of suboptimal SMN antisense oligonucleotide treatment and PLS3 overexpression-a situation resembling the human condition in asymptomatic SMN1-deleted individuals-rescues survival (from 14 to >250 days) and motoric abilities in a severe SMA mouse model. Because PLS3 knockout in yeast impairs endocytosis, we hypothesized that disturbed endocytosis might be a key cellular mechanism underlying impaired neurotransmission and neuromuscular junction maintenance in SMA. Indeed, SMN deficit dramatically reduced endocytosis, which was restored to normal levels by PLS3 overexpression. Upon low-frequency electro-stimulation, endocytotic FM1-43 (SynaptoGreen) uptake in the presynaptic terminal of neuromuscular junctions was restored to control levels in SMA-PLS3 mice. Moreover, proteomics and biochemical analysis revealed CORO1C, another F-actin binding protein, whose direct binding to PLS3 is dependent on calcium. Similar to PLS3 overexpression, CORO1C overexpression restored fluid-phase endocytosis in SMN-knockdown cells by elevating F-actin amounts and rescued the axonal truncation and branching phenotype in Smn-depleted zebrafish. Our findings emphasize the power of genetic modifiers to unravel the cellular pathomechanisms underlying SMA and the power of combinatorial therapy based on splice correction of SMN2 and endocytosis improvement to efficiently treat SMA. Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  6. Metalloprotease-mediated cleavage of PlexinD1 and its sequestration to actin rods in the motoneuron disease spinal muscular atrophy (SMA).

    PubMed

    Rademacher, Sebastian; Verheijen, Bert M; Hensel, Niko; Peters, Miriam; Bora, Gamze; Brandes, Gudrun; Vieira de Sá, Renata; Heidrich, Natascha; Fischer, Silke; Brinkmann, Hella; van der Pol, W Ludo; Wirth, Brunhilde; Pasterkamp, R Jeroen; Claus, Peter

    2017-10-15

    Cytoskeletal rearrangement during axon growth is mediated by guidance receptors and their ligands which act either as repellent, attractant or both. Regulation of the actin cytoskeleton is disturbed in Spinal Muscular Atrophy (SMA), a devastating neurodegenerative disease affecting mainly motoneurons, but receptor-ligand interactions leading to the dysregulation causing SMA are poorly understood. In this study, we analysed the role of the guidance receptor PlexinD1 in SMA pathogenesis. We showed that PlexinD1 is cleaved by metalloproteases in SMA and that this cleavage switches its function from an attractant to repellent. Moreover, we found that the PlexinD1 cleavage product binds to actin rods, pathological aggregate-like structures which had so far been described for age-related neurodegenerative diseases. Our data suggest a novel disease mechanism for SMA involving formation of actin rods as a molecular sink for a cleaved PlexinD1 fragment leading to dysregulation of receptor signaling. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  7. Spinal Muscular Atrophy (SMA)

    MedlinePlus

    ... cally receives Quest, MDA’s award-win- ning quarterly magazine. Quest publishes detailed articles about research findings, medical ... research news, medical findings and disability information through magazines, publications, edu- cational speakers, seminars, videos and newsletters. ...

  8. SMA CARNI-VAL TRIAL PART II: A Prospective, Single-Armed Trial of L-Carnitine and Valproic Acid in Ambulatory Children with Spinal Muscular Atrophy

    PubMed Central

    Kissel, John T.; Scott, Charles B.; Reyna, Sandra P.; Crawford, Thomas O.; Simard, Louise R.; Krosschell, Kristin J.; Acsadi, Gyula; Elsheik, Bakri; Schroth, Mary K.; D'Anjou, Guy; LaSalle, Bernard; Prior, Thomas W.; Sorenson, Susan; Maczulski, Jo Anne; Bromberg, Mark B.; Chan, Gary M.; Swoboda, Kathryn J.

    2011-01-01

    Background Multiple lines of evidence have suggested that valproic acid (VPA) might benefit patients with spinal muscular atrophy (SMA). The SMA CARNIVAL TRIAL was a two part prospective trial to evaluate oral VPA and l-carnitine in SMA children. Part 1 targeted non-ambulatory children ages 2–8 in a 12 month cross over design. We report here Part 2, a twelve month prospective, open-label trial of VPA and L-carnitine in ambulatory SMA children. Methods This study involved 33 genetically proven type 3 SMA subjects ages 3–17 years. Subjects underwent two baseline assessments over 4–6 weeks and then were placed on VPA and L-carnitine for 12 months. Assessments were performed at baseline, 3, 6 and 12 months. Primary outcomes included safety, adverse events and the change at 6 and 12 months in motor function assessed using the Modified Hammersmith Functional Motor Scale Extend (MHFMS-Extend), timed motor tests and fine motor modules. Secondary outcomes included changes in ulnar compound muscle action potential amplitudes (CMAP), handheld dynamometry, pulmonary function, and Pediatric Quality of Life Inventory scores. Results Twenty-eight subjects completed the study. VPA and carnitine were generally well tolerated. Although adverse events occurred in 85% of subjects, they were usually mild and transient. Weight gain of 20% above body weight occurred in 17% of subjects. There was no significant change in any primary outcome at six or 12 months. Some pulmonary function measures showed improvement at one year as expected with normal growth. CMAP significantly improved suggesting a modest biologic effect not clinically meaningful. Conclusions This study, coupled with the CARNIVAL Part 1 study, indicate that VPA is not effective in improving strength or function in SMA children. The outcomes used in this study are feasible and reliable, and can be employed in future trials in SMA. Trial Regsitration Clinicaltrials.gov NCT00227266 PMID:21754985

  9. SMA CARNIVAL TRIAL PART II: a prospective, single-armed trial of L-carnitine and valproic acid in ambulatory children with spinal muscular atrophy.

    PubMed

    Kissel, John T; Scott, Charles B; Reyna, Sandra P; Crawford, Thomas O; Simard, Louise R; Krosschell, Kristin J; Acsadi, Gyula; Elsheik, Bakri; Schroth, Mary K; D'Anjou, Guy; LaSalle, Bernard; Prior, Thomas W; Sorenson, Susan; Maczulski, Jo Anne; Bromberg, Mark B; Chan, Gary M; Swoboda, Kathryn J

    2011-01-01

    Multiple lines of evidence have suggested that valproic acid (VPA) might benefit patients with spinal muscular atrophy (SMA). The SMA CARNIVAL TRIAL was a two part prospective trial to evaluate oral VPA and L-carnitine in SMA children. Part 1 targeted non-ambulatory children ages 2-8 in a 12 month cross over design. We report here Part 2, a twelve month prospective, open-label trial of VPA and L-carnitine in ambulatory SMA children. This study involved 33 genetically proven type 3 SMA subjects ages 3-17 years. Subjects underwent two baseline assessments over 4-6 weeks and then were placed on VPA and L-carnitine for 12 months. Assessments were performed at baseline, 3, 6 and 12 months. Primary outcomes included safety, adverse events and the change at 6 and 12 months in motor function assessed using the Modified Hammersmith Functional Motor Scale Extend (MHFMS-Extend), timed motor tests and fine motor modules. Secondary outcomes included changes in ulnar compound muscle action potential amplitudes (CMAP), handheld dynamometry, pulmonary function, and Pediatric Quality of Life Inventory scores. Twenty-eight subjects completed the study. VPA and carnitine were generally well tolerated. Although adverse events occurred in 85% of subjects, they were usually mild and transient. Weight gain of 20% above body weight occurred in 17% of subjects. There was no significant change in any primary outcome at six or 12 months. Some pulmonary function measures showed improvement at one year as expected with normal growth. CMAP significantly improved suggesting a modest biologic effect not clinically meaningful. This study, coupled with the CARNIVAL Part 1 study, indicate that VPA is not effective in improving strength or function in SMA children. The outcomes used in this study are feasible and reliable, and can be employed in future trials in SMA. TRIAL REGSITRATION: Clinicaltrials.gov NCT00227266.

  10. A Perturbed MicroRNA Expression Pattern Characterizes Embryonic Neural Stem Cells Derived from a Severe Mouse Model of Spinal Muscular Atrophy (SMA)

    PubMed Central

    Luchetti, Andrea; Ciafrè, Silvia Anna; Murdocca, Michela; Malgieri, Arianna; Masotti, Andrea; Sanchez, Massimo; Farace, Maria Giulia; Novelli, Giuseppe; Sangiuolo, Federica

    2015-01-01

    Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder and the leading genetic cause of death in infants. Despite the disease-causing gene, survival motor neuron (SMN1), encodes a ubiquitous protein, SMN1 deficiency preferentially affects spinal motor neurons (MNs), leaving the basis of this selective cell damage still unexplained. As neural stem cells (NSCs) are multipotent self-renewing cells that can differentiate into neurons, they represent an in vitro model for elucidating the pathogenetic mechanism of neurodegenerative diseases such as SMA. Here we characterize for the first time neural stem cells (NSCs) derived from embryonic spinal cords of a severe SMNΔ7 SMA mouse model. SMNΔ7 NSCs behave as their wild type (WT) counterparts, when we consider neurosphere formation ability and the expression levels of specific regional and self-renewal markers. However, they show a perturbed cell cycle phase distribution and an increased proliferation rate compared to wild type cells. Moreover, SMNΔ7 NSCs are characterized by the differential expression of a limited number of miRNAs, among which miR-335-5p and miR-100-5p, reduced in SMNΔ7 NSCs compared to WT cells. We suggest that such miRNAs may be related to the proliferation differences characterizing SMNΔ7 NSCs, and may be potentially involved in the molecular mechanisms of SMA. PMID:26258776

  11. A Perturbed MicroRNA Expression Pattern Characterizes Embryonic Neural Stem Cells Derived from a Severe Mouse Model of Spinal Muscular Atrophy (SMA).

    PubMed

    Luchetti, Andrea; Ciafrè, Silvia Anna; Murdocca, Michela; Malgieri, Arianna; Masotti, Andrea; Sanchez, Massimo; Farace, Maria Giulia; Novelli, Giuseppe; Sangiuolo, Federica

    2015-08-06

    Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder and the leading genetic cause of death in infants. Despite the disease-causing gene, survival motor neuron (SMN1), encodes a ubiquitous protein, SMN1 deficiency preferentially affects spinal motor neurons (MNs), leaving the basis of this selective cell damage still unexplained. As neural stem cells (NSCs) are multipotent self-renewing cells that can differentiate into neurons, they represent an in vitro model for elucidating the pathogenetic mechanism of neurodegenerative diseases such as SMA. Here we characterize for the first time neural stem cells (NSCs) derived from embryonic spinal cords of a severe SMNΔ7 SMA mouse model. SMNΔ7 NSCs behave as their wild type (WT) counterparts, when we consider neurosphere formation ability and the expression levels of specific regional and self-renewal markers. However, they show a perturbed cell cycle phase distribution and an increased proliferation rate compared to wild type cells. Moreover, SMNΔ7 NSCs are characterized by the differential expression of a limited number of miRNAs, among which miR-335-5p and miR-100-5p, reduced in SMNΔ7 NSCs compared to WT cells. We suggest that such miRNAs may be related to the proliferation differences characterizing SMNΔ7 NSCs, and may be potentially involved in the molecular mechanisms of SMA.

  12. Refined physical map of the Spinal Muscular Atrophy gene (SMA) region at 5q13 based on YAC and cosmid contiguous arrays

    SciTech Connect

    Roy, N.; Yaraghi, Z.; McLean, M.D.

    1995-04-10

    The gene for the autosomal recessive neurodegenerative disorder spinal muscular atrophy has been mapped to a region of 5q13 flanked proximally by CMS-1 and distally by D5S557. We present a 2-Mb yeast artificial chromosome (YAC) contig constructed from three libraries encompassing the D5S435/D5S629/CMS-1-SMA-D5S557/D5S112 interval. The D5S629/CMS-1-SMA-D5S557 interval is unusual insofar as chromosome 5-specific repetitive sequences are present and many of the simple tandem repeats (STR) are located at multiple loci that are unstable in our YAC clones. A long-range restriction map that demonstrates the SMA-containing interval to be 550 kb is presented. Moreover, a 210-kb cosmid array from both a YAC-specific and a chromosome 5-specific cosmid library encompassing the multilocus STRs CATT-1, CMS-1, D5F149, D5F150, and D5F153 has been assembled. We have recently reported strong linkage disequilibrium with Type I SMA for two of these STRs, indicating that the gene is located in close proximity to or within our cosmid clone array. 39 refs., 5 figs., 2 tabs.

  13. Intragenic mutations in SMN1 may contribute more significantly to clinical severity than SMN2 copy numbers in some spinal muscular atrophy (SMA) patients.

    PubMed

    Yamamoto, Tomoto; Sato, Hideyuki; Lai, Poh San; Nurputra, Dian Kesumapramudya; Harahap, Nur Imma Fatimah; Morikawa, Satoru; Nishimura, Noriyuki; Kurashige, Takashi; Ohshita, Tomohiko; Nakajima, Hideki; Yamada, Hiroyuki; Nishida, Yoshinobu; Toda, Soichiro; Takanashi, Jun-Ichi; Takeuchi, Atsuko; Tohyama, Yumi; Kubo, Yuji; Saito, Kayoko; Takeshima, Yasuhiro; Matsuo, Masafumi; Nishio, Hisahide

    2014-11-01

    Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by deletion or intragenic mutation of SMN1. SMA is classified into several subtypes based on clinical severity. It has been reported that the copy number of SMN2, a highly homologous gene to SMN1, is associated with clinical severity among SMA patients with homozygous deletion of SMN1. The purpose of this study was to clarify the genotype-phenotype relationship among the patients without homozygous deletion of SMN1. We performed molecular genetic analyses of SMN1 and SMN2 in 112 Japanese patients diagnosed as having SMA based on the clinical findings. For the patients retaining SMN1, the PCR or RT-PCR products of SMN1 were sequenced to identify the mutation. Out of the 112 patients, 106 patients were homozygous for deletion of SMN1, and six patients were compound heterozygous for deletion of one SMN1 allele and intragenic mutation in the retained SMN1 allele. Four intragenic mutations were identified in the six patients: p.Ala2Val, p.Trp92Ser, p.Thr274TyrfsX32 and p.Tyr277Cys. To the best of our knowledge, all mutations except p.Trp92Ser were novel mutations which had never been previously reported. According to our observation, clinical severity of the six patients was determined by the type and location of the mutation rather than SMN2 copy number. SMN2 copy number is not always associated with clinical severity of SMA patients, especially SMA patients retaining one SMN1 allele. Copyright © 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  14. High resolution physical mapping of the spinal muscular atrophy (SMA) region utilizing YAC, PAC, and cosmid clones

    SciTech Connect

    Roy, N.; Yaraghi, Z.; Besner, A.

    1994-09-01

    The childhood SMAs are a group of autosomal recessive disorders characterized by anterior horn cells degeneration resulting in muscular wasting and weakness. All three types have been mapped to a 1.4 Mb region of 5q13.1 flanked centromerically by D5S435 and telomerically by D5S557. Several groups including our own have generated YAC contigs of the region documenting deletion, duplications and repetitive sequences. We have generated a higher resolution contiguous array of cosmid clones encompassing the region containing the microsatellites (MSRs) CATT-1 and CMS-1. These MSRs exist in multiple copies, termed subloci, which are present in a variable number among chromosomes. We have mapped four of the CATT-1 subloci, two of that we have shown to be in linkage disequilibrium with SMA, to a 100 kb interval within our cosmid array. The lack of a representation of all the CMS-1 subloci in our YAC and cosmid clones, in addition to the instability of these MSRs within the YAC clones, has rendered mapping problematic. Due to the reported stability of P1 artificial chromosomes (PAC), we have also constructed a contiguous array of 11 PAC clones spanning this critical interval. The unequivocal orientation of the contig along 5q13 has been confirmed by analysis with 4 genetic markers, 4 single copy probes and 3 STSs. Preliminary analysis has shown greater retention of MSR alleles in the PACs, suggesting their greater stability when compared to YACs. Mapping of cosmid and PAC clones derived from different individuals has allowed us to map the multiple CMS-1 and CATT-1 subloci along 5q13. We have identified a recombination event indicating that the SMA gene lies telomeric to one CMS sublocus. Placement of this sublocus in our physical map has enabled further refinement of the critical SMA region from previous estimates of 700 kb to an approximate 300 kb interval flanked by the markers CMS and D5S557.

  15. Bone and Spinal Muscular Atrophy.

    PubMed

    Vai, Silvia; Bianchi, Maria Luisa; Moroni, Isabella; Mastella, Chiara; Broggi, Francesca; Morandi, Lucia; Arnoldi, Maria Teresa; Bussolino, Chiara; Baranello, Giovanni

    2015-10-01

    Spinal Muscular Atrophy (SMA) is an autosomal recessive neuromuscular disease, leading to progressive denervation atrophy in the involved skeletal muscles. Bone status has been poorly studied. We assessed bone metabolism, bone mineral density (BMD) and fractures in 30 children (age range 15-171 months) affected by SMA types 2 and 3. Eighteen children (60%) had higher than normal levels of CTx (bone resorption marker); 25-OH vitamin D was in the lower range of normal (below 20 ng/ml in 9 children and below 12 ng/ml in 2). Lumbar spine BMAD (bone mineral apparent density) Z-score was below -1.5 in 50% of children. According to clinical records, four children had sustained four peripheral fractures; on spine X-rays, we observed 9 previously undiagnosed vertebral fractures in 7 children. There was a significant inverse regression between PTH and 25-OH D levels, and a significant regression between BMC and BMAD values and the scores of motor-functional tests. Even if this study could not establish the pathogenesis of bone derangements in SMA, its main findings - reduced bone density, low 25OH vitamin D levels, increased bone resorption markers and asymptomatic vertebral fractures also in very young patients - strongly suggest that even young subjects affected by SMA should be considered at risk of osteopenia and even osteoporosis and fractures. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Allelic association and extended haplotype analysis of the spinal muscular atrophy (SMA) candidate region in the French Candadian population

    SciTech Connect

    Simard, L.R.; Prescott, G.; Rochette, C. |

    1994-09-01

    SMA is a common lower motor neuron disease characterized by progressive proximal limb and trunk muscle weakness. Despite the wide range in phenotypic severity, all three clinical types of childhood SMAs map to chromosome 5q11.2-5q13.3. The proximal (D5S557) flanking markers span about 1 Mb. We have previously demonstrated significant linkage disequilibrium between D5S125, D5S435, D5S351, JK53CA1/2 and SMA in the French Canadian population. We now present data for three new DNA markers mapping between D5S435 and D5S557 kindly provided to us by Drs. B. Wirth (A31), A. Burghes (Ag1) and A. MacKenzie (CATT-40G1). We identified 10 different A31 Alleles whose frequencies were similar for both normal and SMA chromosomes. Ag1 is a complex multi-allelic marker and specific primers amplified 1 (Class I), 2 or rarely 3 (Class II) alleles per chromosome. We observed significant association between Ag1 and SMA. For example, the 100 bp Ag1 fragment was typed on 20 of 73 SMA chromosomes and 0 of 74 normal chromosomes (p=<10{sup -4}). We also observed significant association between Ag1 Class genotypes and phenotypic severity. Class I chromosomes predominated in Type I SMA (p=.001) while Type II SMA individuals were generally heterozygous Class I/Class II (p=.001). Finally, we provide evidence for allelic association between Type I SMA and CATT-40G1, a tri-allelic sublocus of CATT-1. All of our Type I SMA chromosomes (n=20) carried a null allele compared to 40% of normal chromosomes (p=<10{sup -4}). Extended haplotype analyses indicated that > 19% of French Canadian SMA chromosomes appear to be ancestrally related to two unique haplotypes indicating their utility for linkage disequilibrium mapping.

  17. Very severe spinal muscular atrophy (Type 0).

    PubMed

    Al Dakhoul, Suleiman

    2017-01-01

    This case report describes a rare phenotype of very severe spinal muscular atrophy (SMA) in a newborn who presented with reduced fetal movements in utero and significant respiratory distress at birth. The patient was homozygously deleted for exon 7 and exon 8 of the survival motor neuron gene 1. Very severe SMA should be considered in the differential diagnosis of respiratory distress at birth, and more research should be dedicated to investigate the genetic determinants of its widely variable phenotypes.

  18. Very severe spinal muscular atrophy (Type 0)

    PubMed Central

    Al Dakhoul, Suleiman

    2017-01-01

    This case report describes a rare phenotype of very severe spinal muscular atrophy (SMA) in a newborn who presented with reduced fetal movements in utero and significant respiratory distress at birth. The patient was homozygously deleted for exon 7 and exon 8 of the survival motor neuron gene 1. Very severe SMA should be considered in the differential diagnosis of respiratory distress at birth, and more research should be dedicated to investigate the genetic determinants of its widely variable phenotypes. PMID:28182029

  19. SMA CARNI-VAL trial part I: double-blind, randomized, placebo-controlled trial of L-carnitine and valproic acid in spinal muscular atrophy.

    PubMed

    Swoboda, Kathryn J; Scott, Charles B; Crawford, Thomas O; Simard, Louise R; Reyna, Sandra P; Krosschell, Kristin J; Acsadi, Gyula; Elsheik, Bakri; Schroth, Mary K; D'Anjou, Guy; LaSalle, Bernard; Prior, Thomas W; Sorenson, Susan L; Maczulski, Jo Anne; Bromberg, Mark B; Chan, Gary M; Kissel, John T

    2010-08-19

    Valproic acid (VPA) has demonstrated potential as a therapeutic candidate for spinal muscular atrophy (SMA) in vitro and in vivo. Two cohorts of subjects were enrolled in the SMA CARNIVAL TRIAL, a non-ambulatory group of "sitters" (cohort 1) and an ambulatory group of "walkers" (cohort 2). Here, we present results for cohort 1: a multicenter phase II randomized double-blind intention-to-treat protocol in non-ambulatory SMA subjects 2-8 years of age. Sixty-one subjects were randomized 1:1 to placebo or treatment for the first six months; all received active treatment the subsequent six months. The primary outcome was change in the modified Hammersmith Functional Motor Scale (MHFMS) score following six months of treatment. Secondary outcomes included safety and adverse event data, and change in MHFMS score for twelve versus six months of active treatment, body composition, quantitative SMN mRNA levels, maximum ulnar CMAP amplitudes, myometry and PFT measures. At 6 months, there was no difference in change from the baseline MHFMS score between treatment and placebo groups (difference = 0.643, 95% CI = -1.22-2.51). Adverse events occurred in >80% of subjects and were more common in the treatment group. Excessive weight gain was the most frequent drug-related adverse event, and increased fat mass was negatively related to change in MHFMS values (p = 0.0409). Post-hoc analysis found that children ages two to three years that received 12 months treatment, when adjusted for baseline weight, had significantly improved MHFMS scores (p = 0.03) compared to those who received placebo the first six months. A linear regression analysis limited to the influence of age demonstrates young age as a significant factor in improved MHFMS scores (p = 0.007). This study demonstrated no benefit from six months treatment with VPA and L-carnitine in a young non-ambulatory cohort of subjects with SMA. Weight gain, age and treatment duration were significant confounding variables that should

  20. SMA CARNI-VAL Trial Part I: Double-Blind, Randomized, Placebo-Controlled Trial of L-Carnitine and Valproic Acid in Spinal Muscular Atrophy

    PubMed Central

    Swoboda, Kathryn J.; Scott, Charles B.; Crawford, Thomas O.; Simard, Louise R.; Reyna, Sandra P.; Krosschell, Kristin J.; Acsadi, Gyula; Elsheik, Bakri; Schroth, Mary K.; D'Anjou, Guy; LaSalle, Bernard; Prior, Thomas W.; Sorenson, Susan L.; Maczulski, Jo Anne; Bromberg, Mark B.; Chan, Gary M.; Kissel, John T.

    2010-01-01

    Background Valproic acid (VPA) has demonstrated potential as a therapeutic candidate for spinal muscular atrophy (SMA) in vitro and in vivo. Methods Two cohorts of subjects were enrolled in the SMA CARNIVAL TRIAL, a non-ambulatory group of “sitters” (cohort 1) and an ambulatory group of “walkers” (cohort 2). Here, we present results for cohort 1: a multicenter phase II randomized double-blind intention-to-treat protocol in non-ambulatory SMA subjects 2–8 years of age. Sixty-one subjects were randomized 1∶1 to placebo or treatment for the first six months; all received active treatment the subsequent six months. The primary outcome was change in the modified Hammersmith Functional Motor Scale (MHFMS) score following six months of treatment. Secondary outcomes included safety and adverse event data, and change in MHFMS score for twelve versus six months of active treatment, body composition, quantitative SMN mRNA levels, maximum ulnar CMAP amplitudes, myometry and PFT measures. Results At 6 months, there was no difference in change from the baseline MHFMS score between treatment and placebo groups (difference = 0.643, 95% CI = −1.22–2.51). Adverse events occurred in >80% of subjects and were more common in the treatment group. Excessive weight gain was the most frequent drug-related adverse event, and increased fat mass was negatively related to change in MHFMS values (p = 0.0409). Post-hoc analysis found that children ages two to three years that received 12 months treatment, when adjusted for baseline weight, had significantly improved MHFMS scores (p = 0.03) compared to those who received placebo the first six months. A linear regression analysis limited to the influence of age demonstrates young age as a significant factor in improved MHFMS scores (p = 0.007). Conclusions This study demonstrated no benefit from six months treatment with VPA and L-carnitine in a young non-ambulatory cohort of subjects with SMA. Weight gain, age

  1. Clinical trials in spinal muscular atrophy.

    PubMed

    Kaufmann, Petra; Iannaccone, Susan T

    2008-08-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by muscle atrophy and weakness due to degeneration of the anterior horn cells in the spinal cord. A great need exists for an effective treatment of SMA, a disease that often causes severe disability in patients who are cognitively intact and can have a normal life expectancy. Unlike many other neurologic diseases, SMA can be easily diagnosed through genetic testing. Also, preclinical progress over the last 2 decades has been major, with the discovery of the gene and of a "druggable" modifying gene that provides one of several promising targets for treatment. SMA is rare but is a common orphan disease, so trials should be feasible, raising the hope that we will find effective treatments for this disorder.

  2. Bed Rest Muscular Atrophy

    NASA Technical Reports Server (NTRS)

    Greenleaf, John E.

    2000-01-01

    A major debilitating response from prolonged bed rest (BR) is muscle atrophy, defined as a "decrease in size of a part of tissue after full development has been attained: a wasting away of tissue as from disuse, old age, injury or disease". Part of the complicated mechanism for the dizziness, increased body instability, and exaggerated gait in patients who arise immediately after BR may be a result of not only foot pain, but also of muscular atrophy and associated reduction in lower limb strength. Also, there seems to be a close association between muscle atrophy and bone atrophy. A discussion of many facets of the total BR homeostatic syndrome has been published. The old adage that use determines form which promotes function of bone (Wolff's law) also applies to those people exposed to prolonged BR (without exercise training) in whom muscle atrophy is a consistent finding. An extreme case involved a 16-year-old boy who was ordered to bed by his mother in 1932: after 50 years in bed he had "a lily-white frame with limbs as thin as the legs of a ladder-back chair". These findings emphasize the close relationship between muscle atrophy and bone atrophy. In addition to loss of muscle mass during deconditioning, there is a significant loss of muscle strength and a decrease in protein synthesis. Because the decreases in force (strength) are proportionately greater than those in fiber size or muscle cross-sectional area, other contributory factors must be involved; muscle fiber dehydration may be important.

  3. Bed Rest Muscular Atrophy

    NASA Technical Reports Server (NTRS)

    Greenleaf, John E.

    2000-01-01

    A major debilitating response from prolonged bed rest (BR) is muscle atrophy, defined as a "decrease in size of a part of tissue after full development has been attained: a wasting away of tissue as from disuse, old age, injury or disease". Part of the complicated mechanism for the dizziness, increased body instability, and exaggerated gait in patients who arise immediately after BR may be a result of not only foot pain, but also of muscular atrophy and associated reduction in lower limb strength. Also, there seems to be a close association between muscle atrophy and bone atrophy. A discussion of many facets of the total BR homeostatic syndrome has been published. The old adage that use determines form which promotes function of bone (Wolff's law) also applies to those people exposed to prolonged BR (without exercise training) in whom muscle atrophy is a consistent finding. An extreme case involved a 16-year-old boy who was ordered to bed by his mother in 1932: after 50 years in bed he had "a lily-white frame with limbs as thin as the legs of a ladder-back chair". These findings emphasize the close relationship between muscle atrophy and bone atrophy. In addition to loss of muscle mass during deconditioning, there is a significant loss of muscle strength and a decrease in protein synthesis. Because the decreases in force (strength) are proportionately greater than those in fiber size or muscle cross-sectional area, other contributory factors must be involved; muscle fiber dehydration may be important.

  4. Analysis of complex repeat sequences within the spinal muscular atrophy (SMA) candidate region in 5q13

    SciTech Connect

    Davies, K.E.; Morrison, K.E.; Daniels, R.I.

    1994-09-01

    We previously reported that the 400 kb interval flanked the polymorphic loci D5S435 and D5S557 contains blocks of a chromosome 5 specific repeat. This interval also defines the SMA candidate region by genetic analysis of recombinant families. A YAC contig of 2-3 Mb encompassing this area has been constructed and a 5.5 kb conserved fragment, isolated from a YAC end clone within the above interval, was used to obtain cDNAs from both fetal and adult brain libraries. We describe the identification of cDNAs with stretches of high DNA sequence homology to exons of {beta} glucuronidase on human chromosome 7. The cDNAs map both to the candidate region and to an area of 5p using FISH and deletion hybrid analysis. Hybridization to bacteriophage and cosmid clones from the YACs localizes the {beta} glucuronidase related sequences within the 400 kb region of the YAC contig. The cDNAs show a polymorphic pattern on hybridization to genomic BamH1 fragments in the size range of 10-250 kb. Further analysis using YAC fragmentation vectors is being used to determine how these {beta} glucuronidase related cDNAs are distributed within 5q13. Dinucleotide repeats within the region are being investigated to determine linkage disequilibrium with the disease locus.

  5. Identification of a Maleimide-Based Glycogen Synthase Kinase-3 (GSK-3) Inhibitor, BIP-135, that Prolongs the Median Survival Time of Δ7 SMA KO Mouse Model of Spinal Muscular Atrophy.

    PubMed

    Chen, Po C; Gaisina, Irina N; El-Khodor, Bassem F; Ramboz, Sylvie; Makhortova, Nina R; Rubin, Lee L; Kozikowski, Alan P

    2012-01-18

    The discovery of upregulated glycogen synthase kinase-3 (GSK-3) in various pathological conditions has led to the development of a host of chemically diverse small molecule GSK-3 inhibitors, such as BIP-135. GSK-3 inhibition emerged as an alternative therapeutic target for treating spinal muscular atrophy (SMA) when a number of GSK-3 inhibitors were shown to elevate survival motor neuron (SMN) levels in vitro and to rescue motor neurons when their intrinsic SMN level was diminished by SMN-specific short hairpin RNA (shRNA). Despite their cellular potency, the in vivo efficacy of GSK-3 inhibitors has yet to be evaluated in an animal model of SMA. Herein, we disclose that a potent and reasonably selective GSK-3 inhibitor, namely BIP-135, was tested in a transgenic Δ7 SMA KO mouse model of SMA, and found to prolong the median survival of these animals. In addition, this compound was shown to elevate the SMN protein level in SMA patient-derived fibroblast cells as determined by western blot, and was neuroprotective in a cell-based, SMA-related model of oxidative stress-induced neurodegeneration.

  6. Emerging treatment options for spinal muscular atrophy.

    PubMed

    Burnett, Barrington G; Crawford, Thomas O; Sumner, Charlotte J

    2009-03-01

    The motor neuron disease spinal muscular atrophy (SMA) is one of the leading genetic killers of infants worldwide. SMA is caused by mutation of the survival motor neuron 1 (SMN1) gene and deficiency of the survival motor neuron (SMN) protein. All patients retain one or more copies of the SMN2 gene, which (by producing a small amount of the SMN protein) rescues embryonic lethality and modifies disease severity. Rapid progress continues in dissecting the cellular functions of the SMN protein, but the mechanisms linking SMN deficiency with dysfunction and loss of functioning motor units remain poorly defined. Clinically, SMA should to be distinguished from other neuromuscular disorders, and the diagnosis can be readily confirmed with genetic testing. Quality of life and survival of SMA patients are improved with aggressive supportive care including optimized respiratory and nutritional care and management of scoliosis and contractures. Because SMA is caused by inadequate amounts of SMN protein, one aim of current SMA therapeutics development is to increase SMN protein levels in SMA patients by activating SMN2 gene expression and/or increasing levels of full-length SMN2 transcripts. Several potential therapeutic compounds are currently being studied in clinical trials in SMA patients.

  7. Spinal muscular atrophy with respiratory distress type 1 (SMARD1).

    PubMed

    Kaindl, Angela M; Guenther, Ulf-Peter; Rudnik-Schöneborn, Sabine; Varon, Raymonda; Zerres, Klaus; Schuelke, Markus; Hübner, Christoph; von Au, Katja

    2008-02-01

    Autosomal recessive spinal muscular atrophy with respiratory distress type 1 (SMARD1), recently referred to as distal spinal muscular atrophy 1 (DSMA1; MIM#604320) and also known as distal hereditary motor neuropathy type 6 (dHMN6 or HMN6), results from mutations in the IGHMBP2 gene on chromosome 11q13.3 encoding the immunoglobulin micro-binding protein 2. In contrast to the infantile spinal muscular atrophy type 1 (SMA1; Werdnig-Hoffmann disease) with weakness predominantly of proximal muscles and bell-shaped thorax deformities due to intercostal muscle atrophy, infants with distal spinal muscular atrophy 1 usually present with distal muscle weakness, foot deformities, and sudden respiratory failure due to diaphragmatic paralysis that often requires urgent intubation. In this article, the authors review the clinical, neuropathological, and genetic aspects of distal spinal muscular atrophy 1 and discuss differential diagnoses.

  8. Large linkage analysis in 100 families with autosomal recessive spinal muscular atrophy (SMA) and 11 EPH families using 15 polymorphic loci in the region 5q11. 2-q13. 3

    SciTech Connect

    Wirth, B.; Pick, E.; Leutner, A.; Dadze, A.; Voosen, B.; Piechaczek-Wappenschmidt, B.; Rudnik-Schoeneborn, S.; Schoenling, J.; Zerres, K. ); Knapp, M. )

    1994-03-01

    The autosomal recessive proximal spinal muscular atrophy (SMA) gene was mapped to the region 5q11.2-q.13.3 in 1990. Here, the authors present a large genetic linkage study of 100 SMA families and 11 CEPH families using 14 polymorphic simple sequence repeats (SSRs) and one RFLP in the region 5q11.2-q.13.3. The genetic interval between the closest SMA flanking loci D5S435 and D5S557 comprises 1 cM at z[sub max] = 27.94. Two recombinants were identified between the SMA gene and the closest telomeric marker D5S557. The first places the SMA gene centromeric to this marker; the second suggests a double recombinant at D5S557, which is very unlikely. More likely explanations are discussed in the paper. No recombinant was found between D5S435 and the SMA gene. They localized a recently described polymorphic marker, D5S351, close to the SMA. Due to its high PIC value of 0.70, it represents a very useful marker for prenatal diagnosis. In addition, they developed a new reverse primer for the nearest centromeric locus D5S435, a useful marker for prenatal diagnosis, which has been very difficult to amplify in the past. Three of the markers presented here are newly developed polymorphic SSRs (one tetranucleotide repeat, D5s507/W15CATT, and two dinucleotide repeats, D5S544/C88.2GT and D5S682/C88.3GT). These markers are too far from the SMA gene to be relevant for cloning; nevertheless, as part of the human genome project, they are contributing to the fine genetic mapping of the region 5q11.2-q.13.3. The most likely order of the loci based on two-point and multipoint linkage analyses as well as on specific recombination events and physical mapping studies is D5S76-D5S507-D5S6-D5S125-D5S680-D5S435-SMA-D5S557-D5S35 -15[prime]MAP1B-3[prime]MAP1B-JK53CA1/2-(D5S127-D5S39)-(D5S544-D5S682). In general, the genetic distances obtained from the SMA and CEPH families are comparable. 25 refs., 4 figs., 5 tabs.

  9. Spinal Muscular Atrophy

    PubMed Central

    Kolb, Stephen J.; Kissel, John T.

    2015-01-01

    Incidence The incidence of SMA is 1:11,000 live births [1]. Prevalence The prevalence of the carrier state is approximately 1 in 54 [1]. Severity The clinical severity of SMA correlates inversely with SMN2 gene copy number and varies from an extreme weakness and paraplegia of infancy to a mild proximal weakness of adulthood. Natural History The natural history of SMA is complex and variable. For this reason, clinical subgroups have been defined based upon best motor function attainment during development. Type 1 SMA infants never sit independently. Type 2 SMA children sit at some point during their childhood, but never walk independently. And Type 3 SMA children and adults are able to walk independently at some point in their childhood. PMID:26515624

  10. Spinal muscular atrophy functional composite score: A functional measure in spinal muscular atrophy.

    PubMed

    Montes, Jacqueline; Glanzman, Allan M; Mazzone, Elena S; Martens, William B; Dunaway, Sally; Pasternak, Amy; Riley, Susan O; Quigley, Janet; Pandya, Shree; De Vivo, Darryl C; Kaufmann, Petra; Chiriboga, Claudia A; Finkel, Richard S; Tennekoon, Gihan I; Darras, Basil T; Pane, Marika; Mercuri, Eugenio; Mcdermott, Michael P

    2015-12-01

    With clinical trials underway, our objective was to construct a composite score of global function that could discriminate among people with spinal muscular atrophy (SMA). Data were collected from 126 participants with SMA types 2 and 3. Scores from the Hammersmith Functional Motor Scale-Expanded and Upper Limb Module were expressed as a percentage of the maximum score and 6-minute walk test as percent of predicted normal distance. A principal component analysis was performed on the correlation matrix for the 3 percentage scores. The first principal component yielded a composite score with approximately equal weighting of the 3 components and accounted for 82% of the total variability. The SMA functional composite score, an unweighted average of the 3 individual percentage scores, correlated almost perfectly with the first principal component. This combination of measures broadens the spectrum of ability that can be quantified in type 2 and 3 SMA patients. © 2015 Wiley Periodicals, Inc.

  11. Therapeutic developments in spinal muscular atrophy

    PubMed Central

    Sproule, Douglas M.; Kaufmann, Petra

    2010-01-01

    Spinal muscular atrophy (SMA), a potentially devastating disease marked by progressive weakness and muscle atrophy resulting from the dysfunction and loss of motor neurons of the spinal cord, has emerged in recent years as an attractive target for therapeutic intervention. Caused by a homozygous mutation to the Survival of Motor Neurons 1 (SMN1) gene on chromosome 5q, the severity of the clinical phenotype in SMA is modulated by the function of a related protein, Survival of Motor Neurons 2 (SMN2). SMN2 predominantly produces an unstable SMN transcript lacking exon 7; only about 10% of the transcription product produces a full-length, functional SMN protein. Several therapeutic strategies have targeted this gene with the goal of producing increased full-length SMN transcript, thereby modifying the underlying mechanism. Drugs that have increased SMN2 function, in vitro, are now explored for potential therapeutic benefit in this disease. Alternative approaches, including neuroprotective, muscle anabolic, gene and cell replacement strategies, also hold promise. The recent advances in preclinical research and the development of a wider range of animal models for SMA continue to provide cautious optimism that effective treatments for SMA will eventually emerge. PMID:21179609

  12. Spinal muscular atrophy: a time for screening.

    PubMed

    Prior, Thomas W

    2010-12-01

    Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by mutations in the survival motor neuron (SMN1) gene, affecting approximately 1 in 10,000 live births. Even though a specific therapy for SMA is not currently available, a newborn screening test may allow the child to be enrolled in a clinical trial before irreversible neuronal loss occurs and enable patients to obtain more proactive treatments. Until an effective treatment is found to cure or arrest the progression of the disease, prevention of new cases through carrier detection and prenatal diagnosis becomes extremely important. The correlation between the SMA phenotype and the SMN2 copy number and the demonstration that sufficient SMN protein from SMN2 in transgenic mice can ameliorate the disease has made the SMN2 gene an obvious target that is being modulated in current therapeutic trials. Most recent work, utilizing gene therapy, has also shown a rescue of the phenotype in the mouse model. Since SMA children are often asymptomatic at birth, newborn screening is a means which will allow the implementation of the most early intervention to take place, before the irreversible loss of motor neurons. Since there is no effective cure for SMA presently, prevention through the identification of carriers becomes an important alternative and has recently been initiated. Treatment and prevention of SMA are complementary responses to the scourge presented by SMA. This review first describes the molecular genetics of SMA and then focuses on newborn screening, as a means of ensuring the earliest intervention, and the prevention through population carrier screening.

  13. Modeling Spinal Muscular Atrophy in Drosophila

    PubMed Central

    Mukherjee, Ashim; Kankel, Mark W.; Sen, Anindya; Sridhar, Vasanthi; Fulga, Tudor A.; Hart, Anne C.; Van Vactor, David; Artavanis-Tsakonas, Spyros

    2008-01-01

    Spinal Muscular Atrophy (SMA), a recessive hereditary neurodegenerative disease in humans, has been linked to mutations in the survival motor neuron (SMN) gene. SMA patients display early onset lethality coupled with motor neuron loss and skeletal muscle atrophy. We used Drosophila, which encodes a single SMN ortholog, survival motor neuron (Smn), to model SMA, since reduction of Smn function leads to defects that mimic the SMA pathology in humans. Here we show that a normal neuromuscular junction (NMJ) structure depends on SMN expression and that SMN concentrates in the post-synaptic NMJ regions. We conducted a screen for genetic modifiers of an Smn phenotype using the Exelixis collection of transposon-induced mutations, which affects approximately 50% of the Drosophila genome. This screen resulted in the recovery of 27 modifiers, thereby expanding the genetic circuitry of Smn to include several genes not previously known to be associated with this locus. Among the identified modifiers was wishful thinking (wit), a type II BMP receptor, which was shown to alter the Smn NMJ phenotype. Further characterization of two additional members of the BMP signaling pathway, Mothers against dpp (Mad) and Daughters against dpp (Dad), also modify the Smn NMJ phenotype. The NMJ defects caused by loss of Smn function can be ameliorated by increasing BMP signals, suggesting that increased BMP activity in SMA patients may help to alleviate symptoms of the disease. These results confirm that our genetic approach is likely to identify bona fide modulators of SMN activity, especially regarding its role at the neuromuscular junction, and as a consequence, may identify putative SMA therapeutic targets. PMID:18791638

  14. Forced oscillation technique in spinal muscular atrophy.

    PubMed

    Gauld, Leanne M; Keeling, Lucy A; Shackleton, Claire E; Sly, Peter D

    2014-09-01

    Spinal muscular atrophy (SMA) causes respiratory compromise that is difficult to assess in young children. The forced oscillation technique (FOT) is commercially available for children as young as 2 years of age and is nonvolitional. The aim of this study was to assess the usefulness of FOT in young children with SMA. Children with SMA aged < 10 years were recruited. FOT was performed every 3 months for 12 months (five visits). Spirometry and assisted and unassisted peak cough flow (PCF) were performed where possible. Polysomnography was performed on children with type 2 SMA. Clinical information included SMA type, chest infections, Cobb angle, medications, and mobility. Regression analysis assessed relationships between FOT and FVC, PCF, and apnea/hypopnea index (AHI). Analysis of variance sought relationships to clinical characteristics. Twelve children (seven male) were recruited; mean age was 6.26 (± 2.59) years. Respiratory reactance at 8 Hz (Xrs8) (mean z score, +1.41; SD, 1.90; P < .03) and respiratory resistance at 8 Hz (Rrs8) (mean z score, +0.66; SD, 1.34; P = .12) were abnormal. Four children performed spirometry. Linear relationships to Xrs8 exist: FVC (R2, 0.54), unassisted PCF (R2, 0.33), assisted PCF (R2, 0.43), and AHI (R2, 0.32). Over 12 months, Xrs8z score worsened (rate of change of +1.08, P < .001) and Rrs8z score worsened (rate of change +0.51, P < .001). No relationship (P > .05) was found between clinical characteristics and FOT values. FOT is feasible in young children with SMA, with abnormal values of reactance and resistance on grouped data, worsening over 12 months. Xrs8 is related to respiratory tests used to monitor progress in SMA (FVC, PCF, AHI). Further research on the value of FOT in managing individuals is warranted.

  15. Spinal muscular atrophy: molecular genetics and diagnostics.

    PubMed

    Ogino, Shuji; Wilson, Robert B

    2004-01-01

    Spinal muscular atrophy is one of the most common autosomal recessive diseases, affecting approximately one in 10,000 live births and with a carrier frequency of approximately one in 50. Spinal muscular atrophy is caused by a deficiency of the ubiquitous protein survival of motor neuron (SMN), which is encoded by the SMN genes, SMN1 and SMN2. Due to a single nucleotide polymorphism (840C>T), SMN2 produces less full-length transcript than SMN1 and cannot entirely prevent neuronal cell death at physiologic gene dosages. The 38-kDa SMN protein comprises 294 amino acids and is involved in the biogenesis of uridine-rich small nuclear ribonucleoproteins, facilitating their cytoplasmic assembly into the spliceosome. Various animal models have been developed to study the pathogenesis of spinal muscular atrophy, as well as to test novel therapeutics. Common PCR-restriction fragment length polymorphism assays can detect the homozygous absence of SMN1 in approximately 94% of patients with clinically typical spinal muscular atrophy. SMN gene dosage analysis can determine the copy number of SMN1 to detect carriers and patients heterozygous for the absence of SMN1. Due to the genetic complexity and the high carrier frequency, accurate risk assessment and genetic counseling are particularly important. Comprehensive SMA genetic testing, combined with appropriate genetic counseling and risk assessment, provides the most complete evaluation of patients and their families at this time. New technologies, such as monosomal analysis techniques, may be widely available in the future. Copyright Future Drugs Ltd.

  16. Spinal Muscular Atrophy: Current Therapeutic Strategies

    NASA Astrophysics Data System (ADS)

    Kiselyov, Alex S.; Gurney, Mark E.

    Proximal spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by death of motor neurons in the spinal cord. SMA is caused by deletion and/or mutation of the survival motor neuron gene (SMN1) on chromosome 5q13. There are variable numbers of copies of a second, related gene named SMN2 located in the proximity to SMN1. Both genes encode the same protein (Smn). Loss of SMN1 and incorrect splicing of SMN2 affect cellular levels of Smn triggering death of motor neurons. The severity of SMA is directly related to the normal number of copies of SMN2 carried by the patient. A considerable effort has been dedicated to identifying modalities including both biological and small molecule agents that increase SMN2 promoter activity to upregulate gene transcription and produce increased quantities of full-length Smn protein. This review summarizes recent progress in the area and suggests potential target product profile for an SMA therapeutic.

  17. The genetics of spinal muscular atrophies.

    PubMed

    Wee, Claribel D; Kong, Lingling; Sumner, Charlotte J

    2010-10-01

    This article reviews clinical, genetic, and therapeutic advances in spinal muscular atrophies (SMAs), inherited disorders characterized by motor neuron loss and muscle weakness. There has been progress in defining the clinical and genetic features of at least 16 distinct forms of SMA. The genes associated with 14 of these disorders have been identified in the last decade, including four within the last year: TRPV4, ATP7A, VRK1, and HSPB3. Genetic testing is now available for many SMAs, providing important diagnostic and prognostic information. Cell and animal models of SMAs have been used to further understand how mutations in SMA-associated genes, which code for proteins involved in diverse functions such as transcriptional regulation, RNA processing, and cytoskeletal dynamics, lead to motor neuron dysfunction and loss. In the last year, there has also been remarkable progress in preclinical therapeutics development for proximal SMA using gene therapy, antisense oligonucleotides, and small molecules. The advances in the clinical and genetic characterization of different forms of SMAs have important implications for clinical evaluation and management of patients. The identification of multiple, novel SMA-causing genes will lead to an improved understanding of motor neuron disease biology and may provide novel targets for therapeutics development.

  18. Defining new borders of the spinal muscular atrophy (SMA) candidate region by two new microsatellites and isolation of cDNAs

    SciTech Connect

    Wirth, B.; Schoenling, J.; Dadze, A.

    1994-09-01

    A high number of cosmids and phages were identified that contained di-, tri-, and tetranucleotide repeats. These clones were isolated from STSs that map to the SMA region as well as from three cosmid and one phage library that had been prepared from YACs which span the SMA candidate interval. We developed two new microsatellites, A31 (D5S823) and 95/23, which enabled us to define new borders of the SMA region and to reduce it to approximately 700 kb. Physically, the marker A31 maps to the overlapping region of the YACs y116, y55 and y122 at about 550 kb distal to the locus D5S435. A recombination in one SMA type I family places A31 proximal to the SMA gene. The multicopy microsatellite, 95/23, developed from a cosmid including the STS y97U revealed in a consanguine SMA type I family different alleles, while all proximal markers were heterozygous. This suggests a location of 95/23 distal to the SMA gene. Furthermore, we tested 157 German SMA families (100 SMA type I, 50 SMA type II and 20 SMA type III) for linkage disequilibrium with the marker AG1-CA which reveals no recombination with the SMA gene. We found in SMA type I families strong allelic association between the 100 bp allele and the SMA gene. In 7 families we got deletions within the AG1-CA microsatellite. On the way to isolate the SMA gene, we hybridized whole cosmid and YAC inserts to cDNA libraries of spinal cord, brain and muscle. Seven cDNAs were initially identified and cDNA walking was used to begin the isolation of whole transcribed sequences.

  19. Newborn screening for spinal muscular atrophy: Anticipating an imminent need.

    PubMed

    Phan, Han C; Taylor, Jennifer L; Hannon, Harry; Howell, Rodney

    2015-04-01

    Spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality. Children with type I SMA typically die by the age of 2 years. Recent progress in gene modification and other innovative therapies suggest that improved outcomes may soon be forthcoming. In animal models, therapeutic intervention initiated before the loss of motor neurons alters SMA phenotype and increases lifespan. Presently, supportive care including respiratory, nutritional, physiatry, and orthopedic management can ameliorate clinical symptoms and improve survival rates if SMA is diagnosed early in life. Newborn screening could help optimize these potential benefits. A recent report demonstrated that SMA detection can be multiplexed at minimal additional cost with the assay for severe combined immunodeficiency, already implemented by many newborn screening programs. The public health community should remain alert to the rapidly changing developments in early detection and treatment of SMA. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. Cervical Spinal Cord Atrophy Profile in Adult SMN1-Linked SMA.

    PubMed

    El Mendili, Mohamed-Mounir; Lenglet, Timothée; Stojkovic, Tanya; Behin, Anthony; Guimarães-Costa, Raquel; Salachas, François; Meininger, Vincent; Bruneteau, Gaelle; Le Forestier, Nadine; Laforêt, Pascal; Lehéricy, Stéphane; Benali, Habib; Pradat, Pierre-François

    2016-01-01

    The mechanisms underlying the topography of motor deficits in spinal muscular atrophy (SMA) remain unknown. We investigated the profile of spinal cord atrophy (SCA) in SMN1-linked SMA, and its correlation with the topography of muscle weakness. Eighteen SMN1-linked SMA patients type III/V and 18 age/gender-matched healthy volunteers were included. Patients were scored on manual muscle testing and functional scales. Spinal cord was imaged using 3T MRI system. Radial distance (RD) and cord cross-sectional area (CSA) measurements in SMA patients were compared to those in controls and correlated with strength and disability scores. CSA measurements revealed a significant cord atrophy gradient mainly located between C3 and C6 vertebral levels with a SCA rate ranging from 5.4% to 23% in SMA patients compared to controls. RD was significantly lower in SMA patients compared to controls in the anterior-posterior direction with a maximum along C4 and C5 vertebral levels (p-values < 10-5). There were no correlations between atrophy measurements, strength and disability scores. Spinal cord atrophy in adult SMN1-linked SMA predominates in the segments innervating the proximal muscles. Additional factors such as neuromuscular junction or intrinsic skeletal muscle defects may play a role in more complex mechanisms underlying weakness in these patients.

  1. Cervical Spinal Cord Atrophy Profile in Adult SMN1-Linked SMA

    PubMed Central

    El Mendili, Mohamed-Mounir; Lenglet, Timothée; Stojkovic, Tanya; Behin, Anthony; Guimarães-Costa, Raquel; Salachas, François; Meininger, Vincent; Bruneteau, Gaelle; Le Forestier, Nadine; Laforêt, Pascal; Lehéricy, Stéphane; Benali, Habib; Pradat, Pierre-François

    2016-01-01

    Purpose The mechanisms underlying the topography of motor deficits in spinal muscular atrophy (SMA) remain unknown. We investigated the profile of spinal cord atrophy (SCA) in SMN1-linked SMA, and its correlation with the topography of muscle weakness. Materials and Methods Eighteen SMN1-linked SMA patients type III/V and 18 age/gender-matched healthy volunteers were included. Patients were scored on manual muscle testing and functional scales. Spinal cord was imaged using 3T MRI system. Radial distance (RD) and cord cross-sectional area (CSA) measurements in SMA patients were compared to those in controls and correlated with strength and disability scores. Results CSA measurements revealed a significant cord atrophy gradient mainly located between C3 and C6 vertebral levels with a SCA rate ranging from 5.4% to 23% in SMA patients compared to controls. RD was significantly lower in SMA patients compared to controls in the anterior-posterior direction with a maximum along C4 and C5 vertebral levels (p-values < 10−5). There were no correlations between atrophy measurements, strength and disability scores. Conclusions Spinal cord atrophy in adult SMN1-linked SMA predominates in the segments innervating the proximal muscles. Additional factors such as neuromuscular junction or intrinsic skeletal muscle defects may play a role in more complex mechanisms underlying weakness in these patients. PMID:27089520

  2. Hybrids monosomal for human chromosome 5 reveal the presence of a spinal muscular atrophy (SMA) carrier with two SMN1 copies on one chromosome.

    PubMed

    Mailman, M D; Hemingway, T; Darsey, R L; Glasure, C E; Huang, Y; Chadwick, R B; Heinz, J W; Papp, A C; Snyder, P J; Sedra, M S; Schafer, R W; Abuelo, D N; Reich, E W; Theil, K S; Burghes, A H; de la Chapelle, A; Prior, T W

    2001-02-01

    We have analyzed the survival motor neuron gene (SMN1) dosage in 100 parents of children with homozygous SMN1 deletions. Of these parents, 96 (96%) demonstrated the expected one-copy SMN1 carrier genotype. However, four parents (4%) were observed to have a normal two-copy SMN1 dosage. The presence of two intact SMN1 genes in the parent of an affected child indicates either the occurrence of a de novo mutation event or a situation in which one chromosome has two copies of SMN1, whereas the other is null. We have separated individual chromosomes from two of these parents with two-copy SMN1 dosage by somatic cell hybridization and have employed a modified quantitative dosage assay to provide direct evidence that one parent is a two-copy/ zero-copy SMN1 carrier, whereas the other parent had an affected child as the result of a de novo mutation. These findings are important for assessing the recurrence risk of parents of children with spinal muscular atrophy and for providing accurate family counseling.

  3. Molecular basis of spinal muscular atrophy in Chinese

    SciTech Connect

    Chang, J.G.; Jong, Y.J.; Huang, J.M.

    1995-12-01

    Proximal spinal muscular atrophy (SMA) is an autosomal recessive disorder that is characterized by degeneration of the anterior horn cells, leading to symmetrical muscle weakness and wasting of voluntary muscles. SMA affects 1/10,000 live births and has an estimated carrier frequency of 1/40. Affected individuals are classified into three groups, depending on the age at onset and progression of the disease, and all three forms of SMA are linked to the same set of genetic markers in the chromosome. 15 refs., 3 figs.

  4. Motor neuron mitochondrial dysfunction in spinal muscular atrophy

    PubMed Central

    Miller, Nimrod; Shi, Han; Zelikovich, Aaron S.; Ma, Yong-Chao

    2016-01-01

    Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, predominantly affects high metabolic tissues including motor neurons, skeletal muscles and the heart. Although the genetic cause of SMA has been identified, mechanisms underlying tissue-specific vulnerability are not well understood. To study these mechanisms, we carried out a deep sequencing analysis of the transcriptome of spinal motor neurons in an SMA mouse model, in which we unexpectedly found changes in many genes associated with mitochondrial bioenergetics. Importantly, functional measurement of mitochondrial activities showed decreased basal and maximal mitochondrial respiration in motor neurons from SMA mice. Using a reduction-oxidation sensitive GFP and fluorescence sensors specifically targeted to mitochondria, we found increased oxidative stress level and impaired mitochondrial membrane potential in motor neurons affected by SMA. In addition, mitochondrial mobility was impaired in SMA disease conditions, with decreased retrograde transport but no effect on anterograde transport. We also found significantly increased fragmentation of the mitochondrial network in primary motor neurons from SMA mice, with no change in mitochondria density. Electron microscopy study of SMA mouse spinal cord revealed mitochondria fragmentation, edema and concentric lamellar inclusions in motor neurons affected by the disease. Intriguingly, these functional and structural deficiencies in the SMA mouse model occur during the presymptomatic stage of disease, suggesting a role in initiating SMA. Altogether, our findings reveal a critical role for mitochondrial defects in SMA pathogenesis and suggest a novel target for improving tissue health in the disease. PMID:27488123

  5. Vascular Defects and Spinal Cord Hypoxia in Spinal Muscular Atrophy.

    PubMed

    Somers, Eilidh; Lees, Robert D; Hoban, Katie; Sleigh, James N; Zhou, Haiyan; Muntoni, Francesco; Talbot, Kevin; Gillingwater, Thomas H; Parson, Simon H

    2016-02-01

    Spinal muscular atrophy (SMA) is a major inherited cause of infant death worldwide. It results from mutations in a single, ubiquitously expressed gene (SMN1), with loss of lower motor neurons being the primary pathological signature. Systemic defects have also been reported in SMA patients and animal models. We investigated whether defects associated with the vasculature contribute to motor neuron pathology in SMA. Development and integrity of the capillary bed was examined in skeletal muscle and spinal cord of SMA mice, and muscle biopsies from SMA patients and controls, using quantitative morphometric approaches on immunohistochemically labeled tissue. Pimonidazole hydrochloride-based assays were used to identify functional hypoxia. The capillary bed in muscle and spinal cord was normal in presymptomatic SMA mice (postnatal day 1), but failed to match subsequent postnatal development in control littermates. At mid- and late-symptomatic time points, the extent of the vascular architecture observed in two distinct mouse models of SMA was ∼50% of that observed in control animals. Skeletal muscle biopsies from human patients confirmed the presence of developmentally similar, significant vascular depletion in severe SMA. Hypovascularity in SMA mouse spinal cord was accompanied by significant functional hypoxia and defects in the blood-spinal cord barrier. Our results indicate that vascular defects are a major feature of severe forms of SMA, present in both mouse models and patients, resulting in functional hypoxia of motor neurons. Thus, abnormal vascular development and resulting hypoxia may contribute to the pathogenesis of SMA. © 2016 American Neurological Association.

  6. Advances and challenges in developing a therapy for spinal muscular atrophy.

    PubMed

    Anderton, Ryan S; Mastaglia, Frank L

    2015-01-01

    Spinal muscular atrophy (SMA) is a debilitating and incurable childhood onset disease characterized by the degeneration of motor neurons in the spinal cord resulting in muscular atrophy and paralysis. Over the past 20 years, there has been significant progress in understanding the molecular basis of the disease, allowing researchers to identify the main causative gene and successfully model SMA in various animals. Despite an improved understanding of the disease, there is still no effective treatment for SMA patients. Here, we discuss the current knowledge surrounding the pathogenesis of SMA, and outline recent advances toward the development of a successful therapy for this devastating disease.

  7. Different atrophy-hypertrophy transcription pathways in muscles affected by severe and mild spinal muscular atrophy.

    PubMed

    Millino, Caterina; Fanin, Marina; Vettori, Andrea; Laveder, Paolo; Mostacciuolo, Maria Luisa; Angelini, Corrado; Lanfranchi, Gerolamo

    2009-04-07

    Spinal muscular atrophy (SMA) is a neurodegenerative disorder associated with mutations of the survival motor neuron gene SMN and is characterized by muscle weakness and atrophy caused by degeneration of spinal motor neurons. SMN has a role in neurons but its deficiency may have a direct effect on muscle tissue. We applied microarray and quantitative real-time PCR to study at transcriptional level the effects of a defective SMN gene in skeletal muscles affected by the two forms of SMA: the most severe type I and the mild type III. The two forms of SMA generated distinct expression signatures: the SMA III muscle transcriptome is close to that found under normal conditions, whereas in SMA I there is strong alteration of gene expression. Genes implicated in signal transduction were up-regulated in SMA III whereas those of energy metabolism and muscle contraction were consistently down-regulated in SMA I. The expression pattern of gene networks involved in atrophy signaling was completed by qRT-PCR, showing that specific pathways are involved, namely IGF/PI3K/Akt, TNF-alpha/p38 MAPK and Ras/ERK pathways. Our study suggests a different picture of atrophy pathways in each of the two forms of SMA. In particular, p38 may be the regulator of protein synthesis in SMA I. The SMA III profile appears as the result of the concurrent presence of atrophic and hypertrophic fibers. This more favorable condition might be due to the over-expression of MTOR that, given its role in the activation of protein synthesis, could lead to compensatory hypertrophy in SMA III muscle fibers.

  8. Descriptive epidemiology of spinal muscular atrophy type I in Estonia.

    PubMed

    Vaidla, Eve; Talvik, Inga; Kulla, Andres; Kahre, Tiina; Hamarik, Malle; Napa, Aita; Metsvaht, Tuuli; Piirsoo, Andres; Talvik, Tiina

    2006-01-01

    Spinal muscular atrophy is the second most frequent autosomal-recessive disorder in Europeans. There are no published epidemiological data on SMA in Estonia and other Baltic countries. The aim of this study was to estimate the incidence of SMA I in Estonia. All patients with SMA I diagnosed between January 1994 and December 2003 were included in the study. The diagnosis was established on the basis of neurological evaluation, ENMG findings, molecular studies and muscle biopsy. PCR and restriction enzyme analysis was used to detect the homozygous deletion of the SMN1 gene. A total of 9 cases of SMA I were identified during this 10-year period. The incidence of SMA I in Estonia is 1 in 14,400 live births, which is similar to the result from Hungary but lower than average incidence in the world. Only one of the patients was female. Typical SMN1 gene deletion was found in all cases.

  9. RASCH ANALYSIS OF CLINICAL OUTCOME MEASURES IN SPINAL MUSCULAR ATROPHY

    PubMed Central

    CANO, STEFAN J.; MAYHEW, ANNA; GLANZMAN, ALLAN M.; KROSSCHELL, KRISTIN J.; SWOBODA, KATHRYN J.; MAIN, MARION; STEFFENSEN, BIRGIT F.; BÉRARD, CAROLE; GIRARDOT, FRANÇOISE; PAYAN, CHRISTINE A.M.; MERCURI, EUGENIO; MAZZONE, ELENA; ELSHEIKH, BAKRI; FLORENCE, JULAINE; HYNAN, LINDA S.; IANNACCONE, SUSAN T.; NELSON, LESLIE L.; PANDYA, SHREE; ROSE, MICHAEL; SCOTT, CHARLES; SADJADI, REZA; YORE, MACKENSIE A.; JOYCE, CYNTHIA; KISSEL, JOHN T.

    2015-01-01

    Introduction Trial design for SMA depends on meaningful rating scales to assess outcomes. In this study Rasch methodology was applied to 9 motor scales in spinal muscular atrophy (SMA). Methods Data from all 3 SMA types were provided by research groups for 9 commonly used scales. Rasch methodology assessed the ordering of response option thresholds, tests of fit, spread of item locations, residual correlations, and person separation index. Results Each scale had good reliability. However, several issues impacting scale validity were identified, including the extent that items defined clinically meaningful constructs and how well each scale measured performance across the SMA spectrum. Conclusions The sensitivity and potential utility of each SMA scale as outcome measures for trials could be improved by establishing clear definitions of what is measured, reconsidering items that misfit and items whose response categories have reversed thresholds, and adding new items at the extremes of scale ranges. PMID:23836324

  10. Rasch analysis of clinical outcome measures in spinal muscular atrophy.

    PubMed

    Cano, Stefan J; Mayhew, Anna; Glanzman, Allan M; Krosschell, Kristin J; Swoboda, Kathryn J; Main, Marion; Steffensen, Birgit F; Bérard, Carole; Girardot, Françoise; Payan, Christine A M; Mercuri, Eugenio; Mazzone, Elena; Elsheikh, Bakri; Florence, Julaine; Hynan, Linda S; Iannaccone, Susan T; Nelson, Leslie L; Pandya, Shree; Rose, Michael; Scott, Charles; Sadjadi, Reza; Yore, Mackensie A; Joyce, Cynthia; Kissel, John T

    2014-03-01

    Trial design for SMA depends on meaningful rating scales to assess outcomes. In this study Rasch methodology was applied to 9 motor scales in spinal muscular atrophy (SMA). Data from all 3 SMA types were provided by research groups for 9 commonly used scales. Rasch methodology assessed the ordering of response option thresholds, tests of fit, spread of item locations, residual correlations, and person separation index. Each scale had good reliability. However, several issues impacting scale validity were identified, including the extent that items defined clinically meaningful constructs and how well each scale measured performance across the SMA spectrum. The sensitivity and potential utility of each SMA scale as outcome measures for trials could be improved by establishing clear definitions of what is measured, reconsidering items that misfit and items whose response categories have reversed thresholds, and adding new items at the extremes of scale ranges. Copyright © 2013 Wiley Periodicals, Inc.

  11. Genetic inhibition of JNK3 ameliorates spinal muscular atrophy

    PubMed Central

    Genabai, Naresh K.; Ahmad, Saif; Zhang, Zhanying; Jiang, Xiaoting; Gabaldon, Cynthia A.; Gangwani, Laxman

    2015-01-01

    Mutation of the Survival Motor Neuron 1 (SMN1) gene causes spinal muscular atrophy (SMA), an autosomal recessive neurodegenerative disorder that occurs in early childhood. Degeneration of spinal motor neurons caused by SMN deficiency results in progressive muscle atrophy and death in SMA. The molecular mechanism underlying neurodegeneration in SMA is unknown. No treatment is available to prevent neurodegeneration and reduce the burden of illness in SMA. We report that the c-Jun NH2-terminal kinase (JNK) signaling pathway mediates neurodegeneration in SMA. The neuron-specific isoform JNK3 is required for neuron degeneration caused by SMN deficiency. JNK3 deficiency reduces degeneration of cultured neurons caused by low levels of SMN. Genetic inhibition of JNK pathway in vivo by Jnk3 knockout results in amelioration of SMA phenotype. JNK3 deficiency prevents the loss of spinal cord motor neurons, reduces muscle degeneration, improves muscle fiber thickness and muscle growth, improves motor function and overall growth and increases lifespan of mice with SMA that shows a systemic rescue of phenotype by a SMN-independent mechanism. JNK3 represents a potential (non-SMN) therapeutic target for the treatment of SMA. PMID:26423457

  12. Therapy Development for Spinal Muscular Atrophy in SMN Independent Targets

    PubMed Central

    Tsai, Li-Kai

    2012-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder, leading to progressive muscle weakness, atrophy, and sometimes premature death. SMA is caused by mutation or deletion of the survival motor neuron-1 (SMN1) gene. An effective treatment does not presently exist. Since the severity of the SMA phenotype is inversely correlated with expression levels of SMN, the SMN-encoded protein, SMN is the most important therapeutic target for development of an effective treatment for SMA. In recent years, numerous SMN independent targets and therapeutic strategies have been demonstrated to have potential roles in SMA treatment. For example, some neurotrophic, antiapoptotic, and myotrophic factors are able to promote survival of motor neurons or improve muscle strength shown in SMA mouse models or clinical trials. Plastin-3, cpg15, and a Rho-kinase inhibitor regulate axonal dynamics and might reduce the influences of SMN depletion in disarrangement of neuromuscular junction. Stem cell transplantation in SMA model mice resulted in improvement of motor behaviors and extension of survival, likely from trophic support. Although most therapies are still under investigation, these nonclassical treatments might provide an adjunctive method for future SMA therapy. PMID:22701806

  13. Differential induction of muscle atrophy pathways in two mouse models of spinal muscular atrophy

    PubMed Central

    Deguise, Marc-Olivier; Boyer, Justin G.; McFall, Emily R.; Yazdani, Armin; De Repentigny, Yves; Kothary, Rashmi

    2016-01-01

    Motor neuron loss and neurogenic atrophy are hallmarks of spinal muscular atrophy (SMA), a leading genetic cause of infant deaths. Previous studies have focused on deciphering disease pathogenesis in motor neurons. However, a systematic evaluation of atrophy pathways in muscles is lacking. Here, we show that these pathways are differentially activated depending on severity of disease in two different SMA model mice. Although proteasomal degradation is induced in skeletal muscle of both models, autophagosomal degradation is present only in Smn2B/− mice but not in the more severe Smn−/−; SMN2 mice. Expression of FoxO transcription factors, which regulate both proteasomal and autophagosomal degradation, is elevated in Smn2B/− muscle. Remarkably, administration of trichostatin A reversed all molecular changes associated with atrophy. Cardiac muscle also exhibits differential induction of atrophy between Smn2B/− and Smn−/−; SMN2 mice, albeit in the opposite direction to that of skeletal muscle. Altogether, our work highlights the importance of cautious analysis of different mouse models of SMA as distinct patterns of atrophy induction are at play depending on disease severity. We also revealed that one of the beneficial impacts of trichostatin A on SMA model mice is via attenuation of muscle atrophy through reduction of FoxO expression to normal levels. PMID:27349908

  14. Management of scoliosis in patients with Duchenne muscular dystrophy and spinal muscular atrophy: A literature review.

    PubMed

    Garg, Sumeet

    2016-01-01

    Scoliosis occurs in nearly all non-ambulatory children with spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD). Non-operative treatments have not been shown to be effective at preventing progression of scoliosis. Progressive scoliosis can impact the ability of patients to sit comfortably, be cosmetically unappealing, and in severe cases exacerbate pulmonary disease. The main goal of operative treatment is to improve sitting balance and prevent progression of scoliosis. Complication rates are high and there is little data on effect of operative treatment on quality of life in children with SMA and DMD. Comprehensive multi-disciplinary pre-operative evaluations are vital to reduce the risks of operative treatment.

  15. Chronic spinal muscular atrophy of facioscapulohumeral type.

    PubMed Central

    Furukawa, T; Toyokura, Y

    1976-01-01

    Chronic spinal muscular atrophy of FSH type affecting a mother and her son and daughter is reported. The relevant literature is reviewed and the relation between this conditon and Kugelberg-Welander (K-W) disease is discussed. Chronic spinal muscular atrophy of FSH type is considered to be a different entity from the eponymous K-W disease. Each type of muscular dystrophy, e.g. limb-girdle, FSH, distal, ocular, or oculopharyngeal type, has its counterpart of nuclear origin. A classification of the chronic spinal muscular atrophies is suggested following the classification of muscular dystrophy. Images PMID:957378

  16. Deletion analysis of SMN1 and NAIP genes in Southern Chinese children with spinal muscular atrophy.

    PubMed

    Liang, Yu-hua; Chen, Xiao-ling; Yu, Zhong-sheng; Chen, Chun-yue; Bi, Sheng; Mao, Lian-gen; Zhou, Bo-lin; Zhang, Xian-ning

    2009-01-01

    Spinal muscular atrophy (SMA) is a disorder characterized by degeneration of lower motor neurons and occasionally bulbar motor neurons leading to progressive limb and trunk paralysis as well as muscular atrophy. Three types of SMA are recognized depending on the age of onset, the maximum muscular activity achieved, and survivorship: SMA1, SMA2, and SMA3. The survival of motor neuron (SMN) gene has been identified as an SMA determining gene, whereas the neuronal apoptosis inhibitory protein (NAIP) gene is considered to be a modifying factor of the severity of SMA. The main objective of this study was to analyze the deletion of SMN1 and NAIP genes in southern Chinese children with SMA. Here, polymerase chain reaction (PCR) combined with restriction fragment length polymorphism (RFLP) was performed to detect the deletion of both exon 7 and exon 8 of SMN1 and exon 5 of NAIP in 62 southern Chinese children with strongly suspected clinical symptoms of SMA. All the 32 SMA1 patients and 76% (13/17) of SMA2 patients showed homozygous deletions for exon 7 and exon 8, and all the 13 SMA3 patients showed single deletion of SMN1 exon 7 along with 24% (4/17) of SMA2 patients. Eleven out of 32 (34%) SMA1 patients showed NAIP deletion, and none of SMA2 and SMA3 patients was found to have NAIP deletion. The findings of homozygous deletions of exon 7 and/or exon 8 of SMN1 gene confirmed the diagnosis of SMA, and suggested that the deletion of SMN1 exon 7 is a major cause of SMA in southern Chinese children, and that the NAIP gene may be a modifying factor for disease severity of SMA1. The molecular diagnosis system based on PCR-RFLP analysis can conveniently be applied in the clinical testing, genetic counseling, prenatal diagnosis and preimplantation genetic diagnosis of SMA.

  17. Establishing a standardized therapeutic testing protocol for spinal muscular atrophy.

    PubMed

    Tsai, Li-Kai; Tsai, Ming-Shung; Lin, Tzer-Bin; Hwu, Wuh-Liang; Li, Hung

    2006-11-01

    Several mice models have been created for spinal muscular atrophy (SMA); however, there is still no standard preclinical testing system for the disease. We previously generated type III-specific SMA model mice, which might be suitable for use as a preclinical therapeutic testing system for SMA. To establish such a system and test its applicability, we first created a testing protocol and then applied it as a means to investigate the use of valproic acid (VPA) as a possible treatment for SMA. These SMA mice revealed tail/ear/foot deformity, muscle atrophy, poorer motor performances, smaller compound muscle action potential and lower spinal motoneuron density at the age of 9 to 12 months in comparison with age-matched wild-type littermate mice. In addition, VPA attenuates motoneuron death, increases spinal SMN protein level and partially normalizes motor function in SMA mice. These results suggest that the testing protocol developed here is well suited for use as a standardized preclinical therapeutic testing system for SMA.

  18. Spinal Muscular Atrophy Therapeutics: Where do we Stand?

    PubMed

    d'Ydewalle, Constantin; Sumner, Charlotte J

    2015-04-01

    Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder pathologically characterized by the degeneration of motor neurons in the spinal cord and muscle atrophy. Motor neuron loss often results in severe muscle weakness causing affected infants to die before reaching 2 years of age. Patients with milder forms of SMA exhibit slowly progressive muscle weakness over many years. SMA is caused by the loss of SMN1 and the retention of at least 1 copy of a highly homologous SMN2. An alternative splicing event in the pre-mRNA arising from SMN2 results in the production of low levels of functional SMN protein. To date, there are no effective treatments available to treat patients with SMA. However, over the last 2 decades, the development of SMA mouse models and the identification of therapeutic targets have resulted in a promising drug pipeline for SMA. Here, we highlight some of the therapeutic strategies that have been developed to activate SMN2 expression, modulate splicing of the SMN2 pre-mRNA, or replace SMN1 by gene therapy. After 2 decades of translational research, we now stand within reach of a treatment for SMA.

  19. Defects in Motoneuron-Astrocyte Interactions in Spinal Muscular Atrophy.

    PubMed

    Zhou, Chunyi; Feng, Zhihua; Ko, Chien-Ping

    2016-02-24

    Spinal muscular atrophy (SMA) is a motoneuron disease caused by loss or mutation in Survival of Motor Neuron 1 (SMN1) gene. Recent studies have shown that selective restoration of SMN protein in astrocytes partially alleviates pathology in an SMA mouse model, suggesting important roles for astrocytes in SMA. Addressing these underlying mechanisms may provide new therapeutic avenues to fight SMA. Using primary cultures of pure motoneurons or astrocytes from SMNΔ7 (SMA) and wild-type (WT) mice, as well as their mixed and matched cocultures, we characterized the contributions of motoneurons, astrocytes, and their interactions to synapse loss in SMA. In pure motoneuron cultures, SMA motoneurons exhibited normal survival but intrinsic defects in synapse formation and synaptic transmission. In pure astrocyte cultures, SMA astrocytes exhibited defects in calcium homeostasis. In motoneuron-astrocyte contact cocultures, synapse formation and synaptic transmission were significantly reduced when either motoneurons, astrocytes or both were from SMA mice compared with those in WT motoneurons cocultured with WT astrocytes. The reduced synaptic activity is unlikely due to changes in motoneuron excitability. This disruption in synapse formation and synaptic transmission by SMN deficiency was not detected in motoneuron-astrocyte noncontact cocultures. Additionally, we observed a downregulation of Ephrin B2 in SMA astrocytes. These findings suggest that there are both cell autonomous and non-cell-autonomous defects in SMA motoneurons and astrocytes. Defects in contact interactions between SMA motoneurons and astrocytes impair synaptogenesis seen in SMA pathology, possibly due to the disruption of the Ephrin B2 pathway. Copyright © 2016 the authors 0270-6474/16/362543-11$15.00/0.

  20. Aquatic Therapy for a Child with Type III Spinal Muscular Atrophy: A Case Report

    ERIC Educational Resources Information Center

    Salem, Yasser; Gropack, Stacy Jaffee

    2010-01-01

    Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by degeneration of alpha motor neurons. This case report describes an aquatic therapy program and the outcomes for a 3-year-old girl with type III SMA. Motor skills were examined using the 88-item Gross Motor Function Measure (GMFM), the Peabody Developmental Motor Scales…

  1. Aquatic Therapy for a Child with Type III Spinal Muscular Atrophy: A Case Report

    ERIC Educational Resources Information Center

    Salem, Yasser; Gropack, Stacy Jaffee

    2010-01-01

    Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by degeneration of alpha motor neurons. This case report describes an aquatic therapy program and the outcomes for a 3-year-old girl with type III SMA. Motor skills were examined using the 88-item Gross Motor Function Measure (GMFM), the Peabody Developmental Motor Scales…

  2. Carrier testing for spinal muscular atrophy

    PubMed Central

    Gitlin, Jonathan M.; Fischbeck, Kenneth; Crawford, Thomas O.; Cwik, Valerie; Fleischman, Alan; Gonye, Karla; Heine, Deborah; Hobby, Kenneth; Kaufmann, Petra; Keiles, Steven; MacKenzie, Alex; Musci, Thomas; Prior, Thomas; Lloyd-Puryear, Michele; Sugarman, Elaine A.; Terry, Sharon F.; Urv, Tiina; Wang, Ching; Watson, Michael; Yaron, Yuval; Frosst, Phyllis; Howell, R. Rodney

    2014-01-01

    Spinal muscular atrophy is the most common fatal hereditary disease among newborns and infants. There is as yet no effective treatment. Although a carrier test is available, currently there is disagreement among professional medical societies who proffer standards of care as to whether or not carrier screening for spinal muscular atrophy should be offered as part of routine reproductive care. This leaves health care providers without clear guidance. In fall 2009, a meeting was held by National Institutes of Health to examine the scientific basis for spinal muscular atrophy carrier screening and to consider the issues that accompany such screening. In this article, the meeting participants summarize the discussions and conclude that pan-ethnic carrier screening for spinal muscular atrophy is technically feasible and that the specific study of implementing a spinal muscular atrophy carrier screening program raises broader issues about determining the scope and specifics of carrier screening in general. PMID:20808230

  3. Deletion of atrophy enhancing genes fails to ameliorate the phenotype in a mouse model of spinal muscular atrophy.

    PubMed

    Iyer, Chitra C; McGovern, Vicki L; Wise, Dawnne O; Glass, David J; Burghes, Arthur H M

    2014-05-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disease causing degeneration of lower motor neurons and muscle atrophy. One therapeutic avenue for SMA is targeting signaling pathways in muscle to ameliorate atrophy. Muscle Atrophy F-box, MAFbx, and Muscle RING Finger 1, MuRF1, are muscle-specific ubiquitin ligases upregulated in skeletal and cardiac muscle during atrophy. Homozygous knock-out of MAFbx or MuRF1 causes muscle sparing in adult mice subjected to atrophy by denervation. We wished to determine whether blockage of the major muscle atrophy pathways by deletion of MAFbx or MuRF1 in a mouse model of SMA would improve the phenotype. Deletion of MAFbx in the Δ7 SMA mouse model had no effect on the weight and the survival of the mice while deletion of MuRF1 was deleterious. MAFbx(-/-)-SMA mice showed a significant alteration in fiber size distribution tending towards larger fibers. In skeletal and cardiac tissue MAFbx and MuRF1 transcripts were upregulated whereas MuRF2 and MuRF3 levels were unchanged in Δ7 SMA mice. We conclude that deletion of the muscle ubiquitin ligases does not improve the phenotype of a Δ7 SMA mouse. Furthermore, it seems unlikely that the beneficial effect of HDAC inhibitors is mediated through inhibition of MAFbx and MuRF1. Copyright © 2014 Elsevier B.V. All rights reserved.

  4. Disease mechanisms and therapeutic approaches in spinal muscular atrophy.

    PubMed

    Tisdale, Sarah; Pellizzoni, Livio

    2015-06-10

    Motor neuron diseases are neurological disorders characterized primarily by the degeneration of spinal motor neurons, skeletal muscle atrophy, and debilitating and often fatal motor dysfunction. Spinal muscular atrophy (SMA) is an autosomal-recessive motor neuron disease of high incidence and severity and the most common genetic cause of infant mortality. SMA is caused by homozygous mutations in the survival motor neuron 1 (SMN1) gene and retention of at least one copy of the hypomorphic gene paralog SMN2. Early studies established a loss-of-function disease mechanism involving ubiquitous SMN deficiency and suggested SMN upregulation as a possible therapeutic approach. In recent years, greater knowledge of the central role of SMN in RNA processing combined with deep characterization of animal models of SMA has significantly advanced our understanding of the cellular and molecular basis of the disease. SMA is emerging as an RNA disease not limited to motor neurons, but one that involves dysfunction of motor circuits that comprise multiple neuronal subpopulations and possibly other cell types. Advances in SMA research have also led to the development of several potential therapeutics shown to be effective in animal models of SMA that are now in clinical trials. These agents offer unprecedented promise for the treatment of this still incurable neurodegenerative disease.

  5. Disease Mechanisms and Therapeutic Approaches in Spinal Muscular Atrophy

    PubMed Central

    Tisdale, Sarah

    2015-01-01

    Motor neuron diseases are neurological disorders characterized primarily by the degeneration of spinal motor neurons, skeletal muscle atrophy, and debilitating and often fatal motor dysfunction. Spinal muscular atrophy (SMA) is an autosomal-recessive motor neuron disease of high incidence and severity and the most common genetic cause of infant mortality. SMA is caused by homozygous mutations in the survival motor neuron 1 (SMN1) gene and retention of at least one copy of the hypomorphic gene paralog SMN2. Early studies established a loss-of-function disease mechanism involving ubiquitous SMN deficiency and suggested SMN upregulation as a possible therapeutic approach. In recent years, greater knowledge of the central role of SMN in RNA processing combined with deep characterization of animal models of SMA has significantly advanced our understanding of the cellular and molecular basis of the disease. SMA is emerging as an RNA disease not limited to motor neurons, but one that involves dysfunction of motor circuits that comprise multiple neuronal subpopulations and possibly other cell types. Advances in SMA research have also led to the development of several potential therapeutics shown to be effective in animal models of SMA that are now in clinical trials. These agents offer unprecedented promise for the treatment of this still incurable neurodegenerative disease. PMID:26063904

  6. Therapeutic strategies for spinal muscular atrophy: SMN and beyond

    PubMed Central

    Becker, Catherina G.; Yáñez-Muñoz, Rafael J.; Ning, Ke; Wood, Matthew J. A.; Gillingwater, Thomas H.

    2017-01-01

    ABSTRACT Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder characterized by loss of motor neurons and muscle atrophy, generally presenting in childhood. SMA is caused by low levels of the survival motor neuron protein (SMN) due to inactivating mutations in the encoding gene SMN1. A second duplicated gene, SMN2, produces very little but sufficient functional protein for survival. Therapeutic strategies to increase SMN are in clinical trials, and the first SMN2-directed antisense oligonucleotide (ASO) therapy has recently been licensed. However, several factors suggest that complementary strategies may be needed for the long-term maintenance of neuromuscular and other functions in SMA patients. Pre-clinical SMA models demonstrate that the requirement for SMN protein is highest when the structural connections of the neuromuscular system are being established, from late fetal life throughout infancy. Augmenting SMN may not address the slow neurodegenerative process underlying progressive functional decline beyond childhood in less severe types of SMA. Furthermore, individuals receiving SMN-based treatments may be vulnerable to delayed symptoms if rescue of the neuromuscular system is incomplete. Finally, a large number of older patients living with SMA do not fulfill the present criteria for inclusion in gene therapy and ASO clinical trials, and may not benefit from SMN-inducing treatments. Therefore, a comprehensive whole-lifespan approach to SMA therapy is required that includes both SMN-dependent and SMN-independent strategies that treat the CNS and periphery. Here, we review the range of non-SMN pathways implicated in SMA pathophysiology and discuss how various model systems can serve as valuable tools for SMA drug discovery. PMID:28768735

  7. SMN1 dosage analysis in spinal muscular atrophy from India

    PubMed Central

    Kesari, Akanchha; Rennert, Hanna; Leonard, Debra GB; Mittal, Balraj

    2005-01-01

    Background Spinal muscular atrophy (SMA) represents the second most common fatal autosomal recessive disorder after cystic fibrosis. Due to the high carrier frequency, the burden of this genetic disorder is very heavy in developing countries like India. As there is no cure or effective treatment, genetic counseling becomes very important in disease management. SMN1 dosage analysis results can be utilized for identifying carriers before offering prenatal diagnosis in the context of genetic counseling. Methods In the present study we analyzed the carrier status of parents and sibs of proven SMA patients. In addition, SMN1 copy number was determined in suspected SMA patients and parents of children with a clinical diagnosis of SMA. Results wenty nine DNA samples were analyzed by quantitative PCR to determine the number of SMN1 gene copies present, and 17 of these were found to have one SMN1 gene copy. The parents of confirmed SMA patients were found to be obligate carriers of the disease. Dosage analysis was useful in ruling out clinical suspicion of SMA in four patients. In a family with history of a deceased floppy infant and two abortions, both parents were found to be carriers of SMA and prenatal diagnosis could be offered in future pregnancies. Conclusion SMN1 copy number analysis is an important parameter for identification of couples at risk for having a child affected with SMA and reduces unwarranted prenatal diagnosis for SMA. The dosage analysis is also useful for the counseling of clinically suspected SMA with a negative diagnostic SMA test. PMID:15910686

  8. Motor neuron mitochondrial dysfunction in spinal muscular atrophy.

    PubMed

    Miller, Nimrod; Shi, Han; Zelikovich, Aaron S; Ma, Yong-Chao

    2016-08-15

    Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, predominantly affects high metabolic tissues including motor neurons, skeletal muscles and the heart. Although the genetic cause of SMA has been identified, mechanisms underlying tissue-specific vulnerability are not well understood. To study these mechanisms, we carried out a deep sequencing analysis of the transcriptome of spinal motor neurons in an SMA mouse model, in which we unexpectedly found changes in many genes associated with mitochondrial bioenergetics. Importantly, functional measurement of mitochondrial activities showed decreased basal and maximal mitochondrial respiration in motor neurons from SMA mice. Using a reduction-oxidation sensitive GFP and fluorescence sensors specifically targeted to mitochondria, we found increased oxidative stress level and impaired mitochondrial membrane potential in motor neurons affected by SMA. In addition, mitochondrial mobility was impaired in SMA disease conditions, with decreased retrograde transport but no effect on anterograde transport. We also found significantly increased fragmentation of the mitochondrial network in primary motor neurons from SMA mice, with no change in mitochondria density. Electron microscopy study of SMA mouse spinal cord revealed mitochondria fragmentation, edema and concentric lamellar inclusions in motor neurons affected by the disease. Intriguingly, these functional and structural deficiencies in the SMA mouse model occur during the presymptomatic stage of disease, suggesting a role in initiating SMA. Altogether, our findings reveal a critical role for mitochondrial defects in SMA pathogenesis and suggest a novel target for improving tissue health in the disease. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  9. Spinal muscular atrophy carriers with two SMN1 copies.

    PubMed

    Ar Rochmah, Mawaddah; Awano, Hiroyuki; Awaya, Tomonari; Harahap, Nur Imma Fatimah; Morisada, Naoya; Bouike, Yoshihiro; Saito, Toshio; Kubo, Yuji; Saito, Kayoko; Lai, Poh San; Morioka, Ichiro; Iijima, Kazumoto; Nishio, Hisahide; Shinohara, Masakazu

    2017-07-01

    Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder. Over 95% of SMA patients have homozygous deletions of the SMA-causative gene, SMN1. Thus, SMA carriers are usually diagnosed based on SMN1 copy number, with one copy indicating SMA carrier status. However, two SMN1 copies do not always exclude carrier status. In this study, we identified SMA carriers with two SMN1 copies. From 33 families, 65 parents of genetically confirmed SMA patients were tested to determine SMA carrier status. Molecular genetic analyses, including multiplex ligation-dependent probe amplification (MLPA) assay, were performed using blood samples from family members. Of the 65 parents, three parents from three families had two SMN1 copies. Accordingly, the frequency of carriers with two SMN1 copies was 4.6%. Two of these families were further studied. Patient 1 was homozygous for SMN1 deletion. Patient 1's mother had two SMN1 copies on one chromosome, with deletion of SMN1 on the other chromosome ([2+0] genotype). Patient 1 inherited SMN1-deleted chromosomes from both parents. Patient 2 was compound heterozygous for two SMN1 mutations: whole-gene deletion and intragenic missense mutation, c.826T>C (p.Tyr276His). Patient 2's father had two SMN1 copies with the same intragenic mutation in one copy ([1+1(d)] genotype, (d) intragenic mutation). Patient 2 inherited the chromosome with an SMN1 mutation from the father and SMN1-deleted chromosome from the mother. SMA carriers with two SMN1 copies may be rare, but its possibility should be taken into consideration in carrier testing and counseling for SMA families or population-based carrier screening. Copyright © 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  10. Spinal muscular atrophy: Factors that modulate motor neurone vulnerability.

    PubMed

    Tu, Wen-Yo; Simpson, Julie E; Highley, J Robin; Heath, Paul R

    2017-02-02

    Spinal muscular atrophy (SMA), a leading genetic cause of infant death, is a neurodegenerative disease characterised by the selective loss of particular groups of motor neurones in the anterior horn of the spinal cord with concomitant muscle weakness. To date, no effective treatment is available, however, there are ongoing clinical trials are in place which promise much for the future. However, there remains an ongoing problem in trying to link a single gene loss to motor neurone degeneration. Fortunately, given successful disease models that have been established and intensive studies on SMN functions in the past ten years, we are fast approaching the stage of identifying the underlying mechanisms of SMA pathogenesis Here we discuss potential disease modifying factors on motor neurone vulnerability, in the belief that these factors give insight into the pathological mechanisms of SMA and therefore possible therapeutic targets.

  11. [Genotypic and clinical features of spinal muscular atrophy type 3].

    PubMed

    Wang, Yan-yun; Feng, Shan-wei; Cao, Ji-qing; Yang, Juan; Li, Ya-qin; Li, Jin; Zhang, Cheng

    2012-04-01

    To explore the genotypic and clinical features and laboratory examinations of spinal muscular atrophy type 3 (SMA III). Results of genetic testing and laboratory exams of 18 SMA III patients were collected and analyzed. The average age of onset of patients was 6.1 years, with the course of disease lasting from 13 months to 28 years. All patients became symptomatic with lower extremity muscle weakness. The symptoms gradually aggregated, with proximal lower limb muscle becoming atrophic and proximal upper limb muscle becoming weak. Genetic testing indicated that all subjects possessed homozygous deletions of SMN1 gene. Electromyography (EMG) of 15 subjects indicated neurogenic damage. Whilst younger patients had normal level of creatine kinase (CK), elder patients had higher level of CK, though no linear correlation was found. Full understanding of Clinical, especially the growth features of SMA III, in combination with genetic testing, can facilitate diagnosis and early intervention of the disease.

  12. Therapeutic strategies for the treatment of spinal muscular atrophy.

    PubMed

    Cherry, Jonathan J; Androphy, Elliot J

    2012-09-01

    Spinal muscular atrophy (SMA) is an inherited neurodegenerative disease that results in progressive dysfunction of motor neurons of the anterior horn of the spinal cord. SMA is caused by the loss of full-length protein expression from the survival of motor neuron 1 (SMN1) gene. The disease has a unique genetic profile as it is autosomal recessive for the loss of SMN1, but a nearly identical homolog, SMN2, acts as a disease modifier whose expression is inversely correlated to clinical severity. Targeted therapeutic approaches primarily focus on increasing the levels of full-length SMN protein, through either gene replacement or regulation of SMN2 expression. There is currently no US FDA approved treatment for SMA. This is an exciting time as multiple efforts from academic and industrial laboratories are reaching the preclinical and clinical testing stages.

  13. Advances in therapeutic development for spinal muscular atrophy

    PubMed Central

    Howell, Matthew D; Singh, Natalia N; Singh, Ravindra N

    2015-01-01

    Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality. The disease originates from low levels of SMN protein due to deletion and/or mutations of SMN1 coupled with the inability of SMN2 to compensate for the loss of SMN1. While SMN1 and SMN2 are nearly identical, SMN2 predominantly generates a truncated protein (SMNΔ7) due to skipping of exon 7, the last coding exon. Several avenues for SMA therapy are being explored, including means to enhance SMN2 transcription, correct SMN2 exon 7 splicing, stabilize SMN/SMNΔ7 protein, manipulate SMN-regulated pathways and SMN1 gene delivery by viral vectors. This review focuses on the aspects of target discovery, validations and outcome measures for a promising therapy of SMA. PMID:25068989

  14. De novo and inherited deletions of the 5q13 region in spinal muscular atrophies

    SciTech Connect

    Melki, J.; Lefebvre, S.; Burglen, L.; Burlet, P.; Clermont, O.; Reboullet, S.; Benichou, B.; Zeviani, M. ); Millasseau, P. ); Le Paslier, D. )

    1994-06-03

    Spinal muscular atrophies (SMAs) represent the second most common fatal autosomal recessive disorder after cystic fibrosis. Childhood spinal muscular atrophies are divided into severe (type I) and mild forms (types II and III). By a combination of genetic and physical mapping, a yeast artificial chromosome contig of the 5q13 region spanning the disease locus was constructed that showed the presence of low copy repeats in this region. Allele segregation was analyzed at the closest genetic loci detected by markers C212 and C272 in 201 SMA families. Inherited and de novo deletions were observed in nine unrelated SMA patients. Moreover, deletions were strongly suggested in at least 18 percent of SMA type I patients by the observation of marked heterozygosity deficiency for the loci studied. These results indicate that deletion events are statistically associated with the severe form of spinal muscular atrophy. 25 refs., 5 figs.

  15. Resistance strength training exercise in children with spinal muscular atrophy.

    PubMed

    Lewelt, Aga; Krosschell, Kristin J; Stoddard, Gregory J; Weng, Cindy; Xue, Mei; Marcus, Robin L; Gappmaier, Eduard; Viollet, Louis; Johnson, Barbara A; White, Andrea T; Viazzo-Trussell, Donata; Lopes, Philippe; Lane, Robert H; Carey, John C; Swoboda, Kathryn J

    2015-10-01

    Preliminary evidence in adults with spinal muscular atrophy (SMA) and in SMA animal models suggests exercise has potential benefits in improving or stabilizing muscle strength and motor function. We evaluated feasibility, safety, and effects on strength and motor function of a home-based, supervised progressive resistance strength training exercise program in children with SMA types II and III. Up to 14 bilateral proximal muscles were exercised 3 times weekly for 12 weeks. Nine children with SMA, aged 10.4 ± 3.8 years, completed the resistance training exercise program. Ninety percent of visits occurred per protocol. Training sessions were pain-free (99.8%), and no study-related adverse events occurred. Trends in improved strength and motor function were observed. A 12-week supervised, home-based, 3-day/week progressive resistance training exercise program is feasible, safe, and well tolerated in children with SMA. These findings can inform future studies of exercise in SMA. © 2015 Wiley Periodicals, Inc.

  16. Resistance Strength Training Exercise in Children with Spinal Muscular Atrophy

    PubMed Central

    Lewelt, Aga; Krosschell, Kristin J.; Stoddard, Gregory J.; Weng, Cindy; Xue, Mei; Marcus, Robin L.; Gappmaier, Eduard; Viollet, Louis; Johnson, Barbara A.; White, Andrea T.; Viazzo-Trussell, Donata; Lopes, Philippe; Lane, Robert H.; Carey, John C.; Swoboda, Kathryn J.

    2015-01-01

    Introduction Preliminary evidence in adults with spinal muscular atrophy (SMA) and in SMA animal models suggests exercise has potential benefits in improving or stabilizing muscle strength and motor function. Methods We evaluated feasibility, safety, and effects on strength and motor function of a home-based, supervised progressive resistance strength training exercise program in children with SMA types II and III. Up to 14 bilateral proximal muscles were exercised 3 times weekly for 12 weeks. Results Nine children with SMA, aged 10.4±3.8 years, completed the resistance training exercise program. Ninety percent of visits occurred per protocol. Training sessions were pain-free (99.8%), and no study-related adverse events occurred. Trends in improved strength and motor function were observed. Conclusions A 12-week supervised, home-based, 3 days/week progressive resistance training exercise program is feasible, safe, and well tolerated in children with SMA. These findings can inform future studies of exercise in SMA. PMID:25597614

  17. Spatial cognition in young children with spinal muscular atrophy.

    PubMed

    Rivière, James; Lécuyer, Roger

    2002-01-01

    Success in visuospatial tasks has often been demonstrated in teenagers with spinal muscular atrophy (SMA). However, what has been tested in these studies, with the Wechsler Intelligence Scale for Children-Revised (Wechsler, 1974) performance scale, does not deal with the spatial capacities that co-occur with the advent of self-produced locomotion. Indeed, various studies have shown that occurrence of locomotion in infancy is correlated with the development of visuospatial cognitive competencies, suggesting that locomotor experience might play a central role in spatial development, especially in the realm of manual search for hidden objects. It is thus of interest to assess spatial search skills in SMA young children suffering total deprivation of locomotor experience. Twelve Type-2 SMA children with a mean age of 30 months were compared with controls with respect to their spatial search skills in a memory-for-locations task. In this search task, hiding containers were rotated 180 degrees before search was permitted. The performance obtained with the SMA group did not differ from that obtained in the healthy control group. SMA patients searched correctly for a hidden object in the 3-choice search task. Locomotor impairment does not appear to be a key risk factor for dramatic slowing down or deviation in the development of spatial search skills, as assumed by some authors. Further research is needed to identify the alternative pathways to normal spatial development that are used by SMA young children.

  18. Optimization of Spinal Muscular Atrophy subject's muscle activity during gait

    NASA Astrophysics Data System (ADS)

    Umat, Gazlia; Rambely, Azmin Sham

    2014-06-01

    Spinal Muscular Atrophy (SMA) is a hereditary disease related muscle nerve disorder caused by degeneration of the anterior cells of the spinal cord. SMA is divided into four types according to the degree of seriousness. SMA patients show different gait with normal people. Therefore, this study focused on the effects of SMA patient muscle actions and the difference that exists between SMA subjects and normal subjects. Therefore, the electromyography (EMG) test will be used to track the behavior of muscle during walking and optimization methods are used to get the muscle stress that is capable of doing the work while walking. Involved objective function is non-linear function of the quadratic and cubic functions. The study concludes with a comparison of the objective function using the force that sought to use the moment of previous studies and the objective function using the data obtained from EMG. The results shows that the same muscles, peroneus longus and bisepsfemoris, were used during walking activity by SMA subjects and control subjects. Muscle stress force best solution achieved from part D in simulation carried out.

  19. Spinal muscular atrophy: from animal model to clinical trial.

    PubMed

    Zanoteli, Edmar; Maximino, Jessica Ruivo; Conti Reed, Umbertina; Chadi, Gerson

    2010-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by degeneration and loss of lower motor neurons in the spinal cord and brainstem. Clinically, SMA has been classified into four types, according to the maximum function attained. The disease is caused by deletion or mutation of the telomeric copy of the SMN gene (SMN1), and the clinical severity is in part determined by the copy number of the centromeric SMN gene (SMN2). The SMN2 mRNA lacks exon 7, resulting in reduced production of the full-length SMN protein. Treatment of SMA consists of supportive care, although many drugs have been demonstrated to improve muscle strength and motor function of patients. The development of animal models of SMA has led to better interpretation of the physiopathology of the disease and testing of potential drug targets. Several mechanisms have been targeted in SMA drug trials, including neuroprotection, neurogenesis, energy metabolism improvement, anabolic stimulation and increment of SMN2 transcripts. Gene therapy and cell transplantation have also been tested in murine SMA.

  20. Moving towards treatments for spinal muscular atrophy: hopes and limits.

    PubMed

    Wirth, Brunhilde; Barkats, Martine; Martinat, Cecile; Sendtner, Michael; Gillingwater, Thomas H

    2015-09-01

    Spinal muscular atrophy (SMA), one of the most frequent and devastating genetic disorders causing neuromuscular degeneration, has reached the forefront of clinical translation. The quite unique genetic situation of SMA patients, who lack functional SMN1 but carry the misspliced SMN2 copy gene, creates the possibility of correcting SMN2 splicing by antisense oligonucleotides or drugs. Both strategies showed impressive results in pre-clinical trials and are now in Phase II-III clinical trials. SMN gene therapy approaches using AAV9-SMN vectors are also highly promising and have entered a Phase I clinical trial. However, careful analysis of SMA animal models and patients has revealed some limitations that need to be taken very seriously, including: i) a limited time-window for successful therapy delivery, making neonatal screening of SMA mandatory; ii) multi-organ impairment, requiring systemic delivery of therapies; and iii) a potential need for combined therapies that both increase SMN levels and target pathways that preserve/rescue motor neuron function over the lifespan. Meeting these challenges will likely be crucial to cure SMA, instead of only ameliorating symptoms, particularly in its most severe form. This review discusses therapies currently in clinical trials, the hopes for SMA therapy, and the potential limitations of these new approaches.

  1. Spectrum of Neuropathophysiology in Spinal Muscular Atrophy Type I

    PubMed Central

    Harding, Brian N.; Kariya, Shingo; Monani, Umrao R.; Chung, Wendy K.; Benton, Maryjane; Yum, Sabrina W.; Tennekoon, Gihan; Finkel, Richard S.

    2014-01-01

    Neuropathological findings within the CNS and PNS in patients with spinal muscular atrophy type I (SMA-I) were examined in relation to genetic, clinical and electrophysiological features. Five infants representing the full clinical spectrum of SMAI were examined clinically for compound motor action potential amplitude and SMN2 gene copy number; morphologic analyses of postmortem CNS, neuromuscular junction and muscle tissue samples were performed and SMN protein was assessed in muscle samples. The 2 clinically most severely affected patients had a single copy of the SMN2 gene; in addition to anterior horn cells, dorsal root ganglia and thalamus, neuronal degeneration in them was widespread in cerebral cortex, basal ganglia, pigmented nuclei, brainstem and cerebellum. Two typical SMA-I patients and a milder case each had 2 copies of the SMN2 gene and more restricted neuropathological abnormalities. Maturation of acetylcholine receptor subunits was delayed and the neuromuscular junctions were abnormally formed in the SMA-1 patients. Thus, the neuropathological findings in human SMA-I are similar to many findings in animal models; factors other than SMN2 copy number modify disease severity. We present a pathophysiologic model for SMA-I as a protein deficiency disease affecting a neuronal network with variable clinical thresholds. Because new treatment strategies improve survival of infants with SMA-I, a better understanding of these factors will guide future treatments. PMID:25470343

  2. Prominent fatigue in spinal muscular atrophy and spinal and bulbar muscular atrophy: evidence of activity-dependent conduction block.

    PubMed

    Noto, Yu-ichi; Misawa, Sonoko; Mori, Masahiro; Kawaguchi, Naoki; Kanai, Kazuaki; Shibuya, Kazumoto; Isose, Sagiri; Nasu, Saiko; Sekiguchi, Yukari; Beppu, Minako; Ohmori, Shigeki; Nakagawa, Masanori; Kuwabara, Satoshi

    2013-09-01

    To clarify whether patients with spinal muscular atrophy (SMA) or spinal and bulbar muscular atrophy (SBMA) suffer disabling muscle fatigue, and whether activity-dependent conduction block (ADCB) contributes to their fatigue. ADCB is usually caused by reduced safety factor for impulse transmission in demyelinating diseases, whereas markedly increased axonal branching associated with collateral sprouting may reduce the safety factor in chronic lower motor neuron disorders. We assessed the fatigue severity scale (FSS) in 22 patients with SMA/SBMA, and in 100 disease controls (multiple sclerosis, myasthenia gravis, chronic inflammatory demyelinating polyneuropathy (CIDP), and axonal neuropathy). We then performed stimulated-single fibre electromyography (s-SFEMG) in the extensor digitorum communis (EDC) muscle of 21 SMA/SBMA patients, 6 CIDP patients, and 10 normal subjects. The FSS score was the highest in SMA/SBMA patients [4.9 ± 1.1 (mean ± SD)], with 81% of them complaining of disabling fatigue, compared with normal controls (3.5 ± 1.0), whereas patients with multiple sclerosis (4.3 ± 1.6), myasthenia gravis (4.0 ± 1.6) or CIDP (4.3 ± 1.4) also showed higher FSS score. When 2000 stimuli were delivered at 20 Hz in s-SFEMG, conduction block of single motor axons developed in 46% of patients with SMA/SBMA, and 40% of CIDP patients, but in none of the normal controls. SMA/SBMA patients frequently suffer from disabling fatigue presumably caused by ADCB induced by voluntary activity. ADCB could be the mechanism for muscle fatigue in chronic lower motor neuron diseases. Copyright © 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  3. Neonatal spinal muscular atrophy with diaphragmatic paralysis is unlinked to 5q11.2-q13.

    PubMed Central

    Novelli, G; Capon, F; Tamisari, L; Grandi, E; Angelini, C; Guerrini, P; Dallapiccola, B

    1995-01-01

    Two sibs affected by the severe neonatal form of spinal muscular atrophy (SMA) with diaphragmatic paralysis are described. The two sibs were discordant for the haplotypes determined by DNA markers flanking the SMA locus. This supports non-linkage of SMA to chromosome 5 in this family and indicates that the uncommon SMA type I variant associated with early onset respiratory failure maps outside the 5q11.2-q13.3 region. Images PMID:7783173

  4. Spinal muscular atrophy disease: a literature review for therapeutic strategies.

    PubMed

    Stavarachi, M; Apostol, P; Toma, M; Cimponeriu, D; Gavrila, L

    2010-01-01

    Currently, there is no cure for the treatment of spinal muscular atrophy (SMA). Based on the available clinical and molecular findings, different therapeutic strategies were tested in vitro and in vivo and clinical trials are ongoing. The main therapeutic direction is focused on the enhancement of SMN expression by increasing the full-length (fl) SMN2 transcript levels, preventing the SMN exon 7 from skipping or from protein stabilizing. In addition, the action of neurotrophic, neuroprotective or anabolic agents is tested and stem cell and gene therapy approaches are in a promising development.

  5. Cardiac pathology in spinal muscular atrophy: a systematic review.

    PubMed

    Wijngaarde, C A; Blank, A C; Stam, M; Wadman, R I; van den Berg, L H; van der Pol, W L

    2017-04-11

    Hereditary proximal spinal muscular atrophy (SMA) is a severe neuromuscular disease of childhood caused by homozygous loss of function of the survival motor neuron (SMN) 1 gene. The presence of a second, nearly identical SMN gene (SMN2) in the human genome ensures production of residual levels of the ubiquitously expressed SMN protein. Alpha-motor neurons in the ventral horns of the spinal cord are most vulnerable to reduced SMN concentrations but the development or function of other tissues may also be affected, and cardiovascular abnormalities have frequently been reported both in patients and SMA mouse models. We systematically reviewed reported cardiac pathology in relation to SMN deficiency. To investigate the relevance of the possible association in more detail, we used clinical classification systems to characterize structural cardiac defects and arrhythmias. Seventy-two studies with a total of 264 SMA patients with reported cardiac pathology were identified, along with 14 publications on SMA mouse models with abnormalities of the heart. Structural cardiac pathology, mainly septal defects and abnormalities of the cardiac outflow tract, was reported predominantly in the most severely affected patients (i.e. SMA type 1). Cardiac rhythm disorders were most frequently reported in patients with milder SMA types (e.g. SMA type 3). All included studies lacked control groups and a standardized approach for cardiac evaluation. The convergence to specific abnormalities of cardiac structure and function may indicate vulnerability of specific cell types or developmental processes relevant for cardiogenesis. Future studies would benefit from a controlled and standardized approach for cardiac evaluation in patients with SMA.

  6. [A case of spinal muscular atrophy type 0 in Japan].

    PubMed

    Okamoto, Kentaro; Saito, Kayoko; Sato, Takatoshi; Ishigaki, Keiko; Funatsuka, Makoto; Osawa, Makiko

    2012-09-01

    The patient was a 2-month-old female infant born at 41 weeks and 2 days of gestation presenting multiple arthrogryposis, severe muscle hypotonia and respiratory distress with difficulty in feeding. She suffered from repeated complications with aspiration pneumonia. On admission to our hospital, she exhibited fasciculation and absence of deep tendon reflexes. Examination of the motor nerve conduction velocity (MCV) revealed no muscle contraction. Deletions of the SMN and NAIP genes were noted. Based on severe clinical course and disease development in utero, she was given a diagnosis of spinal muscular atrophy (SMA) type 0 (very severe type). Arthrogryposis and disappearance of MCV are exclusion criteria for SMA. However, the clinical course of the infant was very severe and included such exclusion items. Consequently, when an infant presents muscle hypotonia and respiratory distress, SMA must be considered as one of the differential diagnoses, even though arthrogryposis is an exclusion criterion for SMA. We discuss this case in relation to the few extant reports on SMA type 0 in Japanese infants in the literature.

  7. Spinal Muscular Atrophy: Overview of Molecular Diagnostic Approaches.

    PubMed

    Prior, Thomas W; Nagan, Narasimhan

    2016-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease and the most common genetic cause of infant mortality, affecting ∼1 in 10,000 live births. The disease is characterized by progressive symmetrical muscle weakness resulting from the degeneration and loss of anterior horn cells in the spinal cord and brain stem nuclei. The disease is classified on the basis of age of onset and clinical course. SMA is caused by mutations in the telomeric copy of the survival motor neuron 1 (SMN1) gene, but all patients retain a centromeric copy of the gene, SMN2. The homozygous absence of the SMN1 exon 7 has been observed in the majority of patients and is being utilized as a reliable and sensitive SMA diagnostic test. In the majority of cases, the disease severity correlates inversely with an increased SMN2 gene copy number. Carrier detection, in the deletion cases, relies on the accurate determination of the SMN1 gene copies. Since SMA is one of the most common lethal genetic disorders, with a carrier frequency of 1 in 40 to 1 in 60, direct carrier dosage testing has been beneficial to many families. This unit attempts to highlight the molecular genetics of SMA with a focus on the advantages and limitations of the current molecular technologies. Copyright © 2016 John Wiley & Sons, Inc.

  8. Deletion mapping of the spinal muscular atrophy region

    SciTech Connect

    Burgein, L.; Lefebvre, S.; Buriet, P.

    1994-09-01

    Autosomal recessive childhood spinal muscular atrophies (SMA) are divided into severe (Type I) and mild forms (Types II and III). Using a combination of fine genetic and physical mapping, we constructed a YAC contig of the 5q13 region spanning the disease locus and showed the presence of low copy-repeats in this region. Allele segregation was analyzed at the closest genetic loci detected by markers C212 and C272 in 201 SMA families. Inherited and de novo deletions were observed in 9 unrelated SMA patients. Moreover, deletion events were statistically associated with type I SMA patients as shown by marked heterozygosity deficiency for the loci studied. Genetic analysis with all polymorphic DNA markers derived from the YAC contig has allowed to define the smallest rearrangement between the loci detected by C161 and the C212-C272-C171, covering a 1Mb interval. A large scale physical map of this region has been constructed using pulsed field gel electrophoresis (PFGE) and rare cutter restriction endonucleases. Comparison of the physical map has been established both in patients harboring deletions and unaffected controls using various anonymous probes derived from the YAC contig. This analysis has allowed us to define a physical interval in which at least a portion of the SMA gene must be located. Search for genes within this interval will contribute to the identification of the disease gene or genes.

  9. Spinal muscular atrophy genetic testing experience at an academic medical center.

    PubMed

    Ogino, Shuji; Leonard, Debra G B; Rennert, Hanna; Wilson, Robert B

    2002-02-01

    Approximately 94% of spinal muscular atrophy (SMA) patients lack both copies of SMN1 exon 7. We report our SMA genetic testing experience (total 1281 cases), using SMA linkage analysis (32 families), SMA diagnostic testing by PCR-RFLP (restriction fragment length polymorphism) to detect the homozygous absence of SMN1 exon 7 (and exon 8) (533 cases), and an assay to determine copy number of SMN1 exon 7 (SMN1 gene dosage analysis) (716 cases). SMN1 gene dosage analysis is used for SMA carrier testing as well as for the confirmation of a heterozygous SMN1 deletion in symptomatic individuals who do not lack both copies of SMN1. We conclude that comprehensive SMA testing, including SMN1 deletion analysis, SMN1 gene dosage analysis, and linkage analysis, offers the most complete evaluation of SMA patients and their families.

  10. Rapid prenatal diagnosis of spinal muscular atrophy by denaturing high-performance liquid chromatography system.

    PubMed

    Shaw, Sheng-Wen; Cheng, Po-Jen; Chang, Shuenn-Dhy; Lin, Yu-Ting; Hung, Chia-Cheng; Chen, Chih-Ping; Su, Yi-Ning

    2008-01-01

    Use of Denaturing High-Performance Liquid Chromatography (DHPLC) in prenatal diagnosis of spinal muscular atrophy (SMA). Thirty-three members of 7 families participated in carrier test and disease detection of SMA. Prenatal genetic diagnosis was performed if both parents were carriers or any family members had SMA. DNA extracted from blood, chorionic villi and amniotic fluid was amplified and used for DHPLC. Twenty SMA carriers, seven SMA affected cases, and six normal individuals were identified. SMA status was demonstrated by genotyping and total copy number determinations of SMN1 and SMN2. Families 1-3 were classified as group one (SMA affecting previously born child). Group two, comprising families 4 and 5, had lost a child due to an unknown muscular disease. Group three (SMA-affected parent) comprised families 6 and 7; carrier testing was done. DHPLC prenatal genetic diagnosis was made in seven pregnancies, one in each family (affected, n=2; carrier, n=3; normal, n=2). Pregnancy was terminated for the two affected fetuses. The others were delivered uneventfully and SMA free. DHPLC prenatal diagnosis of SMA and determination of SMA status in adults is possible, and SMN1 and SMN2 copy numbers can be determined.

  11. Observational Study of Spinal Muscular Atrophy Type 2 and 3

    PubMed Central

    Kaufmann, Petra; McDermott, Michael P.; Darras, Basil T.; Finkel, Richard; Kang, Peter; Oskoui, Maryam; Constantinescu, Andrei; Sproule, Douglas Michael; Foley, A. Reghan; Yang, Michele; Tawil, Rabi; Chung, Wendy; Martens, Bill; Montes, Jacqueline; O'Hagen, Jessica; Dunaway, Sally; Flickinger, Jean M.; Quigley, Janet; Riley, Susan; Glanzman, Allan M.; Benton, Maryjane; Ryan, Patricia A.; Irvine, Carrie; Annis, Christine L.; Butler, Hailly; Caracciolo, Jayson; Montgomery, Megan; Marra, Jonathan; Koo, Benjamin; De Vivo, Darryl C.

    2013-01-01

    Objective To characterize the short-term course of spinal muscular atrophy (SMA) in a genetically and clinically well-defined cohort of patients with SMA. Design A comprehensive multicenter, longitudinal, observational study. Setting The Pediatric Neuromuscular Clinical Research Network for SMA, a consortium of clinical investigators at 3 clinical sites. Participants Sixty-five participants with SMA types 2 and 3, aged 20 months to 45 years, were prospectively evaluated. Intervention We collected demographic and medical history information and determined the SMN2 copy number. Main Outcome Measures Clinical outcomes included measures of motor function (Gross Motor Function Measure and expanded Hammersmith Functional Motor Scale), pulmonary function (forced vital capacity), and muscle strength (myometry). Participants were evaluated every 2 months for the initial 6 months and every 3 months for the subsequent 6 months. We evaluated change over 12 months for all clinical outcomes and examined potential correlates of change over time including age, sex, SMA type, ambulatory status, SMN2 copy number, medication use, and baseline function. Results There were no significant changes over 12 months in motor function, pulmonary function, and muscle strength measures. There was evidence of motor function gain in ambulatory patients, especially in those children younger than 5 years. Scoliosis surgery during the observation period led to a subsequent decline in motor function. Conclusions Our results confirm previous clinical reports suggesting that SMA types 2 and 3 represent chronic phenotypes that have relatively stable clinical courses. We did not detect any measurable clinical disease progression in SMA types 2 and 3 over 12 months, suggesting that clinical trials will have to be designed to measure improvement rather than stabilization of disease progression. PMID:21320981

  12. Spinal Muscular Atrophy Type I: Is It Ethical to Standardize Supportive Care Intervention in Clinical Trials?

    PubMed

    Finkel, Richard S; Bishop, Kathie M; Nelson, Robert M

    2017-02-01

    The natural history of spinal muscular atrophy type I (SMA-I) has changed as improved medical support has become available. With investigational drugs for spinal muscular atrophy now in clinical trials, efficient trial design focuses on enrolling recently diagnosed infants, providing best available supportive care, and minimizing subject variation. The quandary has arisen whether it is ethically appropriate to specify a predefined level of nutritional and/or ventilation support for spinal muscular atrophy type I subjects while participating in these studies. We conducted a survey at 2 spinal muscular atrophy investigator meetings involving physician investigators, clinical evaluators, and study coordinators from North America, Europe, and Asia-Pacific. Each group endorsed the concept that having a predefined degree of nutritional and ventilation support was warranted in this context. We discuss how autonomy, beneficence/non-maleficence, noncoercion, social benefit, and equipoise can be maintained when a predefined level of supportive care is proposed, for participation in a clinical trial.

  13. Spinal Muscular Atrophy Type I: Is It Ethical to Standardize Supportive Care Intervention in Clinical Trials?

    PubMed Central

    Finkel, Richard S.; Bishop, Kathie M.; Nelson, Robert M.

    2016-01-01

    The natural history of spinal muscular atrophy type I (SMA-I) has changed as improved medical support has become available. With investigational drugs for spinal muscular atrophy now in clinical trials, efficient trial design focuses on enrolling recently diagnosed infants, providing best available supportive care, and minimizing subject variation. The quandary has arisen whether it is ethically appropriate to specify a predefined level of nutritional and/or ventilation support for spinal muscular atrophy type I subjects while participating in these studies. We conducted a survey at 2 spinal muscular atrophy investigator meetings involving physician investigators, clinical evaluators, and study coordinators from North America, Europe, and Asia-Pacific. Each group endorsed the concept that having a predefined degree of nutritional and ventilation support was warranted in this context. We discuss how autonomy, beneficence/non-maleficence, noncoercion, social benefit, and equipoise can be maintained when a predefined level of supportive care is proposed, for participation in a clinical trial. PMID:27760875

  14. Developing therapies for spinal muscular atrophy.

    PubMed

    Wertz, Mary H; Sahin, Mustafa

    2016-02-01

    Spinal muscular atrophy is an autosomal-recessive pediatric neurodegenerative disease characterized by loss of spinal motor neurons. It is caused by mutation in the gene survival of motor neuron 1 (SMN1), leading to loss of function of the full-length SMN protein. SMN has a number of functions in neurons, including RNA splicing and snRNP biogenesis in the nucleus, and RNA trafficking in neurites. The expression level of full-length SMN protein from the SMN2 locus modifies disease severity. Increasing full-length SMN protein by a small amount can lead to significant improvements in the neurological phenotype. Currently available interventions for spinal muscular atrophy patients are physical therapy and orthopedic, nutritional, and pulmonary interventions; these are palliative or supportive measures and do not address the etiology of the disease. In the past decade, there has been a push for developing therapeutics to improve motor phenotypes and increase life span of spinal muscular atrophy patients. These therapies are aimed primarily at restoration of full-length SMN protein levels, but other neuroprotective treatments have been investigated as well. Here, we discuss recent advances in basic and clinical studies toward finding safe and effective treatments of spinal muscular atrophy using gene therapy, antisense oligonucleotides, and other small molecule modulators of SMN expression. © 2015 New York Academy of Sciences.

  15. Spinal muscular atrophy: An update on therapeutic progress

    PubMed Central

    Seo, Joonbae; Howell, Matthew D.; Singh, Natalia N.; Singh, Ravindra N.

    2013-01-01

    Humans have two nearly identical copies of survival motor neuron gene: SMN1 and SMN2. Deletion or mutation of SMN1 combined with the inability of SMN2 to compensate for the loss of SMN1 results in spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. SMA affects 1 in ~6000 live births, a frequency much higher than in several genetic diseases. The major known defect of SMN2 is the predominant exon 7 skipping that leads to production of a truncated protein (SMNΔ7), which is unstable. Therefore, SMA has emerged as a model genetic disorder in which almost the entire disease population could be linked to the aberrant splicing of a single exon (i.e. SMN2 exon 7). Diverse treatment strategies aimed at improving the function of SMN2 have been envisioned. These strategies include, but are not limited to, manipulation of transcription, correction of aberrant splicing and stabilization of mRNA, SMN and SMNΔ7. This review summarizes up to date progress and promise of various in vivo studies reported for the treatment of SMA. PMID:23994186

  16. Spinal muscular atrophy: from gene discovery to clinical trials.

    PubMed

    Nurputra, Dian K; Lai, Poh San; Harahap, Nur Imma F; Morikawa, Satoru; Yamamoto, Tomoto; Nishimura, Noriyuki; Kubo, Yuji; Takeuchi, Atsuko; Saito, Toshio; Takeshima, Yasuhiro; Tohyama, Yumi; Tay, Stacey K H; Low, Poh Sim; Saito, Kayoko; Nishio, Hisahide

    2013-09-01

    Spinal muscular atrophy (SMA) is a common neuromuscular disorder with autosomal recessive inheritance, resulting in the degeneration of motor neurons. The incidence of the disease has been estimated at 1 in 6000-10,000 newborns with a carrier frequency of 1 in 40-60. SMA is caused by mutations of the SMN1 gene, located on chromosome 5q13. The gene product, survival motor neuron (SMN) plays critical roles in a variety of cellular activities. SMN2, a homologue of SMN1, is retained in all SMA patients and generates low levels of SMN, but does not compensate for the mutated SMN1. Genetic analysis demonstrates the presence of homozygous deletion of SMN1 in most patients, and allows screening of heterozygous carriers in affected families. Considering high incidence of carrier frequency in SMA, population-wide newborn and carrier screening has been proposed. Although no effective treatment is currently available, some treatment strategies have already been developed based on the molecular pathophysiology of this disease. Current treatment strategies can be classified into three major groups: SMN2-targeting, SMN1-introduction, and non-SMN targeting. Here, we provide a comprehensive and up-to-date review integrating advances in molecular pathophysiology and diagnostic testing with therapeutic developments for this disease including promising candidates from recent clinical trials. © 2013 John Wiley & Sons Ltd/University College London.

  17. Prenatal diagnosis of spinal muscular atrophy in Macedonian families.

    PubMed

    Kocheva, Svetlana A; Plaseska-Karanfilska, Dijana; Trivodalieva, Svetlana; Kuturec, Marija; Vlaski-Jekic, Snezana; Efremov, Georgi Dimitar

    2008-09-01

    Spinal muscular atrophy (SMA) is the second most common lethal autosomal recessive disorder of childhood, affecting approximately 1 in 6,000-10,000 births, with a carrier frequency of 1 in 40-60. There is no effective cure or treatment for this disease. Thus, the availability of prenatal testing is important. The aim of this study was to establish an efficient and rapid method for prenatal diagnosis of SMA and genetic counseling in families with risk for having a child with SMA. In this paper we present the results from prenatal diagnosis in Macedonian SMA families using direct analysis of fetal DNA. The probands of these families were previously found to be homozygous for a deletion of exons 7 and 8 of SMN1 gene. DNA obtained from chorionic villas samples and amniocytes was analyzed for deletions in SMN gene. SMN exon 7 and 8 deletion analysis was performed by polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP). Of the 12 prenatal diagnoses, DNA analysis showed normal results in eight fetuses. Four of the fetuses were homozygote for a deletion of exons 7 and 8 of SMN1. After genetic counseling, the parents of the eight normal fetuses decided to continue the pregnancy, while in the four families with affected fetuses, the pregnancy was terminated. The results were confirmed after birth.

  18. Effect of diet on the survival and phenotype of a mouse model for spinal muscular atrophy.

    PubMed

    Butchbach, Matthew E R; Rose, Ferrill F; Rhoades, Sarah; Marston, John; McCrone, John T; Sinnott, Rachel; Lorson, Christian L

    2010-01-01

    Proximal spinal muscular atrophy (SMA) is a leading genetic cause of infant death. Patients with SMA lose alpha-motor neurons in the ventral horn of the spinal cord which leads to skeletal muscle weakness and atrophy. SMA is the result of reduction in Survival Motor Neuron (SMN) expression. Transgenic mouse models of SMA have been generated and are extremely useful in understanding the mechanisms of motor neuron degeneration in SMA and in developing new therapeutic candidates for SMA patients. Several research groups have reported varying average lifespans of SMNDelta7 SMA mice (SMN2(+/+);SMNDelta7(+/+);mSmn(-/-)), the most commonly used mouse model for preclinical therapeutic candidate testing. One environmental factor that varied between research groups was maternal diet. In this study, we compared the effects of two different commercially available rodent chows (PicoLab20 Mouse diet and Harlan-Teklad 22/5 diet) on the survival and motor phenotype of the SMNDelta7 mouse model of SMA. Specifically, the PicoLab20 diet significantly extends the average lifespan of the SMNDelta7 SMA mice by approximately 25% and improved the motor phenotype as compared to the Harlan diet. These findings indicate that maternal diet alone can have considerable impact on the SMA phenotype. Copyright 2009 Elsevier Inc. All rights reserved.

  19. Impaired Muscle Mitochondrial Biogenesis and Myogenesis in Spinal Muscular Atrophy

    PubMed Central

    Ripolone, Michela; Ronchi, Dario; Violano, Raffaella; Vallejo, Dionis; Fagiolari, Gigliola; Barca, Emanuele; Lucchini, Valeria; Colombo, Irene; Villa, Luisa; Berardinelli, Angela; Balottin, Umberto; Morandi, Lucia; Mora, Marina; Bordoni, Andreina; Fortunato, Francesco; Corti, Stefania; Parisi, Daniela; Toscano, Antonio; Sciacco, Monica; DiMauro, Salvatore; Comi, Giacomo P.; Moggio, Maurizio

    2016-01-01

    IMPORTANCE The important depletion of mitochondrial DNA (mtDNA) and the general depression of mitochondrial respiratory chain complex levels (including complex II) have been confirmed, implying an increasing paucity of mitochondria in the muscle from patients with types I, II, and III spinal muscular atrophy (SMA-I, -II, and -III, respectively). OBJECTIVE To investigate mitochondrial dysfunction in a large series of muscle biopsy samples from patients with SMA. DESIGN, SETTING, AND PARTICIPANTS We studied quadriceps muscle samples from 24 patients with genetically documented SMA and paraspinal muscle samples from 3 patients with SMA-II undergoing surgery for scoliosis correction. Postmortem muscle samples were obtained from 1 additional patient. Age-matched controls consisted of muscle biopsy specimens from healthy children aged 1 to 3 years who had undergone analysis for suspected myopathy. Analyses were performed at the Neuromuscular Unit, Istituto di Ricovero e Cura a Carattere Scientifico Foundation Ca’ Granda Ospedale Maggiore Policlinico-Milano, from April 2011 through January 2015. EXPOSURES We used histochemical, biochemical, and molecular techniques to examine the muscle samples. MAIN OUTCOMES AND MEASURES Respiratory chain activity and mitochondrial content. RESULTS Results of histochemical analysis revealed that cytochrome-c oxidase (COX) deficiency was more evident in muscle samples from patients with SMA-I and SMA-II. Residual activities for complexes I, II, and IV in muscles from patients with SMA-I were 41%, 27%, and 30%, respectively, compared with control samples (P < .005). Muscle mtDNA content and cytrate synthase activity were also reduced in all 3 SMA types (P < .05). We linked these alterations to downregulation of peroxisome proliferator–activated receptor coactivator 1α, the transcriptional activators nuclear respiratory factor 1 and nuclear respiratory factor 2, mitochondrial transcription factor A, and their downstream targets

  20. Evidence of reduced frequency of spinal muscular atrophy type I in the Cuban population.

    PubMed

    Zaldívar, T; Montejo, Y; Acevedo, A M; Guerra, R; Vargas, J; Garofalo, N; Alvarez, R; Alvarez, M A; Hardiman, O

    2005-08-23

    The authors reviewed all cases of type I spinal muscular atrophy (SMA) in Cuba over a 6-year period. The incidence of SMA type I was 3.53 per 100,000 livebirths. When the population was classified according to self-reported ethnicity, the incidence was eight per 100,000 for whites; 0.89 per 100,000 for blacks, and 0.96 per 100,000 for those of mixed ethnicity. Type 1 SMA may occur less frequently in individuals of African ancestry.

  1. What Matters Most: A Perspective From Adult Spinal Muscular Atrophy Patients.

    PubMed

    Hunter, Michael; Heatwole, Chad; Luebbe, Elizabeth; Johnson, Nicholas E

    2016-08-30

    There are multiple symptoms that affect adults with spinal muscular atrophy (SMA). The extent of these symptoms and their impact on individuals' lives is not fully known. We interviewed 15 adults with genetically confirmed SMA. Participants were asked to identify issues that have significant impact on their lives. Interviews were recorded, transcribed, coded, and analyzed. Participants provided 1045 direct quotes. 177 potential symptoms of importance were identified. Symptoms were grouped by like topics into fourteen symptomatic themes. The symptoms and issues identified by SMA patients alter their physical, mental, and social health and may be amendable to therapeutic intervention.

  2. [Fractures in spinal muscular atrophy].

    PubMed

    Febrer, Anna; Vigo, Meritxell; Rodríguez, Natalia; Medina, Julita; Colomer, Jaume; Nascimento, Andrés

    2013-09-01

    Objetivo. Determinar la frecuencia de fracturas en pacientes con atrofia muscular espinal, mecanismo de produccion, edad de aparicion y repercusion funcional. Pacientes y metodos. Se estudian 65 pacientes con atrofia muscular espinal. Se recogen las fracturas diagnosticadas mediante radiografia y se analizan los siguientes parametros: tipo de atrofia muscular espinal, marcha, edad en el momento de la fractura, mecanismo de produccion, localizacion, tratamiento aplicado y repercusion funcional. Resultados. Presentaron fracturas 13 pacientes (20%), con un total de 20 (cuatro presentaron dos o mas fracturas). La edad media fue de 6,35 años. La localizacion fue en su mayoria en el femur y el mecanismo de produccion, en 12 casos por caidas y en 8 por traumatismo menor. No detectamos ninguna fractura vertebral. Todas se trataron de manera conservadora. El unico paciente ambulante que presento una fractura dejo de caminar despues de la inmovilizacion. Conclusiones. La existencia de fracturas en estos pacientes interfiere en su calidad de vida y en el nivel funcional. Es importante la prevencion de las mismas en el manejo del paciente y vigilando la correcta postura en la silla de ruedas con sistemas de sujecion Deberian emprenderse mas estudios sobre la perdida de densidad mineral osea en estos pacientes y su posible relacion con las fracturas.

  3. Cardiac defects contribute to the pathology of spinal muscular atrophy models.

    PubMed

    Shababi, Monir; Habibi, Javad; Yang, Hsiao T; Vale, Spencer M; Sewell, Will A; Lorson, Christian L

    2010-10-15

    Spinal muscular atrophy (SMA) is an autosomal recessive disorder, which is the leading genetic cause of infantile death. SMA is the most common inherited motor neuron disease and occurs in approximately 1:6000 live births. The gene responsible for SMA is called Survival Motor Neuron-1 (SMN1). Interestingly, a human-specific copy gene is present on the same region of chromosome 5q, called SMN2. Motor neurons are the primary tissue affected in SMA. Although it is clear that SMA is a neurodegenerative disease, there are clinical reports that suggest that other tissues contribute to the overall phenotype, especially in the most severe forms of the disease. In severe SMA cases, a growing number of congenital heart defects have been identified upon autopsy. The most common defect is a developmental defect referred to as hypoplastic left heart. The purpose of this report is to determine whether cardiac tissue is altered in SMA models and whether this could contribute to SMA pathogenesis. Here we identified early-stage developmental defects in a severe model of SMA. Additionally, pathological responses including fibrosis and oxidative stress markers were observed shortly after birth in a less severe model of disease. Similarly, functional differences were detected between wild-type and early-stage SMA animals. Collectively, this work demonstrates the importance of cardiac development and function in these severe models of SMA.

  4. Dysregulation of ubiquitin homeostasis and β-catenin signaling promote spinal muscular atrophy

    PubMed Central

    Wishart, Thomas M.; Mutsaers, Chantal A.; Riessland, Markus; Reimer, Michell M.; Hunter, Gillian; Hannam, Marie L.; Eaton, Samantha L.; Fuller, Heidi R.; Roche, Sarah L.; Somers, Eilidh; Morse, Robert; Young, Philip J.; Lamont, Douglas J.; Hammerschmidt, Matthias; Joshi, Anagha; Hohenstein, Peter; Morris, Glenn E.; Parson, Simon H.; Skehel, Paul A.; Becker, Thomas; Robinson, Iain M.; Becker, Catherina G.; Wirth, Brunhilde; Gillingwater, Thomas H.

    2014-01-01

    The autosomal recessive neurodegenerative disease spinal muscular atrophy (SMA) results from low levels of survival motor neuron (SMN) protein; however, it is unclear how reduced SMN promotes SMA development. Here, we determined that ubiquitin-dependent pathways regulate neuromuscular pathology in SMA. Using mouse models of SMA, we observed widespread perturbations in ubiquitin homeostasis, including reduced levels of ubiquitin-like modifier activating enzyme 1 (UBA1). SMN physically interacted with UBA1 in neurons, and disruption of Uba1 mRNA splicing was observed in the spinal cords of SMA mice exhibiting disease symptoms. Pharmacological or genetic suppression of UBA1 was sufficient to recapitulate an SMA-like neuromuscular pathology in zebrafish, suggesting that UBA1 directly contributes to disease pathogenesis. Dysregulation of UBA1 and subsequent ubiquitination pathways led to β-catenin accumulation, and pharmacological inhibition of β-catenin robustly ameliorated neuromuscular pathology in zebrafish, Drosophila, and mouse models of SMA. UBA1-associated disruption of β-catenin was restricted to the neuromuscular system in SMA mice; therefore, pharmacological inhibition of β-catenin in these animals failed to prevent systemic pathology in peripheral tissues and organs, indicating fundamental molecular differences between neuromuscular and systemic SMA pathology. Our data indicate that SMA-associated reduction of UBA1 contributes to neuromuscular pathogenesis through disruption of ubiquitin homeostasis and subsequent β-catenin signaling, highlighting ubiquitin homeostasis and β-catenin as potential therapeutic targets for SMA. PMID:24590288

  5. Genetic correction of human induced pluripotent stem cells from patients with spinal muscular atrophy.

    PubMed

    Corti, Stefania; Nizzardo, Monica; Simone, Chiara; Falcone, Marianna; Nardini, Martina; Ronchi, Dario; Donadoni, Chiara; Salani, Sabrina; Riboldi, Giulietta; Magri, Francesca; Menozzi, Giorgia; Bonaglia, Clara; Rizzo, Federica; Bresolin, Nereo; Comi, Giacomo P

    2012-12-19

    Spinal muscular atrophy (SMA) is among the most common genetic neurological diseases that cause infant mortality. Induced pluripotent stem cells (iPSCs) generated from skin fibroblasts from SMA patients and genetically corrected have been proposed to be useful for autologous cell therapy. We generated iPSCs from SMA patients (SMA-iPSCs) using nonviral, nonintegrating episomal vectors and used a targeted gene correction approach based on single-stranded oligonucleotides to convert the survival motor neuron 2 (SMN2) gene into an SMN1-like gene. Corrected iPSC lines contained no exogenous sequences. Motor neurons formed by differentiation of uncorrected SMA-iPSCs reproduced disease-specific features. These features were ameliorated in motor neurons derived from genetically corrected SMA-iPSCs. The different gene splicing profile in SMA-iPSC motor neurons was rescued after genetic correction. The transplantation of corrected motor neurons derived from SMA-iPSCs into an SMA mouse model extended the life span of the animals and improved the disease phenotype. These results suggest that generating genetically corrected SMA-iPSCs and differentiating them into motor neurons may provide a source of motor neurons for therapeutic transplantation for SMA.

  6. Genetic Correction of Human Induced Pluripotent Stem Cells from Patients with Spinal Muscular Atrophy

    PubMed Central

    Corti, Stefania; Nizzardo, Monica; Simone, Chiara; Falcone, Marianna; Nardini, Martina; Ronchi, Dario; Donadoni, Chiara; Salani, Sabrina; Riboldi, Giulietta; Magri, Francesca; Menozzi, Giorgia; Bonaglia, Clara; Rizzo, Federica; Bresolin, Nereo; Comi, Giacomo P.

    2016-01-01

    Spinal muscular atrophy (SMA) is among the most common genetic neurological diseases that cause infant mortality. Induced pluripotent stem cells (iPSCs) generated from skin fibroblasts from SMA patients and genetically corrected have been proposed to be useful for autologous cell therapy. We generated iPSCs from SMA patients (SMA-iPSCs) using nonviral, nonintegrating episomal vectors and used a targeted gene correction approach based on single-stranded oligonucleotides to convert the survival motor neuron 2 (SMN2) gene into an SMN1-like gene. Corrected iPSC lines contained no exogenous sequences. Motor neurons formed by differentiation of uncorrected SMA-iPSCs reproduced disease-specific features. These features were ameliorated in motor neurons derived from genetically corrected SMA-iPSCs. The different gene splicing profile in SMA-iPSC motor neurons was rescued after genetic correction. The transplantation of corrected motor neurons derived from SMA-iPSCs into an SMA mouse model extended the life span of the animals and improved the disease phenotype. These results suggest that generating genetically corrected SMA-iPSCs and differentiating them into motor neurons may provide a source of motor neurons for therapeutic transplantation for SMA. PMID:23253609

  7. The zinc finger protein ZPR1 is a potential modifier of spinal muscular atrophy

    PubMed Central

    Ahmad, Saif; Wang, Yi; Shaik, Gouse M.; Burghes, Arthur H.; Gangwani, Laxman

    2012-01-01

    Spinal muscular atrophy (SMA) is caused by mutation of the Survival Motor Neurons 1 (SMN1) gene and is characterized by degeneration of spinal motor neurons. The severity of SMA is primarily influenced by the copy number of the SMN2 gene. Additional modifier genes that lie outside the SMA locus exist and one gene that could modify SMA is the Zinc Finger Protein (ZPR1) gene. To test the significance of ZPR1 downregulation in SMA, we examined the effect of reduced ZPR1 expression in mice with mild and severe SMA. We report that the reduced ZPR1 expression causes increase in the loss of motor neurons, hypermyelination in phrenic nerves, increase in respiratory distress and disease severity and reduces the lifespan of SMA mice. The deficiency of SMN-containing sub-nuclear bodies correlates with the severity of SMA. ZPR1 is required for the accumulation of SMN in sub-nuclear bodies. Further, we report that ZPR1 overexpression increases levels of SMN and promotes accumulation of SMN in sub-nuclear bodies in SMA patient fibroblasts. ZPR1 stimulates neurite growth and rescues axonal growth defects in SMN-deficient spinal cord neurons from SMA mice. These data suggest that the severity of disease correlates negatively with ZPR1 levels and ZPR1 may be a protective modifier of SMA. PMID:22422766

  8. Deletion analysis of SMN and NAIP genes in Tunisian patients with spinal muscular atrophy.

    PubMed

    Rekik, Imen; Boukhris, Amir; Ketata, Sourour; Amri, Mohamed; Essid, Nourhene; Feki, Imed; Mhiri, Chokri

    2013-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder involving degeneration of anterior horn cells of spinal cord, resulting in progressive muscle weakness and atrophy. The purpose of our study was to determine the frequency of SMN and NAIP deletions in Tunisian SMA patients. Polymerase chain reaction (PCR) combined with restriction fragment length polymorphism (RFLP) was used to detect the deletion of exon 7 and exon 8 of SMN1 gene, as well as multiplex PCR for exon 5 and 13 of NAIP gene. Fifteen (45.4%) out of 33 SMA patients were homozygously deleted for exons 7 and/or 8 of SMN1. Homozygous deletion of NAIP gene was observed in 20% (3 / 15) of patients. The molecular diagnosis system based on PCR-RFLP analysis can conveniently be applied in the clinical testing, genetic counseling, prenatal diagnosis, and pre-implantation genetic diagnosis of SMA.

  9. [The construction of urine-derived cell lines from patients with spinal muscular atrophy].

    PubMed

    Wanjin, Chen; Qijie, Zhang; Jin, He; Xiang, Lin; Ning, Wang

    2014-11-01

    Spinal muscular atrophy (SMA) is a common neurodegenerative disease in childhood and infancy, clinically characterized by progressive and symmetric muscular weakness and atrophy. Few effective therapies are available now, and SMA is one of the most common genetic causes of infantile mortality. SMA patient-derived cells are beneficial in basic research on this disease, but the most common model cell, fibroblasts can only be obtained through invasive procedures such as muscle or skin biopsy, which are unwelcome to patients and their families. In this study, fresh urine from SMA patients and healthy controls was collected and centrifuged, and the urine sediment was cultured in vitro. The growth characteristics of urine-derived cells were observed, and the survival of motor neuron (SMN) gene, and the amount and localization of SMN protein in different urine cell lines were investigated. In total, 25 urine cell lines from 11 SMA patients and 14 healthy controls were established. These urine-derived cells expand robustly in vitro with stable cell morphological characteristics. The urine cell lines derived from patients carry the SMN1 gene defect and express a low level of SMN protein, while the intracellular localization of SMN protein is normal. Urine-derived cell culture technology is simple, non-invasive and highly reproducible, a way of obtaining and storing rare cell samples from SMA patients with which to study the pathogenesis of SMA.

  10. Neuronal involvement in muscular atrophy.

    PubMed

    Cisterna, Bruno A; Cardozo, Christopher; Sáez, Juan C

    2014-01-01

    The innervation of skeletal myofibers exerts a crucial influence on the maintenance of muscle tone and normal operation. Consequently, denervated myofibers manifest atrophy, which is preceded by an increase in sarcolemma permeability. Recently, de novo expression of hemichannels (HCs) formed by connexins (Cxs) and other none selective channels, including P2X7 receptors (P2X7Rs), and transient receptor potential, sub-family V, member 2 (TRPV2) channels was demonstrated in denervated fast skeletal muscles. The denervation-induced atrophy was drastically reduced in denervated muscles deficient in Cxs 43 and 45. Nonetheless, the transduction mechanism by which the nerve represses the expression of the above mentioned non-selective channels remains unknown. The paracrine action of extracellular signaling molecules including ATP, neurotrophic factors (i.e., brain-derived neurotrophic factor (BDNF)), agrin/LDL receptor-related protein 4 (Lrp4)/muscle-specific receptor kinase (MuSK) and acetylcholine (Ach) are among the possible signals for repression for connexin expression. This review discusses the possible role of relevant factors in maintaining the normal functioning of fast skeletal muscles and suppression of connexin hemichannel expression.

  11. Pathogenesis of proximal autosomal recessive spinal muscular atrophy.

    PubMed

    Simic, Goran

    2008-09-01

    Although it is known that deletions or mutations of the SMN1 gene on chromosome 5 cause decreased levels of the SMN protein in subjects with proximal autosomal recessive spinal muscular atrophy (SMA), the exact sequence of pathological events leading to selective motoneuron cell death is not fully understood yet. In this review, new findings regarding the dual cellular role of the SMN protein (translocation of beta-actin to axonal growth cones and snRNP biogenesis/pre-mRNA splicing) were integrated with recent data obtained by detailed neuropathological examination of SMA and control subjects. A presumptive series of 10 pathogenetic events for SMA is proposed as follows: (1) deletions or mutations of the SMN1 gene, (2) increased SMN mRNA decay and reduction in full-length functional SMN protein, (3) impaired motoneuron axono- and dendrogenesis, (4) failure of motoneurons to form synapses with corticospinal fibers from upper motoneurons, (5) abnormal motoneuron migration towards ventral spinal roots, (6) inappropriate persistence of motoneuron apoptosis due to impaired differentiation and motoneuron displacement, (7) substantial numbers of motoneurons continuing to migrate abnormally ("heterotopic motoneurons") and entering into the ventral roots, (8) attracted glial cells following these heterotopic motoneurons, which form the glial bundles of ventral roots, (9) impaired axonal transport of actin, causing remaining motoneurons to become chromatolytic, and (10) eventual death of all apoptotic, heterotopic and chromatolytic neurons, with apoptosis being more rapid and predominating in the earlier stages, with death of heterotopic and chromatolytic neurons occurring more slowly by necrosis during the later stages of SMA. According to this model, the motoneuron axonopathy is more important for pathogenesis than the ubiquitous nuclear splicing deficit. It is also supposed that individually variable levels of SMN protein, together with influences of other phenotype

  12. Spinal muscular atrophy: a motor neuron disorder or a multi-organ disease?

    PubMed

    Shababi, Monir; Lorson, Christian L; Rudnik-Schöneborn, Sabine S

    2014-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disorder that is the leading genetic cause of infantile death. SMA is characterized by loss of motor neurons in the ventral horn of the spinal cord, leading to weakness and muscle atrophy. SMA occurs as a result of homozygous deletion or mutations in Survival Motor Neuron-1 (SMN1). Loss of SMN1 leads to a dramatic reduction in SMN protein, which is essential for motor neuron survival. SMA disease severity ranges from extremely severe to a relatively mild adult onset form of proximal muscle atrophy. Severe SMA patients typically die mostly within months or a few years as a consequence of respiratory insufficiency and bulbar paralysis. SMA is widely known as a motor neuron disease; however, there are numerous clinical reports indicating the involvement of additional peripheral organs contributing to the complete picture of the disease in severe cases. In this review, we have compiled clinical and experimental reports that demonstrate the association between the loss of SMN and peripheral organ deficiency and malfunction. Whether defective peripheral organs are a consequence of neuronal damage/muscle atrophy or a direct result of SMN loss will be discussed. © 2013 Anatomical Society.

  13. Spinal muscular atrophy: a motor neuron disorder or a multi-organ disease?

    PubMed Central

    Shababi, Monir; Lorson, Christian L; Rudnik-Schöneborn, Sabine S

    2014-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disorder that is the leading genetic cause of infantile death. SMA is characterized by loss of motor neurons in the ventral horn of the spinal cord, leading to weakness and muscle atrophy. SMA occurs as a result of homozygous deletion or mutations in Survival Motor Neuron-1 (SMN1). Loss of SMN1 leads to a dramatic reduction in SMN protein, which is essential for motor neuron survival. SMA disease severity ranges from extremely severe to a relatively mild adult onset form of proximal muscle atrophy. Severe SMA patients typically die mostly within months or a few years as a consequence of respiratory insufficiency and bulbar paralysis. SMA is widely known as a motor neuron disease; however, there are numerous clinical reports indicating the involvement of additional peripheral organs contributing to the complete picture of the disease in severe cases. In this review, we have compiled clinical and experimental reports that demonstrate the association between the loss of SMN and peripheral organ deficiency and malfunction. Whether defective peripheral organs are a consequence of neuronal damage/muscle atrophy or a direct result of SMN loss will be discussed. PMID:23876144

  14. Whole-body vibration training in children with Duchenne muscular dystrophy and spinal muscular atrophy.

    PubMed

    Vry, Julia; Schubert, Isabel J; Semler, Oliver; Haug, Verena; Schönau, Eckhard; Kirschner, Janbernd

    2014-03-01

    Whole-body-vibration training is used to improve muscle strength and function and might therefore constitute a potential supportive therapy for neuromuscular diseases. To evaluate safety of whole-body vibration training in ambulatory children with Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA). 14 children with DMD and 8 with SMA underwent an 8-week vibration training programme on a Galileo MedM at home (3 × 3 min twice a day, 5 days a week). Primary outcome was safety of the training, assessed clinically and by measuring serum creatine kinase levels. Secondary outcome was efficacy as measured by changes in time function tests, muscle strength and angular degree of dorsiflexion of the ankles. All children showed good clinical tolerance. In boys with DMD, creatine kinase increased by 56% after the first day of training and returned to baseline after 8 weeks of continuous whole-body vibration training. No changes in laboratory parameters were observed in children with SMA. Secondary outcomes showed mild, but not significant, improvements with the exception of the distance walked in the 6-min walking test in children with SMA, which rose from 371.3 m to 402.8 m (p < 0.01). Whole-body vibration training is clinically well tolerated in children with DMD and SMA. The relevance of the temporary increase in creatine kinase in DMD during the first days of training is unclear, but it is not related to clinical symptoms or deterioration. Copyright © 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

  15. Spinal muscular atrophy: diagnosis, treatment and future prospects.

    PubMed

    Baioni, Mariana T C; Ambiel, Celia R

    2010-01-01

    To report on recent genetic and molecular discoveries and on future prospects for the treatment of spinal muscular atrophy (SMA), thereby helping healthcare professionals to make a quick diagnosis and provide appropriate and timely therapeutic support. Information was collected from scientific articles published in the last 2 decades, retrieved from the databases SciELO, PubMed, and MEDLINE. SMA is a neurodegenerative disorder with autosomal recessive genetic heredity. It is caused by a homozygous deletion of the survival motor neuron (SMN1) gene. This genetic alteration results in reduced levels of the SMN protein, leading to degeneration of alpha motor neurons of the spinal cord and resulting in muscle weakness and progressive symmetrical proximal paralysis. It is known that basic nutritional and respiratory care and physiotherapy can be important to delaying disease progression and prolonging patients' lives. Several drugs are being tested, some new, others, such as valproic acid, already known; paralysis can be halted, but not reversed. SMA is a difficult to diagnose disorder, because it is little known, and treatment is uncertain. Pharmacological treatments and supportive therapies are not yet able to recover motor neurons or muscle cells that have already been lost, but are aimed at delaying disease progression and improving patients' residual muscle function, as well as offering better quality of life and life expectancy.

  16. Emerging therapies and challenges in spinal muscular atrophy

    PubMed Central

    Park, Susanna B.; Vucic, Steve; Carey, Kate A.; Turner, Bradley J.; Gillingwater, Thomas H.; Swoboda, Kathryn J.; Kiernan, Matthew C.

    2017-01-01

    Spinal muscular atrophy (SMA) is a hereditary neurodegenerative disease with severity ranging from progressive infantile paralysis and premature death (type I) to limited motor neuron loss and normal life expectancy (type IV). Without disease‐modifying therapies, the impact is profound for patients and their families. Improved understanding of the molecular basis of SMA, disease pathogenesis, natural history, and recognition of the impact of standardized care on outcomes has yielded progress toward the development of novel therapeutic strategies and are summarized. Therapeutic strategies in the pipeline are appraised, ranging from SMN1 gene replacement to modulation of SMN2 encoded transcripts, to neuroprotection, to an expanding repertoire of peripheral targets, including muscle. With the advent of preliminary trial data, it can be reasonably anticipated that the SMA treatment landscape will transform significantly. Advancement in presymptomatic diagnosis and screening programs will be critical, with pilot newborn screening studies underway to facilitate preclinical diagnosis. The development of disease‐modifying therapies will necessitate monitoring programs to determine the long‐term impact, careful evaluation of combined treatments, and further acceleration of improvements in supportive care. In advance of upcoming clinical trial results, we consider the challenges and controversies related to the implementation of novel therapies for all patients and set the scene as the field prepares to enter an era of novel therapies. Ann Neurol 2017;81:355–368 PMID:28026041

  17. Genetic risk assessment in carrier testing for spinal muscular atrophy.

    PubMed

    Ogino, Shuji; Leonard, Debra G B; Rennert, Hanna; Ewens, Warren J; Wilson, Robert B

    2002-07-15

    As evidenced by the complete absence of a functionally critical sequence in exon 7, approximately 94% of individuals with clinically typical spinal muscular atrophy (SMA) lack both copies of the SMN1 gene at 5q13. Hence most carriers have only one copy of SMN1. Combining linkage and dosage analyses for SMN1, we observed unaffected individuals who have two copies of SMN1 on one chromosome 5 and zero copies of SMN1 on the other chromosome 5. By dosage analysis alone, such individuals, as well as carriers of non-deletion disease alleles, are indistinguishable from non-carrier individuals. We report that approximately 7% of unaffected individuals without a family history of SMA have three or four copies of SMN1, implying a higher frequency of chromosomes with two copies of SMN1 than previously reported. We present updated calculations for disease and non-disease allele frequencies and we describe how these frequencies can be used for genetic risk assessment in carrier testing for SMA. Copyright 2002 Wiley-Liss, Inc.

  18. Genetic carrier screening for spinal muscular atrophy and spinal muscular atrophy with respiratory distress 1 in an isolated population in Israel.

    PubMed

    Basel-Vanagaite, Lina; Taub, Ellen; Drasinover, Valerie; Magal, Nurit; Brudner, Alona; Zlotogora, Joel; Shohat, Mordechai

    2008-03-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by progressive muscle weakness. It is caused by a mutation in the survival motor neuron gene 1 (SMN1) gene. SMA with respiratory distress 1 (SMARD1), an uncommon variant of infantile SMA also inherited in an autosomal recessive manner, is caused by mutations in the immunoglobulin mu-binding protein 2 (IGHMBP2) gene. We carried out genetic carrier screening among the residents of an isolated Israeli Arab village with a high frequency of SMA in order to identify carriers of SMA type I and SMARD1. During 2006, 168 women were tested for SMA, of whom 13.1% were found to be carriers. Of 111 women tested for SMARD1, 9.9% were found to be carriers. Prenatal diagnosis was performed in one couple where both spouses were carriers of SMARD1; the fetus was found to be affected, and the pregnancy was terminated. To the best of our knowledge, this is the first example of the establishment of a large-scale carrier-screening program for SMA and SMARD1 in an isolated population. SMA has a carrier frequency of 1:33-1:60 in most populations and should be considered for inclusion in a population-based genetic-screening program.

  19. Perceptions of equine-assisted activities and therapies by parents and children with spinal muscular atrophy.

    PubMed

    Lemke, Danielle; Rothwell, Erin; Newcomb, Tara M; Swoboda, Kathryn J

    2014-01-01

    To identify the physical and psychosocial effects of equine-assisted activities and therapies (EAATs) on children with spinal muscular atrophy (SMA) from the perspective of the children and their parents. The families of all eligible children with SMA, who reported participation in EAAT, from a Western metropolitan academic center were contacted and invited to participate. This study implemented qualitative, semistructured interviews of children with SMA and their parents. Three themes emerged from the qualitative content analysis: physical/psychosocial benefits; relationship development with the horses, instructors, and children; and barriers to continued EAAT engagement. The data suggest that the overall EAAT experience was a source of enjoyment, self-confidence, and normalcy for the children with SMA. The results of this study provide preliminary support for the use of EAAT among children with SMA.

  20. Deletions of the survival motor neuron gene in unaffected siblings of patients with spinal muscular atrophy

    SciTech Connect

    Cobben, J.M.; Steege, G. van der; Grootscholten, P.

    1995-10-01

    DNA studies in 103 spinal muscular atrophy (SMA) patients from The Netherlands revealed homozygosity for a survival motor neuron (SMN) deletion in 96 (93%) of 103. Neuronal apoptosis inhibitory protein deletions were found in 38 (37%) of 103 and occurred most frequently in SMA type 1. SMN deletions have not yet been described to occur in healthy subjects. In this study, however, four unaffected sibs from two SMA families showed homozygosity for SMN deletions. Homozygosity for an SMN deletion in unaffected persons seems to be very rare. Therefore, demonstration of a homozygous SMN deletion in a clinically presumed SMA patient should be considered as a confirmation of the diagnosis, whether or not SMN is in fact the causal gene for SMA. 19 refs., 2 figs.

  1. Perceptions of Equine Assisted Activities and Therapies by Parents and Children with Spinal Muscular Atrophy

    PubMed Central

    Lemke, Danielle; Rothwell, Erin; Newcomb, Tara M.; Swoboda, Kathryn J.

    2014-01-01

    Purpose To identify the physical and psychosocial effects of equine assisted activities and therapies (EAAT) on children with Spinal Muscular Atrophy (SMA) from the perspective of the child and their parents. Methods The families of all eligible children with SMA, who reported participation in EAAT, from a western metropolitan academic center were contacted and invited to participate. This study implemented qualitative, semi-structured interviews of children with SMA and their parents. Results Three themes emerged from the qualitative content analysis: physical/psychosocial benefits; relationship development with the horses, instructors, and children; and barriers to continued EAAT engagement. Conclusions The data suggest the overall EAAT experience was a source of enjoyment, self-confidence, and normalcy for the children with SMA. The results of this study provide preliminary support for the use of EAAT among children with SMA. PMID:24675128

  2. SMN-inducing compounds for the treatment of spinal muscular atrophy.

    PubMed

    Lorson, Monique A; Lorson, Christian L

    2012-10-01

    Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality. A neurodegenerative disease, it is caused by loss of SMN1, although low, but essential, levels of SMN protein are produced by the nearly identical gene SMN2. While no effective treatment or therapy currently exists, a new wave of therapeutics has rapidly progressed from cell-based and preclinical animal models to the point where clinical trials have initiated for SMA-specific compounds. There are several reasons why SMA has moved relatively rapidly towards novel therapeutics, including: SMA is monogenic; the molecular understanding of SMN gene regulation has been building for nearly 20 years; and all SMA patients retain one or more copies of SMN2 that produces low levels of full-length, fully functional SMN protein. This review primarily focuses upon the biology behind the disease and examines SMN1- and SMN2-targeted therapeutics.

  3. SMN-inducing compounds for the treatment of spinal muscular atrophy

    PubMed Central

    Lorson, Monique A; Lorson, Christian L

    2013-01-01

    Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality. A neurodegenerative disease, it is caused by loss of SMN1, although low, but essential, levels of SMN protein are produced by the nearly identical gene SMN2. While no effective treatment or therapy currently exists, a new wave of therapeutics has rapidly progressed from cell-based and preclinical animal models to the point where clinical trials have initiated for SMA-specific compounds. There are several reasons why SMA has moved relatively rapidly towards novel therapeutics, including: SMA is monogenic; the molecular understanding of SMN gene regulation has been building for nearly 20 years; and all SMA patients retain one or more copies of SMN2 that produces low levels of full-length, fully functional SMN protein. This review primarily focuses upon the biology behind the disease and examines SMN1- and SMN2-targeted therapeutics. PMID:23157239

  4. Arrhythmia and cardiac defects are a feature of spinal muscular atrophy model mice

    PubMed Central

    Heier, Christopher R.; Satta, Rosalba; Lutz, Cathleen; DiDonato, Christine J.

    2010-01-01

    Proximal spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality. Traditionally, SMA has been described as a motor neuron disease; however, there is a growing body of evidence that arrhythmia and/or cardiomyopathy may present in SMA patients at an increased frequency. Here, we ask whether SMA model mice possess such phenotypes. We find SMA mice suffer from severe bradyarrhythmia characterized by progressive heart block and impaired ventricular depolarization. Echocardiography further confirms functional cardiac deficits in SMA mice. Additional investigations show evidence of both sympathetic innervation defects and dilated cardiomyopathy at late stages of disease. Based upon these data, we propose a model in which decreased sympathetic innervation causes autonomic imbalance. Such imbalance would be characterized by a relative increase in the level of vagal tone controlling heart rate, which is consistent with bradyarrhythmia and progressive heart block. Finally, treatment with the histone deacetylase inhibitor trichostatin A, a drug known to benefit phenotypes of SMA model mice, produces prolonged maturation of the SMA heartbeat and an increase in cardiac size. Treated mice maintain measures of motor function throughout extended survival though they ultimately reach death endpoints in association with a progression of bradyarrhythmia. These data represent the novel identification of cardiac arrhythmia as an early and progressive feature of murine SMA while providing several new, quantitative indices of mouse health. Together with clinical cases that report similar symptoms, this reveals a new area of investigation that will be important to address as we move SMA therapeutics towards clinical success. PMID:20693262

  5. Arrhythmia and cardiac defects are a feature of spinal muscular atrophy model mice.

    PubMed

    Heier, Christopher R; Satta, Rosalba; Lutz, Cathleen; DiDonato, Christine J

    2010-10-15

    Proximal spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality. Traditionally, SMA has been described as a motor neuron disease; however, there is a growing body of evidence that arrhythmia and/or cardiomyopathy may present in SMA patients at an increased frequency. Here, we ask whether SMA model mice possess such phenotypes. We find SMA mice suffer from severe bradyarrhythmia characterized by progressive heart block and impaired ventricular depolarization. Echocardiography further confirms functional cardiac deficits in SMA mice. Additional investigations show evidence of both sympathetic innervation defects and dilated cardiomyopathy at late stages of disease. Based upon these data, we propose a model in which decreased sympathetic innervation causes autonomic imbalance. Such imbalance would be characterized by a relative increase in the level of vagal tone controlling heart rate, which is consistent with bradyarrhythmia and progressive heart block. Finally, treatment with the histone deacetylase inhibitor trichostatin A, a drug known to benefit phenotypes of SMA model mice, produces prolonged maturation of the SMA heartbeat and an increase in cardiac size. Treated mice maintain measures of motor function throughout extended survival though they ultimately reach death endpoints in association with a progression of bradyarrhythmia. These data represent the novel identification of cardiac arrhythmia as an early and progressive feature of murine SMA while providing several new, quantitative indices of mouse health. Together with clinical cases that report similar symptoms, this reveals a new area of investigation that will be important to address as we move SMA therapeutics towards clinical success.

  6. Abnormal motor phenotype in the SMNΔ7 mouse model of spinal muscular atrophy

    PubMed Central

    Butchbach, Matthew E. R.; Edwards, Jonathan D.; Burghes, Arthur H. M.

    2009-01-01

    Spinal muscular atrophy (SMA) is recessive motor neuron disease that affects motor neurons in the anterior horn of the spinal cord. SMA results from the reduction of SMN (survival motor neuron) protein. Even though SMN is ubiquitously expressed, motor neurons are more sensitive to the reduction in SMN than other cell types. We have previously generated mouse models of SMA with varying degrees of clinical severity. So as to more clearly understand the pathogenesis of motor neuron degeneration in SMA, we have characterized the phenotype of the SMNΔ7 SMA mouse which normally lives for 13.6 ± 0.7 days. These mice are smaller than their non-SMA littermates and begin to lose body mass at 10.4 ± 0.4 days. SMNΔ7 SMA mice exhibit impaired responses to surface righting, negative geotaxis and cliff aversion but not to tactile stimulation. Spontaneous motor activity and grip strength are also significantly impaired in SMNΔ7 SMA mice. In summary, we have demonstrated an impairment of neonatal motor responses in SMNΔ7 SMA mice. This phenotype characterization could be used to assess the effectiveness of potential therapies for SMA. PMID:17561409

  7. Spinal muscular atrophy: from tissue specificity to therapeutic strategies

    PubMed Central

    Iascone, Daniel M.; Lee, Justin C.

    2015-01-01

    Spinal muscular atrophy (SMA) is the most frequent genetic cause of death in infants and toddlers. All cases of spinal muscular atrophy result from reductions in levels of the survival motor neuron (SMN) protein, and so SMN upregulation is a focus of many preclinical and clinical studies. We examine four issues that may be important in planning for therapeutic success. First, neuromuscular phenotypes in the SMNΔ7 mouse model closely match those in human patients but peripheral disease manifestations differ, suggesting that endpoints other than mouse lifespan may be more useful in predicting clinical outcome. Second, SMN plays important roles in multiple central and peripheral cell types, not just motor neurons, and it remains unclear which of these cell types need to be targeted therapeutically. Third, should SMN-restoration therapy not be effective in all patients, blocking molecular changes downstream of SMN reduction may confer significant benefit, making it important to evaluate therapeutic targets other than SMN. Lastly, for patients whose disease progression is slowed, but who retain significant motor dysfunction, additional approaches used to enhance regeneration of the neuromuscular system may be of value. PMID:25705387

  8. Gene therapy: a promising approach to treating spinal muscular atrophy.

    PubMed

    Mulcahy, Pádraig J; Iremonger, Kayleigh; Karyka, Evangelia; Herranz-Martín, Saúl; Shum, Ka-To; Tam, Janice Kal Van; Azzouz, Mimoun

    2014-07-01

    Spinal muscular atrophy (SMA) is a severe autosomal recessive disease caused by a genetic defect in the survival motor neuron 1 (SMN1) gene, which encodes SMN, a protein widely expressed in all eukaryotic cells. Depletion of the SMN protein causes muscle weakness and progressive loss of movement in SMA patients. The field of gene therapy has made major advances over the past decade, and gene delivery to the central nervous system (CNS) by in vivo or ex vivo techniques is a rapidly emerging field in neuroscience. Despite Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis being among the most common neurodegenerative diseases in humans and attractive targets for treatment development, their multifactorial origin and complicated genetics make them less amenable to gene therapy. Monogenic disorders resulting from modifications in a single gene, such as SMA, prove more favorable and have been at the fore of this evolution of potential gene therapies, and results to date have been promising at least. With the estimated number of monogenic diseases standing in the thousands, elucidating a therapeutic target for one could have major implications for many more. Recent progress has brought about the commercialization of the first gene therapies for diseases, such as pancreatitis in the form of Glybera, with the potential for other monogenic disease therapies to follow suit. While much research has been carried out, there are many limiting factors that can halt or impede translation of therapies from the bench to the clinic. This review will look at both recent advances and encountered impediments in terms of SMA and endeavor to highlight the promising results that may be applicable to various associated diseases and also discuss the potential to overcome present limitations.

  9. Longitudinal characterization of biomarkers for spinal muscular atrophy.

    PubMed

    Bonati, Ulrike; Holiga, Štefan; Hellbach, Nicole; Risterucci, Céline; Bergauer, Tobias; Tang, Wakana; Hafner, Patricia; Thoeni, Alain; Bieri, Oliver; Gerlach, Irene; Marquet, Anne; Khwaja, Omar; Sambataro, Fabio; Bertolino, Alessandro; Dukart, Juergen; Fischmann, Arne; Fischer, Dirk; Czech, Christian

    2017-05-01

    Recent advances in understanding Spinal Muscular Atrophy (SMA) etiopathogenesis prompted development of potent intervention strategies and raised need for sensitive outcome measures capable of assessing disease progression and response to treatment. Several biomarkers have been proposed; nevertheless, no general consensus has been reached on the most feasible ones. We observed a wide range of measures over 1 year to assess their ability to monitor the disease status and progression. 18 SMA patients and 19 healthy volunteers (HV) were followed in this 52-weeks observational study. Quantitative-MRI (qMRI) of both thighs and clinical evaluation of motor function was performed at baseline, 6, 9 and 12 months follow-up. Blood samples were taken in patients for molecular characterization at screening, 9 and 12 month follow-up. Progression, responsiveness and reliability of collected indices were quantified. Correlation analysis was performed to test for potential associations. QMRI indices, clinical scales and molecular measures showed high to excellent reliability. Significant differences were found between qMRI of SMA patients and HV. Significant associations were revealed between multiple qMRI measures and functional clinical scales. None of the qMRI, clinical, or molecular measures was able to detect significant disease progression over 1 year. We probed a variety of quantitative measures for SMA in a slowly-progressing disease population over 1 year. The presented measures demonstrated potential to provide a closer link to underlying disease biology as compared to conventional functional scales. The proposed biomarker framework can guide implementation of more sensitive endpoints in future clinical trials and prove their utility in search for novel disease-modifying therapies.

  10. Using General Anesthesia plus Muscle Relaxant in a Patient with Spinal Muscular Atrophy Type IV: A Case Report

    PubMed Central

    Liu, Xiu-Fen; Wang, Dong-Xin; Ma, Daqing

    2011-01-01

    Spinal muscular atrophy (SMA) is a rare genetic disease characterized by degeneration of spinal cord motor neurons, which results in hypotonia and muscle weakness. Patients with type IV SMA often have onset of weakness from adulthood. Anesthetic management is often difficult in these patients as a result of muscle weakness and hypersensitivity to neuromuscular blocking agents as shown by (Lunn and Wang; 2008, Simic; 2008, and Cifuentes-Diaz et al.; 2002). Herein we report a case of anesthetic management of a patient with SMA type IV for mammectomy and review some other cases of SMA patients receiving different kinds of anesthesia. PMID:22606392

  11. Mapping of retrotransposon sequences in the unstable region surrounding the spinal muscular atrophy locus in 5q13

    SciTech Connect

    Francis, M.J.; Nesbit, M.A.; Theodosiou, A.M.

    1995-05-20

    The mutation that underlies the autosomal recessive disorder spinal muscular atrophy (SMA) is located on chromosome 5q13. Recent studies show that SMA patients frequently have deletions and rearrangements in this region compared to normal controls. During the isolation of candidate cDNAs for the disease, the authors identified a sequence that shows high homology to the THE-1 retrotransposon gene family. Using YAC fragmentation techniques, they have refined the localization of this sequence to the domain known to show instability in SMA patients. The implication of these results for the mechanism of the mutation in SMA is discussed. 20 refs., 1 fig.

  12. [Upper limb functional assessment scale for children with Duchenne muscular dystrophy and Spinal muscular atrophy].

    PubMed

    Escobar, Raúl G; Lucero, Nayadet; Solares, Carmen; Espinoza, Victoria; Moscoso, Odalie; Olguín, Polín; Muñoz, Karin T; Rosas, Ricardo

    2017-02-01

    Duchenne muscular dystrophy (DMD) and Spinal muscular atrophy (SMA) causes significant disability and progressive functional impairment. Readily available instruments that assess functionality, especially in advanced stages of the disease, are required to monitor the progress of the disease and the impact of therapeutic interventions. To describe the development of a scale to evaluate upper limb function (UL) in patients with DMD and SMA, and describe its validation process, which includes self-training for evaluators. The development of the scale included a review of published scales, an exploratory application of a pilot scale in healthy children and those with DMD, self-training of evaluators in applying the scale using a handbook and video tutorial, and assessment of a group of children with DMD and SMA using the final scale. Reliability was assessed using Cronbach and Kendall concordance and with intra and inter-rater test-retest, and validity with concordance and factorial analysis. A high level of reliability was observed, with high internal consistency (Cronbach a = 0.97), and inter-rater (Kendall W = 0.96) and intra-rater concordance (r = 0.97 to 0.99). The validity was demonstrated by the absence of significant differences between results by different evaluators with an expert evaluator (F = 0.023, p > .5), and by the factor analysis that showed that four factors account for 85.44% of total variance. This scale is a reliable and valid tool for assessing UL functionality in children with DMD and SMA. It is also easily implementable due to the possibility of self-training and the use of simple and inexpensive materials.

  13. [Upper limb functional assessment scale for children with Duchenne muscular dystrophy and Spinal muscular atrophy].

    PubMed

    Escobar, Raúl G; Lucero, Nayadet; Solares, Carmen; Espinoza, Victoria; Moscoso, Odalie; Olguín, Polín; Muñoz, Karin T; Rosas, Ricardo

    2016-08-16

    Duchenne muscular dystrophy (DMD) and Spinal muscular atrophy (SMA) causes significant disability and progressive functional impairment. Readily available instruments that assess functionality, especially in advanced stages of the disease, are required to monitor the progress of the disease and the impact of therapeutic interventions. To describe the development of a scale to evaluate upper limb function (UL) in patients with DMD and SMA, and describe its validation process, which includes self-training for evaluators. The development of the scale included a review of published scales, an exploratory application of a pilot scale in healthy children and those with DMD, self-training of evaluators in applying the scale using a handbook and video tutorial, and assessment of a group of children with DMD and SMA using the final scale. Reliability was assessed using Cronbach and Kendall concordance and with intra and inter-rater test-retest, and validity with concordance and factorial analysis. A high level of reliability was observed, with high internal consistency (Cronbach α=0.97), and inter-rater (Kendall W=0.96) and intra-rater concordance (r=0.97 to 0.99). The validity was demonstrated by the absence of significant differences between results by different evaluators with an expert evaluator (F=0.023, P>.5), and by the factor analysis that showed that four factors account for 85.44% of total variance. This scale is a reliable and valid tool for assessing UL functionality in children with DMD and SMA. It is also easily implementable due to the possibility of self-training and the use of simple and inexpensive materials. Copyright © 2016 Sociedad Chilena de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

  14. A multicopy dinucleotide marker that maps close to the spinal muscular atrophy gene

    SciTech Connect

    Burghes, A.H.M.; Ingraham, S.E.; Kote-Jarai, Z.; Carpten, J.D.; DiDonato, C.J. ); McLean, M.; Surh, L. ); Thompson, T.G.; McPherson, J.D. ); Ikeda, J.E. ); Wirth, B. )

    1994-05-15

    Spinal muscular atrophy (SMA) is a common autosomal recessive disorder resulting in loss of motor neurons. The interval containing the SMA gene has been defined by linkage analysis as 5qcen-D5S435-SMA-D5S557-5qter. The authors have isolated a new dinucleotide repeat marker, CATT1, that lies between these two closest markers. The marker CATT1 has 16 alleles and is highly polymorphic. The marker can have 1 to 4 (or more) copies per chromosome, giving rise to individuals with up to 8 (or more) alleles. All of the subloci map between the markers D5S557 and D5S435 and lie in close proximity to one another. The marker CATT1 is linked to the SMA gene with a lod score of Z[sub max] = 34.42 at [theta] = 0 and crosses all available recombinants. Certain alleles occurred more frequently in either the SMA or normal populations, indicating significant allelic association between CATT1 and the SMA locus. Haplotype analysis combining US and Canadian SMA families reveals that one haplotype group (VII) occurs significantly more frequently in the SMA population than in the normal. This confirms the allelic association of CATT1 with the SMA locus. 37 refs., 4 figs., 3 tabs.

  15. Transmission ratio distortion in the spinal muscular atrophy locus: data from 314 prenatal tests.

    PubMed

    Botta, A; Tacconelli, A; Bagni, I; Giardina, E; Bonifazi, E; Pietropolli, A; Clementi, M; Novelli, G

    2005-11-22

    Spinal muscular atrophy (SMA) is a recessive neurodegenerative disorder characterized by the loss of alpha-motor neurons in the spinal cord and subsequent death of motor neuron cells. SMA occurs with a frequency of 1 in 6,000 live births, with a carrier frequency of 1 in 40, and is a leading genetic cause of infant mortality. SMA is caused by loss or mutation of the telomeric survival motor neuron gene (SMN1), which is deleted in almost 94% of SMA patients To analyze the transmission ratio at the SMA locus, examining the segregation of the SMN1-deleted alleles in 314 fetuses from carrier parents who requested prenatal testing for the disease. Prenatal diagnosis of SMA in families at 25% risk of the disease has been performed on chorionic villous sampling specimens, through direct detection of the SMN1 gene mutation and linkage analysis using microsatellite markers from the 5q13 region. Analysis of the genotypic/allelic frequencies of the SMN1 gene was performed using the chi2 test, assuming a recessive mendelian inheritance. Of 314 fetuses analyzed, 95 were homozygous for the wild-type allele (30.3%), 154 were carriers (49.0%), and the remaining 65 were homozygous for the mutated allele (20.7%). Statistical analysis demonstrated that proportion of fetuses predicted with SMA is lower than 25% expected for a recessive disorder, resulting in a transmission rate of the SMN1-deleted allele deviant from the 50% expected in a random the segregation of a mendelian tract (p = 0.016) This is the first study to evaluate the genotypic frequencies at the spinal muscular atrophy (SMA) locus based on data derived from prenatal analysis, which are not subject to ascertainment bias. The analysis showed a transmission ratio distortion at the SMA locus in favor of the SMN1 wild-type alleles.

  16. Spinal and Bulbar Muscular Atrophy Overview

    PubMed Central

    Fischbeck, Kenneth H.

    2016-01-01

    Spinal and bulbar muscular atrophy is an X-linked neuromuscular disease caused by an expanded repeat in the androgen receptor gene. The mutant protein is toxic to motor neurons and muscle. The toxicity is ligand-dependent and likely involves aberrant interaction of the mutant androgen receptor with other nuclear factors leading to transcriptional dysregulation. Various therapeutic strategies have been effective in transgenic animal models, and the challenge now is to translate these strategies into safe and effective treatment in patients. PMID:26547319

  17. Linkage disequilibrium and haplotype analysis among Polish families with spinal muscular atrophy

    SciTech Connect

    Brzustowicz, L.M.; Wang, C.H.; Matseoane, D.; Kleyn, P.W.; Vitale, E.; Das, K.; Penchaszadeh, G.K.; Gilliam, T.C.; Munsat, T.L.; Hausmanowa-Petrusewicz, I.

    1995-01-01

    Spinal muscular atrophy (SMA) is an inherited degenerative disorder of anterior horn cells that results in progressive muscle weakness and atrophy. The autosomal recessive forms of childhood-onset SMA have been mapped to chromosome 5q11.2-13.3, in a number of studies examining different populations. A total of 9 simple sequence repeat markers were genotyped against 32 Polish families with SMA. The markers span an {approximately}0.7 cM region defined by the SMA flanking markers D5S435 and MAP1B. Significant linkage disequilibrium (corrected P<0.5) was detected at four of these markers, with D/D{sub max} values of {le}.89. Extended haplotype analysis revealed a predominant haplotype associated with SMA. The apparently high mutation rate of some of the markers has resulted in a number of haplotypes that vary slightly from this predominant haplotype. The predominant haplotype and these closely related patterns represent 25% of the disease chromosomes and none of the nontransmitted parental chromosomes. This predominant haplotype is present both in patients with acute (type I) and in chronic (types II and III) forms of SMA and occurs twice in a homozygous state, both times in children with chronic SMA. 34 refs., 2 figs., 2 tabs.

  18. Effect of the butyrate prodrug pivaloyloxymethyl butyrate (AN9) on a mouse model for spinal muscular atrophy

    PubMed Central

    Edwards, Jonathan D.; Butchbach, Matthew E. R.

    2016-01-01

    Spinal muscular atrophy (SMA) is an early-onset motor neuron disease that leads to loss of muscle function. Butyrate (BA)-based compounds markedly improve the survival and motor phenotype of SMA mice. In this study, we examine the protective effects of the BA prodrug pivaloyloxymethyl butyrate (AN9) on the survival of SMNΔ7 SMA mice. Oral administration of AN9 beginning at PND04 almost doubled the average lifespan of SMNΔ7 SMA mice. AN9 treatment also increased the growth rate of SMNΔ7 SMA mice when compared to vehicle-treated SMNΔ7 SMA mice. In conclusion, BA prodrugs like AN9 have ameliorative effects on SMNΔ7 SMA mice. PMID:27911337

  19. Motor neuron cell-nonautonomous rescue of spinal muscular atrophy phenotypes in mild and severe transgenic mouse models

    PubMed Central

    Liu, Ying Hsiu; Sahashi, Kentaro; Rigo, Frank; Bennett, C. Frank

    2015-01-01

    Survival of motor neuron (SMN) deficiency causes spinal muscular atrophy (SMA), but the pathogenesis mechanisms remain elusive. Restoring SMN in motor neurons only partially rescues SMA in mouse models, although it is thought to be therapeutically essential. Here, we address the relative importance of SMN restoration in the central nervous system (CNS) versus peripheral tissues in mouse models using a therapeutic splice-switching antisense oligonucleotide to restore SMN and a complementary decoy oligonucleotide to neutralize its effects in the CNS. Increasing SMN exclusively in peripheral tissues completely rescued necrosis in mild SMA mice and robustly extended survival in severe SMA mice, with significant improvements in vulnerable tissues and motor function. Our data demonstrate a critical role of peripheral pathology in the mortality of SMA mice and indicate that peripheral SMN restoration compensates for its deficiency in the CNS and preserves motor neurons. Thus, SMA is not a cell-autonomous defect of motor neurons in SMA mice. PMID:25583329

  20. Feeding problems and malnutrition in spinal muscular atrophy type II.

    PubMed

    Messina, Sonia; Pane, Marika; De Rose, Paola; Vasta, Isabella; Sorleti, Domenica; Aloysius, Annie; Sciarra, Federico; Mangiola, Fortunato; Kinali, Maria; Bertini, Enrico; Mercuri, Eugenio

    2008-05-01

    The aim of the study was to conduct a survey using a dedicated questionnaire to assess feeding difficulties and weight gain in a population of 122 Spinal Muscular Atrophy (SMA) type II patients, aged between 1 and 47 years. All the answers were entered in a database and were analysed subdividing the cohort into age groups (1-5, 6-10, 11-14, 15-19, 20-29, and 30-50 years). Six out of our 122 patients (5%), all younger than 11 years, had weights more than 2SD above the median for age matched controls, whilst 45 (37%) had weights less than 2SD below the median. Chewing difficulties were reported in 34 of the 122 patients (28%) and limitation in the ability to open the mouth in 36 (30%) and both were increasingly more frequent with age. Swallowing difficulties were reported in 30 patients (25%). The results of our survey suggest that a number of patients with SMA type II have limited jaw opening, and chewing and swallowing difficulties. Our findings raise a few issues concerning standards of care that should be implemented in the monitoring and management of feeding difficulties and weight gain.

  1. Gait assessment with solesound instrumented footwear in spinal muscular atrophy.

    PubMed

    Montes, Jacqueline; Zanotto, Damiano; Dunaway Young, Sally; Salazar, Rachel; De Vivo, Darryl C; Agrawal, Sunil

    2017-08-01

    Gait impairment is common in spinal muscular atrophy (SMA) and is described using clinical assessments and instrumented walkways. Continuous over-ground walking has not been studied. Nine SMA participants completed the 6-minute walk test (6MWT) and 10-meter walk/run wearing instrumented footwear (SoleSound). Data were simultaneously collected using a reference system (GAITRite). The root-mean-square error (RMSE) indicated criterion validity. The decrease in walking speed represented fatigue. Foot loading patterns were evaluated using force sensors. The RMSE for stride time, length, and velocity ranged from 1.3% to 1.7%. Fatigue was 11.6 ± 9.1%, which corresponded to an average deceleration of 0.37 ± 0.28 mm/s(2) . Participants spent most of their stance without heel contact. Forefoot contact occurred early in the gait cycle. These results suggest that footwear-based devices are an alternative to specialized equipment for gait assessment. Better understanding of gait disturbances should inform ongoing treatment efforts and provide a more sensitive outcome measure. Muscle Nerve 56: 230-236, 2017. © 2016 Wiley Periodicals, Inc.

  2. Towards identification of the gene for spinal muscular atrophy

    SciTech Connect

    Steege, G. van der; Cobben, J.M.; Draaijers, T.G.

    1994-09-01

    The proximal spinal muscular atrophies (SMAs) are irreversible lower motor neuron diseases of unknown primary cause. According to age of onset and severity of illness, this group of disorders can be classified into three types: SMA types I, II, and III. All three types of autosomal recessive SMA have been localized to chromosome 5 in bands of q11.2-q13 by genetic analysis. The gene resides in a small genetic interval flanked by the markers D5S435 and D5S557. From a hybrid cell line containing 5q11-q14 as its only human chromosome 5 material we constructed a cosmid library. A cosmid clone mapped by FISH between D5S125 and D5S112 was used to isolate some YACs, from which cosmid libraries were constructed. cDNA libraries are screened by hybridization directly with the YACs and with cosmids that give Northern signals. At present we are analysing 7 different cDNA clones mapping between D5S435 and D5S557.

  3. Mechanistic principles of antisense targets for the treatment of spinal muscular atrophy.

    PubMed

    Singh, Natalia N; Lee, Brian M; DiDonato, Christine J; Singh, Ravindra N

    2015-01-01

    Spinal muscular atrophy (SMA) is a major neurodegenerative disorder of children and infants. SMA is primarily caused by low levels of SMN protein owing to deletions or mutations of the SMN1 gene. SMN2, a nearly identical copy of SMN1, fails to compensate for the loss of the production of the functional SMN protein due to predominant skipping of exon 7. Several compounds, including antisense oligonucleotides (ASOs) that elevate SMN protein from SMN2 hold the promise for treatment. An ASO-based drug currently under Phase III clinical trial employs intronic splicing silencer N1 (ISS-N1) as its target. Cumulative studies on ISS-N1 reveal a wealth of information with significance to the overall therapeutic development for SMA. Here, the authors summarize the mechanistic principles behind various antisense targets currently available for SMA therapy.

  4. Early functional impairment of sensory-motor connectivity in a mouse model of spinal muscular atrophy.

    PubMed

    Mentis, George Z; Blivis, Dvir; Liu, Wenfang; Drobac, Estelle; Crowder, Melissa E; Kong, Lingling; Alvarez, Francisco J; Sumner, Charlotte J; O'Donovan, Michael J

    2011-02-10

    To define alterations of neuronal connectivity that occur during motor neuron degeneration, we characterized the function and structure of spinal circuitry in spinal muscular atrophy (SMA) model mice. SMA motor neurons show reduced proprioceptive reflexes that correlate with decreased number and function of synapses on motor neuron somata and proximal dendrites. These abnormalities occur at an early stage of disease in motor neurons innervating proximal hindlimb muscles and medial motor neurons innervating axial muscles, but only at end-stage disease in motor neurons innervating distal hindlimb muscles. Motor neuron loss follows afferent synapse loss with the same temporal and topographical pattern. Trichostatin A, which improves motor behavior and survival of SMA mice, partially restores spinal reflexes, illustrating the reversibility of these synaptic defects. Deafferentation of motor neurons is an early event in SMA and may be a primary cause of motor dysfunction that is amenable to therapeutic intervention.

  5. Early functional impairment of sensory-motor connectivity in a mouse model of spinal muscular atrophy

    PubMed Central

    Mentis, George Z.; Blivis, Dvir; Liu, Wenfang; Drobac, Estelle; Crowder, Melissa E.; Kong, Lingling; Alvarez, Francisco J.; Sumner, Charlotte J.; O'Donovan, Michael J.

    2011-01-01

    SUMMARY To define alterations of neuronal connectivity that occur during motor neuron degeneration, we characterized the function and structure of spinal circuitry in spinal muscular atrophy (SMA) model mice. SMA motor neurons show reduced proprioceptive reflexes that correlate with decreased number and function of synapses on motor neuron somata and proximal dendrites. These abnormalities occur at an early stage of disease in motor neurons innervating proximal hindlimb muscles and medial motor neurons innervating axial muscles, but only at end-stage disease in motor neurons innervating distal hindlimb muscles. Motor neuron loss follows afferent synapse loss with the same temporal and topographical pattern. Trichostatin A, which improves motor behavior and survival of SMA mice, partially restores spinal reflexes illustrating the reversibility of these synaptic defects. De-afferentation of motor neurons is an early event in SMA and may be a primary cause of motor dysfunction that is amenable to therapeutic intervention. PMID:21315257

  6. Spinal muscular atrophy during human development: where are the early pathogenic findings?

    PubMed

    Tizzano, Eduardo

    2009-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disorder that affects motor neurons. It is caused by mutations in the survival motor neuron gene 1 (SMN1). The SMN2 gene, which is the highly homologous SMN1 copy that is present in all patients, is unable to prevent the disease. SMA patients can be classified into four groups based on age at onset and acquired milestones (type I or severe acute disease, with onset before 6 months; type II, before 18 months; type III, after 18 months and type IV, in adult life). The human developmental period is believed to play an essential role in SMA pathogenesis. However, the neuropathologic study of SMA comes largely from postnatal necropsy samples, which describe the end-stage of the disease. With the exception of severe congenital SMA (or Type 0 SMA), type I patients tend to present a short but variable presymptomatic period after birth. Our main interest lies in studying SMA during human development so as to gain insight into the mechanism of the disease in the prenatal-presymptomatic stage. In fetuses of 12-15 weeks' gestational age we systematically studied histology, cell death and gene expression in spinal cord and muscle, the key tissues involved in the disease. Furthermore, ultrasound parameters were investigated at these stages. These studies may help to delineate an early intervention in SMA, in particular during the potential therapeutic window.

  7. Systemic restoration of UBA1 ameliorates disease in spinal muscular atrophy

    PubMed Central

    Powis, Rachael A.; Karyka, Evangelia; Boyd, Penelope; Côme, Julien; Jones, Ross A.; Zheng, Yinan; Szunyogova, Eva; Groen, Ewout J.N.; Hunter, Gillian; Thomson, Derek; Wishart, Thomas M.; Becker, Catherina G.; Parson, Simon H.; Martinat, Cécile; Azzouz, Mimoun; Gillingwater, Thomas H.

    2016-01-01

    The autosomal recessive neuromuscular disease spinal muscular atrophy (SMA) is caused by loss of survival motor neuron (SMN) protein. Molecular pathways that are disrupted downstream of SMN therefore represent potentially attractive therapeutic targets for SMA. Here, we demonstrate that therapeutic targeting of ubiquitin pathways disrupted as a consequence of SMN depletion, by increasing levels of one key ubiquitination enzyme (ubiquitin-like modifier activating enzyme 1 [UBA1]), represents a viable approach for treating SMA. Loss of UBA1 was a conserved response across mouse and zebrafish models of SMA as well as in patient induced pluripotent stem cell–derive motor neurons. Restoration of UBA1 was sufficient to rescue motor axon pathology and restore motor performance in SMA zebrafish. Adeno-associated virus serotype 9–UBA1 (AAV9-UBA1) gene therapy delivered systemic increases in UBA1 protein levels that were well tolerated over a prolonged period in healthy control mice. Systemic restoration of UBA1 in SMA mice ameliorated weight loss, increased survival and motor performance, and improved neuromuscular and organ pathology. AAV9-UBA1 therapy was also sufficient to reverse the widespread molecular perturbations in ubiquitin homeostasis that occur during SMA. We conclude that UBA1 represents a safe and effective therapeutic target for the treatment of both neuromuscular and systemic aspects of SMA. PMID:27699224

  8. Molecular genetic analyses of five Vietnamese patients with spinal muscular atrophy.

    PubMed

    Khanh, Tran Van; Takeshima, Yasuhiro; Harada, Yosuke; Nishio, Hisahide; Dao, Nguyen Thi Ngoc; Hoan, Nguyen Thi; Thao, Bui Phuong; Matsuo, Masafumi

    2002-12-01

    Most patients with spinal muscular atrophy (SMA) have been reported to show homozygous deletion of the gene responsible for SMA, SMN1. However, whether SMA patients homozygous for the SMN1 deletion exist in Southeast Asian countries, including Vietnam, remains to be determined, because molecular genetic analyses of SMA patients from these countries have not been reported. In this preliminary study, we analyzed five Vietnamese SMA patients and found that SMN1 gene exons 7 and 8 were completely absent in one of them, a 6-month-old girl with hypotonic muscles. Thus, SMN1 deletion can be a cause of SMA in Vietnam, although other genetic abnormalities should be considered as etiological factors in many cases. In conclusion, we identified a homozygous deletion of the SMN1 gene in a Vietnamese SMA patient. Since the number of the patients analyzed in this study was very limited, it is too early to determine whether SMN1 deletion is not a main cause of SMA in Vietnam.

  9. Further evidence of no association between spinal muscular atrophy and increased nuchal translucency.

    PubMed

    Barone, Chiara; Bianca, Sebastiano

    2013-01-01

    Several authors have reported on pregnancy outcomes associated with enlarged nuchal translucency (NT) in cases of spinal muscular atrophy (SMA), and thus, thickened NT has been considered a possible early ultrasound scan sign of SMA. The purpose of our study was to evaluate the association between an increased NT and SMA in order to use an ultrasound scan of NT as a possible marker of this disorder. This is a retrospective and observational study of women who had a fetus or delivered a baby with SMA following a pregnancy in which NT ultrasound has been performed. With the support of 'Famiglie SMA', we acquired copies of ultrasound NT measurements, molecular genetic tests confirming the SMA diagnosis in the fetus/baby, other prenatal ultrasound evaluations and informed consent. Twenty-nine Italian women met the inclusion criteria and sent us the requested reports. All had a normal NT measurement for the SMA-affected fetus, with a mean of 1.8 mm (range 0.9-2.4). This series does not confirm an association between increased NT and SMA. Fetal genetic testing for the survival motor neuron gene 1 on the basis of increased NT is not indicated in couples with no previous history of this genetic condition. Copyright © 2012 S. Karger AG, Basel.

  10. Genetic testing of sperm donors for cystic fibrosis and spinal muscular atrophy: evaluation of clinical utility.

    PubMed

    Landaburu, I; Gonzalvo, M-C; Clavero, A; Ramirez, J-P; Yoldi, A; Mozas, J; Zamora, S; Martinez, L; Castilla, J-A

    2013-09-01

    To evaluate the clinical utility of genetic testing for cystic fibrosis (CF) and spinal muscular atrophy (SMA) in sperm donors. We studied the results of the genetic tests for CF and SMA applied to 372 sperm donor candidates. The CF carrier screening test analysed 32 mutations on the CFTR gene. Regarding SMA, the carrier test studied possible deletions of SMN1/2 by Multiplex Ligation-dependent Probe Amplification (MLPA) methodology. The carrier frequency obtained was greater for SMA than for CF. After adjusting the results obtained for the sensitivity of the tests, and taking into account the prevalence of female carriers in our population, the probability of transmission of the disease to the child from a donor with a negative genetic test was about five times lower in the case of SMA than in CF, although this difference was not statistically significant. The number of donors needed to screen (NNS) to avoid the occurrence of a child being affected by CF and SMA in our population was similar in both cases (1591 vs. 1536). This study demonstrates the need to include SMA among the diseases for which genetic screening is performed in the process of sperm donor selection. We believe that testing donors for SMA is as important and as useful as doing so for CF. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  11. Electrophysiological biomarkers in spinal muscular atrophy: proof of concept

    PubMed Central

    David Arnold, W; Porensky, Paul N; McGovern, Vicki L; Iyer, Chitra C; Duque, Sandra; Li, Xiaobai; Meyer, Kathrin; Schmelzer, Leah; Kaspar, Brian K; Kolb, Stephen J; Kissel, John T; Burghes, Arthur H M

    2014-01-01

    Objective Preclinical therapies that restore survival motor neuron (SMN) protein levels can dramatically extend survival in spinal muscular atrophy (SMA) mouse models. Biomarkers are needed to effectively translate these promising therapies to clinical trials. Our objective was to investigate electrophysiological biomarkers of compound muscle action potential (CMAP), motor unit number estimation (MUNE) and electromyography (EMG) using an SMA mouse model. Methods Sciatic CMAP, MUNE, and EMG were obtained in SMNΔ7 mice at ages 3–13 days and at 21 days in mice with SMN selectively reduced in motor neurons (ChATCre). To investigate these measures as biomarkers of treatment response, measurements were obtained in SMNΔ7 mice treated with antisense oligonucleotide (ASO) or gene therapy. Results CMAP was significantly reduced in SMNΔ7 mice at days 6–13 (P < 0.01), and MUNE was reduced at days 7–13 (P < 0.01). Fibrillations were present on EMG in SMNΔ7 mice but not controls (P = 0.02). Similar findings were seen at 21 days in ChATCre mice. MUNE in ASO-treated SMNΔ7 mice were similar to controls at day 12 and 30. CMAP reduction persisted in ASO-treated SMNΔ7 mice at day 12 but was corrected at day 30. Similarly, CMAP and MUNE responses were corrected with gene therapy to restore SMN. Interpretation These studies confirm features of preserved neuromuscular function in the early postnatal period and subsequent motor unit loss in SMNΔ7 mice. SMN restoring therapies result in preserved MUNE and gradual repair of CMAP responses. This provides preclinical evidence for the utilization of CMAP and MUNE as biomarkers in future SMA clinical trials. PMID:24511555

  12. Mutations in the tail domain of DYNC1H1 cause dominant spinal muscular atrophy

    PubMed Central

    Harms, M.B.; Ori-McKenney, K.M.; Scoto, M.; Tuck, E.P.; Bell, S.; Ma, D.; Masi, S.; Allred, P.; Al-Lozi, M.; Reilly, M.M.; Miller, L.J.; Jani-Acsadi, A.; Pestronk, A.; Shy, M.E.; Muntoni, F.; Vallee, R.B.

    2012-01-01

    Objective: To identify the gene responsible for 14q32-linked dominant spinal muscular atrophy with lower extremity predominance (SMA-LED, OMIM 158600). Methods: Target exon capture and next generation sequencing was used to analyze the 73 genes in the 14q32 linkage interval in 3 SMA-LED family members. Candidate gene sequencing in additional dominant SMA families used PCR and pooled target capture methods. Patient fibroblasts were biochemically analyzed. Results: Regional exome sequencing of all candidate genes in the 14q32 interval in the original SMA-LED family identified only one missense mutation that segregated with disease state—a mutation in the tail domain of DYNC1H1 (I584L). Sequencing of DYNC1H1 in 32 additional probands with lower extremity predominant SMA found 2 additional heterozygous tail domain mutations (K671E and Y970C), confirming that multiple different mutations in the same domain can cause a similar phenotype. Biochemical analysis of dynein purified from patient-derived fibroblasts demonstrated that the I584L mutation dominantly disrupted dynein complex stability and function. Conclusions: We demonstrate that mutations in the tail domain of the heavy chain of cytoplasmic dynein (DYNC1H1) cause spinal muscular atrophy and provide experimental evidence that a human DYNC1H1 mutation disrupts dynein complex assembly and function. DYNC1H1 mutations were recently found in a family with Charcot-Marie-Tooth disease (type 2O) and in a child with mental retardation. Both of these phenotypes show partial overlap with the spinal muscular atrophy patients described here, indicating that dynein dysfunction is associated with a range of phenotypes in humans involving neuronal development and maintenance. PMID:22459677

  13. Spinal Muscular Atrophy: The Development and Implementation of Potential Treatments Running Head: Spinal Muscular Atrophy

    PubMed Central

    Arnold, W. David; Burghes, Arthur H.M.

    2013-01-01

    In neurodegenerative disorders effective treatments are urgently needed, along with methods to detect that the treatment worked. In this review we discuss the rapid progress in the understanding of recessive proximal spinal muscular atrophy and how this is leading to exciting potential treatments of the disease. Spinal muscular atrophy is a caused by loss of the Survival Motor Neuron 1 (SMN1) gene and reduced levels of SMN protein. The critical downstream targets of SMN deficiency that result in motor neuron loss are not known. However, increasing SMN levels has a marked impact in mouse models, and these therapeutics are rapidly moving towards clinical trials. Promising preclinical therapies, the varying degree of impact on the mouse models, and potential measures of treatment effect are reviewed. One key issue discussed is the variable outcome of increasing SMN at different stages of disease progression. PMID:23939659

  14. Cardiac function in types II and III spinal muscular atrophy: should we change standards of care?

    PubMed

    Bianco, Flaviana; Pane, Marika; D'Amico, Adele; Messina, Sonia; Delogu, Angelica Bibiana; Soraru, Gianni; Pera, Maria Carmela; Mongini, Tiziana; Politano, Luisa; Baranello, Giovanni; Vita, Gianluca; Tiziano, Francesco Danilo; Morandi, Lucia; Bertini, Enrico; Mercuri, Eugenio

    2015-02-01

    In the last years, there has been increasing evidence of cardiac involvement in spinal muscular atrophy (SMA). Autonomic dysfunction has been reported in animal models and in several patients with types I and III SMA, these findings raising the question whether heart rate should be routinely investigated in all SMA patients. The aim of our study was to detect possible signs of autonomic dysfunction and, more generally, of cardiac involvement in types II and III SMA. We retrospectively reviewed 24-hour electrocardiography (ECG) in 157 types II and III SMA patients (age range, 2-74 years). Of them, 82 also had echocardiography. None of the patients had signs of bradycardia, atrial fibrillation, or the other previously reported rhythm disturbances regardless of the age at examination or the type of SMA. Echocardiography was also normal. There were no signs of congenital cardiac defects with the exception of one patient with a history of ventricular septal defects. Our results suggest that cardiac abnormalities are not common in type II and type III SMA. These findings provide no evidence to support a more accurate cardiac surveillance or changes in the existing standards of care. Georg Thieme Verlag KG Stuttgart · New York.

  15. Maternal mosaicism for a second mutational event in a type I spinal muscular atrophy family.

    PubMed

    Campbell, L; Daniels, R J; Dubowitz, V; Davies, K E

    1998-07-01

    Spinal muscular atrophy (SMA) is a common fatal motor-neuron disorder characterized by degeneration of the anterior horn cells of the spinal cord, which results in proximal muscle weakness. Three forms of the disease, exhibiting differing phenotypic severity, map to chromosome 5q13 in a region of unusually high genomic variability. The SMA-determining gene (SMN) is deleted or rearranged in patients with SMA of all levels of severity. A high de novo mutation rate has been estimated for SMA, based on the deletion of multicopy microsatellite markers. We present a type I SMA family in which a mutant SMA chromosome has undergone a second mutation event. Both the occurrence of three affected siblings harboring this same mutation in one generation of this family and the obligate-carrier status of their mother indicate the existence of maternal germ-line mosaicism for cells carrying the second mutation. The existence of secondary mutational events and of germ-line mosaicism has implications for the counseling of SMA families undergoing prenatal genetic analysis.

  16. [Role of signs of fetal hypokinesia in the diagnosis of spinal muscular atrophy of neonatal onset].

    PubMed

    González De Dios, J; Martínez Frías, M L; Arroyo Carrera, I; Fondevilla Saucí, J; Sanchís Calvo, A; Hernández Ramón, F; Martínez Guardia, N; García González, M M

    2002-03-01

    Spinal muscular atrophy (SMA) is characterized by early degeneration of anterior horn cells. The most frequent and severe type of neonatal onset is Werdnig-Hoffmann disease. The neurologic and genetic characteristics of SMA are well-known. The aim of this study was to analyze the dysmorphologic features of this disease. We present an analysis of 10 cases of SMA identified among 27,864 infants with congenital defects registered by the Spanish Collaborative Study of Congenital Malformations (ECEMC) between April 1976 and December 1998. We also report a clinical case of neonatal SMA presenting the classical signs of fetal hypokinesia deformation sequence. The minimum estimation of the prevalence of SMA with congenital defects in our population is 0.32 per 100,000 live births. We found a male-to-female ratio of 3.5. The most frequently associated congenital defects in our population of neonatal SMA were located in the extremities (mainly arthrogryposis), face and thorax and could be explained by intrinsic fetal hypomobility secondary to the neuromuscular disorder. The characteristics of fetal hypokinesia deformation sequence are discussed in the case report presented herein: dystocic delivery, short umbilical cord, polyhydramnios, intrauterine growth retardation, craniofacial malformations, skeletal abnormalities with multiple articular contractures, pulmonary hypoplasia, etc. It is important to recognize the congenital defects associated with neuromuscular disorders, because dysmorphologic features are sometimes more marked than neurologic features in the neonatal period and because of the wide spectrum of congenital defects in neonatal SMA that result in a fetal hypokinesia deformation sequence.

  17. Spinal muscular atrophy carrier frequency and estimated prevalence of the disease in Moroccan newborns.

    PubMed

    Lyahyai, Jaber; Sbiti, Aziza; Barkat, Amina; Ratbi, Ilham; Sefiani, Abdelaziz

    2012-03-01

    Spinal muscular atrophy (SMA) is one of the most common autosomal recessive diseases caused by homozygous deletion of exon 7 of the survival motor neuron 1 (SMN1) gene in approximately 95% of SMA patients. Carrier frequency studies of SMA have been reported for various populations. The aim of our study was to estimate the carrier frequency of the common SMN1 exon 7 deletion in the Moroccan population to achieve an insight into the prevalence of SMA in Morocco. In this study, we used a reliable quantitative real-time polymerase chain reaction assay with SYBR Green I dye to determine the copy number of the SMN1 gene. Analysis of 150 Moroccan newborns predicts a carrier frequency of approximately 1:25, which would mean a calculated SMA prevalence of 1:1800 after correction due to consanguinity. These results show as expected that the SMA carrier frequency in Morocco is higher than in the European populations and is close to those of Middle Eastern countries. Genetic carrier testing for genetic counseling should be recommended particularly to families with a clear clinical history of SMA.

  18. [Carrier screening for spinal muscular atrophy in 4719 pregnant women in Shanghai region].

    PubMed

    Gong, Bo; Zhang, Li; Hou, Ya-ping; Hu, He-yu; Li, Hai-chuan; Tan, Mei-yu; Chen, Jin; Yu, Jing

    2013-12-01

    Spinal muscular atrophy (SMA) is a common and fatal autosomal recessive disorder. Approximately 94% of SMA patients are caused by homozygous deletion of SMN1 gene. SMA carrier screening is recommended considering the high carrier frequency (1 in 35-50) as well as severity of the disease. A prospective population-based cohort study was carried out on 4719 pregnant women from Shanghai region. Copy numbers of SMN1 and SMN2 genes were effectively determined with denaturing high performance liquid chromatography (DHPLC) technique. The method has detected 94% of SMA cases with deletion or conversion of the SMN1 genes. Ninety SMA carriers with only one copy of the SMN1 gene were identified among the 4719 pregnant woman. The carrier rate was 1.9%. Respectively, 1.2% and 0.6% of the carriers were caused by SMN1 gene deletion and SMN1 gene conversion. Through this study, we have determined the frequency of SMA mutation carriers in a population of pregnant women. The result may provide a basis for genetic counseling in order to reduce the rate of SMA affected births.

  19. Refined linkage map of chromosome 5 in the region of the spinal muscular atrophy gene

    SciTech Connect

    Melki, J.; Burlet, P.; Clermont, O.; Pascal, F.; Paul, B.; Abdelhak, S.; Munnich, A. ); Sherrington, R.; Gurling, H. Middlesex School of Medicine, London ); Nakamura, Yusuke ); Weissenbach, J. Genethon, Evry ); Lathrop, M. )

    1993-03-01

    The genetic map in the region of human chromosome 5 that harbors the gene for autosomal recessive forms of spinal muscular atrophy (SMA) has been refined by a multilocus linkage study in 50 SMA-segregating families. Among six markers spanning 8 cM for combined sexes, four were shown to be tightly linked to the SMA locus. Multipoing linkage analysis was used to establish the best estimate of the SMA gene location. The data suggest that the most likely location for the SMA locus is between blocks AFM114ye7 (D5S465)/EF5.15 (D5S125) and MAP-1B/JK53 (D5S112) at a sex-combined genetic distance of 2.4 and 1.7 cM, respectively. Thus the SMA gene lies in the 4-cM region between these two blocks. This information is of primary importance for designing strategies for isolating the SMA gene. 16 refs., 2 figs., 4 tabs.

  20. [Spinal muscular atrophy mimicking myotonic dystrophy: a case report and clinical, pathological and genetic analysis].

    PubMed

    Luo, Li-xia; Pan, Qian; Xia, Kun; Tang, Bei-sha; Jiang, Hong

    2012-08-01

    To investigate a patient featuring a complex neuromuscular disease phenotype. A comprehensive analysis integrating clinical investigation, electrophysiological testing, pathological analysis and mutation screening was carried out. The patient has presented clinical and pathological manifestations mimicking Duchenne muscular dystrophy. However, genetic analysis has identified no deletion in 21 exons of Dystrophin gene, no pathologic expansion of CTG repeats in DMPK gene or CCTG repeats in ZFN9 gene. Instead, a homozygous deletion of exons 7 and 8 in SMN gene was discovered. A rare case of spinal muscular atrophy (SMA) was verified by genetic diagnosis. SMA is a group of neuromuscular disorders with great phenotypic heterogeneity and sometimes cannot be diagnosed by clinical manifestations, electrophysiological and pathological changes alone. Genetic diagnosis has become indispensable for accurate diagnosis for patients suspected to have the disease.

  1. Spinal muscular atrophy and the antiapoptotic role of survival of motor neuron (SMN) protein.

    PubMed

    Anderton, Ryan S; Meloni, Bruno P; Mastaglia, Frank L; Boulos, Sherif

    2013-04-01

    Spinal muscular atrophy (SMA) is a devastating and often fatal neurodegenerative disease that affects spinal motor neurons and leads to progressive muscle wasting and paralysis. The survival of motor neuron (SMN) gene is mutated or deleted in most forms of SMA, which results in a critical reduction in SMN protein. Motor neurons appear particularly vulnerable to reduced SMN protein levels. Therefore, understanding the functional role of SMN in protecting motor neurons from degeneration is an essential prerequisite for the design of effective therapies for SMA. To this end, there is increasing evidence indicating a key regulatory antiapoptotic role for the SMN protein that is important in motor neuron survival. The aim of this review is to highlight key findings that support an antiapoptotic role for SMN in modulating cell survival and raise possibilities for new therapeutic approaches.

  2. Small Molecules in Development for the Treatment of Spinal Muscular Atrophy.

    PubMed

    Calder, Alyssa N; Androphy, Elliot J; Hodgetts, Kevin J

    2016-11-23

    Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease resulting from pathologically low levels of survival motor neuron (SMN) protein. The majority of mRNA from the SMN2 allele undergoes alternative splicing and excludes critical codons, causing an SMN protein deficiency. While there is currently no FDA-approved treatment for SMA, early therapeutic efforts have focused on testing repurposed drugs such as phenylbutyrate (2), valproic acid (3), riluzole (6), hydroxyurea (7), and albuterol (9), none of which has demonstrated clinical effectiveness. More recently, clinical trials have focused on novel small-molecule compounds identified from high-throughput screening and medicinal chemistry optimization such as olesoxime (11), CK-2127107, RG7800, LMI070, and RG3039 (17). In this paper, we review both repurposed drugs and small-molecule compounds discovered following medicinal chemistry optimization for the potential treatment of SMA.

  3. [Self-produced locomotion and spatial cognition: a new light from spinal muscular atrophy].

    PubMed

    Rivière, J

    2007-03-01

    Various studies have shown that occurrence of locomotion in infancy is correlated with the development of visuospatial cognitive competencies, suggesting that locomotor experience might play a central role in spatial development, especially in the realm of manual search for hidden objects. However, recent studies indicate that young children with spinal muscular atrophy (SMA), a hereditary neuromuscular disease which results in severe motor impairments, excel in some spatial cognitive skills. Indeed, striking cognitive performances are exhibited by young SMA children in some areas such as the ability to search successfully for hidden objects and the acquisition of the spatial vocabulary. The performances of SMA children suggest that, despite their total deprivation of locomotor experience, they have the capacity to acquire and use rich spatial representations. As a result, locomotor impairment does not appear to be a key risk factor for dramatic slowing down or deviation in the development of spatial search skills.

  4. Spinal muscular atrophy: diagnosis and management in a new therapeutic era.

    PubMed

    Arnold, W David; Kassar, Darine; Kissel, John T

    2015-02-01

    Spinal muscular atrophy (SMA) describes a group of disorders associated with spinal motor neuron loss. In this review we provide an update regarding the most common form of SMA, proximal or 5q-SMA, and discuss the contemporary approach to diagnosis and treatment. Electromyography and muscle biopsy features of denervation were once the basis for diagnosis, but molecular testing for homozygous deletion or mutation of the SMN1 gene allows efficient and specific diagnosis. In combination with loss of SMN1, patients retain variable numbers of copies of a second similar gene, SMN2, which produces reduced levels of the survival motor neuron (SMN) protein that are insufficient for normal motor neuron function. Despite the fact that understanding of how ubiquitous reduction of SMN protein leads to motor neuron loss remains incomplete, several promising therapeutics are now being tested in early-phase clinical trials. © 2014 Wiley Periodicals, Inc.

  5. [Application of droplet digital PCR technology for genetic testing and prenatal diagnosis of spinal muscular atrophy].

    PubMed

    Zou, Yang; Xu, Peiwen; Li, Jie; Huang, Sexin; Gao, Ming; Kang, Ranran; Gao, Xuan; Gao, Yuan

    2016-10-01

    To explore the clinical application of droplet digital PCR (ddPCR) for genetic testing and prenatal diagnosis of spinal muscular atrophy (SMA) with deletion of SMN1 gene exon 7. A total of 138 clinical samples, including 121 peripheral blood, 13 amniotic fluid, 2 umbilical cord blood and 2 chorionic villi from 56 SMA families, were tested by both ddPCR and multiplex ligation-dependent probe amplification (MLPA). Results of the two approaches were analyzed with commercial software QuantaSoft (ddPCR) and Coffalyser (MLPA), respectively. Among the 138 cases, 25 had two copies, 84 had one copy, and 29 had null copy of exon 7 of the SMN1 gene. The results of ddPCR and MLPA were completely consistent. As a rapid, precise and economically efficient method, ddPCR will provide a new choice for genetic testing of SMA.

  6. Spinal Muscular Atrophy: Diagnosis and Management in a New Therapeutic Era

    PubMed Central

    Arnold, W. David; Kassar, Darine; Kissel, John T.

    2014-01-01

    Spinal muscular atrophy (SMA) describes a group of disorders associated with spinal motor neuron loss. In this review we provide an update regarding the most common form of SMA, proximal or 5q SMA, and discuss the contemporary approach to diagnosis and treatment. Electromyography and muscle biopsy features of denervation were once the basis for diagnosis, but molecular testing for homozygous deletion or mutation of the SMN1 gene allows efficient and specific diagnosis. In combination with loss of SMN1, patients retain variable numbers of copies of a second similar gene, SMN2, which produce reduced levels of the survival motor neuron (SMN) protein that are insufficient for normal motor neuron function. Despite the fact that the understanding of how ubiquitous reduction of SMN protein leads to motor neuron loss remains incomplete, several promising therapeutics are now being tested in early phase clinical trials. PMID:25346245

  7. Perspectives on Clinical Trials in Spinal Muscular Atrophy

    PubMed Central

    Swoboda, Kathryn J.; Kissel, John T.; Crawford, Thomas O.; Bromberg, Mark B.; Acsadi, Gyula; D'Anjou, Guy; Krosschell, Kristin J.; Reyna, Sandra P.; Schroth, Mary K.; Scott, Charles B.; Simard, Louise R.

    2011-01-01

    Spinal muscular atrophy is one of the most heterogeneous of the single-gene neuromuscular disorders. The broad spectrum of severity, with onset from the prenatal period to adulthood, presents unique challenges in the design and implementation of clinical trials. The clinical classification of subjects into severe (type 1), intermediate (type 2), and mild (type 3) subtypes has proved useful both in enhancing communication among clinicians internationally and in forging the collaborative development of outcome measures for clinical trials. Ideally, clinical trial design in spinal muscular atrophy must take into account the spinal muscular atrophy type, patient age, severity-of-affection status, nature of the therapeutic approach, timing of the proposed intervention relative to disease progression, and relative homogeneity of the cohort to be studied. Following is an overview of the challenges and opportunities, current and future therapeutic strategies, and progress to date in clinical trials in spinal muscular atrophy. PMID:17761650

  8. Securinine enhances SMN2 exon 7 inclusion in spinal muscular atrophy cells.

    PubMed

    Chen, Yu-Chia; Chang, Jan-Gowth; Liu, Ting-Yuan; Jong, Yuh-Jyh; Cheng, Wei-Lin; Yuo, Chung-Yee

    2017-04-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by the degeneration of motor neurons in the spinal cord, leading to muscular atrophy. SMA is caused by deletions or mutations in the survival motor neuron gene (SMN1) on chromosome 5q13. A second copy of the SMN gene (SMN2) also exists on chromosome 5, and both genes can produce functional protein. However, due to alternative splicing of the exon 7, the majority of SMN protein produced by SMN2 is truncated and unable to compensate for the loss of SMN1. Increasing full-length SMN protein production by promoting the exon 7 inclusion in SMN2 mRNA or increasing SMN2 gene transcription could be a therapeutic approach for SMA. In this study, we screened for the compounds that enhance SMN2 exon 7 inclusion by using SMN2 minigene-luciferase reporter system. We found that securinine can increase luciferase activity, indicating that securinine promoted SMN2 exon 7 inclusion. In addition, securinine increased full-length SMN2 mRNA and SMN protein expression in SMA patient-derived lymphoid cell lines. To investigate the mechanism of securinine effect on SMN2 splicing, we compared the protein levels of relevant splicing factors between securinine-treated and untreated cells. We found that securinine downregulated hnRNP A1 and Sam68 and upregulated Tra2-β1 expression. However, securinine, unlike HDAC inhibitors, did not enhance tra2-β1 gene transcription, indicating a post-transcriptional mechanism for Tra2-β1 upregulation. Furthermore, we treated SMA-like mice with securinine by i.p. injection and found that securinine treatment increased SMN2 exon 7 inclusion and SMN protein expression in the brain and spinal cord. According to our results, securinine might have the potential to become a therapeutic drug for SMA disease. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  9. IGF-1R Reduction Triggers Neuroprotective Signaling Pathways in Spinal Muscular Atrophy Mice.

    PubMed

    Biondi, Olivier; Branchu, Julien; Ben Salah, Amina; Houdebine, Léo; Bertin, Lise; Chali, Farah; Desseille, Céline; Weill, Laure; Sanchez, Gabriel; Lancelin, Camille; Aïd, Saba; Lopes, Philippe; Pariset, Claude; Lécolle, Sylvie; Côté, Jocelyn; Holzenberger, Martin; Chanoine, Christophe; Massaad, Charbel; Charbonnier, Frédéric

    2015-08-26

    Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by the selective loss of spinal motor neurons due to the depletion of the survival of motor neuron (SMN) protein. No therapy is currently available for SMA, which represents the leading genetic cause of death in childhood. In the present study, we report that insulin-like growth factor-1 receptor (Igf-1r) gene expression is enhanced in the spinal cords of SMA-like mice. The reduction of expression, either at the physiological (through physical exercise) or genetic level, resulted in the following: (1) a significant improvement in lifespan and motor behavior, (2) a significant motor neuron protection, and (3) an increase in SMN expression in spinal cord and skeletal muscles through both transcriptional and posttranscriptional mechanisms. Furthermore, we have found that reducing IGF-1R expression is sufficient to restore intracellular signaling pathway activation profile lying downstream of IGF-1R, resulting in both the powerful activation of the neuroprotective AKT/CREB pathway and the inhibition of the ERK and JAK pathways. Therefore, reducing rather than enhancing the IGF-1 pathway could constitute a useful strategy to limit neurodegeneration in SMA. Recent evidence of IGF-1 axis alteration in spinal muscular atrophy (SMA), a very severe neurodegenerative disease affecting specifically the motor neurons, have triggered a renewed interest in insulin-like growth factor-1 (IGF-1) pathway activation as a potential therapeutic approach for motor neuron diseases. The present study challenges this point of view and brings the alternative hypothesis that reducing rather than enhancing the IGF-1 signaling pathway exerts a neuroprotective effect in SMA. Furthermore, the present data substantiate a newly emerging concept that the modulation of IGF-1 receptor expression is a key event selectively determining the activation level of intracellular pathways that lie downstream of the receptor. This aspect

  10. Copy Number Variations in the Survival Motor Neuron Genes: Implications for Spinal Muscular Atrophy and Other Neurodegenerative Diseases.

    PubMed

    Butchbach, Matthew E R

    2016-01-01

    Proximal spinal muscular atrophy (SMA), a leading genetic cause of infant death worldwide, is an early-onset, autosomal recessive neurodegenerative disease characterized by the loss of spinal α-motor neurons. This loss of α-motor neurons is associated with muscle weakness and atrophy. SMA can be classified into five clinical grades based on age of onset and severity of the disease. Regardless of clinical grade, proximal SMA results from the loss or mutation of SMN1 (survival motor neuron 1) on chromosome 5q13. In humans a large tandem chromosomal duplication has lead to a second copy of the SMN gene locus known as SMN2. SMN2 is distinguishable from SMN1 by a single nucleotide difference that disrupts an exonic splice enhancer in exon 7. As a result, most of SMN2 mRNAs lack exon 7 (SMNΔ7) and produce a protein that is both unstable and less than fully functional. Although only 10-20% of the SMN2 gene product is fully functional, increased genomic copies of SMN2 inversely correlates with disease severity among individuals with SMA. Because SMN2 copy number influences disease severity in SMA, there is prognostic value in accurate measurement of SMN2 copy number from patients being evaluated for SMA. This prognostic value is especially important given that SMN2 copy number is now being used as an inclusion criterion for SMA clinical trials. In addition to SMA, copy number variations (CNVs) in the SMN genes can affect the clinical severity of other neurological disorders including amyotrophic lateral sclerosis (ALS) and progressive muscular atrophy (PMA). This review will discuss how SMN1 and SMN2 CNVs are detected and why accurate measurement of SMN1 and SMN2 copy numbers is relevant for SMA and other neurodegenerative diseases.

  11. Copy Number Variations in the Survival Motor Neuron Genes: Implications for Spinal Muscular Atrophy and Other Neurodegenerative Diseases

    PubMed Central

    Butchbach, Matthew E. R.

    2016-01-01

    Proximal spinal muscular atrophy (SMA), a leading genetic cause of infant death worldwide, is an early-onset, autosomal recessive neurodegenerative disease characterized by the loss of spinal α-motor neurons. This loss of α-motor neurons is associated with muscle weakness and atrophy. SMA can be classified into five clinical grades based on age of onset and severity of the disease. Regardless of clinical grade, proximal SMA results from the loss or mutation of SMN1 (survival motor neuron 1) on chromosome 5q13. In humans a large tandem chromosomal duplication has lead to a second copy of the SMN gene locus known as SMN2. SMN2 is distinguishable from SMN1 by a single nucleotide difference that disrupts an exonic splice enhancer in exon 7. As a result, most of SMN2 mRNAs lack exon 7 (SMNΔ7) and produce a protein that is both unstable and less than fully functional. Although only 10–20% of the SMN2 gene product is fully functional, increased genomic copies of SMN2 inversely correlates with disease severity among individuals with SMA. Because SMN2 copy number influences disease severity in SMA, there is prognostic value in accurate measurement of SMN2 copy number from patients being evaluated for SMA. This prognostic value is especially important given that SMN2 copy number is now being used as an inclusion criterion for SMA clinical trials. In addition to SMA, copy number variations (CNVs) in the SMN genes can affect the clinical severity of other neurological disorders including amyotrophic lateral sclerosis (ALS) and progressive muscular atrophy (PMA). This review will discuss how SMN1 and SMN2 CNVs are detected and why accurate measurement of SMN1 and SMN2 copy numbers is relevant for SMA and other neurodegenerative diseases. PMID:27014701

  12. Apparent autosomal recessive inheritance in families with proximal spinal muscular atrophy affecting individuals in two generations

    SciTech Connect

    Rudnik-Schoeneborn, S.; Zerres, K.; Hahnen, E.

    1996-11-01

    With the evidence that deletions in the region responsible for childhood- and juvenile-onset proximal spinal muscular atrophy (SMA) are on chromosome 5 it is now possible to confirm autosomal recessive inheritance in most patients (denoted {open_quotes}SMA 5q{close_quotes}). Homozygous deletions in the telomeric copy of the survival motor neuron (SMN) gene can be detected in 95%-98% of patients with early-onset SMA (types I and II), whereas as many as 10%-20% of patients with the milder, juvenile-onset form (type III SMA) do not show deletions. In families with affected subjects in two generations, it is difficult to decide whether they are autosomal dominantly inherited or caused by three independent recessive mutations (pseudodominant inheritance). Given an incidence of >1/10,000 of SMA 5q, patients with autosomal recessive SMA have an {approximately}1% recurrence risk to their offspring. Although the dominant forms are not linked to chromosome 5q, pseudodominant families can now be identified by the presence of homozygous deletions in the SMN gene. 5 refs., 1 fig., 1 tab.

  13. Bioenergetic status modulates motor neuron vulnerability and pathogenesis in a zebrafish model of spinal muscular atrophy

    PubMed Central

    Boyd, Penelope J.; Shorrock, Hannah K.; Carter, Roderick N.; Powis, Rachael A.; Thomson, Sophie R.; Thomson, Derek; Graham, Laura C.; Motyl, Anna A. L.; Highley, J. Robin; Becker, Thomas; Becker, Catherina G.; Heath, Paul R.

    2017-01-01

    Degeneration and loss of lower motor neurons is the major pathological hallmark of spinal muscular atrophy (SMA), resulting from low levels of ubiquitously-expressed survival motor neuron (SMN) protein. One remarkable, yet unresolved, feature of SMA is that not all motor neurons are equally affected, with some populations displaying a robust resistance to the disease. Here, we demonstrate that selective vulnerability of distinct motor neuron pools arises from fundamental modifications to their basal molecular profiles. Comparative gene expression profiling of motor neurons innervating the extensor digitorum longus (disease-resistant), gastrocnemius (intermediate vulnerability), and tibialis anterior (vulnerable) muscles in mice revealed that disease susceptibility correlates strongly with a modified bioenergetic profile. Targeting of identified bioenergetic pathways by enhancing mitochondrial biogenesis rescued motor axon defects in SMA zebrafish. Moreover, targeting of a single bioenergetic protein, phosphoglycerate kinase 1 (Pgk1), was found to modulate motor neuron vulnerability in vivo. Knockdown of pgk1 alone was sufficient to partially mimic the SMA phenotype in wild-type zebrafish. Conversely, Pgk1 overexpression, or treatment with terazosin (an FDA-approved small molecule that binds and activates Pgk1), rescued motor axon phenotypes in SMA zebrafish. We conclude that global bioenergetics pathways can be therapeutically manipulated to ameliorate SMA motor neuron phenotypes in vivo. PMID:28426667

  14. Bioenergetic status modulates motor neuron vulnerability and pathogenesis in a zebrafish model of spinal muscular atrophy.

    PubMed

    Boyd, Penelope J; Tu, Wen-Yo; Shorrock, Hannah K; Groen, Ewout J N; Carter, Roderick N; Powis, Rachael A; Thomson, Sophie R; Thomson, Derek; Graham, Laura C; Motyl, Anna A L; Wishart, Thomas M; Highley, J Robin; Morton, Nicholas M; Becker, Thomas; Becker, Catherina G; Heath, Paul R; Gillingwater, Thomas H

    2017-04-01

    Degeneration and loss of lower motor neurons is the major pathological hallmark of spinal muscular atrophy (SMA), resulting from low levels of ubiquitously-expressed survival motor neuron (SMN) protein. One remarkable, yet unresolved, feature of SMA is that not all motor neurons are equally affected, with some populations displaying a robust resistance to the disease. Here, we demonstrate that selective vulnerability of distinct motor neuron pools arises from fundamental modifications to their basal molecular profiles. Comparative gene expression profiling of motor neurons innervating the extensor digitorum longus (disease-resistant), gastrocnemius (intermediate vulnerability), and tibialis anterior (vulnerable) muscles in mice revealed that disease susceptibility correlates strongly with a modified bioenergetic profile. Targeting of identified bioenergetic pathways by enhancing mitochondrial biogenesis rescued motor axon defects in SMA zebrafish. Moreover, targeting of a single bioenergetic protein, phosphoglycerate kinase 1 (Pgk1), was found to modulate motor neuron vulnerability in vivo. Knockdown of pgk1 alone was sufficient to partially mimic the SMA phenotype in wild-type zebrafish. Conversely, Pgk1 overexpression, or treatment with terazosin (an FDA-approved small molecule that binds and activates Pgk1), rescued motor axon phenotypes in SMA zebrafish. We conclude that global bioenergetics pathways can be therapeutically manipulated to ameliorate SMA motor neuron phenotypes in vivo.

  15. ML372 blocks SMN ubiquitination and improves spinal muscular atrophy pathology in mice

    PubMed Central

    Abera, Mahlet B.; Xiao, Jingbo; Nofziger, Jonathan; Titus, Steve; Moritz, Kasey E.; Ferrer, Marc; Cherry, Jonathan J.; Androphy, Elliot J.; Wang, Amy; Xu, Xin; Austin, Christopher; Fischbeck, Kenneth H.; Marugan, Juan J.; Burnett, Barrington G.

    2016-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease and one of the leading inherited causes of infant mortality. SMA results from insufficient levels of the survival motor neuron (SMN) protein, and studies in animal models of the disease have shown that increasing SMN protein levels ameliorates the disease phenotype. Our group previously identified and optimized a new series of small molecules, with good potency and toxicity profiles and reasonable pharmacokinetics, that were able to increase SMN protein levels in SMA patient–derived cells. We show here that ML372, a representative of this series, almost doubles the half-life of residual SMN protein expressed from the SMN2 locus by blocking its ubiquitination and subsequent degradation by the proteasome. ML372 increased SMN protein levels in muscle, spinal cord, and brain tissue of SMA mice. Importantly, ML372 treatment improved the righting reflex and extended survival of a severe mouse model of SMA. These results demonstrate that slowing SMN degradation by selectively inhibiting its ubiquitination can improve the motor phenotype and lifespan of SMA model mice. PMID:27882347

  16. Stathmin, a microtubule-destabilizing protein, is dysregulated in spinal muscular atrophy.

    PubMed

    Wen, Hsin-Lan; Lin, Yuan-Ta; Ting, Chen-Hung; Lin-Chao, Sue; Li, Hung; Hsieh-Li, Hsiu Mei

    2010-05-01

    Spinal muscular atrophy (SMA), a motor neuron degeneration disorder, is caused by either mutations or deletions of survival motor neuron 1 (SMN1) gene which result in insufficient SMN protein. Here, we describe a potential link between stathmin and microtubule defects in SMA. Stathmin was identified by screening Smn-knockdown NSC34 cells through proteomics analysis. We found that stathmin was aberrantly upregulated in vitro and in vivo, leading to a decreased level of polymerized tubulin, which was correlated with disease severity. Reduced microtubule densities and beta(III)-tubulin levels in distal axons of affected SMA-like mice and an impaired microtubule network in Smn-deficient cells were observed, suggesting an involvement of stathmin in those microtubule defects. Furthermore, knockdown of stathmin restored the microtubule network defects of Smn-deficient cells, promoted axon outgrowth and reduced the defect in mitochondria transport in SMA-like motor neurons. We conclude that aberrant stathmin levels may play a detrimental role in SMA; this finding suggests a novel approach to treating SMA by enhancing microtubule stability.

  17. The cost-effectiveness of prenatal screening for spinal muscular atrophy.

    PubMed

    Little, Sarah E; Janakiraman, Vanitha; Kaimal, Anjali; Musci, Thomas; Ecker, Jeffrey; Caughey, Aaron B

    2010-03-01

    We sought to investigate the cost-effectiveness of prenatal screening for spinal muscular atrophy (SMA). A decision analytic model was created to compare a policy of universal SMA screening to that of no screening. The primary outcome was incremental cost per maternal quality-adjusted life year. Probabilities, costs, and outcomes were estimated through literature review. Univariate and multivariate sensitivity analyses were performed to test the robustness of our model to changes in baseline assumptions. Universal screening for SMA is not cost-effective at $4.9 million per quality-adjusted life year. In all, 12,500 women need to be screened to prevent 1 case of SMA, at a cost of $5.0 million per case averted. Our results were most sensitive to the baseline prevalence of disease. Universal prenatal screening for SMA is not cost-effective. For populations at high risk, such as those with a family history, SMA testing may be a cost-effective strategy. Copyright 2010 Mosby, Inc. All rights reserved.

  18. Spinal muscular atrophy: clinical spectrum and genetic mutations in Pakistani children.

    PubMed

    Ibrahim, Shahnaz; Moatter, Tariq; Saleem, Ali Faisal

    2012-01-01

    In Pakistan the rate of consanguineous marriages is high, thus, the chance of incidence of autosomal recessive disorders is likely to be high. The aim of this study is to investigate the clinical characteristics and genetics of spinal muscular atrophy (SMA) in children who presented to Aga Khan University, Karachi. This study was a retrospective review of the medical charts of children (neonate: 15 years) with discharge diagnosis of SMA during last 10 years. Demographic features, consanguinity, and diagnostic analysis (including genetic analysis) were noted. During the study period 67 children had a discharge diagnosis of SMA. Werdnig Hoffman disease (SMA type I) was the commonest variant seen in 37 (56%) children. Overall 68% were infants. High parental consanguinity was observed in 68% of the study cohort. The history of delayed development and undiagnosed early death was observed in the families of 19 children. Genetic testing was performed in 22 (33%) children. Survival motor neuron (SMN) 1 gene deletion was found in 19 (86%) of the 22 patients in whom the gene analysis was done and 13 (68%) were also positive for neuronal apoptosis inhibitory proteins (NAIP) deletion. SMA is not an uncommon neurodegenerative disorder in Pakistan and SMA type I was the most common type. SMN1 gene deletion was the most common genetic deletion found in this study. In addition, family history of developmental delay and frequent early deaths highlights the need for implementation of prenatal diagnosis for early detection, effective control, and management of this disorder in Pakistan.

  19. Neurodegeneration in spinal muscular atrophy: from disease phenotype and animal models to therapeutic strategies and beyond

    PubMed Central

    Monani, Umrao R; De Vivo, Darryl C

    2014-01-01

    Of the numerous inherited diseases known to afflict the pediatric population, spinal muscular atrophy (SMA) is among the most common. It has an incidence of approximately one in 10,000 newborns and a carrier frequency of one in 50. Despite its relatively high incidence, SMA remains somewhat obscure among the many neurodegenerative diseases that affect humans. Nevertheless, the last two decades have witnessed remarkable progress in our understanding of the pathology, underlying biology and especially the molecular genetics of SMA. This has led to a genuine expectation within the scientific community that a robust treatment will be available to patients before the end of the decade. The progress made in our understanding of SMA and, therefore, towards a viable therapy for affected individuals is in large measure a consequence of the simple yet fascinating genetics of the disease. Nevertheless, important questions remain. Addressing these questions promises not only to accelerate the march towards a cure for SMA, but also to uncover novel therapies for related neurodegenerative disorders. This review discusses our current understanding of SMA, considers the challenges ahead, describes existing treatment options and highlights state-of-the-art research being conducted as a means to a better, safer and more effective treatment for the disease. PMID:24648831

  20. A qualitative study of perceptions of meaningful change in spinal muscular atrophy.

    PubMed

    McGraw, Sarah; Qian, Ying; Henne, Jeff; Jarecki, Jill; Hobby, Kenneth; Yeh, Wei-Shi

    2017-04-04

    This qualitative study examined how individuals with Spinal Muscular Atrophy (SMA), their caregivers, and clinicians defined meaningful change, primarily in the Type II and non-ambulant type III patient populations, associated with treatment of this condition. In addition, we explored participants' views about two measures of motor function routinely used in clinical trials for these SMA subtypes, namely the expanded version of the Hammersmith Functional Motor Scale (HFMSE) and the Upper Limb Module (ULM). The 123 participants (21 with SMA, 64 parents, and 11 clinicians), recruited through SMA advocacy organizations, participated in one of 16 focus groups or 37 interviews. The sessions were audio-recorded, and verbatim transcripts were analyzed using a grounded theory approach. For the participants, meaningful change was relative to functional ability, and small changes in motor function could have an important impact on quality of life. Because patients and families feared progressive loss of functional ability, the participants saw maintenance of abilities as a meaningful outcome. They believed that measures of motor function covered important items, but worried that the HFMSE and ULM might not be sensitive enough to capture small changes. In addition, they felt that outcome measures should assess other important features of life with SMA, including the ability to perform daily activities, respiratory function, swallowing, fatigue, and endurance. Given the heterogeneity of SMA, it is important to expand the assessment of treatment effects to a broader range of outcomes using measures sensitive enough to detect small changes.

  1. [Physical study of big fragments and search strategy of genes. Application to locus of infant spinal muscular atrophies].

    PubMed

    Melki, J; Lefebvre, S; Burglen, L; Burlet, P; Clermont, O; Millasseau, P; Reboulet, S; Benichou, B; Zeviani, M; Le Paslier, D

    1994-01-01

    Spinal muscular atrophies (SMA) represent the second most common fatal autosomal recessive disorder after cystic fibrosis. Childhood SMAs are divided into severe (type I) and mild forms (types II and III). By a combination of genetic and physical mapping, a YAC contig of the 5q13 region spanning the disease locus was constructed that showed the presence of low copy-repeats in this region. Allele segregation was analyzed at the closest genetic loci detected by markers C212 and C272 in 201 SMA families. Inherited and de novo deletions were observed in 10 SMA patients. Moreover, deletions were strongly suggested in at least 18% of SMA type I patients by the observation of marked heterozygosity deficiency for the loci studied. These results indicate that deletion events are statistically associated with the severe form of SMA.

  2. Permissibility of prenatal diagnosis and abortion for fetuses with severe genetic disorder: type 1 spinal muscular atrophy

    PubMed Central

    Sasongko, Teguh H.; Salmi, Abd Razak; Zilfalil, Bin Alwi; Albar, Mohammed Ali; Mohd Hussin, Zabidi Azhar

    2010-01-01

    Abortion has been largely avoided in Muslim communities. However, Islamic jurists have established rigorous parameters enabling abortion of fetuses with severe congenital abnormalities. This decision-making process has been hindered by an inability to predict the severity of such prenatally-diagnosed conditions, especially in genetic disorders with clinical heterogeneity, such as spinal muscular atrophy (SMA). Heterogeneous phenotypes of SMA range from extremely severe type 1 to very mild type 4. Advances in molecular genetics have made it possible to perform prenatal diagnosis and to predict the types of SMA with its potential subsequent severity. Such techniques will make it possible for clinicians working in predominantly Muslim countries to counsel their patients accurately and in harmony with their religious beliefs. In this paper, we discuss and postulate that with our current knowledge of determining SMA types and severity with great accuracy, abortion is legally applicable for type 1 SMA. PMID:21060155

  3. Permissibility of prenatal diagnosis and abortion for fetuses with severe genetic disorder: type 1 spinal muscular atrophy.

    PubMed

    Sasongko, Teguh H; Salmi, Abd Razak; Zilfalil, Bin Alwi; Albar, Mohammed Ali; Mohd Hussin, Zabidi Azhar

    2010-01-01

    Abortion has been largely avoided in Muslim communities. However, Islamic jurists have established rigorous parameters enabling abortion of fetuses with severe congenital abnormalities. This decision-making process has been hindered by an inability to predict the severity of such prenatally-diagnosed conditions, especially in genetic disorders with clinical heterogeneity, such as spinal muscular atrophy (SMA). Heterogeneous phenotypes of SMA range from extremely severe type 1 to very mild type 4. Advances in molecular genetics have made it possible to perform prenatal diagnosis and to predict the types of SMA with its potential subsequent severity. Such techniques will make it possible for clinicians working in predominantly Muslim countries to counsel their patients accurately and in harmony with their religious beliefs. In this paper, we discuss and postulate that with our current knowledge of determining SMA types and severity with great accuracy, abortion is legally applicable for type 1 SMA.

  4. Abnormal mitochondrial transport and morphology as early pathological changes in human models of spinal muscular atrophy

    PubMed Central

    Xu, Chong-Chong; Denton, Kyle R.; Wang, Zhi-Bo; Zhang, Xiaoqing; Li, Xue-Jun

    2016-01-01

    ABSTRACT Spinal muscular atrophy (SMA), characterized by specific degeneration of spinal motor neurons, is caused by mutations in the survival of motor neuron 1, telomeric (SMN1) gene and subsequent decreased levels of functional SMN. How the deficiency of SMN, a ubiquitously expressed protein, leads to spinal motor neuron-specific degeneration in individuals affected by SMA remains unknown. In this study, we examined the role of SMN in mitochondrial axonal transport and morphology in human motor neurons by generating SMA type 1 patient-specific induced pluripotent stem cells (iPSCs) and differentiating these cells into spinal motor neurons. The initial specification of spinal motor neurons was not affected, but these SMA spinal motor neurons specifically degenerated following long-term culture. Moreover, at an early stage in SMA spinal motor neurons, but not in SMA forebrain neurons, the number of mitochondria, mitochondrial area and mitochondrial transport were significantly reduced in axons. Knocking down of SMN expression led to similar mitochondrial defects in spinal motor neurons derived from human embryonic stem cells, confirming that SMN deficiency results in impaired mitochondrial dynamics. Finally, the application of N-acetylcysteine (NAC) mitigated the impairment in mitochondrial transport and morphology and rescued motor neuron degeneration in SMA long-term cultures. Furthermore, NAC ameliorated the reduction in mitochondrial membrane potential in SMA spinal motor neurons, suggesting that NAC might rescue apoptosis and motor neuron degeneration by improving mitochondrial health. Overall, our data demonstrate that SMN deficiency results in abnormal mitochondrial transport and morphology and a subsequent reduction in mitochondrial health, which are implicated in the specific degeneration of spinal motor neurons in SMA. PMID:26586529

  5. Abnormal mitochondrial transport and morphology as early pathological changes in human models of spinal muscular atrophy.

    PubMed

    Xu, Chong-Chong; Denton, Kyle R; Wang, Zhi-Bo; Zhang, Xiaoqing; Li, Xue-Jun

    2016-01-01

    Spinal muscular atrophy (SMA), characterized by specific degeneration of spinal motor neurons, is caused by mutations in the survival of motor neuron 1, telomeric (SMN1) gene and subsequent decreased levels of functional SMN. How the deficiency of SMN, a ubiquitously expressed protein, leads to spinal motor neuron-specific degeneration in individuals affected by SMA remains unknown. In this study, we examined the role of SMN in mitochondrial axonal transport and morphology in human motor neurons by generating SMA type 1 patient-specific induced pluripotent stem cells (iPSCs) and differentiating these cells into spinal motor neurons. The initial specification of spinal motor neurons was not affected, but these SMA spinal motor neurons specifically degenerated following long-term culture. Moreover, at an early stage in SMA spinal motor neurons, but not in SMA forebrain neurons, the number of mitochondria, mitochondrial area and mitochondrial transport were significantly reduced in axons. Knocking down of SMN expression led to similar mitochondrial defects in spinal motor neurons derived from human embryonic stem cells, confirming that SMN deficiency results in impaired mitochondrial dynamics. Finally, the application of N-acetylcysteine (NAC) mitigated the impairment in mitochondrial transport and morphology and rescued motor neuron degeneration in SMA long-term cultures. Furthermore, NAC ameliorated the reduction in mitochondrial membrane potential in SMA spinal motor neurons, suggesting that NAC might rescue apoptosis and motor neuron degeneration by improving mitochondrial health. Overall, our data demonstrate that SMN deficiency results in abnormal mitochondrial transport and morphology and a subsequent reduction in mitochondrial health, which are implicated in the specific degeneration of spinal motor neurons in SMA.

  6. A large animal model of Spinal Muscular Atrophy and correction of phenotype

    PubMed Central

    Duque, Sandra I.; Arnold, W. David; Odermatt, Philipp; Li, Xiaohui; Porensky, Paul N.; Schmelzer, Leah; Meyer, Kathrin; Kolb, Stephen J.; Schümperli, Daniel; Kaspar, Brian K.; Burghes, Arthur H. M.

    2015-01-01

    Objectives Spinal muscular atrophy (SMA) is caused by reduced levels of SMN which results in motoneuron loss. Therapeutic strategies to increase SMN levels including drug compounds, antisense oligonucleotides or scAAV9 gene therapy have proved effective in mice. We wished to determine whether reduction of SMN in postnatal motoneurons resulted in SMA in a large animal model, whether SMA could be corrected after development of muscle weakness and the response of clinically relevant biomarkers. Methods Using intrathecal delivery of scAAV9 expressing a shRNA targeting pig SMN1, SMN was knocked down in motoneurons postnatally to SMA levels. This resulted in an SMA phenotype representing the first large animal model of SMA. Restoration of SMN was performed at different time points with scAAV9 expressing human SMN (scAAV9-SMN) and electrophysiology measures and pathology were performed. Results Knockdown of SMN in postnatal motoneurons results in overt proximal weakness, fibrillations on electromyography (EMG) indicating active denervation, and reduced compound muscle action potential (CMAP) and motor unit number estimates (MUNE), like human SMA. Neuropathology showed loss of motoneurons and motor axons. Pre-symptomatic delivery of scAAV9-SMN prevented SMA symptoms indicating all changes are SMN dependent. Delivery of scAAV9-SMN after symptom onset had a marked impact on phenotype, electrophysiological measures and pathology. Interpretation High SMN levels are critical in postnatal motoneurons and reduction of SMN results in a SMA phenotype which is SMN dependent. Importantly, clinically relevant biomarkers including CMAP and MUNE are responsive to SMN restoration and abrogation of phenotype can be achieved even after symptom onset. PMID:25516063

  7. Molecular Analysis of Spinal Muscular Atrophy: A genotyping protocol based on TaqMan(®) real-time PCR.

    PubMed

    de Souza Godinho, Fernanda Marques; Bock, Hugo; Gheno, Tailise Conte; Saraiva-Pereira, Maria Luiza

    2012-12-01

    Spinal muscular atrophy (SMA) is an autosomal recessive inherited disorder caused by alterations in the survival motor neuron I (SMN1) gene. SMA patients are classified as type I-IV based on severity of symptoms and age of onset. About 95% of SMA cases are caused by the homozygous absence of SMN1 due to gene deletion or conversion into SMN2. PCR-based methods have been widely used in genetic testing for SMA. In this work, we introduce a new approach based on TaqMan(®)real-time PCR for research and diagnostic settings. DNA samples from 100 individuals with clinical signs and symptoms suggestive of SMA were analyzed. Mutant DNA samples as well as controls were confirmed by DNA sequencing. We detected 58 SMA cases (58.0%) by showing deletion of SMN1 exon 7. Considering clinical information available from 56 of them, the patient distribution was 26 (46.4%) SMA type I, 16 (28.6%) SMA type II and 14 (25.0%) SMA type III. Results generated by the new method was confirmed by PCR-RFLP and by DNA sequencing when required. In conclusion, a protocol based on real-time PCR was shown to be effective and specific for molecular analysis of SMA patients.

  8. Dysphagia in spinal muscular atrophy type II: more than a bulbar problem?

    PubMed

    van den Engel-Hoek, L; Erasmus, C E; van Bruggen, H W; de Swart, B J M; Sie, L T L; Steenks, M H; de Groot, I J M

    2009-11-24

    In patients with spinal muscular atrophy (SMA) type II, feeding problems and dysphagia are common, but the underlying mechanisms of these problems are not well defined. This case control study was designed to determine the underlying mechanisms of dysphagia in SMA type II. Six children with SMA type II and 6 healthy matched controls between 6.4 and 13.4 years of age were investigated during swallowing liquid and solid food in 2 different postures using surface EMG (sEMG) of the submental muscle group (SMG) and a video fluoroscopic swallow study (VFSS). The VFSS showed postswallow residue of solid food in the vallecula and above the upper esophageal sphincter (UES), which can be responsible for indirect aspiration. Better results in swallowing were achieved in a more forward head position. These findings were supported by the sEMG measurements of the SMG during swallowing. Dysphagia in spinal muscular atrophy type II is due to a neurologic dysfunction (lower motor neuron problems from the cranial nerves in the brainstem) influencing the muscle force and efficiency of movement of the tongue and the submental muscle group in combination with a biomechanical component (compensatory head posture). The results suggest an integrated treatment with an adapted posture during meals and the advice of drinking water after meals to prevent aspiration pneumonias.

  9. Long-term exercise-specific neuroprotection in spinal muscular atrophy-like mice.

    PubMed

    Chali, Farah; Desseille, Céline; Houdebine, Léo; Benoit, Evelyne; Rouquet, Thaïs; Bariohay, Bruno; Lopes, Philippe; Branchu, Julien; Della Gaspera, Bruno; Pariset, Claude; Chanoine, Christophe; Charbonnier, Frédéric; Biondi, Olivier

    2016-04-01

    The real impact of physical exercise parameters, i.e. intensity, type of contraction and solicited energetic metabolism, on neuroprotection in the specific context of neurodegeneration remains poorly explored. In this study behavioural, biochemical and cellular analyses were conducted to compare the effects of two different long-term exercise protocols, high intensity swimming and low intensity running, on motor units of a type 3 spinal muscular atrophy (SMA)-like mouse model. Our data revealed a preferential SMA-induced death of intermediate and fast motor neurons which was limited by the swimming protocol only, suggesting a close relationship between neuron-specific protection and their activation levels by specific exercise. The exercise-induced neuroprotection was independent of SMN protein expression and associated with specific metabolic and behavioural adaptations with notably a swimming-induced reduction of muscle fatigability. Our results provide new insight into the motor units' adaptations to different physical exercise parameters and will contribute to the design of new active physiotherapy protocols for patient care. Spinal muscular atrophy (SMA) is a group of autosomal recessive neurodegenerative diseases differing in their clinical outcome, characterized by the specific loss of spinal motor neurons, caused by insufficient level of expression of the protein survival of motor neuron (SMN). No cure is at present available for SMA. While physical exercise might represent a promising approach for alleviating SMA symptoms, the lack of data dealing with the effects of different exercise types on diseased motor units still precludes the use of active physiotherapy in SMA patients. In the present study, we have evaluated the efficiency of two long-term physical exercise paradigms, based on either high intensity swimming or low intensity running, in alleviating SMA symptoms in a mild type 3 SMA-like mouse model. We found that 10 months' physical training

  10. Construction of a yeast artifical chromosome contig spanning the spinal muscular atrophy disease gene region

    SciTech Connect

    Kleyn, P.W.; Wang, C.H.; Vitale, E.; Pan, J.; Ross, B.M.; Grunn, A.; Palmer, D.A.; Warburton, D.; Brzustowicz, L.M.; Gilliam, T.G. ); Lien, L.L.; Kunkel, L.M. )

    1993-07-15

    The childhood spinal muscular atrophies (SMAs) are the most common, serious neuromuscular disorders of childhood second to Duchenne muscular dystrophy. A single locus for these disorders has been mapped by recombination events to a region of 0.7 centimorgan (range, 0.1-2.1 centimorgans) between loci D5S435 and MAP1B on chromosome 5q11.2-13.3. By using PCR amplification to screen yeast artificial chromosome (YAC) DNA pools and the PCR-vectorette method to amplify YAC ends, a YAC contig was constructed across the disease gene region. Nine walk steps identified 32 YACs, including a minimum of seven overlapping YAC clones (average size, 460 kb) that span the SMA region. The contig is characterized by a collection of 30 YAC-end sequence tag sites together with seven genetic markers. The entire YAC contig spans a minimum of 3.2 Mb; the SMA locus is confined to roughly half of this region. Microsatellite markers generated along the YAC contig segregate with the SMA locus in all families where the flanking markers (D5S435 and MAP1B) recombine. Construction of a YAC contig across the disease gene region is an essential step in isolation of the SMA-encoding gene. 26 refs., 3 figs., 1 tab.

  11. Construction of a yeast artificial chromosome contig spanning the spinal muscular atrophy disease gene region.

    PubMed Central

    Kleyn, P W; Wang, C H; Lien, L L; Vitale, E; Pan, J; Ross, B M; Grunn, A; Palmer, D A; Warburton, D; Brzustowicz, L M

    1993-01-01

    The childhood spinal muscular atrophies (SMAs) are the most common, serious neuromuscular disorders of childhood second to Duchenne muscular dystrophy. A single locus for these disorders has been mapped by recombination events to a region of 0.7 centimorgan (range, 0.1-2.1 centimorgans) between loci D5S435 and MAP1B on chromosome 5q11.2-13.3. By using PCR amplification to screen yeast artificial chromosome (YAC) DNA pools and the PCR-vectorette method to amplify YAC ends, a YAC contig was constructed across the disease gene region. Nine walk steps identified 32 YACs, including a minimum of seven overlapping YAC clones (average size, 460 kb) that span the SMA region. The contig is characterized by a collection of 30 YAC-end sequence tag sites together with seven genetic markers. The entire YAC contig spans a minimum of 3.2 Mb; the SMA locus is confined to roughly half of this region. Microsatellite markers generated along the YAC contig segregate with the SMA locus in all families where the flanking markers (D5S435 and MAP1B) recombine. Construction of a YAC contig across the disease gene region is an essential step in isolation of the SMA-encoding gene. Images Fig. 1 PMID:8341701

  12. Molecular analysis of the SMN gene mutations in spinal muscular atrophy patients in China.

    PubMed

    Liu, W L; Li, F; He, Z X; Ai, R; Ma, H W

    2013-09-13

    Spinal muscular atrophy (SMA) is one of the most common autosomal recessive diseases. Survival motor neuron1 (SMN1) is the SMA disease-determining gene. We examined the molecular basis of SMA in 113 Chinese SMA patients. Homozygous exon 7 and 8 deletions in SMN1 were detected by PCR-RFLP. Heterozygous deletion of SMN1 was analyzed based on variation of the sequencing peak height of the two different base pairs of exons 7 and 8 between SMN1 and SMN2. Subtle mutation was detected by genomic sequencing in the patients with heterozygous deletion of SMN1. In our study, the rate of deletion of SMN1 exon 7 and/or 8 was 91.2%; the rate of subtle mutations was 1.8%. We detected the same subtle mutation (p.Leu228X) of SMN exon 5 in two patients (one type I, one type III). The p.Ser8LysfsX23 and p.Leu228X mutations accounted for 13 of the 23 families with subtle mutations reported in the SMN1 gene of Chinese SMA. This is the first report where the phenotype of SMA-type III is associated with p.Leu228X. We found two subtle mutation hotspots (p.Ser8LysfsX23 and p.Leu228X) of SMN1 exons 1 and 5 in Chinese SMA patients. These two mutations have not been reported from America or Europe. It is proposed that the distribution of subtle mutations of SMN1 of SMA is associated with ethnicity or geographic origin.

  13. ROCK inhibition as a therapy for spinal muscular atrophy: understanding the repercussions on multiple cellular targets.

    PubMed

    Coque, Emmanuelle; Raoul, Cédric; Bowerman, Mélissa

    2014-01-01

    Spinal muscular atrophy (SMA) is the most common genetic disease causing infant death, due to an extended loss of motoneurons. This neuromuscular disorder results from deletions and/or mutations within the Survival Motor Neuron 1 (SMN1) gene, leading to a pathological decreased expression of functional full-length SMN protein. Emerging studies suggest that the small GTPase RhoA and its major downstream effector Rho kinase (ROCK), which both play an instrumental role in cytoskeleton organization, contribute to the pathology of motoneuron diseases. Indeed, an enhanced activation of RhoA and ROCK has been reported in the spinal cord of an SMA mouse model. Moreover, the treatment of SMA mice with ROCK inhibitors leads to an increased lifespan as well as improved skeletal muscle and neuromuscular junction pathology, without preventing motoneuron degeneration. Although motoneurons are the primary target in SMA, an increasing number of reports show that other cell types inside and outside the central nervous system contribute to SMA pathogenesis. As administration of ROCK inhibitors to SMA mice was systemic, the improvement in survival and phenotype could therefore be attributed to specific effects on motoneurons and/or on other non-neuronal cell types. In the present review, we will present the various roles of the RhoA/ROCK pathway in several SMA cellular targets including neurons, myoblasts, glial cells, cardiomyocytes and pancreatic cells as well as discuss how ROCK inhibition may ameliorate their health and function. It is most likely a concerted influence of ROCK modulation on all these cell types that ultimately lead to the observed benefits of pharmacological ROCK inhibition in SMA mice.

  14. Genotype-phenotype correlation of SMN locus genes in spinal muscular atrophy children from Argentina.

    PubMed

    Medrano, Sofía; Monges, Soledad; Gravina, Luis Pablo; Alías, Laura; Mozzoni, Julieta; Aráoz, Hilda Verónica; Bernal, Sara; Moresco, Angélica; Chertkoff, Lilien; Tizzano, Eduardo

    2016-11-01

    Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder, considered one of the leading causes of infant mortality. It is caused by mutations in the SMN1 gene. A highly homologous copy of this gene named SMN2 and other neighbouring genes, SERF1A and NAIP, are considered phenotypic modifiers of the disease. In recent years, notable advances have been made in SMA research regarding evaluation, prognosis, and therapeutic options. Thus, genotype-phenotype studies in SMA are important to stratify patients for motor function tests and for envisaged clinical trials. The aim of this study was to provide clinical and molecular data of a series of Argentinean children with SMA to establish a comprehensive genotype-phenotype correlation. 144 Argentinean children with SMA (56 children with type I, 58 with type II, and 30 with type III) were evaluated. The copy number of SMN2, SERF1A, and NAIP genes was established using MLPA (Multiplex Ligation-dependent Probe Amplification) and then correlated with the patients clinical subtypes. To improve clinical characterization we considered the initial symptoms that prompted the consultation, age of acquisition of motor abilities to independent walking and age at loss of gait. We also evaluated clinical and molecular features of sibling pairs in seven families. A strong correlation was observed between the SMN2 copy number and SMA phenotype while SERF1A and NAIP copy number showed a moderate correlation. We observed intra- and inter-family differences among the SMA types. This first genotype-phenotype correlation study in Argentinean SMA children provides data to improve patient stratification and define more adequate follow-up parameters. Copyright © 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

  15. ROCK inhibition as a therapy for spinal muscular atrophy: understanding the repercussions on multiple cellular targets

    PubMed Central

    Coque, Emmanuelle; Raoul, Cédric; Bowerman, Mélissa

    2014-01-01

    Spinal muscular atrophy (SMA) is the most common genetic disease causing infant death, due to an extended loss of motoneurons. This neuromuscular disorder results from deletions and/or mutations within the Survival Motor Neuron 1 (SMN1) gene, leading to a pathological decreased expression of functional full-length SMN protein. Emerging studies suggest that the small GTPase RhoA and its major downstream effector Rho kinase (ROCK), which both play an instrumental role in cytoskeleton organization, contribute to the pathology of motoneuron diseases. Indeed, an enhanced activation of RhoA and ROCK has been reported in the spinal cord of an SMA mouse model. Moreover, the treatment of SMA mice with ROCK inhibitors leads to an increased lifespan as well as improved skeletal muscle and neuromuscular junction pathology, without preventing motoneuron degeneration. Although motoneurons are the primary target in SMA, an increasing number of reports show that other cell types inside and outside the central nervous system contribute to SMA pathogenesis. As administration of ROCK inhibitors to SMA mice was systemic, the improvement in survival and phenotype could therefore be attributed to specific effects on motoneurons and/or on other non-neuronal cell types. In the present review, we will present the various roles of the RhoA/ROCK pathway in several SMA cellular targets including neurons, myoblasts, glial cells, cardiomyocytes and pancreatic cells as well as discuss how ROCK inhibition may ameliorate their health and function. It is most likely a concerted influence of ROCK modulation on all these cell types that ultimately lead to the observed benefits of pharmacological ROCK inhibition in SMA mice. PMID:25221469

  16. Responsiveness of the motor function measure in patients with spinal muscular atrophy.

    PubMed

    Vuillerot, Carole; Payan, Christine; Iwaz, Jean; Ecochard, René; Bérard, Carole

    2013-08-01

    To assess the ability of the Motor Function Measure (MFM) to detect changes in the progression of spinal muscular atrophy (SMA). Observational, retrospective, multicenter cohort study. Seventeen departments of pediatric physical medicine. Volunteer patients with SMA (N=112) aged 5.7 to 59 years with no treatment other than physical therapy and nutritional or respiratory assistance. Not applicable. The distributions of the MFM scores (total score and 3 subscores) were analyzed per SMA subtype. The relationships between scores and age were studied. The slopes of score changes (reflecting MFM responsiveness) were estimated in patients with at least 6 months' follow-up and 2 MFMs. Hypothetical sample sizes for specific effect sizes in clinical trial scenarios are given. In 12 patients with SMA type 2 and 19 with SMA type 3 (mean ± SD follow-up, 25.8 ± 19mo), there was a moderate inverse relationship between age and the MFM total score. Patients with less than 6 months' follow-up showed little score changes. Patients with longer follow-ups showed a slow deterioration (-0.9 points/y for type 2 and -0.6 points/y for type 3). Substantial responsiveness was obtained with the MFM Dimension 2 subscore (proximal and axial motricity) in patients with SMA type 2 (standardized response mean [SRM]=1.29), and with the MFM Dimension 1 subscore (standing and transfers) in patients with SMA type 3 aged 10 to 15 years (SRM=.94). If further confirmed by larger studies, these preliminary results on the relative responsiveness of the MFM in SMA will foster its use in monitoring disease progression in patients who participate in clinical trials. Copyright © 2013 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

  17. Protective Effects of Butyrate-based Compounds on a Mouse Model for Spinal Muscular Atrophy

    PubMed Central

    Butchbach, Matthew E. R.; Lumpkin, Casey J.; Harris, Ashlee W.; Saieva, Luciano; Edwards, Jonathan D.; Workman, Eileen; Simard, Louise R.; Pellizzoni, Livio; Burghes, Arthur H. M.

    2016-01-01

    Proximal spinal muscular atrophy (SMA) is a childhood-onset degenerative disease resulting from the selective loss of motor neurons in the spinal cord. SMA is caused by the loss of SMN1 (survival motor neuron 1) but retention of SMN2. The number of copies of SMN2 modifies disease severity in SMA patients as well as in mouse models, making SMN2 a target for therapeutics development. Sodium butyrate (BA) and its analogue (4PBA) have been shown to increase SMN2 expression in SMA cultured cells. In this study, we examined the effects of BA, 4PBA as well as two BA prodrugs—glyceryl tributyrate (BA3G) and VX563—on the phenotype of SMNΔ7 SMA mice. Treatment with 4PBA, BA3G and VX563 but not BA beginning at PND04 significantly improved the lifespan and delayed disease end stage, with administration of VX563 also improving the growth rate of these mice. 4PBA and VX563 improved the motor phenotype of SMNΔ7 SMA mice and prevented spinal motor neuron loss. Interestingly, neither 4PBA nor VX563 had an effect on SMN expression in the spinal cords of treated SMNΔ7 SMA mice; however, they inhibited histone deacetylase (HDAC) activity and restored the normal phosphorylation states of Akt and glycogen synthase kinase 3β, both of which are altered by SMN deficiency in vivo. These observations show that BA-based compounds with favourable pharmacokinetics ameliorate SMA pathology possibly by modulating HDAC and Akt signaling. PMID:26892876

  18. Protective effects of butyrate-based compounds on a mouse model for spinal muscular atrophy.

    PubMed

    Butchbach, Matthew E R; Lumpkin, Casey J; Harris, Ashlee W; Saieva, Luciano; Edwards, Jonathan D; Workman, Eileen; Simard, Louise R; Pellizzoni, Livio; Burghes, Arthur H M

    2016-05-01

    Proximal spinal muscular atrophy (SMA) is a childhood-onset degenerative disease resulting from the selective loss of motor neurons in the spinal cord. SMA is caused by the loss of SMN1 (survival motor neuron 1) but retention of SMN2. The number of copies of SMN2 modifies disease severity in SMA patients as well as in mouse models, making SMN2 a target for therapeutics development. Sodium butyrate (BA) and its analog (4PBA) have been shown to increase SMN2 expression in SMA cultured cells. In this study, we examined the effects of BA, 4PBA as well as two BA prodrugs-glyceryl tributyrate (BA3G) and VX563-on the phenotype of SMNΔ7 SMA mice. Treatment with 4PBA, BA3G and VX563 but not BA beginning at PND04 significantly improved the lifespan and delayed disease end stage, with administration of VX563 also improving the growth rate of these mice. 4PBA and VX563 improved the motor phenotype of SMNΔ7 SMA mice and prevented spinal motor neuron loss. Interestingly, neither 4PBA nor VX563 had an effect on SMN expression in the spinal cords of treated SMNΔ7 SMA mice; however, they inhibited histone deacetylase (HDAC) activity and restored the normal phosphorylation states of Akt and glycogen synthase kinase 3β, both of which are altered by SMN deficiency in vivo. These observations show that BA-based compounds with favorable pharmacokinetics ameliorate SMA pathology possibly by modulating HDAC and Akt signaling. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Utility of Survival Motor Neuron ELISA for Spinal Muscular Atrophy Clinical and Preclinical Analyses

    PubMed Central

    Kobayashi, Dione T.; Olson, Rory J.; Sly, Laurel; Swanson, Chad J.; Chung, Brett; Naryshkin, Nikolai; Narasimhan, Jana; Bhattacharyya, Anuradha; Mullenix, Michael; Chen, Karen S.

    2011-01-01

    Objectives Genetic defects leading to the reduction of the survival motor neuron protein (SMN) are a causal factor for Spinal Muscular Atrophy (SMA). While there are a number of therapies under evaluation as potential treatments for SMA, there is a critical lack of a biomarker method for assessing efficacy of therapeutic interventions, particularly those targeting upregulation of SMN protein levels. Towards this end we have engaged in developing an immunoassay capable of accurately measuring SMN protein levels in blood, specifically in peripheral blood mononuclear cells (PBMCs), as a tool for validating SMN protein as a biomarker in SMA. Methods A sandwich enzyme-linked immunosorbent assay (ELISA) was developed and validated for measuring SMN protein in human PBMCs and other cell lysates. Protocols for detection and extraction of SMN from transgenic SMA mouse tissues were also developed. Results The assay sensitivity for human SMN is 50 pg/mL. Initial analysis reveals that PBMCs yield enough SMN to analyze from blood volumes of less than 1 mL, and SMA Type I patients' PBMCs show ∼90% reduction of SMN protein compared to normal adults. The ELISA can reliably quantify SMN protein in human and mouse PBMCs and muscle, as well as brain, and spinal cord from a mouse model of severe SMA. Conclusions This SMN ELISA assay enables the reliable, quantitative and rapid measurement of SMN in healthy human and SMA patient PBMCs, muscle and fibroblasts. SMN was also detected in several tissues in a mouse model of SMA, as well as in wildtype mouse tissues. This SMN ELISA has general translational applicability to both preclinical and clinical research efforts. PMID:21904622

  20. Intrathecal Injections in Children With Spinal Muscular Atrophy

    PubMed Central

    Swoboda, Kathryn J.; Sethna, Navil; Farrow-Gillespie, Alan; Khandji, Alexander; Xia, Shuting; Bishop, Kathie M.

    2016-01-01

    Nusinersen (ISIS-SMNRx or ISIS 396443) is an antisense oligonucleotide drug administered intrathecally to treat spinal muscular atrophy. We summarize lumbar puncture experience in children with spinal muscular atrophy during a phase 1 open-label study of nusinersen and its extension. During the studies, 73 lumbar punctures were performed in 28 patients 2 to 14 years of age with type 2/3 spinal muscular atrophy. No complications occurred in 50 (68%) lumbar punctures; in 23 (32%) procedures, adverse events were attributed to lumbar puncture. Most common adverse events were headache (n = 9), back pain (n = 9), and post–lumbar puncture syndrome (n = 8). In a subgroup analysis, adverse events were more frequent in older children, children with type 3 spinal muscular atrophy, and with a 21- or 22-gauge needle compared to a 24-gauge needle or smaller. Lumbar punctures were successfully performed in children with spinal muscular atrophy; lumbar puncture–related adverse event frequency was similar to that previously reported in children. PMID:26823478

  1. Congenital segmental spinal muscular atrophy: a case report.

    PubMed

    Savaş, Tülin; Erol, Ilknur; Özkale, Yasemin; Saygi, Semra

    2015-03-01

    Spinal muscular atrophies are genetic disorders in which anterior horn cells in the spinal cord and motor nuclei of the brainstem are progressively lost. We present a patient with arthrogryposis due to congenital spinal muscular atrophy predominantly affecting the upper limbs. Spinal muscular atrophies with onset at birth may be a cause of arthrogryposis. Localized forms of neurogenic arthrogryposis have been divided into cervical and caudal forms. Our case is similar to the cases described by Hageman et al (J Neurol Neurosurg Psychiatry 1993;56:365-368): severe symmetric lower motor neuron deficit in the upper extremities at the time of birth, no history of injury to the cervical spinal cord or the brachial plexus during delivery, and severe muscle wasting suggesting chronic denervation in utero. Because there was improvement of our patient's situation, her disease was also possibly nonprogressive and sporadic. To our knowledge, this is the first reported case of a Turkish patient with congenital cervical spinal muscular atrophy. Congenital cervical spinal muscular atrophy affecting predominantly the upper limbs is a relatively rare form of motor neuron disease and should be considered in the differential diagnosis of infants with congenital contractures and severe muscle weakness by wasting mainly confined to the upper limbs. © The Author(s) 2014.

  2. Evidence of autosomal dominant mutations in childhood-onset proximal spinal muscular atrophy

    SciTech Connect

    Rudnik-Schoeneborn, S.; Wirth, B.; Zerres, K. )

    1994-07-01

    Autosomal recessive and dominant inheritance of proximal spinal muscular atrophy (SMA) are well documented. Several genetic studies found a significant deviation from the assumption of recessive inheritance in SMA, with affected children in one generation. The existence of new autosomal dominant mutations has been assumed as the most suitable explanation, which is supported by three observations of this study: (1) The segregation ratio calculated in 333 families showed a significant deviation from autosomal recessive inheritance in the milder forms of SMA (= .09[+-].06 for onset at 10-36 mo and .13[+-].07 for onset at >36 mo; and P = .09[+-]0.7 for SMA IIIa and .12[+-].07 for SMA IIIb). (2) Three families with affected subjects in two generations are reported, in whom the disease could have started as an autosomal dominant mutation. (3) Linkage studies with chromosome 5q markers showed that in 5 (5.4%) of 93 informative families the patient shared identical haplotypes with at least one healthy sib. Other mechanisms, such as the existence of phenocopies, pseudodominance, or a second autosomal recessive gene locus, cannot be excluded in single families. The postulation of spontaneous mutations, however, is a suitable explanation for all three observations. Estimated risk figures for genetic counseling are given. 29 refs., 2 figs., 5 tabs.

  3. Nusinersen: antisense oligonucleotide to increase SMN protein production in spinal muscular atrophy.

    PubMed

    Paton, D M

    2017-06-01

    Patients with spinal muscular atrophy (SMA) have an autosomal recessive disease that limits their ability to produce survival motor neuron (SMN) protein in the CNS resulting in progressive wasting of voluntary muscles. Detailed studies over several years have demonstrated that phosphorothioate and 2'-O-methoxyethyl- modified antisense oligonucleotides (ASOs) targeting the ISS-N1 site increase SMN2 exon 7 inclusion, thus increasing levels of SMN protein in a dose- and time-dependent manner in liver, kidney and skeletal muscle, and CNS tissues only when administered intrathecally. On a dose basis, nusinersen was found to be the most potent ASO for SMN2 splicing correction in the CNS of adult mice. After nusinersen was found to increase levels of SMN protein in the CNS of mice and subhuman primates without causing significant adverse events, it was advanced into clinical studies in patients with SMA. These trials in SMA patients have demonstrated significant improvements in various measures of motor function and in progression to movement developments not normally seen in SMA patients. In addition, there have been significant extensions in life expectancy. These findings led to the U.S. and European approval of nusinersen for use in SMA patients of all ages. Copyright 2017 Clarivate Analytics.

  4. Evidence of autosomal dominant mutations in childhood-onset proximal spinal muscular atrophy.

    PubMed Central

    Rudnik-Schöneborn, S.; Wirth, B.; Zerres, K.

    1994-01-01

    Autosomal recessive and dominant inheritance of proximal spinal muscular atrophy (SMA) are well documented. Several genetic studies found a significant deviation from the assumption of recessive inheritance in SMA, with affected children in one generation. The existence of new autosomal dominant mutations has been assumed as the most suitable explantation, which is supported by three observations of this study: (1) The segregation ratio calculated in 333 families showed a significant deviation from autosomal recessive inheritance in the milder forms of SMA (P = .09 +/- .06 for onset at 10-36 mo and .13 +/- .07 for onset at > 36 mo; and P = .09 +/- .07 for SMA IIIa and .12 +/- .07 for SMA IIIb). (2) Three families with affected subjects in two generations are reported, in whom the disease could have started as an autosomal dominant mutation. (3) Linkage studies with chromosome 5q markers showed that in 5 (5.4%) of 93 informative families the patient shared identical haplotypes with at least one healthy sib. Other mechanisms, such as the existence of phenocopies, pseudodominance, or a second autosomal recessive gene locus, cannot be excluded in single families. The postulation of spontaneous mutations, however, is a suitable explanation for all three observations. Estimated risk figures for genetic counseling are given. PMID:8023839

  5. Plastin-3 extends survival and reduces severity in mouse models of spinal muscular atrophy

    PubMed Central

    Kaifer, Kevin A.; Osman, Erkan Y.; Glascock, Jacqueline J.; Arnold, Laura L.; Cornelison, D.D.W.; Lorson, Christian L.

    2017-01-01

    Spinal muscular atrophy (SMA) is a leading genetic cause of infantile death and is caused by the loss of survival motor neuron-1 (SMN1). Importantly, a nearly identical gene is present called SMN2; however, the majority of SMN2-derived transcripts are alternatively spliced and encode a truncated, dysfunctional protein. Recently, several compounds designed to increase SMN protein have entered clinical trials, including antisense oligonucleotides (ASOs), traditional small molecules, and gene therapy. Expanding beyond SMN-centric therapeutics is important, as it is likely that the breadth of the patient spectrum and the inherent complexity of the disease will be difficult to address with a single therapeutic strategy. Several SMN-independent pathways that could impinge upon the SMA phenotype have been examined with varied success. To identify disease-modifying pathways that could serve as stand-alone therapeutic targets or could be used in combination with an SMN-inducing compound, we investigated adeno-associated virus–mediated (AAV-mediated) gene therapy using plastin-3 (PLS3). Here, we report that AAV9-PLS3 extends survival in an intermediate model of SMA mice as well as in a pharmacologically induced model of SMA using a splice-switching ASO that increases SMN production. PLS3 coadministration improves the phenotype beyond the ASO, demonstrating the potential utility of combinatorial therapeutics in SMA that target SMN-independent and SMN-dependent pathways. PMID:28289706

  6. Refinement of the Spinal Muscular Atrophy Locus by Genetic and Physical Mapping

    PubMed Central

    Wang, C. H.; Kleyn, P. W.; Vitale, E.; Ross, B. M.; Lien, L.; Xu, J.; Carter, T. A.; Brzustowicz, L. M.; Obici, S.; Selig, S.; Pavone, L.; Parano, E.; Penchaszadeh, G. K.; Munsat, T.; Kunkel, L. M.; Gilliam, T. C.

    1995-01-01

    We report the mapping and characterization of 12 microsatellite markers including 11 novel markers. All markers were generated from overlapping YAC clones that span the spinal muscular atrophy (SMA) locus. PCR amplification of 32 overlapping YAC clones shows that 9 of the new markers (those set in italics) map to the interval between the two previous closest flanking markers (D5S629 and D5S557): cen - D5S6 - D5S125 - D5S435 - D5S1407-D5S629-D5S1410-D5S1411/D5S1412-D5S1413-D5S1414-D5Z8-D5Z9-CATT1-D5Z10/D5Z6-D5S557-D5S1408-D5S1409-D5S637-D5S351-MAP1B-tel. Four of these new markers detect multiple loci in and out of the SMA gene region. Genetic analysis of recombinant SMA families indicates that D5S1413 is a new proximal flanking locus for the SMA gene. Interestingly, among the 40 physically mapped loci, the 14 multilocus markers map contiguously to a genomic region that overlaps, and perhaps helps define, the minimum genetic region encompassing the SMA gene(s). ImagesFigure 2Figure 5 PMID:7825579

  7. Severe neuromuscular denervation of clinically relevant muscles in a mouse model of spinal muscular atrophy

    PubMed Central

    Ling, Karen K. Y.; Gibbs, Rebecca M.; Feng, Zhihua; Ko, Chien-Ping

    2012-01-01

    Spinal muscular atrophy (SMA), a motoneuron disease caused by a deficiency of the survival of motor neuron (SMN) protein, is characterized by motoneuron loss and muscle weakness. It remains unclear whether widespread loss of neuromuscular junctions (NMJs) is involved in SMA pathogenesis. We undertook a systematic examination of NMJ innervation patterns in >20 muscles in the SMNΔ7 SMA mouse model. We found that severe denervation (<50% fully innervated endplates) occurs selectively in many vulnerable axial muscles and several appendicular muscles at the disease end stage. Since these vulnerable muscles were located throughout the body and were comprised of varying muscle fiber types, it is unlikely that muscle location or fiber type determines susceptibility to denervation. Furthermore, we found a similar extent of neurofilament accumulation at NMJs in both vulnerable and resistant muscles before the onset of denervation, suggesting that neurofilament accumulation does not predict subsequent NMJ denervation. Since vulnerable muscles were initially innervated, but later denervated, loss of innervation in SMA may be attributed to defects in synapse maintenance. Finally, we found that denervation was amendable by trichostatin A (TSA) treatment, which increased innervation in clinically relevant muscles in TSA-treated SMNΔ7 mice. Our findings suggest that neuromuscular denervation in vulnerable muscles is a widespread pathology in SMA, and can serve as a preparation for elucidating the biological basis of synapse loss, and for evaluating therapeutic efficacy. PMID:21968514

  8. Severe neuromuscular denervation of clinically relevant muscles in a mouse model of spinal muscular atrophy.

    PubMed

    Ling, Karen K Y; Gibbs, Rebecca M; Feng, Zhihua; Ko, Chien-Ping

    2012-01-01

    Spinal muscular atrophy (SMA), a motoneuron disease caused by a deficiency of the survival of motor neuron (SMN) protein, is characterized by motoneuron loss and muscle weakness. It remains unclear whether widespread loss of neuromuscular junctions (NMJs) is involved in SMA pathogenesis. We undertook a systematic examination of NMJ innervation patterns in >20 muscles in the SMNΔ7 SMA mouse model. We found that severe denervation (<50% fully innervated endplates) occurs selectively in many vulnerable axial muscles and several appendicular muscles at the disease end stage. Since these vulnerable muscles were located throughout the body and were comprised of varying muscle fiber types, it is unlikely that muscle location or fiber type determines susceptibility to denervation. Furthermore, we found a similar extent of neurofilament accumulation at NMJs in both vulnerable and resistant muscles before the onset of denervation, suggesting that neurofilament accumulation does not predict subsequent NMJ denervation. Since vulnerable muscles were initially innervated, but later denervated, loss of innervation in SMA may be attributed to defects in synapse maintenance. Finally, we found that denervation was amendable by trichostatin A (TSA) treatment, which increased innervation in clinically relevant muscles in TSA-treated SMNΔ7 mice. Our findings suggest that neuromuscular denervation in vulnerable muscles is a widespread pathology in SMA, and can serve as a preparation for elucidating the biological basis of synapse loss, and for evaluating therapeutic efficacy.

  9. Improved single-cell protocol for preimplantation genetic diagnosis of spinal muscular atrophy.

    PubMed

    Burlet, Philippe; Frydman, Nelly; Gigarel, Nadine; Bonnefont, Jean Paul; Kerbrat, Violaine; Tachdjian, Gérard; Frydman, René; Munnich, Arnold; Steffann, Julie; Ray, Pierre F

    2005-09-01

    To develop and validate a simple and reliable single-cell analysis protocol for the preimplantation genetic diagnosis (PGD) of spinal muscular atrophy (SMA). Molecular tests based on specific enzymatic digestion have already been described for SMA diagnosis. We modified the amplified DNA fragments so as to introduce a novel restriction site that provides an internal control for the completeness of the digestion. The genetics and reproduction departments of two teaching hospitals. Six informed couples at risk of transmitting SMA. All patients underwent standard procedures associated with intracytoplasmic sperm injection. Improvement of SMA diagnostic efficiency and accuracy on single cell. One hundred fifty lymphocytes were analyzed with our protocol. One hundred percent diagnostic accuracy was achieved from both homozygous normal and SMN1-deleted leukocytes. Successful molecular analysis was achieved for 36 of 42 biopsied embryos (86%). Twenty-five normal embryos were transferred, but no pregnancy was achieved. We developed an improved protocol for PGD of SMA that is simple, robust, and accurate; unfortunately, no pregnancies were achieved for any of the six patients who have undergone PGD in the program thus far.

  10. Assays for the Identification and Prioritization of Drug Candidates for Spinal Muscular Atrophy

    PubMed Central

    Cherry, Jonathan J.; Kobayashi, Dione T.; Lynes, Maureen M.; Naryshkin, Nikolai N.; Tiziano, Francesco Danilo; Zaworski, Phillip G.; Rubin, Lee L.

    2014-01-01

    Abstract Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder resulting in degeneration of α-motor neurons of the anterior horn and proximal muscle weakness. It is the leading cause of genetic mortality in children younger than 2 years. It affects ∼1 in 11,000 live births. In 95% of cases, SMA is caused by homozygous deletion of the SMN1 gene. In addition, all patients possess at least one copy of an almost identical gene called SMN2. A single point mutation in exon 7 of the SMN2 gene results in the production of low levels of full-length survival of motor neuron (SMN) protein at amounts insufficient to compensate for the loss of the SMN1 gene. Although no drug treatments are available for SMA, a number of drug discovery and development programs are ongoing, with several currently in clinical trials. This review describes the assays used to identify candidate drugs for SMA that modulate SMN2 gene expression by various means. Specifically, it discusses the use of high-throughput screening to identify candidate molecules from primary screens, as well as the technical aspects of a number of widely used secondary assays to assess SMN messenger ribonucleic acid (mRNA) and protein expression, localization, and function. Finally, it describes the process of iterative drug optimization utilized during preclinical SMA drug development to identify clinical candidates for testing in human clinical trials. PMID:25147906

  11. Assays for the identification and prioritization of drug candidates for spinal muscular atrophy.

    PubMed

    Cherry, Jonathan J; Kobayashi, Dione T; Lynes, Maureen M; Naryshkin, Nikolai N; Tiziano, Francesco Danilo; Zaworski, Phillip G; Rubin, Lee L; Jarecki, Jill

    2014-08-01

    Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder resulting in degeneration of α-motor neurons of the anterior horn and proximal muscle weakness. It is the leading cause of genetic mortality in children younger than 2 years. It affects ∼1 in 11,000 live births. In 95% of cases, SMA is caused by homozygous deletion of the SMN1 gene. In addition, all patients possess at least one copy of an almost identical gene called SMN2. A single point mutation in exon 7 of the SMN2 gene results in the production of low levels of full-length survival of motor neuron (SMN) protein at amounts insufficient to compensate for the loss of the SMN1 gene. Although no drug treatments are available for SMA, a number of drug discovery and development programs are ongoing, with several currently in clinical trials. This review describes the assays used to identify candidate drugs for SMA that modulate SMN2 gene expression by various means. Specifically, it discusses the use of high-throughput screening to identify candidate molecules from primary screens, as well as the technical aspects of a number of widely used secondary assays to assess SMN messenger ribonucleic acid (mRNA) and protein expression, localization, and function. Finally, it describes the process of iterative drug optimization utilized during preclinical SMA drug development to identify clinical candidates for testing in human clinical trials.

  12. Central and peripheral defects in motor units of the diaphragm of spinal muscular atrophy mice.

    PubMed

    Neve, Anuja; Trüb, Judith; Saxena, Smita; Schümperli, Daniel

    2016-01-01

    Spinal muscular atrophy (SMA) is characterized by motoneuron loss and muscle weakness. However, the structural and functional deficits that lead to the impairment of the neuromuscular system remain poorly defined. By electron microscopy, we previously found that neuromuscular junctions (NMJs) and muscle fibres of the diaphragm are among the earliest affected structures in the severe mouse SMA model. Because of certain anatomical features, i.e. its thinness and its innervation from the cervical segments of the spinal cord, the diaphragm is particularly suitable to characterize both central and peripheral events. Here we show by immunohistochemistry that, at postnatal day 3, the cervical motoneurons of SMA mice receive less stimulatory synaptic inputs. Moreover, their mitochondria become less elongated which might represent an early stage of degeneration. The NMJs of the diaphragm of SMA mice show a loss of synaptic vesicles and active zones. Moreover, the partly innervated endplates lack S100 positive perisynaptic Schwann cells (PSCs). We also demonstrate the feasibility of comparing the proteomic composition between diaphragm regions enriched and poor in NMJs. By this approach we have identified two proteins that are significantly upregulated only in the NMJ-specific regions of SMA mice. These are apoptosis inducing factor 1 (AIFM1), a mitochondrial flavoprotein that initiates apoptosis in a caspase-independent pathway, and four and a half Lim domain protein 1 (FHL1), a regulator of skeletal muscle mass that has been implicated in several myopathies. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  13. Refinement of the spinal muscular atrophy locus by genetic and physical mapping

    SciTech Connect

    Wang, C.H.; Kleyn, P.W.; Vitale, E.; Ross, B.M.; Xu, J.; Carter, T.A.; Brzustowicz, L.M.; Obici, S.; Lien, L.; Selig, S.

    1995-01-01

    We report the mapping and characterization of 12 microsatellite markers including 11 novel markers. All markers were generated from overlapping YAC clones that span the spinal muscular atrophy (SMA) locus. PCR amplification of 32 overlapping YAC clones show that 9 of the new markers (those set in italics) map to the interval between the two previous closest flanking markers (D5S629 and D5S557):cen - D5S6 - D5S125 - D5S435 - D5S1407 - D5S629 - D5S1410 - D5S1411/D5S1412 - D5S1413 - D5S1414 - D5Z8 - D5Z9 - CATT1 - D5Z10/D5Z6 - D5S557 - D5S1408 - D5S1409 - D5S637 - D5S351 - MAP1B - tel. Four of these new markers detect multiple loci in and out of the SMA gene region. Genetic analysis of recombinant SMA families indicates that D5S1413 is a new proximal flanking locus for the SMA gene. Interestingly, among the 40 physically mapped loci, the 14 multilocus markers map contiguously to a genomic region that overlaps, and perhaps helps define, the minimum genetic region encompassing the SMA gene(s). 24 refs., 5 figs., 1 tab.

  14. Pharmacologically induced mouse model of adult spinal muscular atrophy to evaluate effectiveness of therapeutics after disease onset.

    PubMed

    Feng, Zhihua; Ling, Karen K Y; Zhao, Xin; Zhou, Chunyi; Karp, Gary; Welch, Ellen M; Naryshkin, Nikolai; Ratni, Hasane; Chen, Karen S; Metzger, Friedrich; Paushkin, Sergey; Weetall, Marla; Ko, Chien-Ping

    2016-03-01

    Spinal muscular atrophy (SMA) is a genetic disease characterized by atrophy of muscle and loss of spinal motor neurons. SMA is caused by deletion or mutation of the survival motor neuron 1 (SMN1) gene, and the nearly identical SMN2 gene fails to generate adequate levels of functional SMN protein due to a splicing defect. Currently, several therapeutics targeted to increase SMN protein are in clinical trials. An outstanding issue in the field is whether initiating treatment in symptomatic older patients would confer a therapeutic benefit, an important consideration as the majority of patients with milder forms of SMA are diagnosed at an older age. An SMA mouse model that recapitulates the disease phenotype observed in adolescent and adult SMA patients is needed to address this important question. We demonstrate here that Δ7 mice, a model of severe SMA, treated with a suboptimal dose of an SMN2 splicing modifier show increased SMN protein, survive into adulthood and display SMA disease-relevant pathologies. Increasing the dose of the splicing modifier after the disease symptoms are apparent further mitigates SMA histopathological features in suboptimally dosed adult Δ7 mice. In addition, inhibiting myostatin using intramuscular injection of AAV1-follistatin ameliorates muscle atrophy in suboptimally dosed Δ7 mice. Taken together, we have developed a new murine model of symptomatic SMA in adolescents and adult mice that is induced pharmacologically from a more severe model and demonstrated efficacy of both SMN2 splicing modifiers and a myostatin inhibitor in mice at later disease stages. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  15. Invertebrate models of spinal muscular atrophy: insights into mechanisms and potential therapeutics.

    PubMed

    Grice, Stuart J; Sleigh, James N; Liu, Ji-Long; Sattelle, David B

    2011-12-01

    Invertebrate genetic models with their tractable neuromuscular systems are effective vehicles for the study of human nerve and muscle disorders. This is exemplified by insights made into spinal muscular atrophy (SMA) using the fruit fly Drosophila melanogaster and the nematode worm Caenorhabditis elegans. For speed and economy, these invertebrates offer convenient, whole-organism platforms for genetic screening as well as RNA interference (RNAi) and chemical library screens, permitting the rapid testing of hypotheses related to disease mechanisms and the exploration of new therapeutic routes and drug candidates. Here, we discuss recent developments encompassing synaptic physiology, RNA processing, and screening of compound and genome-scale RNAi libraries, showcasing the importance of invertebrate SMA models. Copyright © 2011 WILEY Periodicals, Inc.

  16. Neuromuscular Junctions as Key Contributors and Therapeutic Targets in Spinal Muscular Atrophy

    PubMed Central

    Boido, Marina; Vercelli, Alessandro

    2016-01-01

    Spinal muscular atrophy (SMA) is a recessive autosomal neuromuscular disease, representing the most common fatal pediatric pathology. Even though, classically and in a simplistic way, it is categorized as a motor neuron (MN) disease, there is an increasing general consensus that its pathogenesis is more complex than expected. In particular, neuromuscular junctions (NMJs) are affected by dramatic alterations, including immaturity, denervation and neurofilament accumulation, associated to impaired synaptic functions: these abnormalities may in turn have a detrimental effect on MN survival. Here, we provide a description of NMJ development/maintenance/maturation in physiological conditions and in SMA, focusing on pivotal molecules and on the time-course of pathological events. Moreover, since NMJs could represent an important target to be exploited for counteracting the pathology progression, we also describe several therapeutic strategies that, directly or indirectly, aim at NMJs. PMID:26869891

  17. Congenital contractural arachnodactyly with neurogenic muscular atrophy: case report.

    PubMed

    Scola, R H; Werneck, L C; Iwamoto, F M; Ribas, L C; Raskin, S; Correa Neto, Y

    2001-06-01

    We report the case of a 3-(1/2)-year-old girl with hypotonia, multiple joint contractures, hip luxation, arachnodactyly, adducted thumbs, dolichostenomelia, and abnormal external ears suggesting the diagnosis of congenital contractural arachnodactyly (CCA). The serum muscle enzymes were normal and the needle electromyography showed active and chronic denervation. The muscle biopsy demonstrated active and chronic denervation compatible with spinal muscular atrophy. Analysis of exons 7 and 8 of survival motor neuron gene through polymerase chain reaction did not show deletions. Neurogenic muscular atrophy is a new abnormality associated with CCA, suggesting that CCA is clinically heterogeneous.

  18. Discovery and Optimization of Small Molecule Splicing Modifiers of Survival Motor Neuron 2 as a Treatment for Spinal Muscular Atrophy.

    PubMed

    Woll, Matthew G; Qi, Hongyan; Turpoff, Anthony; Zhang, Nanjing; Zhang, Xiaoyan; Chen, Guangming; Li, Chunshi; Huang, Song; Yang, Tianle; Moon, Young-Choon; Lee, Chang-Sun; Choi, Soongyu; Almstead, Neil G; Naryshkin, Nikolai A; Dakka, Amal; Narasimhan, Jana; Gabbeta, Vijayalakshmi; Welch, Ellen; Zhao, Xin; Risher, Nicole; Sheedy, Josephine; Weetall, Marla; Karp, Gary M

    2016-07-14

    The underlying cause of spinal muscular atrophy (SMA) is a deficiency of the survival motor neuron (SMN) protein. Starting from hits identified in a high-throughput screening campaign and through structure-activity relationship investigations, we have developed small molecules that potently shift the alternative splicing of the SMN2 exon 7, resulting in increased production of the full-length SMN mRNA and protein. Three novel chemical series, represented by compounds 9, 14, and 20, have been optimized to increase the level of SMN protein by >50% in SMA patient-derived fibroblasts at concentrations of <160 nM. Daily administration of these compounds to severe SMA Δ7 mice results in an increased production of SMN protein in disease-relevant tissues and a significant increase in median survival time in a dose-dependent manner. Our work supports the development of an orally administered small molecule for the treatment of patients with SMA.

  19. Corticomotoneuronal integrity and adaptation in spinal muscular atrophy.

    PubMed

    Farrar, Michelle A; Vucic, Steve; Johnston, Heather M; Kiernan, Matthew C

    2012-04-01

    To gain further insight into disease pathophysiologic process and potential adaptations through investigating whether cortical dysfunction or plasticity is a feature of spinal muscle atrophy (SMA). Prospective, double-center study. Outpatient clinics and research institute. Clinical assessments, combined with threshold-tracking transcranial magnetic stimulation techniques, were completed in 11 genetically characterized patients with SMA. Clinical, functional, and neurophysiologic variables were compared between the 11 patients with SMA types 2 and 3, 24 healthy control participants, and 81 patients with amyotrophic lateral sclerosis (ALS) serving as disease controls. Maximal motor-evoked potential amplitude as a percentage of the compound muscle action potential was significantly increased in patients with SMA compared with the healthy controls but was similar to that in ALS (SMA, mean [SE], 39.7% [4.0%]; ALS, 38.8% [2.8%]; controls, 20.3% [2.5%]; F = 10.1; P < .001). In contrast, short-interval intracortical inhibition (SMA, 14.4% [1.6%]; ALS, 4.3% [1.8%]; controls, 17.0% [2.3%]; F = 11.4; P < .001) and cortical silent-period duration (SMA, 204.4 [9.8] milliseconds; ALS, 182.7 [5.2] milliseconds; controls, 208.8 [3.7] milliseconds; F = 4.8; P = .01), similar between SMA patients and healthy controls, were significantly larger when compared with the findings in ALS. Of relevance, peripheral disease burden as measured by the compound muscle action potential amplitude (SMA, 6.3 [0.8] mV; ALS, 5.9 [0.4] mV; controls, 11.8 [0.5] mV; F = 35.5; P < .001) and Neurophysiological Index (SMA, 0.7 [0.2]; ALS, 0.7 [0.1]; controls, 3.1 [0.2]; F = 108.2; P < .001), were significantly reduced in both SMA and ALS patients when compared with healthy controls. Taken together, findings from the present study suggest that despite spinal motoneuron degeneration there remains preservation of corticomotoneuronal function in SMA. The greater

  20. Physical exercise reduces cardiac defects in type 2 spinal muscular atrophy-like mice

    PubMed Central

    Biondi, Olivier; Lopes, Philippe; Desseille, Céline; Branchu, Julien; Chali, Farah; Salah, Amina Ben; Pariset, Claude; Chanoine, Christophe; Charbonnier, Frédéric

    2012-01-01

    Spinal muscular atrophy (SMA), the leading genetic cause of death in infants worldwide, is due to the misexpression of the survival of motor neuron protein, causing death of motor neurons. Several clinical symptoms suggested that, in addition to motor neurons, the autonomic nervous systems could be implicated in the cardiac function alterations observed in patienst with SMA. These alterations were also found in a severe SMA mouse model, including bradycardia and a reduction of sympathetic innervation, both associated with autonomic imbalance. In the present study, we investigate the extent of autonomic dysfunction and the effects of a running-based exercise on the altered cardiorespiratory function in type 2 SMA-like mice. We observed that the SMA induced: (1) a dramatic alteration of intrinsic cardiac conduction associated with bradycardia; (2) a severe cardiomyopathy associated with extensive ventricular fibrosis; and (3) a delay in cardiac muscle maturation associated with contractile protein expression defects. Furthermore, our data indicate that the sympathetic system is not only functioning, but also likely contributes to alleviate the bradycardia and the arrhythmia in SMA-like mice. Moreover, physical exercise provides many benefits, including the reduction of cardiac protein expression defect, the reduction of fibrosis, the increase in cardiac electrical conduction velocity, and the drastic reduction in bradycardia and arrhythmias resulting in the partial restoration of the cardiac function in these mice. Thus, modulating the cardiorespiratory function in SMA could represent a new target for improving supportive care and for developing new pharmacological and non-pharmacological interventions that would most certainly include physical exercise. PMID:22930275

  1. Physical exercise reduces cardiac defects in type 2 spinal muscular atrophy-like mice.

    PubMed

    Biondi, Olivier; Lopes, Philippe; Desseille, Céline; Branchu, Julien; Chali, Farah; Ben Salah, Amina; Pariset, Claude; Chanoine, Christophe; Charbonnier, Frédéric

    2012-11-15

    Spinal muscular atrophy (SMA), the leading genetic cause of death in infants worldwide, is due to the misexpression of the survival of motor neuron protein, causing death of motor neurons. Several clinical symptoms suggested that, in addition to motor neurons, the autonomic nervous systems could be implicated in the cardiac function alterations observed in patienst with SMA. These alterations were also found in a severe SMA mouse model, including bradycardia and a reduction of sympathetic innervation, both associated with autonomic imbalance. In the present study, we investigate the extent of autonomic dysfunction and the effects of a running-based exercise on the altered cardiorespiratory function in type 2 SMA-like mice. We observed that the SMA induced: (1) a dramatic alteration of intrinsic cardiac conduction associated with bradycardia; (2) a severe cardiomyopathy associated with extensive ventricular fibrosis; and (3) a delay in cardiac muscle maturation associated with contractile protein expression defects. Furthermore, our data indicate that the sympathetic system is not only functioning, but also likely contributes to alleviate the bradycardia and the arrhythmia in SMA-like mice. Moreover, physical exercise provides many benefits, including the reduction of cardiac protein expression defect, the reduction of fibrosis, the increase in cardiac electrical conduction velocity, and the drastic reduction in bradycardia and arrhythmias resulting in the partial restoration of the cardiac function in these mice. Thus, modulating the cardiorespiratory function in SMA could represent a new target for improving supportive care and for developing new pharmacological and non-pharmacological interventions that would most certainly include physical exercise.

  2. A single administration of morpholino antisense oligomer rescues spinal muscular atrophy in mouse.

    PubMed

    Porensky, Paul N; Mitrpant, Chalermchai; McGovern, Vicki L; Bevan, Adam K; Foust, Kevin D; Kaspar, Brain K; Wilton, Stephen D; Burghes, Arthur H M

    2012-04-01

    Spinal muscular atrophy (SMA) is an autosomal-recessive disorder characterized by α-motor neuron loss in the spinal cord anterior horn. SMA results from deletion or mutation of the Survival Motor Neuron 1 gene (SMN1) and retention of SMN2. A single nucleotide difference between SMN1 and SMN2 results in exclusion of exon 7 from the majority of SMN2 transcripts, leading to decreased SMN protein levels and development of SMA. A series of splice enhancers and silencers regulate incorporation of SMN2 exon 7; these splice motifs can be blocked with antisense oligomers (ASOs) to alter SMN2 transcript splicing. We have evaluated a morpholino (MO) oligomer against ISS-N1 [HSMN2Ex7D(-10,-29)], and delivered this MO to postnatal day 0 (P0) SMA pups (Smn-/-, SMN2+/+, SMNΔ7+/+) by intracerebroventricular (ICV) injection. Survival was increased markedly from 15 days to >100 days. Delayed CNS MO injection has moderate efficacy, and delayed peripheral injection has mild survival advantage, suggesting that early CNS ASO administration is essential for SMA therapy consideration. ICV treatment increased full-length SMN2 transcript as well as SMN protein in neural tissue, but only minimally in peripheral tissue. Interval analysis shows a decrease in alternative splice modification over time. We suggest that CNS increases of SMN will have a major impact on SMA, and an early increase of the SMN level results in correction of motor phenotypes. Finally, the early introduction by intrathecal delivery of MO oligomers is a potential treatment for SMA patients.

  3. SMN deficiency negatively impacts red pulp macrophages and spleen development in mouse models of spinal muscular atrophy.

    PubMed

    Khairallah, Marie-Therese; Astroski, Jacob; Custer, Sarah K; Androphy, Elliot J; Franklin, Craig L; Lorson, Christian L

    2017-03-01

    Spinal muscular atrophy (SMA) is a progressive neurodegenerative disease that is the leading genetic cause of infantile death. It is caused by a severe deficiency of the ubiquitously expressed Survival Motor Neuron (SMN) protein. SMA is characterized by α-lower motor neuron loss and muscle atrophy, however, there is a growing list of tissues impacted by a SMN deficiency beyond motor neurons. The non-neuronal defects are observed in the most severe Type I SMA patients and most of the widely used SMA mouse models, however, as effective therapeutics are developed, it is unclear whether additional symptoms will be uncovered in longer lived patients. Recently, the immune system and inflammation has been identified as a contributor to neurodegenerative diseases such as ALS. To determine whether the immune system is comprised in SMA, we analyzed the spleen and immunological components in SMA mice. In this report, we identify: a significant reduction in spleen size in multiple SMA mouse models and a pathological reduction in red pulp and extramedullary hematopoiesis. Additionally, red pulp macrophages, a discrete subset of yolk sac-derived macrophages, were found to be altered in SMA spleens even in pre-symptomatic post-natal day 2 animals. These cells, which are involved in iron metabolism and the phagocytosis of erythrocytes and blood-borne pathogens are significantly reduced prior to the development of the neurodegenerative hallmarks of SMA, implying a differential role of SMN in myeloid cell ontogeny. Collectively, these results demonstrate that SMN deficiency impacts spleen development and suggests a potential role for immunological development in SMA. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  4. Molecular Genetic Analysis of Survival Motor Neuron Gene in 460 Turkish Cases with Suspicious Spinal Muscular Atrophy Disease.

    PubMed

    Rashnonejad, Afrooz; Onay, Huseyin; Atik, Tahir; Atan Sahin, Ozlem; Gokben, Sarenur; Tekgul, Hasan; Ozkinay, Ferda

    2016-01-01

    To describe 12 yr experience of molecular genetic diagnosis of Spinal Muscular Atrophy (SMA) in 460 cases of Turkish patients. A retrospective analysis was performed on data from 460 cases, referred to Medical Genetics Laboratory, Ege University's Hospital, Izmir, Turkey, prediagnosed as SMA or with family history of SMA between 2003 and 2014. The PCR-restriction fragment length polymorphism (RFLP) and the Multiplex ligation-dependent probe amplification (MLPA) analysis were performed to detect the survival motor neuron (SMN)1 deletions and to estimate SMN1 and SMN2 gene copy numbers. Using PCR-RFLP test, 159 of 324 postnatal and 18 of 77 prenatal cases were detected to have SMN1 deletions. From positive samples, 88.13% had a homozygous deletion in both exon 7 and exon 8 of SMN1. Using MLPA, 54.5% of families revealed heterozygous deletions of SMN1, and 2 or 3 copies of SMN2, suggesting a healthy SMA carrier. Among patients referred for SMA testing, the annual percentage of patients diagnosed as SMA has decreased gradually from 90.62% (2003) down to 20.83% (2014). Although PCR-RFLP method is a reliable test for SMA screening, MLPA is a necessary additional test and provide relevant data for genetic counseling of families having previously affected child. The gradual decrease in the percentage of patients molecularly diagnosed as SMA shows that clinicians have begun to use genetic tests in the differential diagnosis of muscular atrophies. Cost and availability of these genetic tests has greatly attributed to their use.

  5. Molecular Genetic Analysis of Survival Motor Neuron Gene in 460 Turkish Cases with Suspicious Spinal Muscular Atrophy Disease

    PubMed Central

    RASHNONEJAD, Afrooz; ONAY, Huseyin; ATIK, Tahir; ATAN SAHIN, Ozlem; GOKBEN, Sarenur; TEKGUL, Hasan; OZKINAY, Ferda

    2016-01-01

    Objective To describe 12 yr experience of molecular genetic diagnosis of Spinal Muscular Atrophy (SMA) in 460 cases of Turkish patients. Materials & Methods A retrospective analysis was performed on data from 460 cases, referred to Medical Genetics Laboratory, Ege University’s Hospital, Izmir, Turkey, prediagnosed as SMA or with family history of SMA between 2003 and 2014. The PCR-restriction fragment length polymorphism (RFLP) and the Multiplex ligation–dependent probe amplification (MLPA) analysis were performed to detect the survival motor neuron (SMN)1 deletions and to estimate SMN1 and SMN2 gene copy numbers. Results Using PCR-RFLP test, 159 of 324 postnatal and 18 of 77 prenatal cases were detected to have SMN1 deletions. From positive samples, 88.13% had a homozygous deletion in both exon 7 and exon 8 of SMN1. Using MLPA, 54.5% of families revealed heterozygous deletions of SMN1, and 2 or 3 copies of SMN2, suggesting a healthy SMA carrier. Among patients referred for SMA testing, the annual percentage of patients diagnosed as SMA has decreased gradually from 90.62% (2003) down to 20.83% (2014). Conclusion Although PCR-RFLP method is a reliable test for SMA screening, MLPA is a necessary additional test and provide relevant data for genetic counseling of families having previously affected child. The gradual decrease in the percentage of patients molecularly diagnosed as SMA shows that clinicians have begun to use genetic tests in the differential diagnosis of muscular atrophies. Cost and availability of these genetic tests has greatly attributed to their use. PMID:27843464

  6. Partial restoration of cardio-vascular defects in a rescued severe model of spinal muscular atrophy.

    PubMed

    Shababi, Monir; Habibi, Javad; Ma, Lixin; Glascock, Jacqueline J; Sowers, James R; Lorson, Christian L

    2012-05-01

    Spinal muscular atrophy (SMA) is a leading genetic cause of infantile death. Loss of a gene called Survival Motor Neuron 1 (SMN1) and, as a result, reduced levels of the Survival Motor Neuron (SMN) protein leads to SMA development. SMA is characterized by the loss of functional motor neurons in the spinal cord. However, accumulating evidence suggests the contribution of other organs to the composite SMA phenotype and disease progression. A growing number of congenital heart defects have been identified in severe SMA patients. Consistent with the clinical cases, we have recently identified developmental and functional heart defects in two SMA mouse models, occurring at embryonic stage in a severe SMA model and shortly after birth in a less severe model (SMN∆7). Our goal was to examine the late stage cardiac abnormalities in untreated SMN∆7 mice and to determine whether gene replacement therapy restores cardiac structure/function in rescued SMN∆7 model. To reveal the extent of the cardiac structural/functional repair in the rescued mice, we analyzed the heart of untreated and treated SMN∆7 model using self-complementary Adeno-associated virus (serotype 9) expressing the full-length SMN cDNA. We examined the characteristics of the heart failure such as remodeling, fibrosis, oxidative stress, and vascular integrity in both groups. Our results clearly indicate that fibrosis, oxidative stress activation, vascular remodeling, and a significant decrease in the number of capillaries exist in the SMA heart. The cardiac structural defects were improved drastically in the rescued animals, however, the level of impairment was still significant compared to the age-matched wildtype littermates. Furthermore, functional analysis by in vivo cardiac magnetic resonance imaging (MRI) revealed that the heart of the treated SMA mice still exhibits functional defects. In conclusion, cardiac abnormalities are only partially rescued in post-birth treated SMA animals and these

  7. Genetics Home Reference: spinal muscular atrophy

    MedlinePlus

    ... by a loss of specialized nerve cells, called motor neurons , in the spinal cord and the part ... the spinal cord ( the brainstem ). The loss of motor neurons leads to weakness and wasting ( atrophy ) of ...

  8. Non-aggregating tau phosphorylation by cyclin-dependent kinase 5 contributes to motor neuron degeneration in spinal muscular atrophy.

    PubMed

    Miller, Nimrod; Feng, Zhihua; Edens, Brittany M; Yang, Ben; Shi, Han; Sze, Christie C; Hong, Benjamin Taige; Su, Susan C; Cantu, Jorge A; Topczewski, Jacek; Crawford, Thomas O; Ko, Chien-Ping; Sumner, Charlotte J; Ma, Long; Ma, Yong-Chao

    2015-04-15

    Mechanisms underlying motor neuron degeneration in spinal muscular atrophy (SMA), the leading inherited cause of infant mortality, remain largely unknown. Many studies have established the importance of hyperphosphorylation of the microtubule-associated protein tau in various neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. However, tau phosphorylation in SMA pathogenesis has yet to be investigated. Here we show that tau phosphorylation on serine 202 (S202) and threonine 205 (T205) is increased significantly in SMA motor neurons using two SMA mouse models and human SMA patient spinal cord samples. Interestingly, phosphorylated tau does not form aggregates in motor neurons or neuromuscular junctions (NMJs), even at late stages of SMA disease, distinguishing it from other tauopathies. Hyperphosphorylation of tau on S202 and T205 is mediated by cyclin-dependent kinase 5 (Cdk5) in SMA disease condition, because tau phosphorylation at these sites is significantly reduced in Cdk5 knock-out mice; genetic knock-out of Cdk5 activating subunit p35 in an SMA mouse model also leads to reduced tau phosphorylation on S202 and T205 in the SMA;p35(-/-) compound mutant mice. In addition, expression of the phosphorylation-deficient tauS202A,T205A mutant alleviates motor neuron defects in a zebrafish SMA model in vivo and mouse motor neuron degeneration in culture, whereas expression of phosphorylation-mimetic tauS202E,T205E promotes motor neuron defects. More importantly, genetic knock-out of tau in SMA mice rescues synapse stripping on motor neurons, NMJ denervation, and motor neuron degeneration in vivo. Altogether, our findings suggest a novel mechanism for SMA pathogenesis in which hyperphosphorylation of non-aggregating tau by Cdk5 contributes to motor neuron degeneration. Copyright © 2015 the authors 0270-6474/15/356038-13$15.00/0.

  9. Non-Aggregating Tau Phosphorylation by Cyclin-Dependent Kinase 5 Contributes to Motor Neuron Degeneration in Spinal Muscular Atrophy

    PubMed Central

    Miller, Nimrod; Feng, Zhihua; Edens, Brittany M.; Yang, Ben; Shi, Han; Sze, Christie C.; Hong, Benjamin Taige; Su, Susan C.; Cantu, Jorge A.; Topczewski, Jacek; Crawford, Thomas O.; Ko, Chien-Ping; Sumner, Charlotte J.; Ma, Long

    2015-01-01

    Mechanisms underlying motor neuron degeneration in spinal muscular atrophy (SMA), the leading inherited cause of infant mortality, remain largely unknown. Many studies have established the importance of hyperphosphorylation of the microtubule-associated protein tau in various neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. However, tau phosphorylation in SMA pathogenesis has yet to be investigated. Here we show that tau phosphorylation on serine 202 (S202) and threonine 205 (T205) is increased significantly in SMA motor neurons using two SMA mouse models and human SMA patient spinal cord samples. Interestingly, phosphorylated tau does not form aggregates in motor neurons or neuromuscular junctions (NMJs), even at late stages of SMA disease, distinguishing it from other tauopathies. Hyperphosphorylation of tau on S202 and T205 is mediated by cyclin-dependent kinase 5 (Cdk5) in SMA disease condition, because tau phosphorylation at these sites is significantly reduced in Cdk5 knock-out mice; genetic knock-out of Cdk5 activating subunit p35 in an SMA mouse model also leads to reduced tau phosphorylation on S202 and T205 in the SMA;p35−/− compound mutant mice. In addition, expression of the phosphorylation-deficient tauS202A,T205A mutant alleviates motor neuron defects in a zebrafish SMA model in vivo and mouse motor neuron degeneration in culture, whereas expression of phosphorylation-mimetic tauS202E,T205E promotes motor neuron defects. More importantly, genetic knock-out of tau in SMA mice rescues synapse stripping on motor neurons, NMJ denervation, and motor neuron degeneration in vivo. Altogether, our findings suggest a novel mechanism for SMA pathogenesis in which hyperphosphorylation of non-aggregating tau by Cdk5 contributes to motor neuron degeneration. PMID:25878277

  10. ERK and ROCK functionally interact in a signaling network that is compensationally upregulated in Spinal Muscular Atrophy.

    PubMed

    Hensel, Niko; Baskal, Svetlana; Walter, Lisa Marie; Brinkmann, Hella; Gernert, Manuela; Claus, Peter

    2017-09-12

    Spinal Muscular Atrophy (SMA) is a motoneuron disease caused by low levels of functional survival of motoneuron protein (SMN). Molecular disease mechanisms downstream of functional SMN loss are still largely unknown. Previous studies suggested an involvement of Rho kinase (ROCK) as well as the extracellular signal-regulated kinases (ERK) pathways in the pathomechanism. Both pathways are bi-directionally linked and inhibit each other. Thus, we hypothesize that both pathways regulate SMA pathophysiology in vivo in a combined manner rather than acting separately. Here, we applied the repurposed drugs, selumetinib, an ERK inhibitor, and the ROCK inhibitor fasudil to severe SMA mice. Thereby, separately applied inhibitors as well as a combination enabled us to explore the impact of the ROCK-ERK signaling network on SMA pathophysiology. ROCK inhibition specifically ameliorated the phenotype of selumetinib-treated SMA mice demonstrating an efficient ROCK to ERK crosstalk relevant for the SMA pathophysiology. However, ERK inhibition alone aggravated the condition of SMA mice and reduced the number of motoneurons indicating a compensatory hyper-activation of ERK in motoneurons. Taken together, we identified a regulatory network acting downstream of SMN depletion and upstream of the SMA pathophysiology thus being a future treatment target in combination with SMN dependent strategies. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Cyclic tetrapeptide HDAC inhibitors as potential therapeutics for spinal muscular atrophy: Screening with iPSC-derived neuronal cells.

    PubMed

    Lai, Jiun-I; Leman, Luke J; Ku, Sherman; Vickers, Chris J; Olsen, Christian A; Montero, Ana; Ghadiri, M Reza; Gottesfeld, Joel M

    2017-08-01

    Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder that is caused by inactivating mutations in the Survival of motor neuron 1 (SMN1) gene, resulting in decreased SMN protein expression. Humans possess a paralog gene, SMN2, which contains a splicing defect in exon 7 leading to diminished expression of full-length, fully functional SMN protein. Increasing SMN2 expression has been a focus of therapeutic development for SMA. Multiple studies have reported the efficacy of histone deacetylase inhibitors (HDACi) in this regard. However, clinical trials involving HDACi have been unsatisfactory, possibly because previous efforts to identify HDACi to treat SMA have employed non-neuronal cells as the screening platform. To address this issue, we generated an SMA-patient specific, induced pluripotent stem cell (iPSC) derived neuronal cell line that contains homogenous Tuj1+neurons. We screened a small library of cyclic tetrapeptide HDACi using this SMA neuronal platform and discovered compounds that elevate SMN2 expression by an impressive twofold or higher. These candidates are also capable of forming gems intranuclearly in SMA neurons, demonstrating biological activity. Our study identifies new potential HDACi therapeutics for SMA screened using a disease-relevant SMA neuronal cellular model. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Reorganization of Cajal bodies and nucleolar targeting of coilin in motor neurons of type I spinal muscular atrophy.

    PubMed

    Tapia, Olga; Bengoechea, Rocío; Palanca, Ana; Arteaga, Rosa; Val-Bernal, J Fernando; Tizzano, Eduardo F; Berciano, María T; Lafarga, Miguel

    2012-05-01

    Type I spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by loss or mutations of the survival motor neuron 1 (SMN1) gene. The reduction in SMN protein levels in SMA leads to degeneration and death of motor neurons. In this study, we have analyzed the nuclear reorganization of Cajal bodies, PML bodies and nucleoli in type I SMA motor neurons with homozygous deletion of exons 7 and 8 of the SMN1 gene. Western blot analysis is is revealed a marked reduction of SMN levels compared to the control sample. Using a neuronal dissociation procedure to perform a careful immunocytochemical and quantitative analysis of nuclear bodies, we demonstrated a severe decrease in the mean number of Cajal bodies per neuron and in the proportion of motor neurons containing these structures in type I SMA. Moreover, most Cajal bodies fail to recruit SMN and spliceosomal snRNPs, but contain the proteasome activator PA28, a molecular marker associated with the cellular stress response. Neuronal stress in SMA motor neurons also increases PML body number. The existence of chromatolysis and eccentric nuclei in SMA motor neurons correlates with Cajal body disruption and nucleolar relocalization of coil in, a Cajal body marker. Our results indicate that the Cajal body is a pathophysiological target in type I SMA motor neurons. They also suggest the Cajal body-dependent dysfunction of snRNP biogenesis and, therefore, pre-mRNA splicing in these neurons seems to be an essential component for SMA pathogenesis.

  13. IPLEX administration improves motor neuron survival and ameliorates motor functions in a severe mouse model of spinal muscular atrophy.

    PubMed

    Murdocca, Michela; Malgieri, Arianna; Luchetti, Andrea; Saieva, Luciano; Dobrowolny, Gabriella; de Leonibus, Elvira; Filareto, Antonio; Quitadamo, Maria Chiara; Novelli, Giuseppe; Musarò, Antonio; Sangiuolo, Federica

    2012-09-25

    Spinal muscular atrophy (SMA) is an inherited neurodegenerative disorder and the first genetic cause of death in childhood. SMA is caused by low levels of survival motor neuron (SMN) protein that induce selective loss of α-motor neurons (MNs) in the spinal cord, resulting in progressive muscle atrophy and consequent respiratory failure. To date, no effective treatment is available to counteract the course of the disease. Among the different therapeutic strategies with potential clinical applications, the evaluation of trophic and/or protective agents able to antagonize MNs degeneration represents an attractive opportunity to develop valid therapies. Here we investigated the effects of IPLEX (recombinant human insulinlike growth factor 1 [rhIGF-1] complexed with recombinant human IGF-1 binding protein 3 [rhIGFBP-3]) on a severe mouse model of SMA. Interestingly, molecular and biochemical analyses of IGF-1 carried out in SMA mice before drug administration revealed marked reductions of IGF-1 circulating levels and hepatic mRNA expression. In this study, we found that perinatal administration of IPLEX, even if does not influence survival and body weight of mice, results in reduced degeneration of MNs, increased muscle fiber size and in amelioration of motor functions in SMA mice. Additionally, we show that phenotypic changes observed are not SMN-dependent, since no significant SMN modification was addressed in treated mice. Collectively, our data indicate IPLEX as a good therapeutic candidate to hinder the progression of the neurodegenerative process in SMA.

  14. Air stacking: effects on pulmonary function in patients with spinal muscular atrophy and in patients with congenital muscular dystrophy*,**

    PubMed Central

    Marques, Tanyse Bahia Carvalho; Neves, Juliana de Carvalho; Portes, Leslie Andrews; Salge, João Marcos; Zanoteli, Edmar; Reed, Umbertina Conti

    2014-01-01

    OBJECTIVE: Respiratory complications are the main causes of morbidity and mortality in patients with neuromuscular disease (NMD). The objectives of this study were to determine the effects that routine daily home air-stacking maneuvers have on pulmonary function in patients with spinal muscular atrophy (SMA) and in patients with congenital muscular dystrophy (CMD), as well as to identify associations between spinal deformities and the effects of the maneuvers. METHODS: Eighteen NMD patients (ten with CMD and eight with SMA) were submitted to routine daily air-stacking maneuvers at home with manual resuscitators for four to six months, undergoing pulmonary function tests before and after that period. The pulmonary function tests included measurements of FVC; PEF; maximum insufflation capacity (MIC); and assisted and unassisted peak cough flow (APCF and UPCF, respectively) with insufflations. RESULTS: After the use of home air-stacking maneuvers, there were improvements in the APCF and UPCF. In the patients without scoliosis, there was also a significant increase in FVC. When comparing patients with and without scoliosis, the increases in APCF and UPCF were more pronounced in those without scoliosis. CONCLUSIONS: Routine daily air-stacking maneuvers with a manual resuscitator appear to increase UPCF and APCF in patients with NMD, especially in those without scoliosis. PMID:25410841

  15. Perioperative complications of scoliosis surgery in patients with Duchenne muscular dystrophy and spinal muscular atrophy, focussing on wound healing disorders.

    PubMed

    Burow, Mareike; Forst, Raimund; Forst, Jürgen; Hofner, Benjamin; Fujak, Albert

    2017-06-01

    Patients with Duchenne muscular dystrophy (DMD) or spinal muscular atrophy (SMA), both neuromuscular diseases, sustain spinal scoliosis in the course of their disease. To reduce the concomitant major morbidity and to improve their quality of life, patients require surgical spine stabilization. This can lead to complications like respiratory, cardiac or neurological complications or wound healing disorders (WHD). To find out the different complexities and risk factors increasing the chance to develop a WHD, the inpatient database was analyzed. We performed a retrospective statistical study. Therefore, we analyzed the inpatient database of 180 patients (142 DMD and 38 SMA patients). The focus was on WHD. To figure out the risk factors leading to WHD, we conducted a logistic regression. Cardiac complications occurred most frequently, followed by pulmonary complications and neurological lesions. Fifty-seven out of 180 patients developed a WHD. In 23 cases the WHD was aseptic, in the other 34 cases dermal organisms, Pseudomonas species and intestinal organisms were responsible. By means of the logistic regression, we were able to identify two more risk factors, in addition to diagnosis and gender, for developing a WHD in our patients: the year of surgery and the direction of pelvic tilt. Most common complications following scoliosis surgery are respiratory and cardiac complications. WHD is a severe complication that implies a prolonged therapy. Some risk factors for developing WHD could be identified in this analysis. Specifically, these were the date of surgery and the direction of pelvic tilt.

  16. ECG in neonate mice with spinal muscular atrophy allows assessment of drug efficacy.

    PubMed

    Heier, Christopher R; DiDonato, Christine J

    2015-01-01

    Molecular technologies have produced diverse arrays of animal models for studying genetic diseases and potential therapeutics. Many have neonatal phenotypes. Spinal muscular atrophy (SMA) is a neuromuscular disorder primarily affecting children, and is of great interest in translational medicine. The most widely used SMA mouse models require all phenotyping to be performed in neonates since they do not survive much past weaning. Pre-clinical studies in neonate mice can be hindered by toxicity and a lack of quality phenotyping assays, since many assays are invalid in pups or require subjective scoring with poor inter-rater variability. We find, however, that passive electrocardiography (ECG) recording in conscious 11-day old SMA mice provides sensitive outcome measures, detecting large differences in heart rate, cardiac conduction, and autonomic control resulting from disease. We find significant drug benefits upon treatment with G418, an aminoglycoside targeting the underlying protein deficiency, even in the absence of overt effects on growth and survival. These findings provide several quantitative physiological biomarkers for SMA preclinical studies, and will be of utility to diverse disease models featuring neonatal cardiac arrhythmias.

  17. Performance of the timed "up & go" test in spinal muscular atrophy.

    PubMed

    Dunaway, Sally; Montes, Jacqueline; Garber, Carol Ewing; Carr, Brendan; Kramer, Samantha S; Kamil-Rosenberg, Shirit; Strauss, Nancy; Sproule, Douglas; De Vivo, Darryl C

    2014-08-01

    The timed "up & go" (TUG) test is a quick measure of balance and mobility. TUG scores correlate with clinical, functional, and strength assessment and decline linearly over time. Reliability and validity have not been tested in spinal muscular atrophy (SMA). Fifteen ambulatory SMA participants performed TUG testing and strength, functional, and clinical assessments. Intraclass correlation coefficients quantified test-retest reliability. Convergent validity was determined using Pearson correlation coefficients. Test-retest reliability was excellent for all participants. TUG was associated significantly with total leg and knee flexor strength, as well as the Hammersmith Functional Motor Scale Expanded, the 10-meter walk/run, and 6-minute walk tests. TUG findings were not associated with knee extensor strength, pulmonary function, or fatigue. In SMA, the TUG test is easily administered, reliable, and correlates with established outcome measures. TUG testing is a potentially useful outcome measure for clinical trials and a measure of disability in ambulatory patients with SMA. Copyright © 2013 Wiley Periodicals, Inc.

  18. Systemic peptide-mediated oligonucleotide therapy improves long-term survival in spinal muscular atrophy

    PubMed Central

    Hazell, Gareth; Shabanpoor, Fazel; Saleh, Amer F.; Bowerman, Melissa; Meijboom, Katharina E.; Zhou, Haiyan; Muntoni, Francesco; Talbot, Kevin; Gait, Michael J.; Wood, Matthew J. A.

    2016-01-01

    The development of antisense oligonucleotide therapy is an important advance in the identification of corrective therapy for neuromuscular diseases, such as spinal muscular atrophy (SMA). Because of difficulties of delivering single-stranded oligonucleotides to the CNS, current approaches have been restricted to using invasive intrathecal single-stranded oligonucleotide delivery. Here, we report an advanced peptide-oligonucleotide, Pip6a-morpholino phosphorodiamidate oligomer (PMO), which demonstrates potent efficacy in both the CNS and peripheral tissues in severe SMA mice following systemic administration. SMA results from reduced levels of the ubiquitously expressed survival motor neuron (SMN) protein because of loss-of-function mutations in the SMN1 gene. Therapeutic splice-switching oligonucleotides (SSOs) modulate exon 7 splicing of the nearly identical SMN2 gene to generate functional SMN protein. Pip6a-PMO yields SMN expression at high efficiency in peripheral and CNS tissues, resulting in profound phenotypic correction at doses an order-of-magnitude lower than required by standard naked SSOs. Survival is dramatically extended from 12 d to a mean of 456 d, with improvement in neuromuscular junction morphology, down-regulation of transcripts related to programmed cell death in the spinal cord, and normalization of circulating insulin-like growth factor 1. The potent systemic efficacy of Pip6a-PMO, targeting both peripheral as well as CNS tissues, demonstrates the high clinical potential of peptide-PMO therapy for SMA. PMID:27621445

  19. CNS uptake of bortezomib is enhanced by P-glycoprotein inhibition: implications for spinal muscular atrophy.

    PubMed

    Foran, Emily; Kwon, Deborah Y; Nofziger, Jonathan H; Arnold, Eveline S; Hall, Matthew D; Fischbeck, Kenneth H; Burnett, Barrington G

    2016-04-01

    The development of therapeutics for neurological disorders is constrained by limited access to the central nervous system (CNS). ATP-binding cassette (ABC) transporters, particularly P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), are expressed on the luminal surface of capillaries in the CNS and transport drugs out of the endothelium back into the blood against the concentration gradient. Survival motor neuron (SMN) protein, which is deficient in spinal muscular atrophy (SMA), is a target of the ubiquitin proteasome system. Inhibiting the proteasome in a rodent model of SMA with bortezomib increases SMN protein levels in peripheral tissues but not the CNS, because bortezomib has poor CNS penetrance. We sought to determine if we could inhibit SMN degradation in the CNS of SMA mice with a combination of bortezomib and the ABC transporter inhibitor tariquidar. In cultured cells we show that bortezomib is a substrate of P-gp. Mass spectrometry analysis demonstrated that intraperitoneal co-administration of tariquidar increased the CNS penetrance of bortezomib, and reduced proteasome activity in the brain and spinal cord. This correlated with increased SMN protein levels and improved survival and motor function of SMA mice. These findings show that CNS penetrance of treatment for this neurological disorder can be improved by inhibiting drug efflux at the blood-brain barrier.

  20. ISS-N1 makes the First FDA-approved Drug for Spinal Muscular Atrophy.

    PubMed

    Ottesen, Eric W

    2017-01-01

    Spinal muscular atrophy (SMA) is one of the leading genetic diseases of children and infants. SMA is caused by deletions or mutations of Survival Motor Neuron 1 (SMN1) gene. SMN2, a nearly identical copy of SMN1, cannot compensate for the loss of SMN1 due to predominant skipping of exon 7. While various regulatory elements that modulate SMN2 exon 7 splicing have been proposed, intronic splicing silencer N1 (ISS-N1) has emerged as the most promising target thus far for antisense oligonucleotide-mediated splicing correction in SMA. Upon procuring exclusive license from the University of Massachussets Medical School in 2010, Ionis Pharmaceuticals (formerly ISIS Pharamaceuticals) began clinical development of Spinraza(™) (synonyms: Nusinersen, IONIS-SMNRX, ISIS-SMNRX), an antisense drug based on ISS-N1 target. Spinraza(™) showed very promising results at all steps of the clinical development and was approved by US Food and Drug Administration (FDA) on December 23, 2016. Spinraza(™) is the first FDA-approved treatment for SMA and the first antisense drug to restore expression of a fully functional protein via splicing correction. The success of Spinraza(™) underscores the potential of intronic sequences as promising therapeutic targets and sets the stage for further improvement of antisense drugs based on advanced oligonucleotide chemistries and delivery protocols.

  1. Survival motor neuron protein in motor neurons determines synaptic integrity in spinal muscular atrophy.

    PubMed

    Martinez, Tara L; Kong, Lingling; Wang, Xueyong; Osborne, Melissa A; Crowder, Melissa E; Van Meerbeke, James P; Xu, Xixi; Davis, Crystal; Wooley, Joe; Goldhamer, David J; Lutz, Cathleen M; Rich, Mark M; Sumner, Charlotte J

    2012-06-20

    The inherited motor neuron disease spinal muscular atrophy (SMA) is caused by deficient expression of survival motor neuron (SMN) protein and results in severe muscle weakness. In SMA mice, synaptic dysfunction of both neuromuscular junctions (NMJs) and central sensorimotor synapses precedes motor neuron cell death. To address whether this synaptic dysfunction is due to SMN deficiency in motor neurons, muscle, or both, we generated three lines of conditional SMA mice with tissue-specific increases in SMN expression. All three lines of mice showed increased survival, weights, and improved motor behavior. While increased SMN expression in motor neurons prevented synaptic dysfunction at the NMJ and restored motor neuron somal synapses, increased SMN expression in muscle did not affect synaptic function although it did improve myofiber size. Together these data indicate that both peripheral and central synaptic integrity are dependent on motor neurons in SMA, but SMN may have variable roles in the maintenance of these different synapses. At the NMJ, it functions at the presynaptic terminal in a cell-autonomous fashion, but may be necessary for retrograde trophic signaling to presynaptic inputs onto motor neurons. Importantly, SMN also appears to function in muscle growth and/or maintenance independent of motor neurons. Our data suggest that SMN plays distinct roles in muscle, NMJs, and motor neuron somal synapses and that restored function of SMN at all three sites will be necessary for full recovery of muscle power.

  2. Update on gene and stem cell therapy approaches for spinal muscular atrophy.

    PubMed

    Donnelly, Eleanor M; Boulis, Nicholas M

    2012-11-01

    Spinal muscular atrophy (SMA) is the leading genetic cause of pediatric death to which at present there is no effective therapeutic. The genetic defect is well characterized as a mutation in exon 7 of the survival of motor neuron (SMN) gene. The current gene therapy approach focuses on two main methodologies, the replacement of SMN1 or augmentation of SMN2 readthrough. The most promising of the current work focuses on the delivery of SMN via AAV9 vectors via intravenous delivery. In the review the authors examine the current research in the field of stem cell and gene therapy approaches for SMA. Also focusing on delivery methods, timing of administration and general caveats that must be considered with translational work for SMA. Gene therapy currently offers the most promising avenue of research for a successful therapeutic for SMA. There are many important practical and ethical considerations which must be carefully considered when dealing with clinical trial in infants such as the invasiveness of the surgery, the correct patient cohort and the potential risks.

  3. Juvenile-onset spinal muscular atrophy caused by compound heterozygosity for mutations in the HEXA gene.

    PubMed

    Navon, R; Khosravi, R; Melki, J; Drucker, L; Fontaine, B; Turpin, J C; N'Guyen, B; Fardeau, M; Rondot, P; Baumann, N

    1997-05-01

    Progressive proximal muscle weakness is present both in spinal muscular atrophy (SMA) type III (Kugelberg-Welander disease) and in GM2 gangliosidosis, diseases that segregate in an autosomal recessive fashion. The SMN gene for SMA and the HEXA gene for GM2 gangliosidosis were investigated in a woman with progressive proximal muscle weakness, long believed to be SMA type III (Kugelberg-Welander type). She and her family underwent biochemical studies for GM2 gangliosidosis. Analysis of SMN excluded SMA. Biochemical studies on GM2 gangliosidosis showed deficiency in hexosaminidase A activity and increased GM2 ganglioside accumulation in the patient's fibroblasts. The HEXA gene was first analyzed for the Gly269-->Ser mutation characteristic for adult GM2 gangliosidosis. Since the patient was carrying the adult mutation heterozygously, all 14 exons and adjacent intron sequences were analyzed. A novel mutation in exon 1 resulting in an A-to-T change in the initiation codon (ATG to TTG) was identified. The adult patient is a compound heterozygote, with each allele containing a different mutation. Although mRNA was transcribed from the novel mutant allele, expression experiments showed no enzyme activity, suggesting that neither the TTG nor an alternative codon serve as an initiation codon in the HEXA gene.

  4. Is spinal muscular atrophy a disease of the motor neurons only: pathogenesis and therapeutic implications?

    PubMed

    Simone, Chiara; Ramirez, Agnese; Bucchia, Monica; Rinchetti, Paola; Rideout, Hardy; Papadimitriou, Dimitra; Re, Diane B; Corti, Stefania

    2016-03-01

    Spinal muscular atrophy (SMA) is a genetic neurological disease that causes infant mortality; no effective therapies are currently available. SMA is due to homozygous mutations and/or deletions in the survival motor neuron 1 gene and subsequent reduction of the SMN protein, leading to the death of motor neurons. However, there is increasing evidence that in addition to motor neurons, other cell types are contributing to SMA pathology. In this review, we will discuss the involvement of non-motor neuronal cells, located both inside and outside the central nervous system, in disease onset and progression. Even if SMN restoration in motor neurons is needed, it has been shown that optimal phenotypic amelioration in animal models of SMA requires a more widespread SMN correction. It has been demonstrated that non-motor neuronal cells are also involved in disease pathogenesis and could have important therapeutic implications. For these reasons it will be crucial to take this evidence into account for the clinical translation of the novel therapeutic approaches.

  5. ISS-N1 makes the First FDA-approved Drug for Spinal Muscular Atrophy

    PubMed Central

    Ottesen, Eric W.

    2017-01-01

    Abstract Spinal muscular atrophy (SMA) is one of the leading genetic diseases of children and infants. SMA is caused by deletions or mutations of Survival Motor Neuron 1 (SMN1) gene. SMN2, a nearly identical copy of SMN1, cannot compensate for the loss of SMN1 due to predominant skipping of exon 7. While various regulatory elements that modulate SMN2 exon 7 splicing have been proposed, intronic splicing silencer N1 (ISS-N1) has emerged as the most promising target thus far for antisense oligonucleotide-mediated splicing correction in SMA. Upon procuring exclusive license from the University of Massachussets Medical School in 2010, Ionis Pharmaceuticals (formerly ISIS Pharamaceuticals) began clinical development of Spinraza™ (synonyms: Nusinersen, IONIS-SMNRX, ISIS-SMNRX), an antisense drug based on ISS-N1 target. Spinraza™ showed very promising results at all steps of the clinical development and was approved by US Food and Drug Administration (FDA) on December 23, 2016. Spinraza™ is the first FDA-approved treatment for SMA and the first antisense drug to restore expression of a fully functional protein via splicing correction. The success of Spinraza™ underscores the potential of intronic sequences as promising therapeutic targets and sets the stage for further improvement of antisense drugs based on advanced oligonucleotide chemistries and delivery protocols. PMID:28400976

  6. Synaptic Defects in the Spinal and Neuromuscular Circuitry in a Mouse Model of Spinal Muscular Atrophy

    PubMed Central

    Zingg, Brian; Feng, Zhihua; Ko, Chien-Ping

    2010-01-01

    Spinal muscular atrophy (SMA) is a major genetic cause of death in childhood characterized by marked muscle weakness. To investigate mechanisms underlying motor impairment in SMA, we examined the spinal and neuromuscular circuitry governing hindlimb ambulatory behavior in SMA model mice (SMNΔ7). In the neuromuscular circuitry, we found that nearly all neuromuscular junctions (NMJs) in hindlimb muscles of SMNΔ7 mice remained fully innervated at the disease end stage and were capable of eliciting muscle contraction, despite a modest reduction in quantal content. In the spinal circuitry, we observed a ∼28% loss of synapses onto spinal motoneurons in the lateral column of lumbar segments 3–5, and a significant reduction in proprioceptive sensory neurons, which may contribute to the 50% reduction in vesicular glutamate transporter 1(VGLUT1)-positive synapses onto SMNΔ7 motoneurons. In addition, there was an increase in the association of activated microglia with SMNΔ7 motoneurons. Together, our results present a novel concept that synaptic defects occur at multiple levels of the spinal and neuromuscular circuitry in SMNΔ7 mice, and that proprioceptive spinal synapses could be a potential target for SMA therapy. PMID:21085654

  7. Synaptic defects in the spinal and neuromuscular circuitry in a mouse model of spinal muscular atrophy.

    PubMed

    Ling, Karen K Y; Lin, Ming-Yi; Zingg, Brian; Feng, Zhihua; Ko, Chien-Ping

    2010-11-11

    Spinal muscular atrophy (SMA) is a major genetic cause of death in childhood characterized by marked muscle weakness. To investigate mechanisms underlying motor impairment in SMA, we examined the spinal and neuromuscular circuitry governing hindlimb ambulatory behavior in SMA model mice (SMNΔ7). In the neuromuscular circuitry, we found that nearly all neuromuscular junctions (NMJs) in hindlimb muscles of SMNΔ7 mice remained fully innervated at the disease end stage and were capable of eliciting muscle contraction, despite a modest reduction in quantal content. In the spinal circuitry, we observed a ∼28% loss of synapses onto spinal motoneurons in the lateral column of lumbar segments 3-5, and a significant reduction in proprioceptive sensory neurons, which may contribute to the 50% reduction in vesicular glutamate transporter 1(VGLUT1)-positive synapses onto SMNΔ7 motoneurons. In addition, there was an increase in the association of activated microglia with SMNΔ7 motoneurons. Together, our results present a novel concept that synaptic defects occur at multiple levels of the spinal and neuromuscular circuitry in SMNΔ7 mice, and that proprioceptive spinal synapses could be a potential target for SMA therapy.

  8. Is Spinal Muscular Atrophy a disease of the motor neurons only: pathogenesis and therapeutic implications?

    PubMed Central

    Simone, Chiara; Ramirez, Agnese; Bucchia, Monica; Rinchetti, Paola; Rideout, Hardy; Papadimitriou, Dimitra; Re, Diane B.; Corti, Stefania

    2016-01-01

    Spinal Muscular Atrophy (SMA) is a genetic neurological disease that causes infant mortality; no effective therapies are currently available. SMA is due to homozygous mutations and/or deletions in the Survival Motor Neuron 1 (SMN1) gene and subsequent reduction of the SMN protein, leading to the death of motor neurons. However, there is increasing evidence that in addition to motor neurons, other cell types are contributing to SMA pathology. In this review, we will discuss the involvement of non-motor neuronal cells, located both inside and outside the central nervous system, in disease onset and progression. These contribution of non-motor neuronal cells to disease pathogenesis has important therapeutic implications: in fact, even if SMN restoration in motor neurons is needed, it has been shown that optimal phenotypic amelioration in animal models of SMA requires a more widespread SMN correction. It will be crucial to take this evidence into account before clinical translation of the novel therapeutic approaches that are currently under development. PMID:26681261

  9. Clinical Trial of L-Carnitine and Valproic Acid in Spinal Muscular Atrophy Type I.

    PubMed

    Krosschell, Kristin J; Kissel, John T; Townsend, Elise L; Simeone, Sarah D; Zhang, Ren Zhe; Reyna, Sandra P; Thomas, O Crawford; Schroth, Mary K; Acsadi, Gyula; Kishnani, Priya S; von Kleist-Retzow, Jürgen-Christoph; Hero, Barbara; D'Anjou, Guy; Smith, Edward C; Elsheikh, Bakri; Simard, Louise R; Prior, Thomas W; Scott, Charles B; LaSalle, Bernard; Sakonju, Ai; Wirth, Brunhilde; Swoboda, Kathryn J

    2017-08-18

    To explore safety and therapeutic potential of L-carnitine and valproic acid (VPA) in infants with spinal muscular atrophy (SMA). Open-label phase 2 multicenter trial of L-carnitine and VPA in infants with SMA type I with retrospective comparison to an untreated, matched cohort. Primary outcomes were safety and adverse events (AEs); secondary outcomes were survival, time to death/> 16 hours/day ventilator support, motor outcomes and maximum ulnar compound motor action potential amplitude. 245 AEs were observed in 35 of 37 treated subjects (95%). Respiratory events accounted for 49% of all AEs, resulting in 14 deaths. Survival was not significantly different between treated and untreated cohorts. This trial provides evidence that in infants with SMA type I, L-carnitine/VPA is ineffective in altering survival. The substantial proportion of infants reaching endpoints within 6 months of enrollment underscores the urgent need for pre-symptomatic treatment in SMA type I. This article is protected by copyright. All rights reserved. © 2017 Wiley Periodicals, Inc.

  10. Lentivector-mediated SMN replacement in a mouse model of spinal muscular atrophy.

    PubMed

    Azzouz, Mimoun; Le, Thanh; Ralph, G Scott; Walmsley, Lucy; Monani, Umrao R; Lee, Debbie C P; Wilkes, Fraser; Mitrophanous, Kyriacos A; Kingsman, Susan M; Burghes, Arthur H M; Mazarakis, Nicholas D

    2004-12-01

    Spinal muscular atrophy (SMA) is a frequent recessive autosomal disorder. It is caused by mutations or deletion of the telomeric copy of the survival motor neuron (SMN) gene, leading to depletion in SMN protein levels. The treatment rationale for SMA is to halt or delay the degeneration of motor neurons, but to date there are no effective drug treatments for this disease. We have previously demonstrated that pseudotyping of the nonprimate equine infectious anemia virus (using the lentivector gene transfer system) with the glycoprotein of the Evelyn-Rokitnicki-Abelseth strain of the rabies virus confers retrograde axonal transport on these vectors. Here, we report that lentivector expressing human SMN was successfully used to restore SMN protein levels in SMA type 1 fibroblasts. Multiple single injections of a lentiviral vector expressing SMN in various muscles of SMA mice restored SMN to motor neurons, reduced motor neuron death, and increased the life expectancy by an average of 3 and 5 days (20% and 38%) compared with LacZ and untreated animals, respectively. Further extension of survival by SMN expression constructs will likely require a knowledge of when and/or where high levels of SMN are needed.

  11. SMN in motor neurons determines synaptic integrity in spinal muscular atrophy

    PubMed Central

    Martinez, Tara L.; Kong, Lingling; Wang, Xueyong; Osborne, Melissa A.; Crowder, Melissa E.; Van Meerbeke, James P.; Xu, Xixi; Davis, Crystal; Wooley, Joe; Goldhamer, David J.; Lutz, Cathleen M.; Rich, Mark. M.; Sumner, Charlotte J.

    2012-01-01

    The inherited motor neuron disease spinal muscular atrophy (SMA) is caused by deficient expression of survival motor neuron (SMN) protein and results in severe muscle weakness. In SMA mice, synaptic dysfunction of both neuromuscular junctions (NMJs) and central sensorimotor synapses precedes motor neuron cell death. To address whether this synaptic dysfunction is due to SMN deficiency in motor neurons, muscle, or both, we generated three lines of conditional SMA mice with tissue-specific increases in SMN expression. All three lines of mice showed increased survival, weights, and improved motor behavior. While increased SMN expression in motor neurons prevented synaptic dysfunction at the NMJ and restored motor neuron somal synapses, increased SMN expression in muscle did not affect synaptic function although it did improve myofiber size. Together these data indicate that both peripheral and central synaptic integrity are dependent on motor neurons in SMA, but SMN may have variable roles in the maintenance of these different synapses. At the NMJ, it functions at the presynaptic terminal in a cell-autonomous fashion, but may be necessary for retrograde trophic signaling to presynaptic inputs onto motor neurons. Importantly, SMN also appears to function in muscle growth and/or maintenance independent of motor neurons. Our data suggest that SMN plays distinct roles in muscle, NMJs, and motor neuron somal synapses and that restored function of SMN at all three sites will be necessary for full recovery of muscle power. PMID:22723710

  12. [Detection of homozygous deletions in spinal muscular atrophy with genomic DNA sequencing].

    PubMed

    Cao, Yan-yan; Qu, Yu-jin; Song, Fang; Bai, Jin-li; Jin, Yu-wei; Wang, Hong; Li, Yan; Zhang, Wen-hui

    2013-08-01

    To detect homozygous deletions of survival motor neuron (SMN) gene with genomic DNA sequencing, and to assess the value of genetic testing for the diagnosis of spinal muscular atrophy (SMA). Polymerase chain reaction (PCR) was used for amplifying SMN gene in 100 SMA patients and 110 controls. Four different bases (g.31957, g.32006, g.32154 and g.32269) between SMN1 and SMN2 within the amplified segments were identified with genomic DNA sequencing. Homozygous deletion of SMN1 or SMN2 was determined by the presence or absence of base peaks at such four sites. Multiplex ligation-dependent probe amplification (MLPA) was carried out to confirm the results of genomic DNA sequencing. In the 100 SMA samples, only SMN2 specific base peaks were detected at the four sites, for which the copy numbers of SMN1 and SMN2 was 0:2 or 0:3, suggesting homozygous deletion of SMN1 gene. By contrast, only SMN1 specific base peaks were detected in 5 samples, for which the ratio of SMN1:SMN2 was 2:0, indicating homozygous deletion of SMN2. At four different sites, SMN1/SMN2 heterozygous peaks were detected in the remaining 105 samples, for which SMN1:SMN2was 2:2, suggesting non-deletion of SMN1 or SMN2. The results of sequencing were consistent with those of MLPA. Genomic DNA sequencing is a rapid, accurate and economic method for the diagnosis of homozygous deletion of SMA.

  13. Non-invasive prenatal diagnosis of spinal muscular atrophy by relative haplotype dosage.

    PubMed

    Parks, Michael; Court, Samantha; Bowns, Benjamin; Cleary, Siobhan; Clokie, Samuel; Hewitt, Julie; Williams, Denise; Cole, Trevor; MacDonald, Fiona; Griffiths, Mike; Allen, Stephanie

    2017-04-01

    Although technically possible, few clinical laboratories across the world have implemented non-invasive prenatal diagnosis (NIPD) for selected single-gene disorders, mostly owing to the elevated costs incurred. Having previously proven that NIPD for X-linked disorders can be feasibly implemented in clinical practice, we have now developed a test for the NIPD of an autosomal-recessive disorder, spinal muscular atrophy (SMA). Cell-free DNA was extracted from maternal blood and prepared for massively parallel sequencing on an Illumina MiSeq by targeted capture enrichment of single-nucleotide polymorphisms across a 6 Mb genomic window on chromosome 5 containing the SMN1 gene. Maternal, paternal and proband DNA samples were also tested for haplotyping purposes. Sequencing data was analysed by relative haplotype dosage (RHDO). Six pregnant SMA carriers and 10 healthy pregnant donors were recruited through the NIPSIGEN study. Inheritance of the maternally and paternally derived alleles of the affected SMN1 gene was determined in the foetus by RHDO analysis for autosomal-recessive disorders. DNA from the proband (for SMA carriers) or an invasively obtained foetal sample (for healthy pregnant donors) was used to identify the maternal and paternal reference haplotypes associated with the affected SMN1 gene. Results for all patients correlated with known outcomes and showed a testing specificity and sensitivity of 100%. On top of showing high accuracy and reliability throughout the stages of validation, our novel test for NIPD of SMA is also affordable and viable for implementation into clinical service.

  14. Isolation of cDNAs from the spinal muscular atrophy gene region with yeast artificial chromosomes

    SciTech Connect

    Deng, H.X.; He, X.X.; Hung, W.Y.

    1994-09-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by degeneration of anterior horn cells, leading to progressive paralysis of voluntary muscles. The SMA gene(s) is located at 5q11.2-q13.3, between D5S435 and D5S112. To isolate potential candidate gene(s) responsible for SMA, we used the YACs within the SMA gene region as probes to screen a human brainstem cDNA library. Thirteen cDNA clones were isolated. Their sizes range from 0.7 kb to 5 kb. Seven clones were found to be unique in sequence; the remaining six clones contain repetitive sequences. Five out of these seven unique clones have been used as probes to screen a phage genomic DNA library. Phage genomic clones isolated with individual unique cDNA were used for fluorescence in situ hybridization to identify the origin of cDNAs. These five unique sequences are all located in the 5q13 region, indicating the reliability of our screening method. All the thirteen clones have been partially sequenced (about 300 bp) from each end. No homology has been found with any known EST or known genes. No cross hybridization was detected among the unique clones, suggesting that there may be distinct new genes encoded in this region.

  15. Early heart failure in the SMNDelta7 model of spinal muscular atrophy and correction by postnatal scAAV9-SMN delivery.

    PubMed

    Bevan, Adam K; Hutchinson, Kirk R; Foust, Kevin D; Braun, Lyndsey; McGovern, Vicki L; Schmelzer, Leah; Ward, Jennifer G; Petruska, Jeffrey C; Lucchesi, Pamela A; Burghes, Arthur H M; Kaspar, Brian K

    2010-10-15

    Proximal spinal muscular atrophy (SMA) is a debilitating neurological disease marked by isolated lower motor neuron death and subsequent atrophy of skeletal muscle. Historically, SMA pathology was thought to be limited to lower motor neurons and the skeletal muscles they control, yet there are several reports describing the coincidence of cardiovascular abnormalities in SMA patients. As new therapies for SMA emerge, it is necessary to determine whether these non-neuromuscular systems need to be targeted. Therefore, we have characterized left ventricular (LV) function of SMA mice (SMN2+/+; SMNΔ7+/+; Smn-/-) and compared it with that of their unaffected littermates at 7 and 14 days of age. Anatomical and physiological measurements made by electrocardiogram and echocardiography show that affected mouse pups have a dramatic decrease in cardiac function. At 14 days of age, SMA mice have bradycardia and develop a marked dilated cardiomyopathy with a concomitant decrease in contractility. Signs of decreased cardiac function are also apparent as early as 7 days of age in SMA animals. Delivery of a survival motor neuron-1 transgene using a self-complementary adeno-associated virus serotype 9 abolished the symptom of bradycardia and significantly decreased the severity of the heart defect. We conclude that severe SMA animals have compromised cardiac function resulting at least partially from early bradycardia, which is likely attributable to aberrant autonomic signaling. Further cardiographic studies of human SMA patients are needed to clarify the clinical relevance of these findings from this SMA mouse.

  16. Early heart failure in the SMNΔ7 model of spinal muscular atrophy and correction by postnatal scAAV9-SMN delivery

    PubMed Central

    Bevan, Adam K.; Hutchinson, Kirk R.; Foust, Kevin D.; Braun, Lyndsey; McGovern, Vicki L.; Schmelzer, Leah; Ward, Jennifer G.; Petruska, Jeffrey C.; Lucchesi, Pamela A.; Burghes, Arthur H.M.; Kaspar, Brian K.

    2010-01-01

    Proximal spinal muscular atrophy (SMA) is a debilitating neurological disease marked by isolated lower motor neuron death and subsequent atrophy of skeletal muscle. Historically, SMA pathology was thought to be limited to lower motor neurons and the skeletal muscles they control, yet there are several reports describing the coincidence of cardiovascular abnormalities in SMA patients. As new therapies for SMA emerge, it is necessary to determine whether these non-neuromuscular systems need to be targeted. Therefore, we have characterized left ventricular (LV) function of SMA mice (SMN2+/+; SMNΔ7+/+; Smn−/−) and compared it with that of their unaffected littermates at 7 and 14 days of age. Anatomical and physiological measurements made by electrocardiogram and echocardiography show that affected mouse pups have a dramatic decrease in cardiac function. At 14 days of age, SMA mice have bradycardia and develop a marked dilated cardiomyopathy with a concomitant decrease in contractility. Signs of decreased cardiac function are also apparent as early as 7 days of age in SMA animals. Delivery of a survival motor neuron-1 transgene using a self-complementary adeno-associated virus serotype 9 abolished the symptom of bradycardia and significantly decreased the severity of the heart defect. We conclude that severe SMA animals have compromised cardiac function resulting at least partially from early bradycardia, which is likely attributable to aberrant autonomic signaling. Further cardiographic studies of human SMA patients are needed to clarify the clinical relevance of these findings from this SMA mouse. PMID:20639395

  17. [Genetic tests and clinical re-evaluation of 85 children with suspected spinal muscular atrophy].

    PubMed

    Ji, Xing; Liu, Xiao-qing; Shen, Jia-wei; Li, Xi-hua; Tao, Jiong

    2010-06-01

    Spinal muscular atrophy (SMA), characterized by degeneration of the anterior horn cells in the spinal cord and symmetric proximal muscle weakness, is the most common autosomal recessive neuromuscular disease in infants and children. In Caucasian population, about 95% of clinically typical patients lack both copies of the telomeric survival motor neuron gene (SMN 1). However, the detection rate of the homozygous absence in Chinese patients is still controversial, which may lead to reduced confidence in the SMA genetic testing in clinical practice. The purpose of the current study was to determine the frequency of homozygous deletions of SMN 1 in Chinese patients, to evaluate the significance of the SMN 1 homozygous deletion assay in clinical applications, and the impact of the clinical re-visit followed by the genetic testing. Totally 85 patients initially suspected of SMA were referred for SMA genetic testing. A polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) assay was used to detect the homozygous absence of SMN 1. Clinical re-visit was performed by the pediatric neurology specialists according to the international SMA diagnostic criteria, and histological examinations were carried out when they were necessary. Absence of both copies of SMN 1 exon 7 were found in 57 (67%) of the 85 patients, and 28 patients (33%) had at least one copy. For the 28 patients with negative results, 19 were followed up by the pediatric neurologists. The clinical diagnosis of SMA could be excluded in 15 patients, but retained in the other 4 patients after the clinical re-evaluation and histological examinations. Thus, approximately 95% of the patients with clinically typical SMA in our cohort lacked both copies of SMN 1. Homozygous deletions of SMN 1 were detected in 96% (22/23), 93% (28/30) and 100% (7/7) of the patients with SMA type I, type II and type III, respectively. There was no significant difference in the deletion frequency among the subtypes

  18. Swallowing markers in spinal and bulbar muscular atrophy.

    PubMed

    Banno, Haruhiko; Katsuno, Masahisa; Suzuki, Keisuke; Tanaka, Seiya; Suga, Noriaki; Hashizume, Atsushi; Mano, Tomoo; Araki, Amane; Watanabe, Hirohisa; Fujimoto, Yasushi; Yamamoto, Masahiko; Sobue, Gen

    2017-08-01

    We examined the characteristics of dysphagia in spinal and bulbar muscular atrophy, a hereditary neuromuscular disease causing weakness of limb, facial, and oropharyngeal muscles via a videofluoroscopic swallowing study, and investigated the plausibility of using these outcome measures for quantitative analysis. A videofluoroscopic swallowing study was performed on 111 consecutive patients with genetically confirmed spinal and bulbar muscular atrophy and 53 age- and sex-matched healthy controls. Swallowing of 3-mL liquid barium was analyzed by the Logemann's Videofluorographic Examination of Swallowing worksheet. Of more than 40 radiographic findings, the most pertinent abnormal findings in patients with spinal and bulbar muscular atrophy, included vallecular residue after swallow (residue just behind the tongue base), nasal penetration, and insufficient tongue movement (P < 0.001 for each) compared with healthy controls. Quantitative analyses showed that pharyngeal residue after initial swallowing, oral residue after initial swallowing, multiple swallowing sessions, and the penetration-aspiration scale were significantly worse in these patients (P ≤ 0.005 for each) than in controls. In patients with spinal and bulbar muscular atrophy, laryngeal penetration was observed more frequently in those without subjective dysphagia. Dysphagia of spinal and bulbar muscular atrophy was characterized by impaired tongue movement in the oral phase and nasal penetration followed by pharyngeal residues, which resulted in multiple swallowing sessions and laryngeal penetration. Although major limitations of reproducibility and radiation exposure still exist with videofluoroscopy, pharyngeal residue after initial swallowing and the penetration-aspiration scale might serve as potential outcome measures in clinical studies.

  19. Motor Neuron Rescue in Spinal Muscular Atrophy Mice Demonstrates That Sensory-Motor Defects Are a Consequence, Not a Cause, of Motor Neuron Dysfunction

    PubMed Central

    Gogliotti, Rocky G.; Quinlan, Katharina A.; Barlow, Courtenay B.; Heier, Christopher R.; Heckman, C. J.

    2012-01-01

    The loss of motor neurons (MNs) is a hallmark of the neuromuscular disease spinal muscular atrophy (SMA); however, it is unclear whether this phenotype autonomously originates within the MN. To address this question, we developed an inducible mouse model of severe SMA that has perinatal lethality, decreased motor function, motor unit pathology, and hyperexcitable MNs. Using an Hb9-Cre allele, we increased Smn levels autonomously within MNs and demonstrate that MN rescue significantly improves all phenotypes and pathologies commonly described in SMA mice. MN rescue also corrects hyperexcitability in SMA motor neurons and prevents sensory-motor synaptic stripping. Survival in MN-rescued SMA mice is extended by only 5 d, due in part to failed autonomic innervation of the heart. Collectively, this work demonstrates that the SMA phenotype autonomously originates in MNs and that sensory-motor synapse loss is a consequence, not a cause, of MN dysfunction. PMID:22423102

  20. Label-free proteomics identifies Calreticulin and GRP75/Mortalin as peripherally accessible protein biomarkers for spinal muscular atrophy

    PubMed Central

    2013-01-01

    Background Spinal muscular atrophy (SMA) is a neuromuscular disease resulting from mutations in the survival motor neuron 1 (SMN1) gene. Recent breakthroughs in preclinical research have highlighted several potential novel therapies for SMA, increasing the need for robust and sensitive clinical trial platforms for evaluating their effectiveness in human patient cohorts. Given that most clinical trials for SMA are likely to involve young children, there is a need for validated molecular biomarkers to assist with monitoring disease progression and establishing the effectiveness of therapies being tested. Proteomics technologies have recently been highlighted as a potentially powerful tool for such biomarker discovery. Methods We utilized label-free proteomics to identify individual proteins in pathologically-affected skeletal muscle from SMA mice that report directly on disease status. Quantitative fluorescent western blotting was then used to assess whether protein biomarkers were robustly changed in muscle, skin and blood from another mouse model of SMA, as well as in a small cohort of human SMA patient muscle biopsies. Results By comparing the protein composition of skeletal muscle in SMA mice at a pre-symptomatic time-point with the muscle proteome at a late-symptomatic time-point we identified increased expression of both Calreticulin and GRP75/Mortalin as robust indicators of disease progression in SMA mice. We report that these protein biomarkers were consistently modified in different mouse models of SMA, as well as across multiple skeletal muscles, and were also measurable in skin biopsies. Furthermore, Calreticulin and GRP75/Mortalin were measurable in muscle biopsy samples from human SMA patients. Conclusions We conclude that label-free proteomics technology provides a powerful platform for biomarker identification in SMA, revealing Calreticulin and GRP75/Mortalin as peripherally accessible protein biomarkers capable of reporting on disease progression in

  1. Spinal muscular atrophy patient detection and carrier screening using dried blood spots on filter paper.

    PubMed

    Harahap, Nur Imma Fatimah; Harahap, Indra Sari Kusuma; Kaszynski, Richard Hideki; Nurputra, Dian Kesuma Pramudya; Hartomo, Tri Budi; Pham, Huyen Thi Van; Yamamoto, Tomoto; Morikawa, Satoru; Nishimura, Noriyuki; Rusdi, Imam; Widiastuti, Retno; Nishio, Hisahide

    2012-02-01

    Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder. It is caused by mutations in the SMN1, and its clinical severity is modified by copy number variations of the SMN2. According to previous studies, deletion of SMN1 exon 7 is the most frequently observed in patients with SMA. Therefore, molecular analyses exploiting this genetic lesion could be beneficial in the diagnosis of SMA. Unfortunately, in many geographical regions, physicians do not have the latest molecular screening technologies at their immediate disposal. Thus, to overcome this issue, we developed an SMA-diagnosing system using dried blood spots (DBS) placed on filter paper to facilitate remote diagnosis. In this study, we validate the applicability of DBS on Flinders Technology Associates (FTA) filter paper for detecting SMN1 exon 7 deletions and copy number variations of SMN1 and SMN2. To detect exon 7 deletions in SMN1, polymerase chain reaction (PCR)-restriction fragment length polymorphism analysis was conducted by using DNA extracted from the DBS on FTA filter paper that had been stored at room temperature for a period of up to 4 years. To determine the copy numbers of SMN1 and SMN2, we carried out SYBR green-based real-time PCR by using the same blood specimens. The results obtained from the DBS on FTA filter paper were in complete concordance with those analyses using fresh blood specimens. This indicates that DBS on filter papers is a reliable method for SMA patient detection and carrier screenings. The SMA-diagnosing system, combined with the mailing of DBS on filter paper, will be beneficial for patients suffering from neuromuscular disorders in areas with limited or no access to diagnostic facilities with molecular capabilities.

  2. Characterization of a protein kinase gene in allelic association with the spinal muscular atrophy locus

    SciTech Connect

    Wang, C.H.; Carter, T.A.; Kleyn, P.W.

    1994-09-01

    A protein kinase gene has been identified from a 400 Kb minimal genetic region which defines the spinal muscular atrophy (SMA) locus. A highly polymorphic microsatellite marker (D5S1414) isolated from a yeast artificial chromosome (YAC) clone within this interval detects linkage disequilibrium with the SMA locus in 32 Polish families (Yule`s coefficient: 0.92) and maps to an intron of the protein kinase gene. Exon amplification was used to isolate coding sequences from a YAC-derived phage subclone containing D5S1414. Five exons were identified and a GenBank search using the BLAST program showed complete homology of these exons with a protein kinase gene. The gene is expressed in all tissues checked to far. Full-length cDNAs have been identified from both normal and SMA brain libraries and by reverse-transcriptase (RT) PCR from RNA of various tissues. The cDNA sequences will be reported. The genomic sequences flanking each exon were determined by direct sequencing of the homologous phage. The marker D5S1414 was located within the intronic sequence between exons 6 and 7. To screen for disease mutations, PCR was performed across each exon including the flanking splice sites in normal controls and SMA samples shown to be homozygous across the region by haplotyping. Comparative sequence analysis of the products together with the RT-PCR from normal and SMA brain RNA has identified several candidate polymorphisms. To date, the most interesting lead is an intronic polymorphism possibly affecting exon splicing in a homozygous SMA patient. An updated mutation search will be reported.

  3. Autosomal dominant congenital spinal muscular atrophy: a true form of spinal muscular atrophy caused by early loss of anterior horn cells.

    PubMed

    Oates, Emily C; Reddel, Stephen; Rodriguez, Michael L; Gandolfo, Luke C; Bahlo, Melanie; Hawke, Simon H; Lamandé, Shireen R; Clarke, Nigel F; North, Kathryn N

    2012-06-01

    Autosomal dominant congenital spinal muscular atrophy is characterized by predominantly lower limb weakness and wasting, and congenital or early-onset contractures of the hip, knee and ankle. Mutations in TRPV4, encoding a cation channel, have recently been identified in one large dominant congenital spinal muscular atrophy kindred, but the genetic basis of dominant congenital spinal muscular atrophy in many families remains unknown. It has been hypothesized that differences in the timing and site of anterior horn cell loss in the central nervous system account for the variations in clinical phenotype between different forms of spinal muscular atrophy, but there has been a lack of neuropathological data to support this concept in dominant congenital spinal muscular atrophy. We report clinical, electrophysiology, muscle magnetic resonance imaging and histopathology findings in a four generation family with typical dominant congenital spinal muscular atrophy features, without mutations in TRPV4, and in whom linkage to other known dominant neuropathy and spinal muscular atrophy genes has been excluded. The autopsy findings in the proband, who died at 14 months of age from an unrelated illness, provided a rare opportunity to study the neuropathological basis of dominant congenital spinal muscular atrophy. There was a reduction in anterior horn cell number in the lumbar and, to a lesser degree, the cervical spinal cord, and atrophy of the ventral nerve roots at these levels, in the absence of additional peripheral nerve pathology or abnormalities elsewhere along the neuraxis. Despite the young age of the child at the time of autopsy, there was no pathological evidence of ongoing loss or degeneration of anterior horn cells suggesting that anterior horn cell loss in dominant congenital spinal muscular atrophy occurs in early life, and is largely complete by the end of infancy. These findings confirm that dominant congenital spinal muscular atrophy is a true form of spinal

  4. SMN2 copy number predicts acute or chronic spinal muscular atrophy but does not account for intrafamilial variability in siblings.

    PubMed

    Cuscó, I; Barceló, M J; Rojas-García, R; Illa, I; Gámez, J; Cervera, C; Pou, A; Izquierdo, G; Baiget, M; Tizzano, E F

    2006-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disorder that affects motor neurons. It is caused by mutations in the survival motor neuron gene 1 (SMN1). The SMN2 gene, which is the highly homologous SMN1 copy that is present in all the patients, is unable to prevent the disease. An SMN2 dosage method was applied to 45 patients with the three SMA types (I-III) and to four pairs of siblings with chronic SMA (II-III) and different phenotypes. Our results confirm that the SMN2 copy number plays a key role in predicting acute or chronic SMA. However, siblings with different SMA phenotypes show an identical SMN2 copy number and identical markers, indicating that the genetic background around the SMA locus is insufficient to account for the intrafamilial variability. In our results, age of onset appears to be the most important predictor of disease severity in affected members of the same family. Given that SMN2 is regarded as a target for potential pharmacological therapies in SMA, the identification of genetic factors other than the SMN genes is necessary to better understand the pathogenesis of the disease in order to implement additional therapeutic approaches.

  5. [The role of RNA splicing in the pathogenesis of spinal muscular atrophy and development of its therapeutics].

    PubMed

    Sahashi, Kentaro; Sobue, Gen

    2014-12-01

    Loss-of-function mutations in SMN1 cause spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. Degeneration of alpha-motor neurons that results in progressive paralysis is a pathological hallmark of SMA. Recently, peripheral-tissue involvement has also been reported in SMA. Patients have low levels of functional SMN which is attributed to alternative splicing in SMN2, a gene closely-related to SMN1. This decrease in the expression of SMN, a ubiquitously expressed protein involved in promoting snRNP assembly required for splicing, is responsible for SMA. However, the mechanism through which decrease in SMN levels causes SMA remains unclear. Currently, no curative treatment is available for SMA, but SMN restoration is thought to be necessary and sufficient for cure. Antisense oligonucleotides (ASOs) can be designed to specifically alter splicing patterns of target pre-mRNAs. We identified an ASO that redirects SMN2 splicing and is currently in clinical trials for use as RNA-targeting therapeutics. Further, we have also reported a novel application of splicing-modulating ASOs--creation of animal phenocopy models of diseases by inducing mis-splicing. Exploring the relationship between the spatial and temporal effects of therapeutic and pathogenic ASOs yields relevant insights into the roles of SMN in SMA pathogenesis and into its normal physiological functions. This knowledge, in turn, contributes to the ongoing development of targeted therapeutics.

  6. Spinal Muscular Atrophy Patient iPSC-Derived Motor Neurons Have Reduced Expression of Proteins Important in Neuronal Development

    PubMed Central

    Fuller, Heidi R.; Mandefro, Berhan; Shirran, Sally L.; Gross, Andrew R.; Kaus, Anjoscha S.; Botting, Catherine H.; Morris, Glenn E.; Sareen, Dhruv

    2016-01-01

    Spinal muscular atrophy (SMA) is an inherited neuromuscular disease primarily characterized by degeneration of spinal motor neurons, and caused by reduced levels of the SMN protein. Previous studies to understand the proteomic consequences of reduced SMN have mostly utilized patient fibroblasts and animal models. We have derived human motor neurons from type I SMA and healthy controls by creating their induced pluripotent stem cells (iPSCs). Quantitative mass spectrometry of these cells revealed increased expression of 63 proteins in control motor neurons compared to respective fibroblasts, whereas 30 proteins were increased in SMA motor neurons vs. their fibroblasts. Notably, UBA1 was significantly decreased in SMA motor neurons, supporting evidence for ubiquitin pathway defects. Subcellular distribution of UBA1 was predominantly cytoplasmic in SMA motor neurons in contrast to nuclear in control motor neurons; suggestive of neurodevelopmental abnormalities. Many of the proteins that were decreased in SMA motor neurons, including beta III-tubulin and UCHL1, were associated with neurodevelopment and differentiation. These neuron-specific consequences of SMN depletion were not evident in fibroblasts, highlighting the importance of iPSC technology. The proteomic profiles identified here provide a useful resource to explore the molecular consequences of reduced SMN in motor neurons, and for the identification of novel biomarker and therapeutic targets for SMA. PMID:26793058

  7. Histopathological Defects in Intestine in Severe Spinal Muscular Atrophy Mice Are Improved by Systemic Antisense Oligonucleotide Treatment

    PubMed Central

    Sintusek, Palittiya; Catapano, Francesco; Angkathunkayul, Napat; Marrosu, Elena; Parson, Simon H.; Morgan, Jennifer E.; Muntoni, Francesco; Zhou, Haiyan

    2016-01-01

    Gastrointestinal (GI) defects, including gastroesophageal reflux, constipation and delayed gastric emptying, are common in patients with spinal muscular atrophy (SMA). Similar GI dysmotility has been identified in mouse models with survival of motor neuron (SMN) protein deficiency. We previously described vascular defects in skeletal muscle and spinal cord of SMA mice and we hypothesized that similar defects could be involved in the GI pathology observed in these mice. We therefore investigated the gross anatomical structure, enteric vasculature and neurons in the small intestine in a severe mouse model of SMA. We also assessed the therapeutic response of GI histopathology to systemic administration of morpholino antisense oligonucleotide (AON) designed to increase SMN protein expression. Significant anatomical and histopathological abnormalities, with striking reduction of vascular density, overabundance of enteric neurons and increased macrophage infiltration, were detected in the small intestine in SMA mice. After systemic AON treatment in neonatal mice, all the abnormalities observed were significantly restored to near-normal levels. We conclude that the observed GI histopathological phenotypes and functional defects observed in these SMA mice are strongly linked to SMN deficiency which can be rescued by systemic administration of AON. This study on the histopathological changes in the gastrointestinal system in severe SMA mice provides further indication of the complex role that SMN plays in multiple tissues and suggests that at least in SMA mice restoration of SMN production in peripheral tissues is essential for optimal outcome. PMID:27163330

  8. Modeling the phenotype of spinal muscular atrophy by the direct conversion of human fibroblasts to motor neurons.

    PubMed

    Zhang, Qi-Jie; Li, Jin-Jing; Lin, Xiang; Lu, Ying-Qian; Guo, Xin-Xin; Dong, En-Lin; Zhao, Miao; He, Jin; Wang, Ning; Chen, Wan-Jin

    2017-02-14

    Spinal muscular atrophy (SMA) is a lethal autosomal recessive neurological disease characterized by selective degeneration of motor neurons in the spinal cord. In recent years, the development of cellular reprogramming technology has provided an alternative and effective method for obtaining patient-specific neurons in vitro. In the present study, we applied this technology to the field of SMA to acquire patient-specific induced motor neurons that were directly converted from fibroblasts via the forced expression of 8 defined transcription factors. The infected fibroblasts began to grow in a dipolar manner, and the nuclei gradually enlarged. Typical Tuj1-positive neurons were generated at day 23. After day 35, induced neurons with multiple neurites were observed, and these neurons also expressed the hallmarks of Tuj1, HB9, ISL1 and CHAT. The conversion efficiencies were approximately 5.8% and 5.5% in the SMA and control groups, respectively. Additionally, the SMA-induced neurons exhibited a significantly reduced neurite outgrowth rate compared with the control neurons. After day 60, the SMA-induced neurons also exhibited a liability of neuronal degeneration and remarkable fracturing of the neurites was observed. By directly reprogramming fibroblasts, we established a feeder-free conversion system to acquire SMA patient-specific induced motor neurons that partially modeled the phenotype of SMA in vitro.

  9. Histopathological Defects in Intestine in Severe Spinal Muscular Atrophy Mice Are Improved by Systemic Antisense Oligonucleotide Treatment.

    PubMed

    Sintusek, Palittiya; Catapano, Francesco; Angkathunkayul, Napat; Marrosu, Elena; Parson, Simon H; Morgan, Jennifer E; Muntoni, Francesco; Zhou, Haiyan

    2016-01-01

    Gastrointestinal (GI) defects, including gastroesophageal reflux, constipation and delayed gastric emptying, are common in patients with spinal muscular atrophy (SMA). Similar GI dysmotility has been identified in mouse models with survival of motor neuron (SMN) protein deficiency. We previously described vascular defects in skeletal muscle and spinal cord of SMA mice and we hypothesized that similar defects could be involved in the GI pathology observed in these mice. We therefore investigated the gross anatomical structure, enteric vasculature and neurons in the small intestine in a severe mouse model of SMA. We also assessed the therapeutic response of GI histopathology to systemic administration of morpholino antisense oligonucleotide (AON) designed to increase SMN protein expression. Significant anatomical and histopathological abnormalities, with striking reduction of vascular density, overabundance of enteric neurons and increased macrophage infiltration, were detected in the small intestine in SMA mice. After systemic AON treatment in neonatal mice, all the abnormalities observed were significantly restored to near-normal levels. We conclude that the observed GI histopathological phenotypes and functional defects observed in these SMA mice are strongly linked to SMN deficiency which can be rescued by systemic administration of AON. This study on the histopathological changes in the gastrointestinal system in severe SMA mice provides further indication of the complex role that SMN plays in multiple tissues and suggests that at least in SMA mice restoration of SMN production in peripheral tissues is essential for optimal outcome.

  10. Use of genetic and physical mapping to locate the spinal muscular atrophy locus between two new highly polymorphic DNA markers

    SciTech Connect

    Clermont, O.; Burlet, P.; Burglen, L.; Lefebvre, S.; Pascal, F.; McPherson, J.; Wasmuth, J.J.; Cohen, D.; Le Paslier, D.; Weissenbach, J.

    1994-04-01

    The gene for autosomal recessive forms of spinal muscular atrophy (SMA) has recently been mapped to chromosome 5q13, within a 4-cM region between the blocks D5S465/D5S125 and MAP-1B/D5S112. The authors identified two new highly polymorphic microsatellite DNA markers - namely, AFM265wf5 (D5S629) and AFM281yh9 (D5S637) - which are the closest markers to the SMA locus. Multilocus analysis by the location-score method was used to establish the best estimate of the SMA gene location. The data suggest that the most likely location for SMA is between locus D5S629 and the block D5S637/D5S351/MAP-1B/D5S112/D5S357. Genetic analysis of inbred SMA families, based on homozygosity by descent and physical mapping using meta-YACs, gave additional information for the loci order as follows: cen-D5S6-D5S125/D5S465-D5S435-D5S629-SMA-D5S637-D5S351-MAP-1B/D5S112-D5S357-D5S39-tel. These data give the direction for bidirectional walking in order to clone this interval and isolate the SMA gene. 16 refs., 4 figs., 2 tabs.

  11. Acid ceramidase deficiency associated with spinal muscular atrophy with progressive myoclonic epilepsy.

    PubMed

    Gan, Joanna J; Garcia, Virginie; Tian, Jane; Tagliati, Michele; Parisi, Joseph E; Chung, Jeffrey M; Lewis, Richard; Baloh, Robert; Levade, Thierry; Pierson, Tyler Mark

    2015-12-01

    Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is an extremely rare disorder related to the lysosomal storage disease, Farber lipogranulomatosis. Both disorders are autosomal recessive conditions caused by mutations in the ASAH1 gene encoding acid ceramidase. Farber disease is associated with joint deformities, lipomatous skin nodules, and often is fatal by 2-3 years of age; while SMA-PME is characterized by childhood-onset motor neuron disease and progressive myoclonic epilepsy. We report a case of SMA-PME with a novel mutation in the ASAH1 gene encoding acid ceramidase. The proband presented with childhood-onset of diffuse muscle atrophy and hypotonia. He also had diffuse weakness with greater proximal than distal involvement. Tongue fasciculations were present and his reflexes were either diminished or absent. He ambulated with an unsteady and hesitant gait. He subsequently developed myoclonic epilepsy along with other associated features including tremor, polymyoclonus, and sensorineural hearing loss. Neurophysiological studies revealed a motor neuron disorder and generalized epilepsy. Exome sequencing analysis identified compound heterozygous variants and biochemical analysis indicated acid ceramidase activity was approximately 12 percent of normal controls. Our proband was phenotypically similar to other cases of SMA-PME, albeit with somewhat lesser severity, slower progression, and greater longevity. As lysosomal disorders are sometimes amendable to early interventions, it is important to make early diagnoses in these cases. The combination of motor neuron disease and progressive myoclonic epilepsy should prompt genetic evaluation of ASAH1. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. SMN deficiency in severe models of spinal muscular atrophy causes widespread intron retention and DNA damage

    PubMed Central

    Jangi, Mohini; Fleet, Christina; Cullen, Patrick; Gupta, Shipra V.; Mekhoubad, Shila; Chiao, Eric; Allaire, Norm; Bennett, C. Frank; Rigo, Frank; Krainer, Adrian R.; Hurt, Jessica A.; Carulli, John P.; Staropoli, John F.

    2017-01-01

    Spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disease, is the leading monogenic cause of infant mortality. Homozygous loss of the gene survival of motor neuron 1 (SMN1) causes the selective degeneration of lower motor neurons and subsequent atrophy of proximal skeletal muscles. The SMN1 protein product, survival of motor neuron (SMN), is ubiquitously expressed and is a key factor in the assembly of the core splicing machinery. The molecular mechanisms by which disruption of the broad functions of SMN leads to neurodegeneration remain unclear. We used an antisense oligonucleotide (ASO)-based inducible mouse model of SMA to investigate the SMN-specific transcriptome changes associated with neurodegeneration. We found evidence of widespread intron retention, particularly of minor U12 introns, in the spinal cord of mice 30 d after SMA induction, which was then rescued by a therapeutic ASO. Intron retention was concomitant with a strong induction of the p53 pathway and DNA damage response, manifesting as γ-H2A.X positivity in neurons of the spinal cord and brain. Widespread intron retention and markers of the DNA damage response were also observed with SMN depletion in human SH-SY5Y neuroblastoma cells and human induced pluripotent stem cell-derived motor neurons. We also found that retained introns, high in GC content, served as substrates for the formation of transcriptional R-loops. We propose that defects in intron removal in SMA promote DNA damage in part through the formation of RNA:DNA hybrid structures, leading to motor neuron death. PMID:28270613

  13. SMN deficiency in severe models of spinal muscular atrophy causes widespread intron retention and DNA damage.

    PubMed

    Jangi, Mohini; Fleet, Christina; Cullen, Patrick; Gupta, Shipra V; Mekhoubad, Shila; Chiao, Eric; Allaire, Norm; Bennett, C Frank; Rigo, Frank; Krainer, Adrian R; Hurt, Jessica A; Carulli, John P; Staropoli, John F

    2017-03-21

    Spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disease, is the leading monogenic cause of infant mortality. Homozygous loss of the gene survival of motor neuron 1 (SMN1) causes the selective degeneration of lower motor neurons and subsequent atrophy of proximal skeletal muscles. The SMN1 protein product, survival of motor neuron (SMN), is ubiquitously expressed and is a key factor in the assembly of the core splicing machinery. The molecular mechanisms by which disruption of the broad functions of SMN leads to neurodegeneration remain unclear. We used an antisense oligonucleotide (ASO)-based inducible mouse model of SMA to investigate the SMN-specific transcriptome changes associated with neurodegeneration. We found evidence of widespread intron retention, particularly of minor U12 introns, in the spinal cord of mice 30 d after SMA induction, which was then rescued by a therapeutic ASO. Intron retention was concomitant with a strong induction of the p53 pathway and DNA damage response, manifesting as γ-H2A.X positivity in neurons of the spinal cord and brain. Widespread intron retention and markers of the DNA damage response were also observed with SMN depletion in human SH-SY5Y neuroblastoma cells and human induced pluripotent stem cell-derived motor neurons. We also found that retained introns, high in GC content, served as substrates for the formation of transcriptional R-loops. We propose that defects in intron removal in SMA promote DNA damage in part through the formation of RNA:DNA hybrid structures, leading to motor neuron death.

  14. Neurocalcin Delta Suppression Protects against Spinal Muscular Atrophy in Humans and across Species by Restoring Impaired Endocytosis.

    PubMed

    Riessland, Markus; Kaczmarek, Anna; Schneider, Svenja; Swoboda, Kathryn J; Löhr, Heiko; Bradler, Cathleen; Grysko, Vanessa; Dimitriadi, Maria; Hosseinibarkooie, Seyyedmohsen; Torres-Benito, Laura; Peters, Miriam; Upadhyay, Aaradhita; Biglari, Nasim; Kröber, Sandra; Hölker, Irmgard; Garbes, Lutz; Gilissen, Christian; Hoischen, Alexander; Nürnberg, Gudrun; Nürnberg, Peter; Walter, Michael; Rigo, Frank; Bennett, C Frank; Kye, Min Jeong; Hart, Anne C; Hammerschmidt, Matthias; Kloppenburg, Peter; Wirth, Brunhilde

    2017-02-02

    Homozygous SMN1 loss causes spinal muscular atrophy (SMA), the most common lethal genetic childhood motor neuron disease. SMN1 encodes SMN, a ubiquitous housekeeping protein, which makes the primarily motor neuron-specific phenotype rather unexpected. SMA-affected individuals harbor low SMN expression from one to six SMN2 copies, which is insufficient to functionally compensate for SMN1 loss. However, rarely individuals with homozygous absence of SMN1 and only three to four SMN2 copies are fully asymptomatic, suggesting protection through genetic modifier(s). Previously, we identified plastin 3 (PLS3) overexpression as an SMA protective modifier in humans and showed that SMN deficit impairs endocytosis, which is rescued by elevated PLS3 levels. Here, we identify reduction of the neuronal calcium sensor Neurocalcin delta (NCALD) as a protective SMA modifier in five asymptomatic SMN1-deleted individuals carrying only four SMN2 copies. We demonstrate that NCALD is a Ca(2+)-dependent negative regulator of endocytosis, as NCALD knockdown improves endocytosis in SMA models and ameliorates pharmacologically induced endocytosis defects in zebrafish. Importantly, NCALD knockdown effectively ameliorates SMA-associated pathological defects across species, including worm, zebrafish, and mouse. In conclusion, our study identifies a previously unknown protective SMA modifier in humans, demonstrates modifier impact in three different SMA animal models, and suggests a potential combinatorial therapeutic strategy to efficiently treat SMA. Since both protective modifiers restore endocytosis, our results confirm that endocytosis is a major cellular mechanism perturbed in SMA and emphasize the power of protective modifiers for understanding disease mechanism and developing therapies. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  15. Astrocyte-produced miR-146a as a mediator of motor neuron loss in spinal muscular atrophy.

    PubMed

    Sison, Samantha L; Patitucci, Teresa N; Seminary, Emily R; Villalon, Eric; Lorson, Christian L; Ebert, Allison D

    2017-09-01

    Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, is caused by the loss of the survival motor neuron-1 (SMN1) gene, which leads to motor neuron loss, muscle atrophy, respiratory distress, and death. Motor neurons exhibit the most profound loss, but the mechanisms underlying disease pathogenesis are not fully understood. Recent evidence suggests that motor neuron extrinsic influences, such as those arising from astrocytes, contribute to motor neuron malfunction and loss. Here we investigated both loss-of-function and toxic gain-of-function astrocyte mechanisms that could play a role in SMA pathology. We had previously found that glial derived neurotrophic factor (GDNF) is reduced in SMA astrocytes. However, reduced GDNF expression does not play a major role in SMA pathology as viral-mediated GDNF re-expression did not improve astrocyte function or motor neuron loss. In contrast, we found that SMA astrocytes increased microRNA (miR) production and secretion compared to control astrocytes, suggesting potential toxic gain-of-function properties. Specifically, we found that miR-146a was significantly upregulated in SMA induced pluripotent stem cell (iPSC)-derived astrocytes and SMNΔ7 mouse spinal cord. Moreover, increased miR-146a was sufficient to induce motor neuron loss in vitro, whereas miR-146a inhibition prevented SMA astrocyte-induced motor neuron loss. Together, these data indicate that altered astrocyte production of miR-146a may be a contributing factor in astrocyte-mediated SMA pathology. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  16. Feasibility of Using Microsoft Kinect to Assess Upper Limb Movement in Type III Spinal Muscular Atrophy Patients.

    PubMed

    Chen, Xing; Siebourg-Polster, Juliane; Wolf, Detlef; Czech, Christian; Bonati, Ulrike; Fischer, Dirk; Khwaja, Omar; Strahm, Martin

    2017-01-01

    Although functional rating scales are being used increasingly as primary outcome measures in spinal muscular atrophy (SMA), sensitive and objective assessment of early-stage disease progression and drug efficacy remains challenging. We have developed a game based on the Microsoft Kinect sensor, specifically designed to measure active upper limb movement. An explorative study was conducted to determine the feasibility of this new tool in 18 ambulant SMA type III patients and 19 age- and gender-matched healthy controls. Upper limb movement was analysed elaborately through derived features such as elbow flexion and extension angles, arm lifting angle, velocity and acceleration. No significant differences were found in the active range of motion between ambulant SMA type III patients and controls. Hand velocity was found to be different but further validation is necessary. This study presents an important step in the process of designing and handling digital biomarkers as complementary outcome measures for clinical trials.

  17. Feasibility of Using Microsoft Kinect to Assess Upper Limb Movement in Type III Spinal Muscular Atrophy Patients

    PubMed Central

    Siebourg-Polster, Juliane; Wolf, Detlef; Czech, Christian; Bonati, Ulrike; Fischer, Dirk; Khwaja, Omar; Strahm, Martin

    2017-01-01

    Although functional rating scales are being used increasingly as primary outcome measures in spinal muscular atrophy (SMA), sensitive and objective assessment of early-stage disease progression and drug efficacy remains challenging. We have developed a game based on the Microsoft Kinect sensor, specifically designed to measure active upper limb movement. An explorative study was conducted to determine the feasibility of this new tool in 18 ambulant SMA type III patients and 19 age- and gender-matched healthy controls. Upper limb movement was analysed elaborately through derived features such as elbow flexion and extension angles, arm lifting angle, velocity and acceleration. No significant differences were found in the active range of motion between ambulant SMA type III patients and controls. Hand velocity was found to be different but further validation is necessary. This study presents an important step in the process of designing and handling digital biomarkers as complementary outcome measures for clinical trials. PMID:28122039

  18. Motor neuron disease. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy.

    PubMed

    Naryshkin, Nikolai A; Weetall, Marla; Dakka, Amal; Narasimhan, Jana; Zhao, Xin; Feng, Zhihua; Ling, Karen K Y; Karp, Gary M; Qi, Hongyan; Woll, Matthew G; Chen, Guangming; Zhang, Nanjing; Gabbeta, Vijayalakshmi; Vazirani, Priya; Bhattacharyya, Anuradha; Furia, Bansri; Risher, Nicole; Sheedy, Josephine; Kong, Ronald; Ma, Jiyuan; Turpoff, Anthony; Lee, Chang-Sun; Zhang, Xiaoyan; Moon, Young-Choon; Trifillis, Panayiota; Welch, Ellen M; Colacino, Joseph M; Babiak, John; Almstead, Neil G; Peltz, Stuart W; Eng, Loren A; Chen, Karen S; Mull, Jesse L; Lynes, Maureen S; Rubin, Lee L; Fontoura, Paulo; Santarelli, Luca; Haehnke, Daniel; McCarthy, Kathleen D; Schmucki, Roland; Ebeling, Martin; Sivaramakrishnan, Manaswini; Ko, Chien-Ping; Paushkin, Sergey V; Ratni, Hasane; Gerlach, Irene; Ghosh, Anirvan; Metzger, Friedrich

    2014-08-08

    Spinal muscular atrophy (SMA) is a genetic disease caused by mutation or deletion of the survival of motor neuron 1 (SMN1) gene. A paralogous gene in humans, SMN2, produces low, insufficient levels of functional SMN protein due to alternative splicing that truncates the transcript. The decreased levels of SMN protein lead to progressive neuromuscular degeneration and high rates of mortality. Through chemical screening and optimization, we identified orally available small molecules that shift the balance of SMN2 splicing toward the production of full-length SMN2 messenger RNA with high selectivity. Administration of these compounds to Δ7 mice, a model of severe SMA, led to an increase in SMN protein levels, improvement of motor function, and protection of the neuromuscular circuit. These compounds also extended the life span of the mice. Selective SMN2 splicing modifiers may have therapeutic potential for patients with SMA. Copyright © 2014, American Association for the Advancement of Science.

  19. CNS-targeted gene therapy improves survival and motor function in a mouse model of spinal muscular atrophy

    PubMed Central

    Passini, Marco A.; Bu, Jie; Roskelley, Eric M.; Richards, Amy M.; Sardi, S. Pablo; O’Riordan, Catherine R.; Klinger, Katherine W.; Shihabuddin, Lamya S.; Cheng, Seng H.

    2010-01-01

    Spinal muscular atrophy (SMA) is a neuromuscular disease caused by a deficiency of survival motor neuron (SMN) due to mutations in the SMN1 gene. In this study, an adeno-associated virus (AAV) vector expressing human SMN (AAV8-hSMN) was injected at birth into the CNS of mice modeling SMA. Western blot analysis showed that these injections resulted in widespread expression of SMN throughout the spinal cord, and this translated into robust improvement in skeletal muscle physiology, including increased myofiber size and improved neuromuscular junction architecture. Treated mice also displayed substantial improvements on behavioral tests of muscle strength, coordination, and locomotion, indicating that the neuromuscular junction was functional. Treatment with AAV8-hSMN increased the median life span of mice with SMA-like disease to 50 days compared with 15 days for untreated controls. Moreover, injecting mice with SMA-like disease with a human SMN–expressing self-complementary AAV vector — a vector that leads to earlier onset of gene expression compared with standard AAV vectors — led to improved efficacy of gene therapy, including a substantial extension in median survival to 157 days. These data indicate that CNS-directed, AAV-mediated SMN augmentation is highly efficacious in addressing both neuronal and muscular pathologies in a severe mouse model of SMA. PMID:20234094

  20. Spinal muscular atrophy: development and implementation of potential treatments.

    PubMed

    Arnold, W David; Burghes, Arthur H M

    2013-09-01

    In neurodegenerative disorders, effective treatments are urgently needed, along with methods to determine whether treatment worked. In this review, we discuss the rapid progress in the understanding of recessive proximal spinal muscular atrophy and how this is leading to exciting potential treatments of the disease. Spinal muscular atrophy is caused by loss of the survival motor neuron 1 (SMN1) gene and reduced levels of SMN protein. The critical downstream targets of SMN deficiency that result in motor neuron loss are not known. However, increasing SMN levels has a marked impact in mouse models, and these therapeutics are rapidly moving toward clinical trials. Promising preclinical therapies, the varying degree of impact on the mouse models, and potential measures of treatment effect are reviewed. One key issue discussed is the variable outcome of increasing SMN at different stages of disease progression.

  1. Observational study of spinal muscular atrophy type I and implications for clinical trials

    PubMed Central

    McDermott, Michael P.; Kaufmann, Petra; Darras, Basil T.; Chung, Wendy K.; Sproule, Douglas M.; Kang, Peter B.; Foley, A. Reghan; Yang, Michelle L.; Martens, William B.; Oskoui, Maryam; Glanzman, Allan M.; Flickinger, Jean; Montes, Jacqueline; Dunaway, Sally; O'Hagen, Jessica; Quigley, Janet; Riley, Susan; Benton, Maryjane; Ryan, Patricia A.; Montgomery, Megan; Marra, Jonathan; Gooch, Clifton; De Vivo, Darryl C.

    2014-01-01

    Objectives: Prospective cohort study to characterize the clinical features and course of spinal muscular atrophy type I (SMA-I). Methods: Patients were enrolled at 3 study sites and followed for up to 36 months with serial clinical, motor function, laboratory, and electrophysiologic outcome assessments. Intervention was determined by published standard of care guidelines. Palliative care options were offered. Results: Thirty-four of 54 eligible subjects with SMA-I (63%) enrolled and 50% of these completed at least 12 months of follow-up. The median age at reaching the combined endpoint of death or requiring at least 16 hours/day of ventilation support was 13.5 months (interquartile range 8.1–22.0 months). Requirement for nutritional support preceded that for ventilation support. The distribution of age at reaching the combined endpoint was similar for subjects with SMA-I who had symptom onset before 3 months and after 3 months of age (p = 0.58). Having 2 SMN2 copies was associated with greater morbidity and mortality than having 3 copies. Baseline electrophysiologic measures indicated substantial motor neuron loss. By comparison, subjects with SMA-II who lost sitting ability (n = 10) had higher motor function, motor unit number estimate and compound motor action potential, longer survival, and later age when feeding or ventilation support was required. The mean rate of decline in The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders motor function scale was 1.27 points/year (95% confidence interval 0.21–2.33, p = 0.02). Conclusions: Infants with SMA-I can be effectively enrolled and retained in a 12-month natural history study until a majority reach the combined endpoint. These outcome data can be used for clinical trial design. PMID:25080519

  2. Newborn screening for spinal muscular atrophy: The views of affected families and adults

    PubMed Central

    Young, Philip J.; Griffiths, Frances E.

    2017-01-01

    Spinal muscular atrophy (SMA) is one of the leading genetic causes of infant death worldwide. However, due to a lack of treatments, SMA has historically fallen short of Wilson‐Jungner criteria. While studies have explored the acceptability of expanded newborn screening to the general public, the views of affected families have been largely overlooked. This is in spite of the potential for direct impacts on them and their unique positioning to consider the value of early diagnosis. We have previously reported data on attitudes toward pre‐conception and prenatal genetic screening for SMA among affected families (adults with SMA [n = 82] and family members [n = 255]). Here, using qualitative interview [n = 36] and survey data [n = 337], we report the views of this same cohort toward newborn screening. The majority (70%) of participants were in favor, however, all subgroups (except adults with type II) preferred pre‐conception and/or prenatal screening to newborn screening. Key reasons for newborn screening support were: (1) the potential for improved support; (2) the possibility of enrolling pre‐symptomatic children on clinical trials. Key reasons for non‐support were: (1) concerns about impact on the early experiences of the family; (2) inability to treat. Importantly, participants did not view the potential for inaccurate typing as a significant obstacle to the launch of a population‐wide screening program. This study underscores the need to include families affected by genetic diseases within consultations on screening. This is particularly important for conditions such as SMA which challenge traditional screening criteria, and for which new therapeutics are emerging. PMID:28374951

  3. Defining the therapeutic window in a severe animal model of spinal muscular atrophy.

    PubMed

    Robbins, Kate L; Glascock, Jacqueline J; Osman, Erkan Y; Miller, Madeline R; Lorson, Christian L

    2014-09-01

    Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by the loss of a single gene, Survival Motor Neuron-1 (SMN1). Administration of a self-complementary Adeno-Associated Virus vector expressing full-length SMN cDNA (scAAV-SMN) has proven an effective means to rescue the SMA phenotype in SMA mice, either by intravenous (IV) or intracerebroventricular (ICV) administration at very early time points. We have recently shown that ICV delivery of scAAV9-SMN is more effective than a similar dose of vector administered via an IV injection, thereby providing an important mechanism to examine a timeline for rescuing the disease and determining the therapeutic window in a severe model of SMA. In this report, we utilized a relatively severe mouse model of SMA, SMNΔ7. Animals were injected with scAAV9-SMN vector via ICV injection on a single day, from P2 through P8. At each delivery point from P2 through P8, scAAV9-SMN decreased disease severity. A near complete rescue was obtained following P2 injection while a P8 injection produced a ∼ 40% extension in survival. Analysis of the underlying neuromuscular junction (NMJ) pathology revealed that late-stage delivery of the vector failed to provide protection from NMJ defects despite robust SMN expression in the central nervous system. While our study demonstrates that a maximal benefit is obtained when treatment is delivered during pre-symptomatic stages, significant therapeutic benefit can still be achieved after the onset of disease symptoms. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  4. Targeting SR proteins improves SMN expression in spinal muscular atrophy cells.

    PubMed

    Wee, Claribel D; Havens, Mallory A; Jodelka, Francine M; Hastings, Michelle L

    2014-01-01

    Spinal muscular atrophy (SMA) is one of the most common inherited causes of pediatric mortality. SMA is caused by deletions or mutations in the survival of motor neuron 1 (SMN1) gene, which results in SMN protein deficiency. Humans have a centromeric copy of the survival of motor neuron gene, SMN2, which is nearly identical to SMN1. However, SMN2 cannot compensate for the loss of SMN1 because SMN2 has a single-nucleotide difference in exon 7, which negatively affects splicing of the exon. As a result, most mRNA produced from SMN2 lacks exon 7. SMN2 mRNA lacking exon 7 encodes a truncated protein with reduced functionality. Improving SMN2 exon 7 inclusion is a goal of many SMA therapeutic strategies. The identification of regulators of exon 7 inclusion may provide additional therapeutic targets or improve the design of existing strategies. Although a number of regulators of exon 7 inclusion have been identified, the function of most splicing proteins in exon 7 inclusion is unknown. Here, we test the role of SR proteins and hnRNP proteins in SMN2 exon 7 inclusion. Knockdown and overexpression studies reveal that SRSF1, SRSF2, SRSF3, SRSF4, SRSF5, SRSF6, SRSF7, SRSF11, hnRNPA1/B1 and hnRNP U can inhibit exon 7 inclusion. Depletion of two of the most potent inhibitors of exon 7 inclusion, SRSF2 or SRSF3, in cell lines derived from SMA patients, increased SMN2 exon 7 inclusion and SMN protein. Our results identify novel regulators of SMN2 exon 7 inclusion, revealing potential targets for SMA therapeutics.

  5. Targeting SR Proteins Improves SMN Expression in Spinal Muscular Atrophy Cells

    PubMed Central

    Hastings, Michelle L.

    2014-01-01

    Spinal muscular atrophy (SMA) is one of the most common inherited causes of pediatric mortality. SMA is caused by deletions or mutations in the survival of motor neuron 1 (SMN1) gene, which results in SMN protein deficiency. Humans have a centromeric copy of the survival of motor neuron gene, SMN2, which is nearly identical to SMN1. However, SMN2 cannot compensate for the loss of SMN1 because SMN2 has a single-nucleotide difference in exon 7, which negatively affects splicing of the exon. As a result, most mRNA produced from SMN2 lacks exon 7. SMN2 mRNA lacking exon 7 encodes a truncated protein with reduced functionality. Improving SMN2 exon 7 inclusion is a goal of many SMA therapeutic strategies. The identification of regulators of exon 7 inclusion may provide additional therapeutic targets or improve the design of existing strategies. Although a number of regulators of exon 7 inclusion have been identified, the function of most splicing proteins in exon 7 inclusion is unknown. Here, we test the role of SR proteins and hnRNP proteins in SMN2 exon 7 inclusion. Knockdown and overexpression studies reveal that SRSF1, SRSF2, SRSF3, SRSF4, SRSF5, SRSF6, SRSF7, SRSF11, hnRNPA1/B1 and hnRNP U can inhibit exon 7 inclusion. Depletion of two of the most potent inhibitors of exon 7 inclusion, SRSF2 or SRSF3, in cell lines derived from SMA patients, increased SMN2 exon 7 inclusion and SMN protein. Our results identify novel regulators of SMN2 exon 7 inclusion, revealing potential targets for SMA therapeutics. PMID:25506695

  6. A feedback loop regulates splicing of the spinal muscular atrophy-modifying gene, SMN2.

    PubMed

    Jodelka, Francine M; Ebert, Allison D; Duelli, Dominik M; Hastings, Michelle L

    2010-12-15

    Spinal muscular atrophy (SMA) is a neurological disorder characterized by motor neuron degeneration and progressive muscle paralysis. The disease is caused by a reduction in survival of motor neuron (SMN) protein resulting from homozygous deletion of the SMN1 gene. SMN protein is also encoded by SMN2. However, splicing of SMN2 exon 7 is defective, and consequently, the majority of the transcripts produce a truncated, unstable protein. SMN protein itself has a role in splicing. The protein is required for the biogenesis of spliceosomal snRNPs, which are essential components of the splicing reaction. We now show that SMN protein abundance affects the splicing of SMN2 exon 7, revealing a feedback loop inSMN expression. The reduced SMN protein concentration observed in SMA samples and in cells depleted of SMN correlates with a decrease in cellular snRNA levels and a decrease in SMN2 exon 7 splicing. Furthermore, altering the relative abundance or activity of individual snRNPs has distinct effects on exon 7 splicing, demonstrating that core spliceosomal snRNPs influence SMN2 alternative splicing. Our results identify a feedback loop in SMN expression by which low SMN protein levels exacerbate SMN exon 7 skipping, leading to a further reduction in SMN protein. These results imply that a modest increase in SMN protein abundance may cause a disproportionately large increase in SMN expression, a finding that is important for assessing the therapeutic potential of SMA treatments and understanding disease pathogenesis.

  7. Aquatic therapy for a child with type III spinal muscular atrophy: a case report.

    PubMed

    Salem, Yasser; Gropack, Stacy Jaffee

    2010-11-01

    Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by degeneration of alpha motor neurons. This case report describes an aquatic therapy program and the outcomes for a 3-year-old girl with type III SMA. Motor skills were examined using the 88-item Gross Motor Function Measure (GMFM), the Peabody Developmental Motor Scales (PDMS-2), and the GAITRite system. The child received aquatic therapy twice per week for 45-min sessions, for 14 weeks. The intervention included aquatic activities designed to improve gross motor skills and age-appropriate functional mobility. The GMFM total score improved by 11% following the intervention. The Standing Dimension score improved by 28% and the Walking, Running, and Jumping Dimension score improved by 18%. The gross motor quotient for the PDMS-2 improved from 66 to 74. The child's gait showed improvement in walking velocity, stride length, and single-limb support time as a percentage of the gait cycle. The outcomes of this case report demonstrate the successful improvement of gross motor function and gait in a 3-year-old child with SMA. This study provides clinical information for therapists utilizing aquatic therapy as a modality for children with neuromuscular disorders.

  8. Splicing regulation in spinal muscular atrophy by an RNA structure formed by long-distance interactions.

    PubMed

    Singh, Natalia N; Lee, Brian M; Singh, Ravindra N

    2015-04-01

    Humans carry two copies of the survival motor neuron gene: SMN1 and SMN2. Loss of SMN1 coupled with skipping of SMN2 exon 7 causes spinal muscular atrophy (SMA), a leading genetic disease associated with infant mortality. Our discovery of intronic splicing silencer N1 (ISS-N1) is a promising target, currently in a phase III clinical trial, for an antisense oligonucleotide-mediated splicing correction in SMA. We have recently shown that the first residue of ISS-N1 is locked in a unique RNA structure that we term ISTL1 (internal stem through long-distance interaction-1). Complementary strands of ISTL1 are separated from each other by 279 nucleotides. Using site-specific mutations and chemical structure probing, we confirmed the formation and functional significance of ISTL1. Located in the middle of intron 7, the 3' strand of ISTL1 falls within an inhibitory region that we term ISS-N2. We demonstrate that an antisense oligonucleotide-mediated sequestration of ISS-N2 fully corrects SMN2 exon 7 splicing and restores high levels of SMN in SMA patient cells. These results underscore the therapeutic potential of the regulatory information present in a secondary and high-order RNA structure of a human intron.

  9. Prospective cohort study of spinal muscular atrophy types 2 and 3

    PubMed Central

    Kaufmann, Petra; McDermott, Michael P.; Darras, Basil T.; Finkel, Richard S.; Sproule, Douglas M.; Kang, Peter B.; Oskoui, Maryam; Constantinescu, Andrei; Gooch, Clifton L.; Foley, A. Reghan; Yang, Michele L.; Tawil, Rabi; Chung, Wendy K.; Martens, William B.; Montes, Jacqueline; Battista, Vanessa; O'Hagen, Jessica; Dunaway, Sally; Flickinger, Jean; Quigley, Janet; Riley, Susan; Glanzman, Allan M.; Benton, Maryjane; Ryan, Patricia A.; Punyanitya, Mark; Montgomery, Megan J.; Marra, Jonathan; Koo, Benjamin

    2012-01-01

    Objective: To characterize the natural history of spinal muscular atrophy type 2 and type 3 (SMA 2/3) beyond 1 year and to report data on clinical and biological outcomes for use in trial planning. Methods: We conducted a prospective observational cohort study of 79 children and young adults with SMA 2/3 who participated in evaluations for up to 48 months. Clinically, we evaluated motor and pulmonary function, quality of life, and muscle strength. We also measured SMN2 copy number, hematologic and biochemical profiles, muscle mass by dual x-ray absorptiometry (DXA), and the compound motor action potential (CMAP) in a hand muscle. Data were analyzed for associations between clinical and biological/laboratory characteristics cross-sectionally, and for change over time in outcomes using all available data. Results: In cross-sectional analyses, certain biological measures (specifically, CMAP, DXA fat-free mass index, and SMN2 copy number) and muscle strength measures were associated with motor function. Motor and pulmonary function declined over time, particularly at time points beyond 12 months of follow-up. Conclusion: The intermediate and mild phenotypes of SMA show slow functional declines when observation periods exceed 1 year. Whole body muscle mass, hand muscle compound motor action potentials, and muscle strength are associated with clinical measures of motor function. The data from this study will be useful for clinical trial planning and suggest that CMAP and DXA warrant further evaluation as potential biomarkers. PMID:23077013

  10. Muscle magnetic resonance imaging in spinal muscular atrophy type 3: Selective and progressive involvement.

    PubMed

    Durmus, Hacer; Yilmaz, Ravza; Gulsen-Parman, Yesim; Oflazer-Serdaroglu, Piraye; Cuttini, Marina; Dursun, Memduh; Deymeer, Feza

    2017-05-01

    In this study we sought to identify magnetic resonance imaging (MRI) signs of selective muscle involvement and disease progression in patients with spinal muscular atrophy type 3b (SMA3b). Twenty-five patients with genetically confirmed SMA3b underwent MRI on a 1.5-Tesla MR scanner. MRI showed significantly more severe involvement of the iliopsoas than of the gluteus maximus muscles, and more severe involvement of the triceps brachii than of the biceps brachii muscles. The quadriceps femoris muscles were severely involved. The deltoid, adductor longus, portions of the hamstrings, gracilis, sartorius, and rectus abdominis muscles were well preserved. We found a significant positive correlation between MRI changes and disease duration for gluteus maximus and triceps brachii. Follow-up MRIs of 4 patients showed disease progression. This study confirms the pattern of selective muscle involvement suggested by previous studies and further refines muscle MRI changes in SMA3b. Progressive muscle involvement is implicated. Muscle Nerve 55: 651-656, 2017. © 2016 Wiley Periodicals, Inc.

  11. Antisense Oligonucleotides Delivered to the Mouse CNS Ameliorate Symptoms of Severe Spinal Muscular Atrophy

    PubMed Central

    Passini, Marco A.; Bu, Jie; Richards, Amy M.; Kinnecom, Cathrine; Sardi, S. Pablo; Stanek, Lisa M.; Hua, Yimin; Rigo, Frank; Matson, John; Hung, Gene; Kaye, Edward M.; Shihabuddin, Lamya S.; Krainer, Adrian R.; Bennett, C. Frank; Cheng, Seng H.

    2011-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by mutations in the SMN1 gene that result in a deficiency of SMN protein. One approach to treat SMA is to use antisense oligonucleotides (ASOs) to redirect the splicing of a paralogous gene, SMN2, to boost production of functional SMN. Injection of a 2′-O-2-methoxyethyl–modified ASO (ASO-10-27) into the cerebral lateral ventricles of mice with a severe form of SMA resulted in splice-mediated increases in SMN protein and in the number of motor neurons in the spinal cord, which led to improvements in muscle physiology, motor function and survival. Intrathecal infusion of ASO-10-27 into cynomolgus monkeys delivered putative therapeutic levels of the oligonucleotide to all regions of the spinal cord. These data demonstrate that central nervous system–directed ASO therapy is efficacious and that intrathecal infusion may represent a practical route for delivering this therapeutic in the clinic. PMID:21368223

  12. Small Molecule Suppressors of Drosophila Kinesin Deficiency Rescue Motor Axon Development in a Zebrafish Model of Spinal Muscular Atrophy

    PubMed Central

    Gassman, Andrew; Hao, Le T.; Bhoite, Leena; Bradford, Chad L.; Chien, Chi-Bin; Beattie, Christine E.; Manfredi, John P.

    2013-01-01

    Proximal spinal muscular atrophy (SMA) is the most common inherited motor neuropathy and the leading hereditary cause of infant mortality. Currently there is no effective treatment for the disease, reflecting a need for pharmacologic interventions that restore performance of dysfunctional motor neurons or suppress the consequences of their dysfunction. In a series of assays relevant to motor neuron biology, we explored the activities of a collection of tetrahydroindoles that were reported to alter the metabolism of amyloid precursor protein (APP). In Drosophila larvae the compounds suppressed aberrant larval locomotion due to mutations in the Khc and Klc genes, which respectively encode the heavy and light chains of kinesin-1. A representative compound of this class also suppressed the appearance of axonal swellings (alternatively termed axonal spheroids or neuritic beads) in the segmental nerves of the kinesin-deficient Drosophila larvae. Given the importance of kinesin-dependent transport for extension and maintenance of axons and their growth cones, three members of the class were tested for neurotrophic effects on isolated rat spinal motor neurons. Each compound stimulated neurite outgrowth. In addition, consistent with SMA being an axonopathy of motor neurons, the three axonotrophic compounds rescued motor axon development in a zebrafish model of SMA. The results introduce a collection of small molecules as pharmacologic suppressors of SMA-associated phenotypes and nominate specific members of the collection for development as candidate SMA therapeutics. More generally, the results reinforce the perception of SMA as an axonopathy and suggest novel approaches to treating the disease. PMID:24023935

  13. Decreasing disease severity in symptomatic, Smn(-/-);SMN2(+/+), spinal muscular atrophy mice following scAAV9-SMN delivery.

    PubMed

    Glascock, Jacqueline J; Osman, Erkan Y; Wetz, Mary J; Krogman, Megan M; Shababi, Monir; Lorson, Christian L

    2012-03-01

    Spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disorder, is the leading genetic cause of infant mortality. SMA is caused by the homozygous loss of Survival Motor Neuron-1 (SMN1). In humans, a nearly identical copy gene is present, SMN2. SMN2 is retained in all SMA patients and encodes the same protein as SMN1. However, SMN1 and SMN2 differ by a silent C-to-T transition at the 5' end of exon 7, causing alternative splicing of SMN2 transcripts and low levels of full-length SMN. SMA is monogenic and therefore well suited for gene-replacement strategies. Recently, self-complementary adeno-associated virus (scAAV) vectors have been used to deliver the SMN cDNA to an animal model of disease, the SMNΔ7 mouse. In this study, we examine a severe model of SMA, Smn(-/-);SMN2(+/+), to determine whether gene replacement is viable in a model in which disease development begins in utero. Using two delivery paradigms, intracerebroventricular injections and intravenous injections, we delivered scAAV9-SMN and demonstrated a two to four fold increase in survival, in addition to improving many of the phenotypic parameters of the model. This represents the longest extension in survival for this severe model for any therapeutic intervention and suggests that postsymptomatic treatment of SMA may lead to significant improvement of disease severity.

  14. A missense mutation in the 3-ketodihydrosphingosine reductase FVT1 as candidate causal mutation for bovine spinal muscular atrophy.

    PubMed

    Krebs, Stefan; Medugorac, Ivica; Röther, Susanne; Strässer, Katja; Förster, Martin

    2007-04-17

    The bovine form of the autosomal recessive neurodegenerative disease spinal muscular atrophy (SMA) shows striking similarity to the human form of the disease. It has, however, been mapped to a genomic region not harboring the bovine orthologue of the SMN gene, mutation of which causes human SMA. After refinement of the mapping results we analyzed positional and functional candidate genes. One of three candidate genes, FVT1, encoding 3-ketodihydrosphingosine reductase, which catalyzes a crucial step in the glycosphingolipid metabolism, showed a G-to-A missense mutation that changes Ala-175 to Thr. The identified mutation is limited to SMA-affected animals and carriers and always appears in context of the founder haplotype. The Ala variant found in healthy animals showed the expected 3-ketodihydrosphingosine reductase activity in an in vitro enzyme assay. Importantly, the Thr variant found in SMA animals showed no detectable activity. Surprisingly, in an in vivo assay the mutated gene complements the growth defect of a homologous yeast knockout strain as well as the healthy variant. This finding explains the viability of affected newborn calves and the later neuron-specific onset of the disease, which might be due to the high sensitivity of these neurons to changes in housekeeping functions. Taken together, the described mutation in FVT1 is a strong candidate for causality of SMA in cattle. This result provides an animal model for understanding the underlying mechanisms of the development of SMA and will allow efficient selection against the disease in cattle.

  15. A missense mutation in the 3-ketodihydrosphingosine reductase FVT1 as candidate causal mutation for bovine spinal muscular atrophy

    PubMed Central

    Krebs, Stefan; Medugorac, Ivica; Röther, Susanne; Strässer, Katja; Förster, Martin

    2007-01-01

    The bovine form of the autosomal recessive neurodegenerative disease spinal muscular atrophy (SMA) shows striking similarity to the human form of the disease. It has, however, been mapped to a genomic region not harboring the bovine orthologue of the SMN gene, mutation of which causes human SMA. After refinement of the mapping results we analyzed positional and functional candidate genes. One of three candidate genes, FVT1, encoding 3-ketodihydrosphingosine reductase, which catalyzes a crucial step in the glycosphingolipid metabolism, showed a G-to-A missense mutation that changes Ala-175 to Thr. The identified mutation is limited to SMA-affected animals and carriers and always appears in context of the founder haplotype. The Ala variant found in healthy animals showed the expected 3-ketodihydrosphingosine reductase activity in an in vitro enzyme assay. Importantly, the Thr variant found in SMA animals showed no detectable activity. Surprisingly, in an in vivo assay the mutated gene complements the growth defect of a homologous yeast knockout strain as well as the healthy variant. This finding explains the viability of affected newborn calves and the later neuron-specific onset of the disease, which might be due to the high sensitivity of these neurons to changes in housekeeping functions. Taken together, the described mutation in FVT1 is a strong candidate for causality of SMA in cattle. This result provides an animal model for understanding the underlying mechanisms of the development of SMA and will allow efficient selection against the disease in cattle. PMID:17420465

  16. Spinal muscular atrophy phenotype is ameliorated in human motor neurons by SMN increase via different novel RNA therapeutic approaches

    PubMed Central

    Nizzardo, Monica; Simone, Chiara; Dametti, Sara; Salani, Sabrina; Ulzi, Gianna; Pagliarani, Serena; Rizzo, Federica; Frattini, Emanuele; Pagani, Franco; Bresolin, Nereo; Comi, Giacomo; Corti, Stefania

    2015-01-01

    Spinal muscular atrophy (SMA) is a primary genetic cause of infant mortality due to mutations in the Survival Motor Neuron (SMN) 1 gene. No cure is available. Antisense oligonucleotides (ASOs) aimed at increasing SMN levels from the paralogous SMN2 gene represent a possible therapeutic strategy. Here, we tested in SMA human induced pluripotent stem cells (iPSCs) and iPSC-differentiated motor neurons, three different RNA approaches based on morpholino antisense targeting of the ISSN-1, exon-specific U1 small nuclear RNA (ExSpeU1), and Transcription Activator-Like Effector-Transcription Factor (TALE-TF). All strategies act modulating SMN2 RNA: ASO affects exon 7 splicing, TALE-TF increase SMN2 RNA acting on the promoter, while ExSpeU1 improves pre-mRNA processing. These approaches induced up-regulation of full-length SMN mRNA and differentially affected the Delta-7 isoform: ASO reduced this isoform, while ExSpeU1 and TALE-TF increased it. All approaches upregulate the SMN protein and significantly improve the in vitro SMA motor neurons survival. Thus, these findings demonstrate that therapeutic tools that act on SMN2 RNA are able to rescue the SMA disease phenotype. Our data confirm the feasibility of SMA iPSCs as in vitro disease models and we propose novel RNA approaches as potential therapeutic strategies for treating SMA and other genetic neurological disorders. PMID:26123042

  17. Systems Biology Investigation of cAMP Modulation to Increase SMN Levels for the Treatment of Spinal Muscular Atrophy

    PubMed Central

    Mack, Sean G.; Cook, Daniel J.; Dhurjati, Prasad; Butchbach, Matthew E. R.

    2014-01-01

    Spinal muscular atrophy (SMA), a leading genetic cause of infant death worldwide, is an autosomal recessive disorder caused by the loss of SMN1 (survival motor neuron 1), which encodes the protein SMN. The loss of SMN1 causes a deficiency in SMN protein levels leading to motor neuron cell death in the anterior horn of the spinal cord. SMN2, however, can also produce some functional SMN to partially compensate for loss of SMN1 in SMA suggesting increasing transcription of SMN2 as a potential therapy to treat patients with SMA. A cAMP response element was identified on the SMN2 promoter, implicating cAMP activation as a step in the transcription of SMN2. Therefore, we investigated the effects of modulating the cAMP signaling cascade on SMN production in vitro and in silico. SMA patient fibroblasts were treated with the cAMP signaling modulators rolipram, salbutamol, dbcAMP, epinephrine and forskolin. All of the modulators tested were able to increase gem formation, a marker for SMN protein in the nucleus, in a dose-dependent manner. We then derived two possible mathematical models simulating the regulation of SMN2 expression by cAMP signaling. Both models fit well with our experimental data. In silico treatment of SMA fibroblasts simultaneously with two different cAMP modulators resulted in an additive increase in gem formation. This study shows how a systems biology approach can be used to develop potential therapeutic targets for treating SMA. PMID:25514431

  18. Spinal muscular atrophy phenotype is ameliorated in human motor neurons by SMN increase via different novel RNA therapeutic approaches.

    PubMed

    Nizzardo, Monica; Simone, Chiara; Dametti, Sara; Salani, Sabrina; Ulzi, Gianna; Pagliarani, Serena; Rizzo, Federica; Frattini, Emanuele; Pagani, Franco; Bresolin, Nereo; Comi, Giacomo; Corti, Stefania

    2015-06-30

    Spinal muscular atrophy (SMA) is a primary genetic cause of infant mortality due to mutations in the Survival Motor Neuron (SMN) 1 gene. No cure is available. Antisense oligonucleotides (ASOs) aimed at increasing SMN levels from the paralogous SMN2 gene represent a possible therapeutic strategy. Here, we tested in SMA human induced pluripotent stem cells (iPSCs) and iPSC-differentiated motor neurons, three different RNA approaches based on morpholino antisense targeting of the ISSN-1, exon-specific U1 small nuclear RNA (ExSpeU1), and Transcription Activator-Like Effector-Transcription Factor (TALE-TF). All strategies act modulating SMN2 RNA: ASO affects exon 7 splicing, TALE-TF increase SMN2 RNA acting on the promoter, while ExSpeU1 improves pre-mRNA processing. These approaches induced up-regulation of full-length SMN mRNA and differentially affected the Delta-7 isoform: ASO reduced this isoform, while ExSpeU1 and TALE-TF increased it. All approaches upregulate the SMN protein and significantly improve the in vitro SMA motor neurons survival. Thus, these findings demonstrate that therapeutic tools that act on SMN2 RNA are able to rescue the SMA disease phenotype. Our data confirm the feasibility of SMA iPSCs as in vitro disease models and we propose novel RNA approaches as potential therapeutic strategies for treating SMA and other genetic neurological disorders.

  19. Motor unit loss estimation by the multipoint incremental MUNE method in children with spinal muscular atrophy--a preliminary study.

    PubMed

    Gawel, Malgorzata; Kostera-Pruszczyk, Anna; Lusakowska, Anna; Jedrzejowska, Maria; Ryniewicz, Barbara; Lipowska, Marta; Gawel, Damian; Kaminska, Anna

    2015-03-01

    Quantitative EMG reflects denervation of muscles after lower motor neuron degeneration in spinal muscular atrophy (SMA) but does not reflect actual motor unit loss. The aim of our study was to assess the value of the multipoint incremental motor unit number estimation (MUNE) method in the modification by Shefner in estimating motor unit loss in SMA. The number of motor units, the mean amplitude of an average surface-detected single motor unit potential (SMUP), and the amplitude of compound motor action potentials (CMAP) were estimated in 14 children with SMA in the abductor pollicis brevis (ABP). Significant differences in MUNE values and SMUP and CMAP amplitude were found between the SMA and control groups (P < 0.0001). MUNE values correlated with Hammersmith Functional Motor Scale (HFMS) scores (P < 0.05). Increased SMUP amplitude values correlated with decreased HFMS scores (P < 0.05). The study confirms that MUNE method in the modification by Shefner is a useful tool reflecting motor unit loss in SMA, and it is easy to perform and well tolerated. MUNE and SMUP amplitude seemed to be sensitive parameters reflecting motor dysfunction in SMA but a longitudinal study in a larger number of subjects is needed.

  20. PTEN depletion decreases disease severity and modestly prolongs survival in a mouse model of spinal muscular atrophy.

    PubMed

    Little, Daniel; Valori, Chiara F; Mutsaers, Chantal A; Bennett, Ellen J; Wyles, Matthew; Sharrack, Basil; Shaw, Pamela J; Gillingwater, Thomas H; Azzouz, Mimoun; Ning, Ke

    2015-02-01

    Spinal muscular atrophy (SMA) is the second most common genetic cause of death in childhood. However, no effective treatment is available to halt disease progression. SMA is caused by mutations in the survival motor neuron 1 (SMN1) gene. We previously reported that PTEN depletion leads to an increase in survival of SMN-deficient motor neurons. Here, we aimed to establish the impact of PTEN modulation in an SMA mouse model in vivo. Initial experiments using intramuscular delivery of adeno-associated vector serotype 6 (AAV6) expressing shRNA against PTEN in an established mouse model of severe SMA (SMNΔ7) demonstrated the ability to ameliorate the severity of neuromuscular junction pathology. Subsequently, we developed self-complementary AAV9 expressing siPTEN (scAAV9-siPTEN) to allow evaluation of the effect of systemic suppression of PTEN on the disease course of SMA in vivo. Treatment with a single injection of scAAV9-siPTEN at postnatal day 1 resulted in a modest threefold extension of the lifespan of SMNΔ7 mice, increasing mean survival to 30 days, compared to 10 days in untreated mice. Our data revealed that systemic PTEN depletion is an important disease modifier in SMNΔ7 mice, and therapies aimed at lowering PTEN expression may therefore offer a potential therapeutic strategy for SMA.

  1. Fine mapping and narrowing of the genetic interval of the spinal muscular atrophy region by linkage studies

    SciTech Connect

    Wirth, B.; Voosen, B.; Roehrig, D.; Piechaczek, B.; Ruonk-Schoeneborn, S.; Zerres, K. ); Knapp, M. )

    1993-01-01

    The gene for autosomal recessive proximal spinal muscular atrophy (SMA) has recently been mapped to chromosome 5q12.2-q13, within a genetic distance of about 6 cM, and is proximally flanked by the locus D5S6 and distally by D5S112. Here, we report linkage analyses in 64 SMA families with nine polymorphic markers closely linked to the SMA gene which allowed us to narrow the SMA region to about 4cM and to define a new proximal genetic border by the locus D5S125 EF(TG/AG)[sub n]. Based on haplotype analysis and specific recombination event,the following order of the loci was determined: 5cen- D5S76-D5S6-D5S125-SMA-(5[prime]MAP-1B-3[prime]MApP[center dot]1 B)/D5S112-JK53CAI/2-(D5S39-D5S127)-5qter. The location of the SMA gene between D5Sl25 and MAP[center dot]1B is further supported by multipoint linkage analysis. 18 refs., 3 figs., 4 tabs.

  2. VPAC2 receptor agonist BAY 55-9837 increases SMN protein levels and moderates disease phenotype in severe spinal muscular atrophy mouse models

    PubMed Central

    2014-01-01

    Background Spinal Muscular Atrophy (SMA) is one of the most common inherited causes of infant death and is caused by the loss of functional survival motor neuron (SMN) protein due to mutations or deletion in the SMN1 gene. One of the treatment strategies for SMA is to induce the expression of the protein from the homologous SMN2 gene, a rescuing paralog for SMA. Methods and results Here we demonstrate the promise of pharmacological modulation of SMN2 gene by BAY 55-9837, an agonist of the vasoactive intestinal peptide receptor 2 (VPAC2), a member of G protein coupled receptor family. Treatment with BAY 55-9837 lead to induction of SMN protein levels via activation of MAPK14 or p38 pathway in vitro. Importantly, BAY 55-9837 also ameliorated disease phenotype in severe SMA mouse models. Conclusion Our findings suggest the VPAC2 pathway is a potential SMA therapeutic target. PMID:24405637

  3. Mapping of human microtubule-associated protein 1B in proximity to the spinal muscular atrophy locus at 5q13

    SciTech Connect

    Lien, L.L. Children's Hospital, Boston, MA ); Boyce, F.M.; Kunkel, L.M. ); Kleyn, P.; Brzustowicz, L.M.; Gilliam, T.C. New York State Psychiatric Inst., New York, NY ); Menninger, J.; Ward, D.C. )

    1991-09-01

    A polyclonal antiserum directed against the C-terminal domain of dystrophin was used to isolate a cDNA clone encoding an antigenically cross-reactive protein, microtubule-associated protein 1B (MAP-1B). Physical mapping of the human MAP-1B locus places its chromosomal location at 5q13, in proximity to the spinal muscular atrophy (SMA) locus. SMA is a degenerative disorder primarily affecting motor neurons. Genetic linkage analysis of SMA families using a human dinucleotide repeat polymorphism just 3{prime} of the MAP-1B gene has shown tight linkage to SMA mutations. These mapping data together with the postulated role of MAP-1B in neuronal morphogenesis and its localization in anterior horn motor neurons suggest a possible association with SMA.

  4. Ribonucleoprotein assembly defects correlate with spinal muscular atrophy severity and preferentially affect a subset of spliceosomal snRNPs.

    PubMed

    Gabanella, Francesca; Butchbach, Matthew E R; Saieva, Luciano; Carissimi, Claudia; Burghes, Arthur H M; Pellizzoni, Livio

    2007-09-26

    Spinal muscular atrophy (SMA) is a motor neuron disease caused by reduced levels of the survival motor neuron (SMN) protein. SMN together with Gemins2-8 and unrip proteins form a macromolecular complex that functions in the assembly of small nuclear ribonucleoproteins (snRNPs) of both the major and the minor splicing pathways. It is not known whether the levels of spliceosomal snRNPs are decreased in SMA. Here we analyzed the consequence of SMN deficiency on snRNP metabolism in the spinal cord of mouse models of SMA with differing phenotypic severities. We demonstrate that the expression of a subset of Gemin proteins and snRNP assembly activity are dramatically reduced in the spinal cord of severe SMA mice. Comparative analysis of different tissues highlights a similar decrease in SMN levels and a strong impairment of snRNP assembly in tissues of severe SMA mice, although the defect appears smaller in kidney than in neural tissue. We further show that the extent of reduction in both Gemin proteins expression and snRNP assembly activity in the spinal cord of SMA mice correlates with disease severity. Remarkably, defective SMN complex function in snRNP assembly causes a significant decrease in the levels of a subset of snRNPs and preferentially affects the accumulation of U11 snRNP--a component of the minor spliceosome--in tissues of severe SMA mice. Thus, impairment of a ubiquitous function of SMN changes the snRNP profile of SMA tissues by unevenly altering the normal proportion of endogenous snRNPs. These findings are consistent with the hypothesis that SMN deficiency affects the splicing machinery and in particular the minor splicing pathway of a rare class of introns in SMA.

  5. An Integrative Transcriptomic Analysis for Identifying Novel Target Genes Corresponding to Severity Spectrum in Spinal Muscular Atrophy

    PubMed Central

    Yang, Chung-Wei; Chen, Chien-Lin; Chou, Wei-Chun; Lin, Ho-Chen; Jong, Yuh-Jyh; Tsai, Li-Kai; Chuang, Chun-Yu

    2016-01-01

    Spinal muscular atrophy (SMA) is an inherited neuromuscular disease resulting from a recessive mutation in the SMN1 gene. This disease affects multiple organ systems with varying degrees of severity. Exploration of the molecular pathological changes occurring in different cell types in SMA is crucial for developing new therapies. This study collected 39 human microarray datasets from ArrayExpress and GEO databases to build an integrative transcriptomic analysis for recognizing novel SMA targets. The transcriptomic analysis was conducted through combining weighted correlation network analysis (WGCNA) for gene module detection, gene set enrichment analysis (GSEA) for functional categorization and filtration, and Cytoscape (visual interaction gene network analysis) for target gene identification. Seven novel target genes (Bmp4, Serpine1, Gata6, Ptgs2, Bcl2, IL6 and Cntn1) of SMA were revealed, and are all known in the regulation of TNFα for controlling neural, cardiac and bone development. Sequentially, the differentially expressed patterns of these 7 target genes in mouse tissues (e.g., spinal cord, heart, muscles and bone) were validated in SMA mice of different severities (pre-symptomatic, mildly symptomatic, and severely symptomatic). In severely symptomatic SMA mice, TNFα was up-regulated with attenuation of Bmp4 and increase of Serpine1 and Gata6 (a pathway in neural and cardiac development), but not in pre-symptomatic and mildly symptomatic SMA mice. The severely symptomatic SMA mice also had the elevated levels of Ptgs2 and Bcl2 (a pathway in skeletal development) as well as IL6 and Cntn1 (a pathway in nervous system development). Thus, the 7 genes identified in this study might serve as potential target genes for future investigations of disease pathogenesis and SMA therapy. PMID:27331400

  6. Edaravone is a candidate agent for spinal muscular atrophy: In vitro analysis using a human induced pluripotent stem cells-derived disease model.

    PubMed

    Ando, Shiori; Funato, Michinori; Ohuchi, Kazuki; Kameyama, Tsubasa; Inagaki, Satoshi; Seki, Junko; Kawase, Chizuru; Tsuruma, Kazuhiro; Shimazawa, Masamitsu; Kaneko, Hideo; Hara, Hideaki

    2017-08-18

    Spinal muscular atrophy (SMA) is an intractable disease characterized by a progressive loss of spinal motor neurons, which leads to skeletal muscle weakness and atrophy. Currently, there are no curative agents for SMA, although it is understood to be caused by reduced levels of survival motor neuron (SMN) protein. Additionally, why reduced SMN protein level results in selective apoptosis in spinal motor neurons is still not understood. Our purpose in this study was to evaluate the therapeutic potential of edaravone, a free radical scavenger, by using induced pluripotent stem cells from an SMA patient (SMA-iPSCs) and to address oxidative stress-induced apoptosis in spinal motor neurons. We first found that edaravone could improve impaired neural development of SMA-iPSCs-derived spinal motor neurons with limited effect on nuclear SMN protein expression. Furthermore, edaravone inhibited the generation of reactive oxygen species and mitochondrial reactive oxygen species upregulated in SMA-iPSCs-derived spinal motor neurons, and reversed oxidative-stress induced apoptosis. In this study, we suggest that oxidative stress might be partly the reason for selective apoptosis in spinal motor neurons in SMA pathology, and that oxidative stress-induced apoptosis might be the therapeutic target of SMA. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Chronic treatment with lithium does not improve neuromuscular phenotype in a mouse model of severe spinal muscular atrophy.

    PubMed

    Dachs, E; Piedrafita, L; Hereu, M; Esquerda, J E; Calderó, J

    2013-10-10

    Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by defective levels of the survival motor neuron (SMN) protein. SMA causes spinal motoneuron (MN) loss, and progressive muscle weakness and paralysis. Currently, there is no effective therapy to cure this disease. Although different strategies focused on increasing the expression of functional SMN protein have been assayed, numerous SMN-independent therapeutic approaches have been demonstrated to have potential effectiveness in improving the SMA phenotype in mouse models and clinical trials. Recent works have shown that compounds which inhibit GSK-3β activity are effective in promoting MN survival and ameliorating lifespan in models of MN diseases including SMA. Taking into account the reported neuroprotective actions of lithium (Li) through the inhibition of GSK-3β in different studies, we tested here its potential efficiency as a therapeutic agent in a mouse model of severe SMA (SMNΔ7 mice). We show that the chronic treatment with Li initiated before the appearance of disease symptoms, although inhibited GSK-3β, did not improve the median survival, motor behavior, and spinal MN loss linked to SMA. Li administration did not either ameliorate the microglial and astroglial reaction in the spinal cord or the depletion of glutamatergic synapses on MNs observed in SMNΔ7 animals. Moreover, Li treatment did not mitigate muscle atrophy or calcitonin gene-related peptide (CGRP) downregulation in the neuromuscular junctions linked to the disease. However, a significant reduction in apoptotic cell death found in the skeletal muscle of SMA mice was observed after Li treatment. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

  8. Clinical Characteristics of Spinal Muscular Atrophy in Korea Confirmed by Genetic Analysis.

    PubMed

    Hwang, Heewon; Lee, Jung Hwan; Choi, Young Chul

    2017-09-01

    The objective of this study was to review the clinical characteristics of patients with spinal muscular atrophy and to emphasize the importance of performing genetic mutational analysis at initial patient assessment. This is a single center oriented, retrospective, and descriptive study conducted in Seoul, South Korea. Genetic mutational analysis to detect the deletion of exon 7 of the SMN1 gene on chromosome 5q13 was performed by multiplex ligation-dependent probe amplification. Clinical features, electrodiagnostic study results, muscle biopsy results, and laboratory test results were reviewed from patient medical records. Of all 28 patients (15 males and 13 females), all showed bilateral symmetric proximal dominant weakness. Among them, 3 patients were classified as type I, 14 patients as type II, and 11 patients as type III. Twenty-five patients had scoliosis and eight of these patients received surgical treatment for scoliosis with improvement in clinical outcomes. Ventilator support was used in 15 patients. In terms of the diagnostic process, 15 patients had completed an electrodiagnostic study and muscle biopsy before genetic testing, and six of these patients were initially misdiagnosed with myopathy. Owing to the similar clinical features of SMA and congenital myopathy, an electrodiagnostic study and muscle biopsy could create confusion in the correct diagnosis in some cases. Therefore, it is recommended that genetic mutation analysis should be conducted along with an electrodiagnostic study or muscle biopsy in the diagnostic process for spinal muscular atrophy. © Copyright: Yonsei University College of Medicine 2017.

  9. Clinical and molecular features and therapeutic perspectives of spinal muscular atrophy with respiratory distress type 1.

    PubMed

    Vanoli, Fiammetta; Rinchetti, Paola; Porro, Francesca; Parente, Valeria; Corti, Stefania

    2015-09-01

    Spinal muscular atrophy with respiratory distress (SMARD1) is an autosomal recessive neuromuscular disease caused by mutations in the IGHMBP2 gene, encoding the immunoglobulin μ-binding protein 2, leading to motor neuron degeneration. It is a rare and fatal disease with an early onset in infancy in the majority of the cases. The main clinical features are muscular atrophy and diaphragmatic palsy, which requires prompt and permanent supportive ventilation. The human disease is recapitulated in the neuromuscular degeneration (nmd) mouse. No effective treatment is available yet, but novel therapeutical approaches tested on the nmd mouse, such as the use of neurotrophic factors and stem cell therapy, have shown positive effects. Gene therapy demonstrated effectiveness in SMA, being now at the stage of clinical trial in patients and therefore representing a possible treatment for SMARD1 as well. The significant advancement in understanding of both SMARD1 clinical spectrum and molecular mechanisms makes ground for a rapid translation of pre-clinical therapeutic strategies in humans. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  10. Lung clearance in children with Duchenne muscular dystrophy or spinal muscular atrophy with and without CPAP (continuous positive airway pressure).

    PubMed

    Klefbeck, B; Svartengren, K; Camner, P; Philipson, K; Svartengren, M; Sejersen, T; Mattsson, E

    2001-09-01

    Bronchiolar clearance was studied in 7 boys in the age range of 8 to 17 years, 6 with Duchenne muscular dystrophy (DMD) and 1 with spinal muscular atrophy type II (SMA-II). These boys had healthy lungs but a severely reduced muscular strength (wheelchair dependent). In 6 of the boys, clearance was studied twice, at one occasion as a control and at the other occasion following treatment with continuous positive airway pressure (CPAP). A control group of healthy adults was used. In the clearance examinations, 6-microm Teflon particles, labeled with III In was inhaled extremely slowly, 0.05 L/s. This gives a deposition mainly in the bronchioles. Lung retention was measured after 0,24,48, and 72 hours. A model for deposition of particles in the adult lung was scaled down to represent the children in this study. Deposition in various airway generations was calculated to be similar in children and adults. Also the measured retentions were similar in the boys and the adults. In the clearance experiments during CPAP treatment, there was a significantly lower retention after 72 hours (but not after 24 and 48 hours) than in the control experiments. Theresults indicate that a severe reduction of muscular strength, and thereby a reduction of mechanical movement of the lung, does not affect clearance from large and small airways. However, some effect of clearance from small airways cannot be excluded due to the short measuring period. The small but significant effect of the CPAP treatment might have potential clinical importance and suggest that bronchiolar clearance can be affected by some form of mechanical force.

  11. Hyperleptinemia in children with autosomal recessive spinal muscular atrophy type I-III

    PubMed Central

    Kölbel, Heike; Hauffa, Berthold P.; Wudy, Stefan A.; Bouikidis, Anastasios; Della Marina, Adela; Schara, Ulrike

    2017-01-01

    Background Autosomal-recessive proximal spinal muscular atrophies (SMA) are disorders characterized by a ubiquitous deficiency of the survival of motor neuron protein that leads to a multisystemic disorder, which mostly affects alpha motor neurons. Disease progression is clinically associated with failure to thrive or weight loss, mainly caused by chewing and swallowing difficulties. Although pancreatic involvement has been described in animal models, systematic endocrinological evaluation of the energy metabolism in humans is lacking. Methods In 43 patients with SMA type I-III (8 type I; 22 type II; 13 type III), aged 0.6–21.8 years, auxological parameters, pubertal stage, motor function (Motor Function Measurement 32 –MFM32) as well as levels of leptin, insulin glucose, hemoglobin A1c, Homeostasis Model Assessment index and an urinary steroid profile were determined. Results Hyperleptinemia was found in 15/35 (43%) of our patients; 9/15 (60%) of the hyperleptinemic patients were underweight, whereas 1/15 (7%) was obese. Hyperleptinemia was associated with SMA type (p = 0.018). There was a significant association with decreased motor function (MFM32 total score in hyperleptinemia 28.5%, in normoleptinemia 54.7% p = 0.008, OR 0.969; 95%-CI: 0.946–0.992). In addition, a higher occurrence of hirsutism, premature pubarche and a higher variability of the urinary steroid pattern were found. Conclusion Hyperleptinemia is highly prevalent in underweight children with SMA and is associated with disease severity and decreased motor function. Neuronal degradation of hypothalamic cells or an increase in fat content by muscle remodeling could be the cause of hyperleptinemia. PMID:28278160

  12. [Ethical attitudes of intensive care paediatricians as regards patients with spinal muscular atrophy type 1].

    PubMed

    Agra Tuñas, María Carmen; Hernández Rastrollo, Ramón; Hernández González, Arturo; Ramil Fraga, Carmen; Cambra Lasaosa, Francisco José; Quintero Otero, Sebastián; Ruiz Extremera, Angela; Rodríguez Núñez, Antonio

    2017-03-01

    Spinal muscular atrophy type 1 (SMA-1) is a progressive and fatal disease that leads to ethical problems for Paediatric professionals. Our objective was to determine the ethical options of Paediatric Intensive Care Unit (PICU) paediatricians as regards a child with SMA-1 and respiratory failure. A cross-sectional descriptive study was conducted using an anonymous questionnaire sent to PICUs in Spain (which can be accessed through the Spanish Society of Paediatric Critical Care web page). Of the 124 responses analysed, 70% were from women, 51% younger than 40 years, 54% from a PICU with more than 10 beds, 69% with prior experience in such cases, and 53% with religious beliefs. In the last patient cared for, most paediatricians opted for non-invasive mechanical ventilation (NIV) and limitation of therapeutic effort (LET) in case of NIV failure. Confronted with a future hypothetical case, half of paediatricians would opt for the same plan (NIV+LET), and 74% would support the family's decision, even in case of disagreement. Age, prior experience and sex were not related to the preferred options. Paediatricians with religious beliefs were less in favour of initial LET. Less than two-thirds (63%) scored the quality of life of a child with SMA-1 and invasive mechanical ventilation as very poor. Faced with child with SMA-1 and respiratory failure, most paediatricians are in favour of initiating NIV and LET when such support is insufficient, but they would accept the family's decision, even in case of disagreement. Copyright © 2015 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

  13. Quantitative studies on SMN1 gene and carrier testing of spinal muscular atrophy.

    PubMed

    Chen, Wan-jin; Wu, Zhi-ying; Wang, Ning; Lin, Min-ting; Mu-rong, Shen-xing

    2005-12-01

    To construct a method for detecting the copy number of survival of motor neuron 1 gene (SMN1) with single copy difference based on real-time fluorescence quantitative PCR, and to make practical use of the method for acquiring the data on SMN1 copy number in Chinese as well as for screening the carriers of spinal muscular atrophy (SMA) from healthy individuals and SMA families. Exon 7 and flanking area of SMN1 gene were amplified by real-time fluorescence quantitative PCR in 264 healthy individuals, in 1 standard sample having 2 SMN1 but having no SMN2, and in 88 parents of SMA patients. The samples for detecting were diluted to 30 ng/microL and the standard sample was diluted to 15 ng/microL, 30 ng/microL, 45 ng/microL, 60 ng/microL; the unknown samples and 4 standard samples with different concentrations were amplified at the same time, a standard curve could be drawn out according to the results of the 4 standard samples, then the copy number of samples could be calculated. Of 88 parents' samples, 84 samples each had 1 copy of SMN1, and the rest 4 each had 2 copies of SMN1. Of 264 healthy individuals' samples, 5 samples each had only 1 copy of SMN1 (an indicator of definite gene carriers), 232 samples each had 2 copies of SMN1, 25 samples each had 3 copies of SMN1, and 2 samples each had 4 copies of SMN1. Of the samples of 32 members of SMA families, 2 samples each had only 1 copy of SMN1 indicating definite gene carriers, 25 samples each had 2 copies of SMN1, and 5 samples each had 3 copies of SMN1. SMN1 copy number could be detected precisely by real-time fluorescence quantitative PCR; the screening of gene carriers could provide essential data for genetic counseling.

  14. Recent developments in the treatment of Duchenne muscular dystrophy and spinal muscular atrophy

    PubMed Central

    Liew, Wendy K. M.

    2013-01-01

    Pediatric neuromuscular disorders comprise a large variety of disorders that can be classified based on their neuroanatomical localization, patterns of weakness, and laboratory test results. Over the last decade, the field of translational research has been active with many ongoing clinical trials. This is particularly so in two common pediatric neuromuscular disorders: Duchenne muscular dystrophy and spinal muscular atrophy. Although no definitive therapy has yet been found, numerous active areas of research raise the potential for novel therapies in these two disorders, offering hope for improved quality of life and life expectancy for affected individuals. PMID:23634188

  15. Fasciculations masquerading as minipolymyoclonus in bulbospinal muscular atrophy

    PubMed Central

    Bhat, Sushanth; Ma, Wei; Kozochonok, Elena; Chokroverty, Sudhansu

    2015-01-01

    Minipolymyoclonus has been described in both anterior horn cell disorders and central nervous system degenerative conditions. While its etiology remains unclear and speculative, a central generator has been previously proposed. We describe a case of bulbospinal muscular atrophy (Kennedy's disease), where minipolymyoclonus-like movements corresponded to fasciculations in neurophysiological studies. Our novel finding suggests that the etiologies of minipolymyoclonus in central and peripheral nervous system disorders are distinct, despite outward clinical similarity. The term “minipolyfasciculations” may be more reflective of the underlying process causing minipolymyoclonus-like movements in lower motor neuron disorders. PMID:26019432

  16. Smn deficiency causes neuritogenesis and neurogenesis defects in the retinal neurons of a mouse model of spinal muscular atrophy.

    PubMed

    Liu, Hong; Beauvais, Ariane; Baker, Adam N; Tsilfidis, Catherine; Kothary, Rashmi

    2011-02-01

    The eye is an excellent model for the study of neuronal development and pathogenesis of central nervous system disorders because of its relative ease of accessibility and the well-characterized cellular makeup. We have used this model to study spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disease caused by deletions or mutations in the survival of motor neuron 1 gene (SMN1). We have investigated the expression pattern of mouse Smn mRNA and protein in the neural retina and the optic nerve of wild type mice. Smn protein is present in retinal ganglion cells and amacrine cells within the neural retina as well as in glial cells in the optic nerve. Histopathological analysis in phenotype stage SMA mice revealed that Smn deficiency is associated with a reduction in ganglion cell axon and glial cell number in the optic nerve, as well as compromised cellular processes and altered organization of neurofilaments in the neural retina. Whole mount preparation and retinal neuron primary culture provided further evidence of abnormal synaptogenesis and neurofilament accumulation in the neurites of Smn-deficient retinal neurons. A subset of amacrine cells is absent, in a cell-autonomous fashion, in the retina of SMA mice. Finally, the retinas of SMA mice have altered electroretinograms. Altogether, our study has demonstrated defects in axodendritic outgrowth and cellular composition in Smn-depleted retinal neurons, indicating a role for Smn in neuritogenesis and neurogenesis, and providing us with an insight into pathogenesis of SMA. Copyright © 2010 Wiley Periodicals, Inc.

  17. Sensory neurons do not induce motor neuron loss in a human stem cell model of spinal muscular atrophy.

    PubMed

    Schwab, Andrew J; Ebert, Allison D

    2014-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disorder leading to paralysis and early death due to reduced SMN protein. It is unclear why there is such a profound motor neuron loss, but recent evidence from fly and mouse studies indicate that cells comprising the whole sensory-motor circuit may contribute to motor neuron dysfunction and loss. Here, we used induced pluripotent stem cells derived from SMA patients to test whether sensory neurons directly contribute to motor neuron loss. We generated sensory neurons from SMA induced pluripotent stem cells and found no difference in neuron generation or survival, although there was a reduced calcium response to depolarizing stimuli. Using co-culture of SMA induced pluripotent stem cell derived sensory neurons with control induced pluripotent stem cell derived motor neurons, we found no significant reduction in motor neuron number or glutamate transporter boutons on motor neuron cell bodies or neurites. We conclude that SMA sensory neurons do not overtly contribute to motor neuron loss in this human stem cell system.

  18. DNA Damage Response and DNA Repair in Skeletal Myocytes From a Mouse Model of Spinal Muscular Atrophy.

    PubMed

    Fayzullina, Saniya; Martin, Lee J

    2016-09-01

    We studied DNA damage response (DDR) and DNA repair capacities of skeletal muscle cells from a mouse model of infantile spinal muscular atrophy (SMA) caused by loss-of-function mutation of survival of motor neuron (Smn). Primary myocyte cultures derived from skeletal muscle satellite cells of neonatal control and mutant SMN mice had similar myotube length, myonuclei, satellite cell marker Pax7 and differentiated myotube marker myosin, and acetylcholine receptor clustering. DNA damage was induced in differentiated skeletal myotubes by γ-irradiation, etoposide, and methyl methanesulfonate (MMS). Unexposed control and SMA myotubes had stable genome integrity. After γ-irradiation and etoposide, myotubes repaired most DNA damage equally. Control and mutant myotubes exposed to MMS exhibited equivalent DNA damage without repair. Control and SMA myotube nuclei contained DDR proteins phospho-p53 and phospho-H2AX foci that, with DNA damage, dispersed and then re-formed similarly after recovery. We conclude that mouse primary satellite cell-derived myotubes effectively respond to and repair DNA strand-breaks, while DNA alkylation repair is underrepresented. Morphological differentiation, genome stability, genome sensor, and DNA strand-break repair potential are preserved in mouse SMA myocytes; thus, reduced SMN does not interfere with myocyte differentiation, genome integrity, and DNA repair, and faulty DNA repair is unlikely pathogenic in SMA. © 2016 American Association of Neuropathologists, Inc. All rights reserved.

  19. Restoration of SMN in Schwann cells reverses myelination defects and improves neuromuscular function in spinal muscular atrophy

    PubMed Central

    Brophy, Peter J.; Gillingwater, Thomas H.

    2016-01-01

    Spinal muscular atrophy (SMA) is a neuromuscular disease caused by low levels of SMN protein, primarily affecting lower motor neurons. Recent evidence from SMA and related conditions suggests that glial cells can influence disease severity. Here, we investigated the role of glial cells in the peripheral nervous system by creating SMA mice selectively overexpressing SMN in myelinating Schwann cells (Smn−/−;SMN2tg/0;SMN1SC). Restoration of SMN protein levels restricted solely to Schwann cells reversed myelination defects, significantly improved neuromuscular function and ameliorated neuromuscular junction pathology in SMA mice. However, restoration of SMN in Schwann cells had no impact on motor neuron soma loss from the spinal cord or ongoing systemic and peripheral pathology. This study provides evidence for a defined, intrinsic contribution of glial cells to SMA disease pathogenesis and suggests that therapies designed to include Schwann cells in their target tissues are likely to be required in order to rescue myelination defects and associated disease symptoms. PMID:27170316

  20. Postsymptomatic restoration of SMN rescues the disease phenotype in a mouse model of severe spinal muscular atrophy

    PubMed Central

    Lutz, Cathleen M.; Kariya, Shingo; Patruni, Sunita; Osborne, Melissa A.; Liu, Don; Henderson, Christopher E.; Li, Darrick K.; Pellizzoni, Livio; Rojas, José; Valenzuela, David M.; Murphy, Andrew J.; Winberg, Margaret L.; Monani, Umrao R.

    2011-01-01

    Spinal muscular atrophy (SMA) is a common neuromuscular disorder in humans. In fact, it is the most frequently inherited cause of infant mortality, being the result of mutations in the survival of motor neuron 1 (SMN1) gene that reduce levels of SMN protein. Restoring levels of SMN protein in individuals with SMA is perceived to be a viable therapeutic option, but the efficacy of such a strategy once symptoms are apparent has not been determined. We have generated mice harboring an inducible Smn rescue allele and used them in a model of SMA to investigate the effects of turning on SMN expression at different time points during the course of the disease. Restoring SMN protein even after disease onset was sufficient to reverse neuromuscular pathology and effect robust rescue of the SMA phenotype. Importantly, our findings also indicated that there was a therapeutic window of opportunity from P4 through P8 defined by the extent of neuromuscular synapse pathology and the ability of motor neurons to respond to SMN induction, following which restoration of the protein to the organism failed to produce therapeutic benefit. Nevertheless, our results suggest that even in severe SMA, timely reinstatement of the SMN protein may halt the progression of the disease and serve as an effective postsymptomatic treatment. PMID:21785219

  1. DNA Damage Response and DNA Repair in Skeletal Myocytes From a Mouse Model of Spinal Muscular Atrophy

    PubMed Central

    Fayzullina, Saniya

    2016-01-01

    We studied DNA damage response (DDR) and DNA repair capacities of skeletal muscle cells from a mouse model of infantile spinal muscular atrophy (SMA) caused by loss-of-function mutation of survival of motor neuron (Smn). Primary myocyte cultures derived from skeletal muscle satellite cells of neonatal control and mutant SMN mice had similar myotube length, myonuclei, satellite cell marker Pax7 and differentiated myotube marker myosin, and acetylcholine receptor clustering. DNA damage was induced in differentiated skeletal myotubes by γ-irradiation, etoposide, and methyl methanesulfonate (MMS). Unexposed control and SMA myotubes had stable genome integrity. After γ-irradiation and etoposide, myotubes repaired most DNA damage equally. Control and mutant myotubes exposed to MMS exhibited equivalent DNA damage without repair. Control and SMA myotube nuclei contained DDR proteins phospho-p53 and phospho-H2AX foci that, with DNA damage, dispersed and then re-formed similarly after recovery. We conclude that mouse primary satellite cell-derived myotubes effectively respond to and repair DNA strand-breaks, while DNA alkylation repair is underrepresented. Morphological differentiation, genome stability, genome sensor, and DNA strand-break repair potential are preserved in mouse SMA myocytes; thus, reduced SMN does not interfere with myocyte differentiation, genome integrity, and DNA repair, and faulty DNA repair is unlikely pathogenic in SMA. PMID:27452406

  2. Selective loss of alpha motor neurons with sparing of gamma motor neurons and spinal cord cholinergic neurons in a mouse model of spinal muscular atrophy.

    PubMed

    Powis, Rachael A; Gillingwater, Thomas H

    2016-03-01

    Spinal muscular atrophy (SMA) is a neuromuscular disease characterised primarily by loss of lower motor neurons from the ventral grey horn of the spinal cord and proximal muscle atrophy. Recent experiments utilising mouse models of SMA have demonstrated that not all motor neurons are equally susceptible to the disease, revealing that other populations of neurons can also be affected. Here, we have extended investigations of selective vulnerability of neuronal populations in the spinal cord of SMA mice to include comparative assessments of alpha motor neuron (α-MN) and gamma motor neuron (γ-MN) pools, as well as other populations of cholinergic neurons. Immunohistochemical analyses of late-symptomatic SMA mouse spinal cord revealed that numbers of α-MNs were significantly reduced at all levels of the spinal cord compared with controls, whereas numbers of γ-MNs remained stable. Likewise, the average size of α-MN cell somata was decreased in SMA mice with no change occurring in γ-MNs. Evaluation of other pools of spinal cord cholinergic neurons revealed that pre-ganglionic sympathetic neurons, central canal cluster interneurons, partition interneurons and preganglionic autonomic dorsal commissural nucleus neuron numbers all remained unaffected in SMA mice. Taken together, these findings indicate that α-MNs are uniquely vulnerable among cholinergic neuron populations in the SMA mouse spinal cord, with γ-MNs and other cholinergic neuronal populations being largely spared.

  3. DcpS as a Therapeutic Target for Spinal Muscular Atrophy

    PubMed Central

    Singh, Jasbir; Salcius, Michael; Liu, Shin-Wu; Staker, Bart L.; Mishra, Rama; Thurmond, John; Michaud, Gregory; Mattoon, Dawn R.; Printen, John; Pollok, Brian A.; Kiledjian, Megerditch; Christensen, Jeffery; Stewart, Lance; Jarecki, Jill; Bjornsson, Jon Mar; Gurney, Mark E

    2009-01-01

    Spinal muscular atrophy (SMA) is caused by deletion or mutation of both copies of the SMN1 gene which produces an essential protein known as SMN. The severity of SMA is modified by variable copy number of a second gene, SMN2 that produces an mRNA that is incorrectly spliced with deletion of the last exon. We described previously the discovery of potent C5-substituted quinazolines that increase SMN2 gene expression by two-fold. Discovery of potent SMN2 promoter inducers relied on a cellular assay without knowledge of the molecular target. Using protein microarray scanning with a radiolabeled C5-quinazoline probe, we identified the scavenger decapping enzyme, DcpS as a potential binder. We show that the C5-quinazolines potently inhibit DcpS decapping activity, and that the potency of inhibition correlates with potency for SMN2 promoter induction. Binding of C5-quinazolines to DcpS holds the enzyme in an open, catalytically incompetent conformation. DcpS is a nuclear shuttling protein that binds and hydrolyzes the m7GpppN mRNA cap structure and a modulator of RNA metabolism. Therefore DcpS represents a novel therapeutic target for modulating gene expression by a small molecule. PMID:18839960

  4. Isolation and characterization of candidate genes of the 5q13 region in spinal muscular atrophy

    SciTech Connect

    Lefebvre, S.; Reboullet, S.; Benichou, B.

    1994-09-01

    Based on a fine genetic and physical map of the region deleted in spinal muscular atrophy, we defined the smallest rearrangements encompassing the SMA gene. This interval is entirely contained in the 903D1 YAC clone. Several approaches to identify candidate genes were applied, including the search for interspecies conservation, exon trapping amplification and direct cDNA selection. Combining these strategies, six different cDNA molecules mapping to the YAC contig were isolated. Four cDNA molecules were isolated using the exon trapping system. They map to chromosome 5p and to more than one locus within the 5q13 region. They are homologous to each other and share sequence homology with the {beta}-glucuronidase gene. Based on interspecies conservation, a fifth candidate gene was identified. Sequence analyses of the cDNAs revealed no homologies with any other described genes. This gene mapped to two loci within the 5q13 region. Two other cDNA molecules isolated by direct cDNA selection are also under investigation. Complete characterization and fine physical mapping of those genes with respect to the physical interval defined by the deletions of the SMA region will allow the identification of the disease gene (or genes).

  5. Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2.

    PubMed

    Mailman, Matthew D; Heinz, John W; Papp, Audrey C; Snyder, Pamela J; Sedra, Mary S; Wirth, Brunhilde; Burghes, Arthur H M; Prior, Thomas W

    2002-01-01

    This study describes SMN1 deletion frequency, carrier studies, and the effect of the modifying SMN2 gene on the spinal muscular atrophy (SMA) phenotype. A novel allele-specific intragenic mutation panel increases the sensitivity of SMN1 testing. From 1995 to 2001, 610 patients were tested for SMN1 deletions and 399 relatives of probands have been tested for carrier status. SMN2 copy number was compared between 52 type I and 90 type III patients, and between type I and type III patients with chimeric SMN genes. A fluorescent allele-specific polymerase chain reaction (PCR) -based strategy detected intragenic mutations in potential compound heterozygotes and was used on 366 patients. Less than half of the patients tested were homozygously deleted for SMN1. A PCR-based panel detected the seven most common intragenic mutations. SMN2 copy number was significantly different between mild and severely affected patients. SMN1 molecular testing is essential for the diagnosis of SMA and allows for accurate carrier testing. Screening for intragenic mutations in SMN1 increases the sensitivity of diagnostic testing. Finally, SMN2 copy number is conclusively shown to ameliorate the phenotype and provide valuable prognostic information.

  6. An investigation of genetic heterogeneity and linkage disequilibrium in 161 families with spinal muscular atrophy

    SciTech Connect

    Merette, C.; Gilliam, T.C.; Brzustowicz, L.M. ); Daniels, R.J.; Davies, K.E. ); Melki, J.; Munnich, A. ); Pericak-Vance, M.A. ); Siddique, T. ); Voosen, B. )

    1994-05-01

    The authors performed linkage analysis of 161 families with spinal muscular atrophy (SMA) in which affected individuals suffer from the intermediate or mild form of the disease (Types II or III). Markers for six loci encompassing the chromosome 5q11.2-q13.3 region were typed. The best map location for the disease locus was found to be between D5S6 and MAP1B. The corresponding 1 lod unit support interval is confined to this interval and spans 0.5 cM. The data strongly support the hypothesis of linkage heterogeneity (likelihood ratio, 1.14 [times] 10[sup 4]), with 5% of the families unlinked. Four families have a probability of less than 50% of segregating the SMA gene linked to the region 5q11.2-q13.3. A likelihood approach to test for linkage disequilibrium revealed no significant departure from Hardy-Weinberg equilibrium with any marker under study. 28 refs., 4 figs., 3 tabs.

  7. Physical and transcriptional mapping of the spinal muscular atrophy disease gene region

    SciTech Connect

    Brahe, C.; Zappata, S.; Anzevino, R.

    1994-09-01

    The locus responsible for childhood-onset spinal muscular atrophies (SMA) has recently been mapped to an area of approximately 1.6 Mb at 5q13, flanked by the loci D5S435 and D5S557. From this region we have isolated cosmids derived from four different libraries, one constructed from a radiation hybrid and the other three from large overlapping YACs (Y116, Y122 and Y97) covering approximately 1.3 Mb of the YAC contig established by Kleyn et al. (1993). Pulsed field maps were constructed of these YACs and the cosmids were located and aligned in partial contigs. To identify genes we screened the cosmids both for the presence of exons using oligonucleotides corresponding to splice-site junctions and for the presence of evolutionarily conserved sequences. So far we detected a 5{prime} splice site in two sets of overlapping clones. Partial sequencing of subclones revealed long open reading frames, displaying no homology with known sequences. Conserved sequences were found in one of these and three additional cosmids. These DNA fragments potentially mark the sites of candidate SMA genes. Isolation of corresponding cDNAs is in progress.

  8. Complex repetitive arrangements of gene sequence in the candidate region of the spinal muscular atrophy gene in 5q13

    SciTech Connect

    Theodosiou, A.M.; Nesbit, A.M.; Daniels, R.J.; Campbell, L.; Francis, M.J.; Christodoulou, Z.; Morrison, K.E.; Davies, K.E. |

    1994-12-01

    Childhood-onset proximal spinal muscular atrophy (SMA) is a heritable neurological disorder, which has been mapped by genetic linkage analysis to chromosome 5q13, in the interval between markers D5S435 and D5S557. Here, we present gene sequences that have been isolated from this interval, several of which show sequence homologies to exons of {beta}-glucuronidase. These gene sequences are repeated several times across the candidate region and are also present on chromosome 5p. The arrangement of these repetitive gene motifs is polymorphic between individuals. The high degree of variability observed may have some influence on the expression of the genes in the region. Since SMA is not inherited as a classical autosomal recessive disease, novel genomic rearrangements arising from aberrant recombination events between the complex repeats may be associated with the phenotype observed.

  9. [Clinical application of real-time PCR for the detection of genetic mutations underlying spinal muscular atrophy].

    PubMed

    Jiang, Yu; Peng, Guilan; Wu, Qichang; Zhou, Yulin

    2014-04-01

    To verify the reliability of real-time PCR for the detection of genetic mutations underlying spinal muscular atrophy (SMA) and establish quality control for clinical testing. Thirty-five patients, 61 first-degree relatives, 61 healthy controls and 7 prenatal cases which were previously genotyped by multiplex ligation-dependent probe amplification (MLPA) were tested with Roche LightCycler 480 and Bio-Rad CFX96 (TM) real-time PCR machines for relative quantification of copy number of SMN1 exon 7. Genotyping detected by relative quantitative real-time PCR were consistent with the results of MLPA. Both types of real-time PCR machines could accurately distinguish different SMN1 copy numbers despite certain systematic differences between the two platforms. The reliability of real-time PCR assay for detecting SMA depends on quality control. Standard database generated with known SMN1 copy number variations should be established for different instruments.

  10. Mitochondrial implications in bulbospinal muscular atrophy (Kennedy disease).

    PubMed

    Finsterer, Josef; Mishra, Anushree; Wakil, Salma; Pennuto, Maria; Soraru, Gianni

    2015-01-01

    There is increasing evidence that mitochondrial functions are secondarily disturbed in bulbospinal muscular atrophy (BSMA). This review focuses on the relation between BSMA and the effect of the expanded polyglutamine (poly-Q) androgen receptor (AR) on mitochondrial functions. Mitochondrial functions in bulbospinal muscular atrophy (SBMA) are affected on the molecular, clinical, and therapeutic level. On the molecular level there is down-regulation of various nuclear-DNA-encoded mitochondrial proteins by mutant androgen receptor (mAR), colocalization of the mAR with various mitochondrial proteins, association of mAR aggregates with mitochondria resulting in abnormal distribution of mitochondria, mtDNA depletion or multiple mtDNA deletions, mitochondrial membrane depolarization, increase in reactive oxidative species, and activation of the mitochondrial caspase pathway. On the clinical level various mitochondrial disorders mimic SBMA, and on the therapeutic level pioglitazone expresses PPAR-γ, cyclosporine-A restores mitochondrial membrane potentials, coenzyme-Q and idebenone reduce oxidative stress, and geldanamycin up-regulates protective mitochondrial heat shock proteins. In conclusion, in BSMA mitochondrial dysfunction results from various interactions of elongated poly-Q AR with mitochondria, mitochondrial proteins, nuclear or mitochondrial DNA, causing oxidative stress, decreased mitochondrial membrane potential, or activation of the mitochondrial caspase pathway. Additionally, mitochondrial disease may mimic BSMA and therapeutic approaches may depend on modifications of mitochondrial pathways.

  11. False homozygous deletions of SMN1 exon 7 using Dra I PCR-RFLP caused by a novel mutation in spinal muscular atrophy.

    PubMed

    Kang, Seong-Ho; Cho, Sung Im; Chae, Jong-Hee; Chung, Kyu Nam; Ra, Eun Kyung; Kim, So Yeon; Seong, Moon-Woo; Kim, Ji Yeon; Park, Sung Sup

    2009-08-01

    Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder, and about 95% of SMA patients are homozygous for deletions in the SMN1 gene. Herein, classical polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) using DraI yielded false homozygous deletions of SMN1 exon 7 in a patient with SMA, but multiple ligation-dependent probe amplification analysis revealed one remaining copy of SMN1 exon 7. Sequencing showed that this false deletion in the PCR-RFLP resulted from a novel mutation of one SMN1 copy that was not deleted (c.863G > T, p.R288M). This novel sequence variant introduced a mismatch that interfered with primer binding. These findings demonstrate that comprehensive analysis using PCR-RFLP, multiple ligation-dependent probe amplification, and sequencing can reliably and correctly diagnose SMA.

  12. Pharmacokinetics, pharmacodynamics, and efficacy of a small-molecule SMN2 splicing modifier in mouse models of spinal muscular atrophy

    PubMed Central

    Zhao, Xin; Feng, Zhihua; Ling, Karen K. Y.; Mollin, Anna; Sheedy, Josephine; Yeh, Shirley; Petruska, Janet; Narasimhan, Jana; Dakka, Amal; Welch, Ellen M.; Karp, Gary; Chen, Karen S.; Metzger, Friedrich; Ratni, Hasane; Lotti, Francesco; Tisdale, Sarah; Naryshkin, Nikolai A.; Pellizzoni, Livio; Paushkin, Sergey; Ko, Chien-Ping; Weetall, Marla

    2016-01-01

    Spinal muscular atrophy (SMA) is caused by the loss or mutation of both copies of the survival motor neuron 1 (SMN1) gene. The related SMN2 gene is retained, but due to alternative splicing of exon 7, produces insufficient levels of the SMN protein. Here, we systematically characterize the pharmacokinetic and pharmacodynamics properties of the SMN splicing modifier SMN-C1. SMN-C1 is a low-molecular weight compound that promotes the inclusion of exon 7 and increases production of SMN protein in human cells and in two transgenic mouse models of SMA. Furthermore, increases in SMN protein levels in peripheral blood mononuclear cells and skin correlate with those in the central nervous system (CNS), indicating that a change of these levels in blood or skin can be used as a non-invasive surrogate to monitor increases of SMN protein levels in the CNS. Consistent with restored SMN function, SMN-C1 treatment increases the levels of spliceosomal and U7 small-nuclear RNAs and corrects RNA processing defects induced by SMN deficiency in the spinal cord of SMNΔ7 SMA mice. A 100% or greater increase in SMN protein in the CNS of SMNΔ7 SMA mice robustly improves the phenotype. Importantly, a ∼50% increase in SMN leads to long-term survival, but the SMA phenotype is only partially corrected, indicating that certain SMA disease manifestations may respond to treatment at lower doses. Overall, we provide important insights for the translation of pre-clinical data to the clinic and further therapeutic development of this series of molecules for SMA treatment. PMID:26931466

  13. [Application of real-time PCR analysis of the SMN1gene in the carrier testing of spinal muscular atrophy].

    PubMed

    Lu, Li-Ping; Ma, Hong-Wei; Jiang, Jun; Wang, Tao; Hu, Bin

    2007-10-01

    Spinal muscular atrophy (SMA) is one of common autosomal recessive diseases and is characterized by degeneration of the anterior horn cells of the spinal cord. The reported prevalence is 1/10,000 live births with a carrier rate of one in 50. It is important in genetic counseling to identify the carriers with one copy deletion for the survival motor neuron (SMN(1)) gene. However, the duplication of the SMA locus makes the detection of SMA carriers difficult. This study aimed to determine the potential of the quantitative PCR analysis in the identification of SMA carriers. The SMN(1) gene copy number was detected by realdouble ended arrowtime PCR with TaqMan technology in 109 SMA parents of affected children and 40 normal controls. The average copy numbers of SMN(1) in the individuals with known one copy of the SMN(1) gene and with the two copies were 0.777 +/-0.035 (CV=4.5%) and 2.064 +/-0.120 (CV= 5.8%) respectively. The average copy number of SMN(1) in all of the parents with affected individuals was 0.798 +/-0.108 (CV=13.5%), and that of normal controls was 2.106 +/-0.18 (CV=8.5%). About 98% of SMA patients' parents carried 1 copy SMN(1), and 95% of normal controls carried 2 copies. The gene copy numbers for SMN(1) were one and two for SMA carriers and non-carriers, respectively. Our results suggested that the quantitative PCR analysis can distinguish the SMN(1) deletion carriers from non-carriers.

  14. Pharmacokinetics, pharmacodynamics, and efficacy of a small-molecule SMN2 splicing modifier in mouse models of spinal muscular atrophy.

    PubMed

    Zhao, Xin; Feng, Zhihua; Ling, Karen K Y; Mollin, Anna; Sheedy, Josephine; Yeh, Shirley; Petruska, Janet; Narasimhan, Jana; Dakka, Amal; Welch, Ellen M; Karp, Gary; Chen, Karen S; Metzger, Friedrich; Ratni, Hasane; Lotti, Francesco; Tisdale, Sarah; Naryshkin, Nikolai A; Pellizzoni, Livio; Paushkin, Sergey; Ko, Chien-Ping; Weetall, Marla

    2016-05-15

    Spinal muscular atrophy (SMA) is caused by the loss or mutation of both copies of the survival motor neuron 1 (SMN1) gene. The related SMN2 gene is retained, but due to alternative splicing of exon 7, produces insufficient levels of the SMN protein. Here, we systematically characterize the pharmacokinetic and pharmacodynamics properties of the SMN splicing modifier SMN-C1. SMN-C1 is a low-molecular weight compound that promotes the inclusion of exon 7 and increases production of SMN protein in human cells and in two transgenic mouse models of SMA. Furthermore, increases in SMN protein levels in peripheral blood mononuclear cells and skin correlate with those in the central nervous system (CNS), indicating that a change of these levels in blood or skin can be used as a non-invasive surrogate to monitor increases of SMN protein levels in the CNS. Consistent with restored SMN function, SMN-C1 treatment increases the levels of spliceosomal and U7 small-nuclear RNAs and corrects RNA processing defects induced by SMN deficiency in the spinal cord of SMNΔ7 SMA mice. A 100% or greater increase in SMN protein in the CNS of SMNΔ7 SMA mice robustly improves the phenotype. Importantly, a ∼50% increase in SMN leads to long-term survival, but the SMA phenotype is only partially corrected, indicating that certain SMA disease manifestations may respond to treatment at lower doses. Overall, we provide important insights for the translation of pre-clinical data to the clinic and further therapeutic development of this series of molecules for SMA treatment. © The Author 2016. Published by Oxford University Press.

  15. Neuroblastoma in a Patient With Spinal Muscular Atrophy Type I: Is It Just a Coincidence?

    PubMed

    Sag, Erdal; Sen, Hilal Susam; Haliloglu, Goknur; Yalcin, Bilgehan; Kutluk, Tezer

    2015-07-01

    Spinal muscular atrophy is an autosomal recessive disorder characterized by progressive degeneration of anterior horn cells of the spinal cord resulting in hypotonia, skeletal muscle atrophy, and weakness. Herein, we report a 4-month-old male infant who presented to our hospital with an abdominal mass that was diagnosed as neuroblastoma and spinal muscular atrophy type I. We would like to discuss the course and differential diagnosis with an algorithm leading to the diagnosis in this peculiar patient. To our knowledge, coexistence of spinal muscular atrophy type I and neuroblastoma is defined for the first time in the literature. © The Author(s) 2014.

  16. Increased levels of UCHL1 are a compensatory response to disrupted ubiquitin homeostasis in spinal muscular atrophy and do not represent a viable therapeutic target.

    PubMed

    Powis, Rachael A; Mutsaers, Chantal A; Wishart, Thomas M; Hunter, Gillian; Wirth, Brunhilde; Gillingwater, Thomas H

    2014-12-01

    Levels of ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) are robustly increased in spinal muscular atrophy (SMA) patient fibroblasts and mouse models. We therefore wanted to establish whether changes in UCHL1 contribute directly to disease pathogenesis, and to assess whether pharmacological inhibition of UCHL1 represents a viable therapeutic option for SMA. SMA mice and control littermates received a pharmacological UCHL1 inhibitor (LDN-57444) or DMSO vehicle. Survival and weight were monitored daily, a righting test of motor performance was performed, and motor neurone loss, muscle fibre atrophy and neuromuscular junction pathology were all quantified. Ubiquitin-like modifier activating enzyme 1 (Uba1) was then pharmacologically inhibited in neurones in vitro to examine the relationship between Uba1 levels and UCHL1 in SMA. Pharmacological inhibition of UCHL1 failed to improve survival, motor symptoms or neuromuscular pathology in SMA mice and actually precipitated the onset of weight loss. LDN-57444 treatment significantly decreased spinal cord mono-ubiquitin levels, further exacerbating ubiquitination defects in SMA mice. Pharmacological inhibition of Uba1, levels of which are robustly reduced in SMA, was sufficient to induce accumulation of UCHL1 in primary neuronal cultures. Pharmacological inhibition of UCHL1 exacerbates rather than ameliorates disease symptoms in a mouse model of SMA. Thus, pharmacological inhibition of UCHL1 is not a viable therapeutic target for SMA. Moreover, increased levels of UCHL1 in SMA likely represent a downstream consequence of decreased Uba1 levels, indicative of an attempted supportive compensatory response to defects in ubiquitin homeostasis caused by low levels of SMN protein. © 2014 British Neuropathological Society.

  17. Lower incidence of deletions in the survival of motor neuron gene and the neuronal apoptosis inhibitory protein gene in children with spinal muscular atrophy from Serbia.

    PubMed

    Miskovic, Marijana; Lalic, Tanja; Radivojevic, Danijela; Cirkovic, Sanja; Vlahovic, Gordana; Zamurovic, Dragan; Guc-Scekic, Marija

    2011-11-01

    Spinal muscular atrophy (SMA) is the second most frequent autosomal recessive disease characterized by degeneration of the anterior horn cells of the spinal cord, leading to muscular atrophy. SMA is classified into three types according to disease severity and age-onset: severe (type I), intermediate (type II) and mild (type III). Deletions in the survival motor neuron (SMN) gene, located in the chromosome region 5q11.2- 5q13.3, are major determinants of SMA phenotype. Extended deletions that include the neuronal apoptosis inhibitory protein (NAIP) gene may correlate with the severtity of SMA. SMN gene is present in two highly homologous copies, SMN1 and SMN2, but only deletions of the SMN1 gene (exons 7 and 8 or exon 7) are responsible for clinical manifestations of SMA. Here, we present the deletion profiling of SMN1 and NAIP genes in 89 children with SMA from Serbia: 52 patients with type I, 26 with type II, and 11 with type III. The homozygous deletion of the SMN1 gene was confirmed in 72 of 89 (81%) patients, being the most frequent in SMA type I (48/52): 68 patients (94.4%) with deletion of exons 7 and 8 and 4 patients (5.6%) with deletion of exon 7. The extended deletion including the NAIP gene was detected in 18 of 89 (20.2%) patients, mostly affected with type I. This study has revealed the lower incidence of deletions in the SMN1 and NAIP genes in families with SMA in Serbia and will provide important information for genetic counselling in these families.

  18. Pain in adolescents with spinal muscular atrophy and Duchenne and Becker muscular dystrophy.

    PubMed

    Lager, Christina; Kroksmark, Anna-Karin

    2015-09-01

    The purpose of this study was to explore the prevalence, nature and scope of pain in adolescents with spinal muscular atrophy and Duchenne and Becker muscular dystrophy and whether the pain differs between diagnostic groups or between adolescents with different ambulation status. Furthermore to study the consequences of pain and to identify pain-exacerbating and pain-relieving factors. In a national survey, fifty-five adolescents with spinal muscular atrophy and dystrophinopathy completed a questionnaire assessing pain frequency, duration, location using a body map, intensity and discomfort using visual analogue scales, pain interference using a modified version of Brief Pain Inventory and factors exacerbating and relieving pain. Sixty-nine per cent of the adolescents reported pain during the past three months and 50% reported chronic pain. The pain prevalence did not differ significantly between diagnostic groups or between ambulators and non-ambulators. The average pain intensity was graded as mild and the worst pain as moderate. The pain typically occurred weekly, most frequently in the neck/back or legs. General activity and mood were the areas that were most affected by pain. Common pain-exacerbating factors were sitting, too much movement/activity and being lifted or transferred. Pain is a frequent problem in adolescents with spinal muscular atrophy and dystrophinopathy. The assessments used enable an understanding both of the nature and scope of pain and of the impact of pain in everyday life. The study highlights the importance of assessing pain in a systematic manner and offering an individual approach to interventions designed to reduce pain in this population. Copyright © 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

  19. RNA-sequencing of a mouse-model of spinal muscular atrophy reveals tissue-wide changes in splicing of U12-dependent introns.

    PubMed

    Doktor, Thomas Koed; Hua, Yimin; Andersen, Henriette Skovgaard; Brøner, Sabrina; Liu, Ying Hsiu; Wieckowska, Anna; Dembic, Maja; Bruun, Gitte Hoffmann; Krainer, Adrian R; Andresen, Brage Storstein

    2017-01-09

    Spinal Muscular Atrophy (SMA) is a neuromuscular disorder caused by insufficient levels of the Survival of Motor Neuron (SMN) protein. SMN is expressed ubiquitously and functions in RNA processing pathways that include trafficking of mRNA and assembly of snRNP complexes. Importantly, SMA severity is correlated with decreased snRNP assembly activity. In particular, the minor spliceosomal snRNPs are affected, and some U12-dependent introns have been reported to be aberrantly spliced in patient cells and animal models. SMA is characterized by loss of motor neurons, but the underlying mechanism is largely unknown. It is likely that aberrant splicing of genes expressed in motor neurons is involved in SMA pathogenesis, but increasing evidence indicates that pathologies also exist in other tissues. We present here a comprehensive RNA-seq study that covers multiple tissues in an SMA mouse model. We show elevated U12-intron retention in all examined tissues from SMA mice, and that U12-dependent intron retention is induced upon siRNA knock-down of SMN in HeLa cells. Furthermore, we show that retention of U12-dependent introns is mitigated by ASO treatment of SMA mice and that many transcriptional changes are reversed. Finally, we report on missplicing of several Ca(2+) channel genes that may explain disrupted Ca(2+) homeostasis in SMA and activation of Cdk5. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

  20. RNA-sequencing of a mouse-model of spinal muscular atrophy reveals tissue-wide changes in splicing of U12-dependent introns

    PubMed Central

    Doktor, Thomas Koed; Hua, Yimin; Andersen, Henriette Skovgaard; Brøner, Sabrina; Liu, Ying Hsiu; Wieckowska, Anna; Dembic, Maja; Bruun, Gitte Hoffmann; Krainer, Adrian R.; Andresen, Brage Storstein

    2017-01-01

    Spinal Muscular Atrophy (SMA) is a neuromuscular disorder caused by insufficient levels of the Survival of Motor Neuron (SMN) protein. SMN is expressed ubiquitously and functions in RNA processing pathways that include trafficking of mRNA and assembly of snRNP complexes. Importantly, SMA severity is correlated with decreased snRNP assembly activity. In particular, the minor spliceosomal snRNPs are affected, and some U12-dependent introns have been reported to be aberrantly spliced in patient cells and animal models. SMA is characterized by loss of motor neurons, but the underlying mechanism is largely unknown. It is likely that aberrant splicing of genes expressed in motor neurons is involved in SMA pathogenesis, but increasing evidence indicates that pathologies also exist in other tissues. We present here a comprehensive RNA-seq study that covers multiple tissues in an SMA mouse model. We show elevated U12-intron retention in all examined tissues from SMA mice, and that U12-dependent intron retention is induced upon siRNA knock-down of SMN in HeLa cells. Furthermore, we show that retention of U12-dependent introns is mitigated by ASO treatment of SMA mice and that many transcriptional changes are reversed. Finally, we report on missplicing of several Ca2+ channel genes that may explain disrupted Ca2+ homeostasis in SMA and activation of Cdk5. PMID:27557711

  1. Altered Levels of MicroRNA-9, -206, and -132 in Spinal Muscular Atrophy and Their Response to Antisense Oligonucleotide Therapy

    PubMed Central

    Catapano, Francesco; Zaharieva, Irina; Scoto, Mariacristina; Marrosu, Elena; Morgan, Jennifer; Muntoni, Francesco; Zhou, Haiyan

    2016-01-01

    The identification of noninvasive biomarkers to monitor the disease progression in spinal muscular atrophy (SMA) is becoming increasingly important. MicroRNAs (miRNAs) regulate gene expression and are implicated in the pathogenesis of neuromuscular diseases, including motor neuron degeneration. In this study, we selectively characterized the expression of miR-9, miR-206, and miR-132 in spinal cord, skeletal muscle, and serum from SMA transgenic mice, and in serum from SMA patients. A systematic analysis of miRNA expression was conducted in SMA mice with different disease severities (severe type I-like and mild type III-like) at different disease stages (pre-, mid-, and late-symptomatic stages), and in morpholino antisense oligonucleotide-treated mice. There was differential expression of all three miRNAs in spinal cord, skeletal muscle and serum samples in SMA mice. Serum miRNAs were altered prior to the changes in spinal cord and skeletal muscle at the presymptomatic stage. The altered miR-132 levels in spinal cord, muscle, and serum transiently reversed to normal level after a single-dose morpholino antisense oligomer PMO25 treatment in SMA mice. We also confirmed a significant alteration of miR-9 and miR-132 level in serum samples from SMA patients. Our study indicates the potential of developing miRNAs as noninvasive biomarkers in SMA. PMID:27377135

  2. Novel mutations expand the clinical spectrum of DYNC1H1-associated spinal muscular atrophy

    PubMed Central

    Scoto, Mariacristina; Rossor, Alexander M.; Harms, Matthew B.; Cirak, Sebahattin; Calissano, Mattia; Robb, Stephanie; Manzur, Adnan Y.; Martínez Arroyo, Amaia; Rodriguez Sanz, Aida; Mansour, Sahar; Fallon, Penny; Hadjikoumi, Irene; Klein, Andrea; Yang, Michele; De Visser, Marianne; Overweg-Plandsoen, W.C.G. (Truus); Baas, Frank; Taylor, J. Paul; Benatar, Michael; Connolly, Anne M.; Al-Lozi, Muhammad T.; Nixon, John; de Goede, Christian G.E.L.; Foley, A. Reghan; Mcwilliam, Catherine; Pitt, Matthew; Sewry, Caroline; Phadke, Rahul; Hafezparast, Majid; Chong, W.K. “Kling”; Mercuri, Eugenio; Baloh, Robert H.; Reilly, Mary M.

    2015-01-01

    Objective: To expand the clinical phenotype of autosomal dominant congenital spinal muscular atrophy with lower extremity predominance (SMA-LED) due to mutations in the dynein, cytoplasmic 1, heavy chain 1 (DYNC1H1) gene. Methods: Patients with a phenotype suggestive of a motor, non–length-dependent neuronopathy predominantly affecting the lower limbs were identified at participating neuromuscular centers and referred for targeted sequencing of DYNC1H1. Results: We report a cohort of 30 cases of SMA-LED from 16 families, carrying mutations in the tail and motor domains of DYNC1H1, including 10 novel mutations. These patients are characterized by congenital or childhood-onset lower limb wasting and weakness frequently associated with cognitive impairment. The clinical severity is variable, ranging from generalized arthrogryposis and inability to ambulate to exclusive and mild lower limb weakness. In many individuals with cognitive impairment (9/30 had cognitive impairment) who underwent brain MRI, there was an underlying structural malformation resulting in polymicrogyric appearance. The lower limb muscle MRI shows a distinctive pattern suggestive of denervation characterized by sparing and relative hypertrophy of the adductor longus and semitendinosus muscles at the thigh level, and diffuse involvement with relative sparing of the anterior-medial muscles at the calf level. Proximal muscle histopathology did not always show classic neurogenic features. Conclusion: Our report expands the clinical spectrum of DYNC1H1-related SMA-LED to include generalized arthrogryposis. In addition, we report that the neurogenic peripheral pathology and the CNS neuronal migration defects are often associated, reinforcing the importance of DYNC1H1 in both central and peripheral neuronal functions. PMID:25609763

  3. Adiposity is increased among High-Functioning, Non-Ambulatory Patients with Spinal Muscular Atrophy

    PubMed Central

    Sproule, Douglas M.; Montes, Jacqueline; Dunaway, Sally; Montgomery, Megan; Battista, Vanessa; Koenigsberger, Dorcas; Martens, Bill; Shen, Wei; Punyanitya, Mark; Benton, Maryjane; Butler, Hailly; Caracciolo, Jayson; Mercuri, Eugenio; Finkel, Richard; Darras, Basil; De Vivo, Darryl C.; Kaufmann, Petra

    2010-01-01

    The relationship between body composition and function in spinal muscular atrophy (SMA) is poorly understood. 53 subjects with SMA were stratified by type and Hammersmith Functional Motor Scale, Expanded score into three cohorts: Low-Functioning Non-Ambulatory (type 2 with Hammersmith score <12, n=19), High-Functioning Non-Ambulatory (type 2 with Hammersmith Score ≥ 12 or non-ambulatory type 3, n=17), and Ambulatory (n=17). Lean and fat mass was estimated using dual-energy x-ray absorptiometry. Anthropometric data was incorporated to measure fat-free (lean mass in kg /stature in m2) and fat (fat mass in kg /stature in m2) mass indices, the latter compared to published age and sex norms. Feeding dysfunction among type 2 subjects was assessed by questionnaire. Fat mass index was increased in the High-Functioning Non-Ambulatory cohort (10.4 ± 4.5) compared with both the ambulatory (7.2 ± 2.1, p = 0.013) and Low-Functioning Non-Ambulatory (7.6 ± 3.1, p = 0.040) cohorts. 12 of 17 subjects (71%) in the High-Functioning Non-Ambulatory cohort had fat mass index >85th percentile for age and gender (connoting “at risk of overweight”) versus 9 of 19 subjects (47%) in the Low-Functioning Non-Ambulatory cohort and 8 of 17 ambulatory subjects (47%). Despite differences in clinical function, a similar proportion of low functioning (7/18, 39%) and high functioning (2/7, 29%) type 2 subjects reported swallowing or feeding dysfunction. Non-ambulatory patients with relatively high clinical function may be at particular risk of excess adiposity, perhaps reflecting access to excess calories despite relative immobility, emphasizing the importance of individualized nutritional management in SMA. PMID:20610154

  4. Oxidative Stress Triggers Body-Wide Skipping of Multiple Exons of the Spinal Muscular Atrophy Gene

    PubMed Central

    Seo, Joonbae; Singh, Natalia N.; Ottesen, Eric W.; Sivanesan, Senthilkumar; Shishimorova, Maria; Singh, Ravindra N.

    2016-01-01

    Humans carry two nearly identical copies of Survival Motor Neuron gene: SMN1 and SMN2. Loss of SMN1 leads to spinal muscular atrophy (SMA), the most frequent genetic cause of infant mortality. While SMN2 cannot compensate for the loss of SMN1 due to predominant skipping of exon 7, correction of SMN2 exon 7 splicing holds the promise of a cure for SMA. Previously, we used cell-based models coupled with a multi-exon-skipping detection assay (MESDA) to demonstrate the vulnerability of SMN2 exons to aberrant splicing under the conditions of oxidative stress (OS). Here we employ a transgenic mouse model and MESDA to examine the OS-induced splicing regulation of SMN2 exons. We induced OS using paraquat that is known to trigger production of reactive oxygen species and cause mitochondrial dysfunction. We show an overwhelming co-skipping of SMN2 exon 5 and exon 7 under OS in all tissues except testis. We also show that OS increases skipping of SMN2 exon 3 in all tissues except testis. We uncover several new SMN2 splice isoforms expressed at elevated levels under the conditions of OS. We analyze cis-elements and transacting factors to demonstrate the diversity of mechanisms for splicing misregulation under OS. Our results of proteome analysis reveal downregulation of hnRNP H as one of the potential consequences of OS in brain. Our findings suggest SMN2 as a sensor of OS with implications to SMA and other diseases impacted by low levels of SMN protein. PMID:27111068

  5. [Spinal muscular atrophy and respiratory failure. How do primary care pediatricians act in a simulated scenario?].

    PubMed

    Agra Tuñas, M C; Sánchez Santos, L; Busto Cuiñas, M; Rodríguez Núñez, A

    2015-11-01

    Spinal muscular atrophy type 1 (SMA-1) tends to be fatal in the first year of life if there is no ventilatory support. The decision whether to start such support is an ethical conflict for healthcare professionals. A scenario of acute respiratory failure in an infant with SMA-1 has been included in a training program using advanced simulation for Primary Care pediatricians (PCP). The performances of 34 groups of 4 pediatricians, who participated in 17 courses, were systematically analyzed. Clinical, ethical and communication aspects with parents were evaluated. The initial technical assistance (Administration of oxygen and immediate ventilatory support) was correctly performed by 94% of the teams. However, the PCP had problems in dealing with the ethical aspects of the case. Of the 85% of the teams that raised the ethical conflict with parents, 29% did so on their own initiative, 23% actively excluded them, and only 6% involved them and took their opinion into account in making decisions. Only 11.7% asked about the quality of life of children and 12% for their knowledge of the prognosis of the disease. None explained treatment alternatives, nor tried to contact the pediatrician responsible for the child. When faced with a simulated SMA-1 infant with respiratory failure, PCP have difficulties in interacting with the family, and to involve it in the decision making process. Practical training of all pediatricians should include case scenarios with an ethical clinical problem. Copyright © 2014 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.

  6. Activin Receptor Type IIB Inhibition Improves Muscle Phenotype and Function in a Mouse Model of Spinal Muscular Atrophy

    PubMed Central

    Barton, Elisabeth R.; Sweeney, H. Lee

    2016-01-01

    Spinal muscular atrophy (SMA) is a devastating neurodegenerative disorder that causes progressive muscle atrophy and weakness. Using adeno-associated virus-mediated gene transfer, we evaluated the potential to improve skeletal muscle weakness via systemic, postnatal inhibition of either myostatin or all signaling via the activin receptor type IIB (ActRIIB). After demonstrating elevated p-SMAD3 content and differential content of ActRIIB ligands, 4-week-old male C/C SMA model mice were treated intraperitoneally with 1x1012 genome copies of pseudotype 2/8 virus encoding a soluble form of the ActRIIB extracellular domain (sActRIIB) or protease-resistant myostatin propeptide (dnMstn) driven by a liver specific promoter. At 12 weeks of age, muscle mass and function were improved in treated C/C mice by both treatments, compared to controls. The fast fiber type muscles had a greater response to treatment than did slow muscles, and the greatest therapeutic effects were found with sActRIIB treatment. Myostatin/activin inhibition, however, did not rescue C/C mice from the reduction in motor unit numbers of the tibialis anterior muscle. Collectively, this study indicates that myostatin/activin inhibition represents a potential therapeutic strategy to increase muscle mass and strength, but not neuromuscular junction defects, in less severe forms of SMA. PMID:27870893

  7. Activin Receptor Type IIB Inhibition Improves Muscle Phenotype and Function in a Mouse Model of Spinal Muscular Atrophy.

    PubMed

    Liu, Min; Hammers, David W; Barton, Elisabeth R; Sweeney, H Lee

    2016-01-01

    Spinal muscular atrophy (SMA) is a devastating neurodegenerative disorder that causes progressive muscle atrophy and weakness. Using adeno-associated virus-mediated gene transfer, we evaluated the potential to improve skeletal muscle weakness via systemic, postnatal inhibition of either myostatin or all signaling via the activin receptor type IIB (ActRIIB). After demonstrating elevated p-SMAD3 content and differential content of ActRIIB ligands, 4-week-old male C/C SMA model mice were treated intraperitoneally with 1x1012 genome copies of pseudotype 2/8 virus encoding a soluble form of the ActRIIB extracellular domain (sActRIIB) or protease-resistant myostatin propeptide (dnMstn) driven by a liver specific promoter. At 12 weeks of age, muscle mass and function were improved in treated C/C mice by both treatments, compared to controls. The fast fiber type muscles had a greater response to treatment than did slow muscles, and the greatest therapeutic effects were found with sActRIIB treatment. Myostatin/activin inhibition, however, did not rescue C/C mice from the reduction in motor unit numbers of the tibialis anterior muscle. Collectively, this study indicates that myostatin/activin inhibition represents a potential therapeutic strategy to increase muscle mass and strength, but not neuromuscular junction defects, in less severe forms of SMA.

  8. Sodium vanadate combined with l-ascorbic acid delays disease progression, enhances motor performance, and ameliorates muscle atrophy and weakness in mice with spinal muscular atrophy

    PubMed Central

    2013-01-01

    Background Proximal spinal muscular atrophy (SMA), a neurodegenerative disorder that causes infant mortality, has no effective treatment. Sodium vanadate has shown potential for the treatment of SMA; however, vanadate-induced toxicity in vivo remains an obstacle for its clinical application. We evaluated the therapeutic potential of sodium vanadate combined with a vanadium detoxification agent, L-ascorbic acid, in a SMA mouse model. Methods Sodium vanadate (200 μM), L-ascorbic acid (400 μM), or sodium vanadate combined with L-ascorbic acid (combined treatment) were applied to motor neuron-like NSC34 cells and fibroblasts derived from a healthy donor and a type II SMA patient to evaluate the cellular viability and the efficacy of each treatment in vitro. For the in vivo studies, sodium vanadate (20 mg/kg once daily) and L-ascorbic acid (40 mg/kg once daily) alone or in combination were orally administered daily on postnatal days 1 to 30. Motor performance, pathological studies, and the effects of each treatment (vehicle, L-ascorbic acid, sodium vanadate, and combined treatment) were assessed and compared on postnatal days (PNDs) 30 and 90. The Kaplan-Meier method was used to evaluate the survival rate, with P < 0.05 indicating significance. For other studies, one-way analysis of variance (ANOVA) and Student's t test for paired variables were used to measure significant differences (P < 0.05) between values. Results Combined treatment protected cells against vanadate-induced cell death with decreasing B cell lymphoma 2-associated X protein (Bax) levels. A month of combined treatment in mice with late-onset SMA beginning on postnatal day 1 delayed disease progression, improved motor performance in adulthood, enhanced survival motor neuron (SMN) levels and motor neuron numbers, reduced muscle atrophy, and decreased Bax levels in the spinal cord. Most importantly, combined treatment preserved hepatic and renal function and substantially decreased vanadium accumulation

  9. Established Stem Cell Model of Spinal Muscular Atrophy Is Applicable in the Evaluation of the Efficacy of Thyrotropin-Releasing Hormone Analog

    PubMed Central

    Ohuchi, Kazuki; Kato, Zenichiro; Seki, Junko; Kawase, Chizuru; Tamai, Yuya; Ono, Yoko; Nagahara, Yuki; Noda, Yasuhiro; Kameyama, Tsubasa; Ando, Shiori; Tsuruma, Kazuhiro; Shimazawa, Masamitsu; Hara, Hideaki; Kaneko, Hideo

    2016-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by the degeneration of spinal motor neurons. This disease is mainly caused by mutation or deletion of the survival motor neuron 1 (SMN1) gene. Currently, no effective treatment is available, and only symptomatic treatment can be provided. Our purpose in the present study was to establish a human SMA-derived induced pluripotent stem cell (SMA-iPSC) disease model and assay a therapeutic drug in preparation for the development of a novel treatment of SMA. We generated iPSCs from the skin fibroblasts of a patient with SMA and confirmed that they were pluripotent and undifferentiated. The neural differentiation of SMA-iPSCs shortened the dendrite and axon length and increased the apoptosis of the spinal motor neurons. In addition, we found activated astrocytes in differentiated SMA-iPSCs. Using this model, we confirmed that treatment with the thyrotropin-releasing hormone (TRH) analog, 5-oxo-l-prolyl-l-histidyl-l-prolinamide, which had marginal effects in clinical trials, increases the SMN protein level. This increase was mediated through the transcriptional activation of the SMN2 gene and inhibition of glycogen synthase kinase-3β activity. Finally, the TRH analog treatment resulted in dendrite and axon development of spinal motor neurons in differentiated SMA-iPSCs. These results suggest that this human in vitro disease model stimulates SMA pathology and reveal the potential efficacy of TRH analog treatment for SMA. Therefore, we can screen novel therapeutic drugs such as TRH for SMA easily and effectively using the human SMA-iPSC model. Significance Platelet-derived growth factor (PDGF) has recently been reported to produce the greatest increase in survival motor neuron protein levels by inhibiting glycogen synthase kinase (GSK)-3β; however, motor neurons lack PDGF receptors. A human in vitro spinal muscular atrophy-derived induced pluripotent stem cell model was established

  10. Established Stem Cell Model of Spinal Muscular Atrophy Is Applicable in the Evaluation of the Efficacy of Thyrotropin-Releasing Hormone Analog.

    PubMed

    Ohuchi, Kazuki; Funato, Michinori; Kato, Zenichiro; Seki, Junko; Kawase, Chizuru; Tamai, Yuya; Ono, Yoko; Nagahara, Yuki; Noda, Yasuhiro; Kameyama, Tsubasa; Ando, Shiori; Tsuruma, Kazuhiro; Shimazawa, Masamitsu; Hara, Hideaki; Kaneko, Hideo

    2016-02-01

    Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by the degeneration of spinal motor neurons. This disease is mainly caused by mutation or deletion of the survival motor neuron 1 (SMN1) gene. Currently, no effective treatment is available, and only symptomatic treatment can be provided. Our purpose in the present study was to establish a human SMA-derived induced pluripotent stem cell (SMA-iPSC) disease model and assay a therapeutic drug in preparation for the development of a novel treatment of SMA. We generated iPSCs from the skin fibroblasts of a patient with SMA and confirmed that they were pluripotent and undifferentiated. The neural differentiation of SMA-iPSCs shortened the dendrite and axon length and increased the apoptosis of the spinal motor neurons. In addition, we found activated astrocytes in differentiated SMA-iPSCs. Using this model, we confirmed that treatment with the thyrotropin-releasing hormone (TRH) analog, 5-oxo-l-prolyl-l-histidyl-l-prolinamide, which had marginal effects in clinical trials, increases the SMN protein level. This increase was mediated through the transcriptional activation of the SMN2 gene and inhibition of glycogen synthase kinase-3β activity. Finally, the TRH analog treatment resulted in dendrite and axon development of spinal motor neurons in differentiated SMA-iPSCs. These results suggest that this human in vitro disease model stimulates SMA pathology and reveal the potential efficacy of TRH analog treatment for SMA. Therefore, we can screen novel therapeutic drugs such as TRH for SMA easily and effectively using the human SMA-iPSC model. Significance: Platelet-derived growth factor (PDGF) has recently been reported to produce the greatest increase in survival motor neuron protein levels by inhibiting glycogen synthase kinase (GSK)-3β; however, motor neurons lack PDGF receptors. A human in vitro spinal muscular atrophy-derived induced pluripotent stem cell model was

  11. Identification of a Peptide for Systemic Brain Delivery of a Morpholino Oligonucleotide in Mouse Models of Spinal Muscular Atrophy.

    PubMed

    Shabanpoor, Fazel; Hammond, Suzan M; Abendroth, Frank; Hazell, Gareth; Wood, Matthew J A; Gait, Michael J

    2017-06-01

    Splice-switching antisense oligonucleotides are emerging treatments for neuromuscular diseases, with several splice-switching oligonucleotides (SSOs) currently undergoing clinical trials such as for Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA). However, the development of systemically delivered antisense therapeutics has been hampered by poor tissue penetration and cellular uptake, including crossing of the blood-brain barrier (BBB) to reach targets in the central nervous system (CNS). For SMA application, we have investigated the ability of various BBB-crossing peptides for CNS delivery of a splice-switching phosphorodiamidate morpholino oligonucleotide (PMO) targeting survival motor neuron 2 (SMN2) exon 7 inclusion. We identified a branched derivative of the well-known ApoE (141-150) peptide, which as a PMO conjugate was capable of exon inclusion in the CNS following systemic administration, leading to an increase in the level of full-length SMN2 transcript. Treatment of newborn SMA mice with this peptide-PMO (P-PMO) conjugate resulted in a significant increase in the average lifespan and gains in weight, muscle strength, and righting reflexes. Systemic treatment of adult SMA mice with this newly identified P-PMO also resulted in small but significant increases in the levels of SMN2 pre-messenger RNA (mRNA) exon inclusion in the CNS and peripheral tissues. This work provides proof of principle for the ability to select new peptide paradigms to enhance CNS delivery and activity of a PMO SSO through use of a peptide-based delivery platform for the treatment of SMA potentially extending to other neuromuscular and neurodegenerative diseases.

  12. Identification of a Peptide for Systemic Brain Delivery of a Morpholino Oligonucleotide in Mouse Models of Spinal Muscular Atrophy

    PubMed Central

    Shabanpoor, Fazel; Hammond, Suzan M; Abendroth, Frank; Hazell, Gareth; Wood, Matthew J.A.

    2017-01-01

    Splice-switching antisense oligonucleotides are emerging treatments for neuromuscular diseases, with several splice-switching oligonucleotides (SSOs) currently undergoing clinical trials such as for Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA). However, the development of systemically delivered antisense therapeutics has been hampered by poor tissue penetration and cellular uptake, including crossing of the blood–brain barrier (BBB) to reach targets in the central nervous system (CNS). For SMA application, we have investigated the ability of various BBB-crossing peptides for CNS delivery of a splice-switching phosphorodiamidate morpholino oligonucleotide (PMO) targeting survival motor neuron 2 (SMN2) exon 7 inclusion. We identified a branched derivative of the well-known ApoE (141–150) peptide, which as a PMO conjugate was capable of exon inclusion in the CNS following systemic administration, leading to an increase in the level of full-length SMN2 transcript. Treatment of newborn SMA mice with this peptide-PMO (P-PMO) conjugate resulted in a significant increase in the average lifespan and gains in weight, muscle strength, and righting reflexes. Systemic treatment of adult SMA mice with this newly identified P-PMO also resulted in small but significant increases in the levels of SMN2 pre-messenger RNA (mRNA) exon inclusion in the CNS and peripheral tissues. This work provides proof of principle for the ability to select new peptide paradigms to enhance CNS delivery and activity of a PMO SSO through use of a peptide-based delivery platform for the treatment of SMA potentially extending to other neuromuscular and neurodegenerative diseases. PMID:28118087

  13. SMN1 and SMN2 copy numbers in cell lines derived from patients with spinal muscular atrophy as measured by array digital PCR.

    PubMed

    Stabley, Deborah L; Harris, Ashlee W; Holbrook, Jennifer; Chubbs, Nicholas J; Lozo, Kevin W; Crawford, Thomas O; Swoboda, Kathryn J; Funanage, Vicky L; Wang, Wenlan; Mackenzie, William; Scavina, Mena; Sol-Church, Katia; Butchbach, Matthew E R

    2015-07-01

    Proximal spinal muscular atrophy (SMA) is an early-onset motor neuron disease characterized by loss of α-motor neurons and associated muscle atrophy. SMA is caused by deletion or other disabling mutation of survival motor neuron 1 (SMN1). In the human genome, a large duplication of the SMN-containing region gives rise to a second copy of this gene (SMN2) that is distinguishable by a single nucleotide change in exon 7. Within the SMA population, there is substantial variation in SMN2 copy number; in general, those individuals with SMA who have a high SMN2 copy number have a milder disease. Because SMN2 functions as a disease modifier, its accurate copy number determination may have clinical relevance. In this study, we describe the development of an assay to assess SMN1 and SMN2 copy numbers in DNA samples using an array-based digital PCR (dPCR) system. This dPCR assay can accurately and reliably measure the number of SMN1 and SMN2 copies in DNA samples. In a cohort of SMA patient-derived cell lines, the assay confirmed a strong inverse correlation between SMN2 copy number and disease severity. Array dPCR is a practical technique to determine, accurately and reliably, SMN1 and SMN2 copy numbers from SMA samples.

  14. SMN1 and SMN2 copy numbers in cell lines derived from patients with spinal muscular atrophy as measured by array digital PCR

    PubMed Central

    Stabley, Deborah L; Harris, Ashlee W; Holbrook, Jennifer; Chubbs, Nicholas J; Lozo, Kevin W; Crawford, Thomas O; Swoboda, Kathryn J; Funanage, Vicky L; Wang, Wenlan; Mackenzie, William; Scavina, Mena; Sol-Church, Katia; Butchbach, Matthew E R

    2015-01-01

    Proximal spinal muscular atrophy (SMA) is an early-onset motor neuron disease characterized by loss of α-motor neurons and associated muscle atrophy. SMA is caused by deletion or other disabling mutation of survival motor neuron 1 (SMN1). In the human genome, a large duplication of the SMN-containing region gives rise to a second copy of this gene (SMN2) that is distinguishable by a single nucleotide change in exon 7. Within the SMA population, there is substantial variation in SMN2 copy number; in general, those individuals with SMA who have a high SMN2 copy number have a milder disease. Because SMN2 functions as a disease modifier, its accurate copy number determination may have clinical relevance. In this study, we describe the development of an assay to assess SMN1 and SMN2 copy numbers in DNA samples using an array-based digital PCR (dPCR) system. This dPCR assay can accurately and reliably measure the number of SMN1 and SMN2 copies in DNA samples. In a cohort of SMA patient-derived cell lines, the assay confirmed a strong inverse correlation between SMN2 copy number and disease severity. Array dPCR is a practical technique to determine, accurately and reliably, SMN1 and SMN2 copy numbers from SMA samples. PMID:26247043

  15. Phase II open label study of valproic acid in spinal muscular atrophy.

    PubMed

    Swoboda, Kathryn J; Scott, Charles B; Reyna, Sandra P; Prior, Thomas W; LaSalle, Bernard; Sorenson, Susan L; Wood, Janine; Acsadi, Gyula; Crawford, Thomas O; Kissel, John T; Krosschell, Kristin J; D'Anjou, Guy; Bromberg, Mark B; Schroth, Mary K; Chan, Gary M; Elsheikh, Bakri; Simard, Louise R

    2009-01-01

    Preliminary in vitro and in vivo studies with valproic acid (VPA) in cell lines and patients with spinal muscular atrophy (SMA) demonstrate increased expression of SMN, supporting the possibility of therapeutic benefit. We performed an open label trial of VPA in 42 subjects with SMA to assess safety and explore potential outcome measures to help guide design of future controlled clinical trials. Subjects included 2 SMA type I ages 2-3 years, 29 SMA type II ages 2-14 years and 11 type III ages 2-31 years, recruited from a natural history study. VPA was well-tolerated and without evident hepatotoxicity. Carnitine depletion was frequent and temporally associated with increased weakness in two subjects. Exploratory outcome measures included assessment of gross motor function via the modified Hammersmith Functional Motor Scale (MHFMS), electrophysiologic measures of innervation including maximum ulnar compound muscle action potential (CMAP) amplitudes and motor unit number estimation (MUNE), body composition and bone density via dual-energy X-ray absorptiometry (DEXA), and quantitative blood SMN mRNA levels. Clear decline in motor function occurred in several subjects in association with weight gain; mean fat mass increased without a corresponding increase in lean mass. We observed an increased mean score on the MHFMS scale in 27 subjects with SMA type II (p

  16. Phase II Open Label Study of Valproic Acid in Spinal Muscular Atrophy

    PubMed Central

    Swoboda, Kathryn J.; Scott, Charles B.; Reyna, Sandra P.; Prior, Thomas W.; LaSalle, Bernard; Sorenson, Susan L.; Wood, Janine; Acsadi, Gyula; Crawford, Thomas O.; Kissel, John T.; Krosschell, Kristin J.; D'Anjou, Guy; Bromberg, Mark B.; Schroth, Mary K.; Chan, Gary M.; Elsheikh, Bakri; Simard, Louise R.

    2009-01-01

    Preliminary in vitro and in vivo studies with valproic acid (VPA) in cell lines and patients with spinal muscular atrophy (SMA) demonstrate increased expression of SMN, supporting the possibility of therapeutic benefit. We performed an open label trial of VPA in 42 subjects with SMA to assess safety and explore potential outcome measures to help guide design of future controlled clinical trials. Subjects included 2 SMA type I ages 2–3 years, 29 SMA type II ages 2–14 years and 11 type III ages 2–31 years, recruited from a natural history study. VPA was well-tolerated and without evident hepatotoxicity. Carnitine depletion was frequent and temporally associated with increased weakness in two subjects. Exploratory outcome measures included assessment of gross motor function via the modified Hammersmith Functional Motor Scale (MHFMS), electrophysiologic measures of innervation including maximum ulnar compound muscle action potential (CMAP) amplitudes and motor unit number estimation (MUNE), body composition and bone density via dual-energy X-ray absorptiometry (DEXA), and quantitative blood SMN mRNA levels. Clear decline in motor function occurred in several subjects in association with weight gain; mean fat mass increased without a corresponding increase in lean mass. We observed an increased mean score on the MHFMS scale in 27 subjects with SMA type II (p≤0.001); however, significant improvement was almost entirely restricted to participants <5 years of age. Full length SMN levels were unchanged and Δ7SMN levels were significantly reduced for 2 of 3 treatment visits. In contrast, bone mineral density (p≤0.0036) and maximum ulnar CMAP scores (p≤0.0001) increased significantly. Conclusions While VPA appears safe and well-tolerated in this initial pilot trial, these data suggest that weight gain and carnitine depletion are likely to be significant confounding factors in clinical trials. This study highlights potential strengths and limitations of various

  17. Neuroprotective Effect of Non-viral Gene Therapy Treatment Based on Tetanus Toxin C-fragment in a Severe Mouse Model of Spinal Muscular Atrophy.

    PubMed

    Oliván, Sara; Calvo, Ana C; Rando, Amaya; Herrando-Grabulosa, Mireia; Manzano, Raquel; Zaragoza, Pilar; Tizzano, Eduardo F; Aquilera, Jose; Osta, Rosario

    2016-01-01

    Spinal muscular atrophy (SMA) is a hereditary childhood disease that causes paralysis and progressive degeneration of skeletal muscles and spinal motor neurons. SMA is associated with reduced levels of full-length Survival of Motor Neuron (SMN) protein, due to mutations in the Survival of Motor Neuron 1 gene. Nowadays there are no effective therapies available to treat patients with SMA, so our aim was to test whether the non-toxic carboxy-terminal fragment of tetanus toxin heavy chain (TTC), which exhibits neurotrophic properties, might have a therapeutic role or benefit in SMA. In this manuscript, we have demonstrated that TTC enhance the SMN expression in motor neurons "in vitro" and evaluated the effect of intramuscular injection of TTC-encoding plasmid in the spinal cord and the skeletal muscle of SMNdelta7 mice. For this purpose, we studied the weight and the survival time, as well as, the survival and cell death pathways and muscular atrophy. Our results showed that TTC treatment reduced the expression of autophagy markers (Becn1, Atg5, Lc3, and p62) and pro-apoptotic genes such as Bax and Casp3 in spinal cord. In skeletal muscle, TTC was able to downregulate the expression of the main marker of autophagy, Lc3, to wild-type levels and the expression of the apoptosis effector protein, Casp3. Regarding the genes related to muscular atrophy (Ankrd1, Calm1, Col19a1, Fbox32, Mt2, Myod1, NogoA, Pax7, Rrad, and Sln), TTC suggest a compensatory effect for muscle damage response, diminished oxidative stress and modulated calcium homeostasis. These preliminary findings suggest the need for further experiments to depth study the effect of TTC in SMA disease.

  18. Neuroprotective Effect of Non-viral Gene Therapy Treatment Based on Tetanus Toxin C-fragment in a Severe Mouse Model of Spinal Muscular Atrophy

    PubMed Central

    Oliván, Sara; Calvo, Ana C.; Rando, Amaya; Herrando-Grabulosa, Mireia; Manzano, Raquel; Zaragoza, Pilar; Tizzano, Eduardo F.; Aquilera, Jose; Osta, Rosario

    2016-01-01

    Spinal muscular atrophy (SMA) is a hereditary childhood disease that causes paralysis and progressive degeneration of skeletal muscles and spinal motor neurons. SMA is associated with reduced levels of full-length Survival of Motor Neuron (SMN) protein, due to mutations in the Survival of Motor Neuron 1 gene. Nowadays there are no effective therapies available to treat patients with SMA, so our aim was to test whether the non-toxic carboxy-terminal fragment of tetanus toxin heavy chain (TTC), which exhibits neurotrophic properties, might have a therapeutic role or benefit in SMA. In this manuscript, we have demonstrated that TTC enhance the SMN expression in motor neurons “in vitro” and evaluated the effect of intramuscular injection of TTC-encoding plasmid in the spinal cord and the skeletal muscle of SMNdelta7 mice. For this purpose, we studied the weight and the survival time, as well as, the survival and cell death pathways and muscular atrophy. Our results showed that TTC treatment reduced the expression of autophagy markers (Becn1, Atg5, Lc3, and p62) and pro-apoptotic genes such as Bax and Casp3 in spinal cord. In skeletal muscle, TTC was able to downregulate the expression of the main marker of autophagy, Lc3, to wild-type levels and the expression of the apoptosis effector protein, Casp3. Regarding the genes related to muscular atrophy (Ankrd1, Calm1, Col19a1, Fbox32, Mt2, Myod1, NogoA, Pax7, Rrad, and Sln), TTC suggest a compensatory effect for muscle damage response, diminished oxidative stress and modulated calcium homeostasis. These preliminary findings suggest the need for further experiments to depth study the effect of TTC in SMA disease. PMID:27605908

  19. Improved Antisense Oligonucleotide Design to Suppress Aberrant SMN2 Gene Transcript Processing: Towards a Treatment for Spinal Muscular Atrophy

    PubMed Central

    Mitrpant, Chalermchai; Porensky, Paul; Zhou, Haiyan; Price, Loren; Muntoni, Francesco; Fletcher, Sue; Wilton, Steve D.; Burghes, Arthur H. M.

    2013-01-01

    Spinal muscular atrophy (SMA) is caused by loss of the Survival Motor Neuron 1 (SMN1) gene, resulting in reduced SMN protein. Humans possess the additional SMN2 gene (or genes) that does produce low level of full length SMN, but cannot adequately compensate for loss of SMN1 due to aberrant splicing. The majority of SMN2 gene transcripts lack exon 7 and the resultant SMNΔ7 mRNA is translated into an unstable and non-functional protein. Splice intervention therapies to promote exon 7 retention and increase amounts of full-length SMN2 transcript offer great potential as a treatment for SMA patients. Several splice silencing motifs in SMN2 have been identified as potential targets for antisense oligonucleotide mediated splice modification. A strong splice silencer is located downstream of exon 7 in SMN2 intron 7. Antisense oligonucleotides targeting this motif promoted SMN2 exon 7 retention in the mature SMN2 transcripts, with increased SMN expression detected in SMA fibroblasts. We report here systematic optimisation of phosphorodiamidate morpholino oligonucleotides (PMO) that promote exon 7 retention to levels that rescued the phenotype in a severe mouse model of SMA after intracerebroventricular delivery. Furthermore, the PMO gives the longest survival reported to date after a single dosing by ICV. PMID:23630626

  20. The Antisense Transcript SMN-AS1 Regulates SMN Expression and Is a Novel Therapeutic Target for Spinal Muscular Atrophy.

    PubMed

    d'Ydewalle, Constantin; Ramos, Daniel M; Pyles, Noah J; Ng, Shi-Yan; Gorz, Mariusz; Pilato, Celeste M; Ling, Karen; Kong, Lingling; Ward, Amanda J; Rubin, Lee L; Rigo, Frank; Bennett, C Frank; Sumner, Charlotte J

    2017-01-04

    The neuromuscular disorder spinal muscular atrophy (SMA), the most common inherited killer of infants, is caused by insufficient expression of survival motor neuron (SMN) protein. SMA therapeutics development efforts have focused on identifying strategies to increase SMN expression. We identified a long non-coding RNA (lncRNA) that arises from the antisense strand of SMN, SMN-AS1, which is enriched in neurons and transcriptionally represses SMN expression by recruiting the epigenetic Polycomb repressive complex-2. Targeted degradation of SMN-AS1 with antisense oligonucleotides (ASOs) increases SMN expression in patient-derived cells, cultured neurons, and the mouse central nervous system. SMN-AS1 ASOs delivered together with SMN2 splice-switching oligonucleotides additively increase SMN expression and improve survival of severe SMA mice. This study is the first proof of concept that targeting a lncRNA to transcriptionally activate SMN2 can be combined with SMN2 splicing modification to ameliorate SMA and demonstrates the promise of combinatorial ASOs for the treatment of neurogenetic disorders. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. A common spinal muscular atrophy deletion mutation is present on a single founder haplotype in the US Hutterites.

    PubMed

    Chong, Jessica X; Oktay, A Afşin; Dai, Zunyan; Swoboda, Kathryn J; Prior, Thomas W; Ober, Carole

    2011-10-01

    Spinal muscular atrophy (SMA) is an autosomal recessive (AR) neuromuscular disease that is one of the most common lethal genetic disorders in children, with carrier frequencies as high as ∼1 in 35 in US Whites. As part of our genetic studies in the Hutterites from South Dakota, we identified a large 22 Mb run of homozygosity, spanning the SMA locus in an affected child, of which 10 Mb was also homozygous in three affected Hutterites from Montana, supporting a single founder origin for the mutation. We developed a haplotype-based method for identifying carriers of the SMN1 deletion that leveraged existing genome-wide SNP genotype data for ∼1400 Hutterites. In combination with two direct PCR-based assays, we identified 176 carriers of the SMN1 deletion, one asymptomatic homozygous adult and three carriers of a de novo deletion. This corresponds to a carrier frequency of one in eight (12.5%) in the South Dakota Hutterites, representing the highest carrier frequency reported to date for SMA and for an AR disease in the Hutterite population. Lastly, we show that 26 SNPs can be used to predict SMA carrier status in the Hutterites, with 99.86% specificity and 99.71% sensitivity.

  2. Increased fat mass and high incidence of overweight despite low body mass index in patients with Spinal Muscular Atrophy

    PubMed Central

    Sproule, Douglas M.; Montes, Jacqueline; Montgomery, Megan; Battista, Vanessa; Koenigsberger, Dorcas; Shen, Wei; Punyanitya, Mark; De Vivo, Darryl C.; Kaufmann, Petra

    2009-01-01

    Body composition is sparsely described in spinal muscular atrophy (SMA). Body (BMI, mass/height in m2), fat-free (FFMI, lean mass/height in m2) and fat (FMI, fat mass/height in m2) mass indexes were estimated in 25 children (ages 5–18) with SMA (2 type I, 13 type II, 10 type III) using dual-energy radiograph absorptiometry and anthropometric data referenced to gender and age-matched healthy children (NHANES III, New York Pediatric Rosetta Body Project). BMI was ≥ 50th percentile in 11 (44%) and ≥ 85th in 5 (20%). FFMI was reduced (p<0.005) and FMI was increased (P<0.005) in the overall study cohort. FMI was ≥ 50th, ≥ 85th and 95th percentiles in 19 (76%), 10 (40%) and 5 (20%) subjects, respectively. Using a receiver operator characteristic curve, BMI above 75th, 50th and 3rd percentiles maximized sensitivity and specificity for FMI ≥ 95th, ≥ 85th and ≥ 50th percentiles, respectively. Children with SMA have reduced lean and increased fat mass compared to healthy children. Obesity is a potentially important modifiable source of morbidity in SMA. PMID:19427208

  3. A Role for SMN Exon 7 Splicing in the Selective Vulnerability of Motor Neurons in Spinal Muscular Atrophy

    PubMed Central

    Ruggiu, Matteo; McGovern, Vicki L.; Lotti, Francesco; Saieva, Luciano; Li, Darrick K.; Kariya, Shingo; Monani, Umrao R.; Burghes, Arthur H. M.

    2012-01-01

    Spinal muscular atrophy (SMA) is an inherited motor neuron disease caused by homozygous loss of the Survival Motor Neuron 1 (SMN1) gene. In the absence of SMN1, inefficient inclusion of exon 7 in transcripts from the nearly identical SMN2 gene results in ubiquitous SMN decrease but selective motor neuron degeneration. Here we investigated whether cell type-specific differences in the efficiency of exon 7 splicing contribute to the vulnerability of SMA motor neurons. We show that normal motor neurons express markedly lower levels of full-length SMN mRNA from SMN2 than do other cells in the spinal cord. This is due to inefficient exon 7 splicing that is intrinsic to motor neurons under normal conditions. We also find that SMN depletion in mammalian cells decreases exon 7 inclusion through a negative feedback loop affecting the splicing of its own mRNA. This mechanism is active in vivo and further decreases the efficiency of exon 7 inclusion specifically in motor neurons of severe-SMA mice. Consistent with expression of lower levels of full-length SMN, we find that SMN-dependent downstream molecular defects are exacerbated in SMA motor neurons. These findings suggest a mechanism to explain the selective vulnerability of motor neurons to loss of SMN1. PMID:22037760

  4. Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens.

    PubMed

    Sugarman, Elaine A; Nagan, Narasimhan; Zhu, Hui; Akmaev, Viatcheslav R; Zhou, Zhaoqing; Rohlfs, Elizabeth M; Flynn, Kerry; Hendrickson, Brant C; Scholl, Thomas; Sirko-Osadsa, Deborah Alexa; Allitto, Bernice A

    2012-01-01

    Spinal muscular atrophy (SMA) is a leading inherited cause of infant death with a reported incidence of ~1 in 10,000 live births and is second to cystic fibrosis as a common, life-shortening autosomal recessive disorder. The American College of Medical Genetics has recommended population carrier screening for SMA, regardless of race or ethnicity, to facilitate informed reproductive options, although other organizations have cited the need for additional large-scale studies before widespread implementation. We report our data from carrier testing (n = 72,453) and prenatal diagnosis (n = 121) for this condition. Our analysis of large-scale population carrier screening data (n = 68,471) demonstrates the technical feasibility of high throughput testing and provides mutation carrier and allele frequencies at a level of accuracy afforded by large data sets. In our United States pan-ethnic population, the calculated a priori carrier frequency of SMA is 1/54 with a detection rate of 91.2%, and the pan-ethnic disease incidence is calculated to be 1/11,000. Carrier frequency and detection rates provided for six major ethnic groups in the United States range from 1/47 and 94.8% in the Caucasian population to 1/72 and 70.5% in the African American population, respectively. This collective experience can be utilized to facilitate accurate pre- and post-test counseling in the settings of carrier screening and prenatal diagnosis for SMA.

  5. Ten years of experience in molecular prenatal diagnosis and carrier testing for spinal muscular atrophy among families from Serbia.

    PubMed

    Miskovic, Marijana; Lalic, Tanja; Radivojevic, Danijela; Cirkovic, Sanja; Ostojic, Slavica; Guc-Scekic, Marija

    2014-01-01

    To describe 10 years of experience of prenatal analysis of spinal muscular atrophy (SMA). Data were retrospectively evaluated from prenatal analysis and carrier screening among parents and close relatives between January 2003 and December 2012. Screening was done before the parents were offered prenatal diagnosis. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) were used to detect the most frequent homozygous deletions in the SMN1 gene in fetal samples. A commercial MLPA kit (SALSA P060) was used to analyze SMN1 copy number for carrier status determination among healthy individuals. Bayesian calculation was used to accurately assess the risk of having a child affected with SMA. During the study period, 66 fetal samples from 44 Serbian families were analyzed, and 13 (19.7%) showed a homozygous deletion in the SMN1 gene. Among 28 healthy individuals, carrier status was confirmed for 16 (57.1%). For 7 couples, quantitative analyses and Bayesian calculation reduced the final risk of having a child with SMA from 1 in 200 to 1 in 2448. Owing to disease severity and lack of a curative treatment, prenatal diagnosis of SMA is the best way to prevent recurrence. Carrier detection allows accurate risk assessment and appropriate genetic counseling for all family members. © 2013.

  6. [Development of therapeutics for spinal and bulbar muscular atrophy (SBMA)].

    PubMed

    Sobue, Gen

    2003-11-01

    Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is a hereditary motor neuron disease that affects males, caused by the expansion of a polyglutamine (polyQ) tract in androgen receptor (AR). Female carriers are usually asymptomatic. The transgenic mouse (Tg) model carrying a full-length human AR with expanded polyQ has significant gender-related motor impairment. This phenotype is inhibited by castration, which prevents nuclear translocation of mutant AR. Leuprorelin, an LHRH agonist that reduces testosterone release from the testis, also rescues motor dysfunction and nuclear accumulation of mutant AR in the male Tg. Over-expression of a molecular chaperone HSP70, which renatures misfolded mutant AR, ameliorates neuromuscular phenotypes of the Tg by reducing nuclear-localized mutant AR. HSP70 appears to enhance the degradation of mutant AR via ubiquitin-proteasome pathway. These experimental approaches indicate the possibility of clinical application of drugs, such as leuprorelin, for SBMA patients.

  7. Repeated low doses of morpholino antisense oligomer: an intermediate mouse model of spinal muscular atrophy to explore the window of therapeutic response

    PubMed Central

    Zhou, Haiyan; Meng, Jinhong; Marrosu, Elena; Janghra, Narinder; Morgan, Jennifer; Muntoni, Francesco

    2015-01-01

    The human SMN2 transgenic mice are well-established models of spinal muscular atrophy (SMA). While the severe type I mouse model has a rapidly progressive condition mimicking type I SMA in humans, the mild type III mice do not faithfully recapitulate chronic SMA variants affecting children. A SMA mouse model that clinically mimics the features of type II and III SMA in human is therefore needed. In this study, we generated intermediately affected SMA mice by delivering low-dose morpholino oligomer (PMO25) into the existing severe SMA mice. We show that a single low-dose administration of PMO25 moderately extended the survival of severe type I SMA mice. The neuromuscular pathology is also modestly but significantly improved in these mice. A second administration of PMO25 at postnatal day 5 (PND5) demonstrated an additive effect on survival. Additional systemic administration of low-dose PMO25 at 2-week intervals suppressed the occurrence of distal necrosis beyond postnatal day 100, and induced more complete phenotypic rescue than a single bolus high-dose injection at PND0. Our study demonstrates that survival of motor neuron (SMN) is required early at a critical threshold to prevent symptoms and suggests that subsequent systemic administration of low-dose PMO25 in SMA mice can provide therapeutic benefit and phenotypic rescue, presumably via peripheral SMN restoration. Our work also provides additional insight into the time window of response to administration of antisense oligonucleotides to SMA mice with an intermediate phenotype. This information is crucial at a time when a number of therapeutic interventions are in clinical trials in SMA patients. PMID:26264577

  8. Clinical and genetic diversity of SMN1-negative proximal spinal muscular atrophies

    PubMed Central

    Jordanova, Albena

    2014-01-01

    Hereditary spinal muscular atrophy is a motor neuron disorder characterized by muscle weakness and atrophy due to degeneration of the anterior horn cells of the spinal cord. Initially, the disease was considered purely as an autosomal recessive condition caused by loss-of-function SMN1 mutations on 5q13. Recent developments in next generation sequencing technologies, however, have unveiled a growing number of clinical conditions designated as non-5q forms of spinal muscular atrophy. At present, 16 different genes and one unresolved locus are associated with proximal non-5q forms, having high phenotypic variability and diverse inheritance patterns. This review provides an overview of the current knowledge regarding the phenotypes, causative genes, and disease mechanisms associated with proximal SMN1-negative spinal muscular atrophies. We describe the molecular and cellular functions enriched among causative genes, and discuss the challenges in the post-genomics era of spinal muscular atrophy research. PMID:24970098

  9. Congenital Bone Fractures in Spinal Muscular Atrophy: Functional Role for SMN Protein in Bone Remodeling

    PubMed Central

    Shanmugarajan, Srinivasan; Swoboda, Kathryn J.; Iannaccone, Susan T.; Ries, William L.; Maria, Bernard L.; Reddy, Sakamuri V.

    2009-01-01

    Spinal muscular atrophy is the second most common fatal childhood disorder. Core clinical features include muscle weakness caused by degenerating lower motor neurons and a high incidence of bone fractures and hypercalcemia. Fractures further compromise quality of life by progression of joint contractures or additional loss of motor function. Recent observations suggest that bone disease in spinal muscular atrophy may not be attributed entirely to lower motor neuron degeneration. The presence of the spinal muscular atrophy disease-determining survival motor neuron gene (SMN), SMN expression, and differential splicing in bone-resorbing osteoclasts was recently discovered. Its ubiquitous expression and the differential expression of splice variants suggest that SMN has specific roles in bone cell function. SMN protein also interacts with osteoclast stimulatory factor. Mouse models of human spinal muscular atrophy disease suggest a potential role of SMN protein in skeletal development. Dual energy x-ray absorptiometry analysis demonstrated a substantial decrease in total bone area and poorly developed caudal vertebra in the mouse model. These mice also had pelvic bone fractures. Studies delineating SMN signaling mechanisms and gene transcription in a cell-specific manner will provide important molecular insights into the pathogenesis of bone disease in children with spinal muscular atrophy. Moreover, understanding bone remodeling in spinal muscular atrophy may lead to novel therapeutic approaches to enhance skeletal health and quality of life. This article reviews the skeletal complications associated with spinal muscular atrophy and describes a functional role for SMN protein in osteoclast development and bone resorption activity. PMID:17761651

  10. Independent mobility after early introduction of a power wheelchair in spinal muscular atrophy.

    PubMed

    Dunaway, Sally; Montes, Jacqueline; O'Hagen, Jessica; Sproule, Douglas M; Vivo, Darryl C De; Kaufmann, Petra

    2013-05-01

    Weakness resulting from spinal muscular atrophy causes severe limitations in functional mobility. The early introduction of power mobility has potential to enhance development and mitigate disability. These outcomes are achieved by simulating normal skill acquisition and by promoting motor learning, visuospatial system development, self-exploration, cognition, and social development. There are few reports on early power mobility in spinal muscular atrophy, and it is typically not prescribed until school age. The authors evaluated 6 children under age 2 years with neuromuscular disease (5 spinal muscular atrophy, 1 congenital muscular dystrophy) for power mobility. Parents recorded the practice hours necessary to achieve independence using the Power Mobility Skills Checklist. Four children achieved independence in all items on the checklist by 7.9 months (range: 73-458 days). Introduction of early power mobility is feasible in spinal muscular atrophy patients under age 2 years and should be introduced in late infancy when children typically acquire locomotor skills.

  11. Pathogenesis and therapy of spinal and bulbar muscular atrophy (SBMA).

    PubMed

    Katsuno, Masahisa; Tanaka, Fumiaki; Adachi, Hiroaki; Banno, Haruhiko; Suzuki, Keisuke; Watanabe, Hirohisa; Sobue, Gen

    2012-12-01

    Spinal and bulbar muscular atrophy (SBMA) is a late-onset motor neuron disease characterized by slowly progressive muscle weakness and atrophy. During the last two decades, basic and clinical research has provided important insights into the disease phenotype and pathophysiology. The cause of SBMA is the expansion of a trinucleotide CAG repeat encoding a polyglutamine tract within the first exon of the androgen receptor (AR) gene. SBMA exclusively affects adult males, whereas females homozygous for the AR mutation do not manifest neurological symptoms. The ligand-dependent nuclear accumulation of the polyglutamine-expanded AR protein is central to the gender-specific pathogenesis of SBMA, although additional steps, e.g., DNA binding, inter-domain interactions, and post-translational modification of AR, modify toxicity. The interactions with co-regulators are another requisite for the toxic properties of the polyglutamine-expanded AR. It is also shown that the polyglutamine-expanded AR induces diverse molecular events, such as transcriptional dysregulation, axonal transport disruption, and mitochondrial dysfunction, which play causative roles in the neurodegeneration in SBMA. The pathogenic AR-induced myopathy also contributes to the non-cell autonomous degeneration of motor neurons. Pre-clinical studies using animal models show that the pathogenic AR-mediated neurodegeneration is suppressed by androgen inactivation, the efficacy of which has been tested in clinical trials. Pharmacological activation of cellular defense machineries, such as molecular chaperones, ubiquitin-proteasome system, and autophagy, also exerts neuroprotective effects in experimental models of SBMA.

  12. Transgenic mouse models of spinal and bulbar muscular atrophy (SBMA).

    PubMed

    Katsuno, M; Adachi, H; Inukai, A; Sobue, G

    2003-01-01

    Spinal and bulbar muscular atrophy (SBMA) is a late-onset motor neuron disease characterized by proximal muscle atrophy, weakness, contraction fasciculations, and bulbar involvement. Only males develop symptoms, while female carriers usually are asymptomatic. A specific treatment for SBMA has not been established. The molecular basis of SBMA is the expansion of a trinucleotide CAG repeat, which encodes the polyglutamine (polyQ) tract, in the first exon of the androgen receptor (AR) gene. The pathologic hallmark is nuclear inclusions (NIs) containing the mutant and truncated AR with expanded polyQ in the residual motor neurons in the brainstem and spinal cord as well as in some other visceral organs. Several transgenic (Tg) mouse models have been created for studying the pathogenesis of SBMA. The Tg mouse model carrying pure 239 CAGs under human AR promoter and another model carrying truncated AR with expanded CAGs show motor impairment and nuclear NIs in spinal motor neurons. Interestingly, Tg mice carrying full-length human AR with expanded polyQ demonstrate progressive motor impairment and neurogenic pathology as well as sexual difference of phenotypes. These models recapitulate the phenotypic expression observed in SBMA. The ligand-dependent nuclear localization of the mutant AR is found to be involved in the disease mechanism, and hormonal therapy is suggested to be a therapeutic approach applicable to SBMA.

  13. Inherited Paediatric Motor Neuron Disorders: Beyond Spinal Muscular Atrophy

    PubMed Central

    Sampaio, Hugo; Mowat, David; Roscioli, Tony

    2017-01-01

    Paediatric motor neuron diseases encompass a group of neurodegenerative diseases characterised by the onset of muscle weakness and atrophy before the age of 18 years, attributable to motor neuron loss across various neuronal networks in the brain and spinal cord. While the genetic underpinnings are diverse, advances in next generation sequencing have transformed diagnostic paradigms. This has reinforced the clinical phenotyping and molecular genetic expertise required to navigate the complexities of such diagnoses. In turn, improved genetic technology and subsequent gene identification have enabled further insights into the mechanisms of motor neuron degeneration and how these diseases form part of a neurodegenerative disorder spectrum. Common pathophysiologies include abnormalities in axonal architecture and function, RNA processing, and protein quality control. This review incorporates an overview of the clinical manifestations, genetics, and pathophysiology of inherited paediatric motor neuron disorders beyond classic SMN1-related spinal muscular atrophy and describes recent advances in next generation sequencing and its clinical application. Specific disease-modifying treatment is becoming a clinical reality in some disorders of the motor neuron highlighting the importance of a timely and specific diagnosis. PMID:28634552

  14. Compensatory axon sprouting for very slow axonal die-back in a transgenic model of spinal muscular atrophy type III.

    PubMed

    Udina, Esther; Putman, Charles T; Harris, Luke R; Tyreman, Neil; Cook, Victoria E; Gordon, Tessa

    2017-03-01

    Smn(+/-) transgenic mouse is a model of the mildest form of spinal muscular atrophy. Although there is a loss of spinal motoneurons in 11-month-old animals, muscular force is maintained. This maintained muscular force is mediated by reinnervation of the denervated fibres by surviving motoneurons. The spinal motoneurons in these animals do not show an increased susceptibility to death after nerve injury and they retain their regenerative capacity. We conclude that the hypothesized immaturity of the neuromuscular system in this model cannot explain the loss of motoneurons by systematic die-back. Spinal muscular atrophy (SMA) is a common autosomal recessive disorder in humans and is the leading genetic cause of infantile death. Patients lack the SMN1 gene with the severity of the disease depending on the number of copies of the highly homologous SMN2 gene. Although motoneuron death in the Smn(+/-) transgenic mouse model of the mildest form of SMA, SMA type III, has been reported, we have used retrograde tracing of sciatic and femoral motoneurons in the hindlimb with recording of muscle and motor unit isometric forces to count the number of motoneurons with intact neuromuscular connections. Thereby, we investigated whether incomplete maturation of the neuromuscular system induced by survival motoneuron protein (SMN) defects is responsible for die-back of axons relative to survival of motoneurons. First, a reduction of ∼30% of backlabelled motoneurons began relatively late, at 11 months of age, with a significant loss of 19% at 7 months. Motor axon die-back was affirmed by motor unit number estimation. Loss of functional motor units was fully compensated by axonal sprouting to retain normal contractile force in four hindlimb muscles (three fast-twitch and one slow-twitch) innervated by branches of the sciatic nerve. Second, our evaluation of whether axotomy of motoneurons in the adult Smn(+/-) transgenic mouse increases their susceptibility to cell death

  15. Fibrosis, adipogenesis, and muscle atrophy in congenital muscular torticollis.

    PubMed

    Chen, Huan-Xiong; Tang, Sheng-Ping; Gao, Fu-Tang; Xu, Jiang-Long; Jiang, Xian-Ping; Cao, Juan; Fu, Gui-Bing; Sun, Ke; Liu, Shi-Zhe; Shi, Wei

    2014-11-01

    In the traditional view, muscle atrophy and interstitial fibrosis were regarded as the basic pathological features of congenital muscular torticollis (CMT). But in the ultrastructure study, the mesenchyme-like cells, myoblasts, myofibroblasts, and fibroblasts were found in the proliferation of interstitium of CMT. To investigate the characteristics of pathological features and the mechanisms of muscle atrophy in CMT, we retrospectively reviewed the medical records of 185 CMT patients from July 2009 to July 2011 in Shenzhen Children's Hospital in China and performed pathological studies. According to age, the 185 CMT patients were divided into 4 groups. All resected surgical specimens were processed for hematoxylin and eosin staining and Masson trichromic staining. Sudan III staining was used for frozen sections, whereas immunohistochemical staining for S-100, calpain-1, ubiquitin, and 20S proteasome was carried out on 40 CMT specimens. Eight adductor muscle specimens from 8 patients with development dysplasia of the hip were taken as control group in the immunohistochemical staining. By Masson trichromic staining, the differences in the percent area of fibrous tissue in each CMT groups were significant. In Sudan III staining and immunostaining for S-100, adipocyte hyperplasia was the pathological feature of CMT. Moreover, compared with controls, most atrophic muscle fibers in CMT specimens were found to show strong immunoreactivity for calpain-1, ubiquitin, and 20S proteasome. With increasing age, fibrosis peaked at both sides and it was low in middle age group. Adipocytes increased with age. The characteristics of pathological features in CMT are changeable with age. The calpain and the ubiquitin-proteasome system may play a role in muscle atrophy of CMT. In the CMT, adipogenesis, fibrogenesis, and myogenesis may be the results of mesenchyme-like cells in SCM (sternocleidomastoid muscle). In conclusion, the present study furthermore supports maldevelopment of the

  16. Willingness to Pay for a Newborn Screening Test for Spinal Muscular Atrophy.

    PubMed

    Lin, Pei-Jung; Yeh, Wei-Shi; Neumann, Peter J

    2017-01-01

    The current US mandatory newborn screening panel does not include spinal muscular atrophy, the most common fatal genetic disease among children. We assessed population preferences for newborn screening for spinal muscular atrophy, and how test preferences varied depending on immediate treatment implications. We conducted an online willingness-to-pay survey of US adults (n = 982). Respondents were asked to imagine being parents of a newborn. Each respondent was presented with two hypothetical scenarios following the spinal muscular atrophy screening test: current standard of care (no treatment available) and one of three randomly assigned scenarios (new treatment available to improve functioning, survival, or both). We used a bidding game to elicit willingness to pay for the spinal muscular atrophy test, and performed a two-part model to estimate median and mean willingness-to-pay values. Most respondents (79% to 87%) would prefer screening their newborns for spinal muscular atrophy. People expressed a willingness to pay for spinal muscular atrophy screening even without an available therapy (median: $142; mean: $253). Willingness to pay increased with treatment availability (median: $161 to $182; mean: $270 to $297) and respondent income. Most respondents considered test accuracy, treatment availability, and treatment effectiveness very important or important factors in deciding willingness to pay. Most people would prefer and would be willing to pay for testing their newborn for spinal muscular atrophy, even in the absence of direct treatment. People perceive the spinal muscular atrophy test more valuable if treatment were available to improve the newborn's functioning and survival. Despite preferences for the test information, adding spinal muscular atrophy to newborn screening programs remains controversial. Future studies are needed to determine how early detection may impact long-term patient outcomes. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Delay in Diagnosis of Spinal Muscular Atrophy: A Systematic Literature Review.

    PubMed

    Lin, Chia-Wei; Kalb, Stephanie J; Yeh, Wei-Shi

    2015-10-01

    Spinal muscular atrophy is a rare genetic disease with devastating neurodegenerative consequences. Timing of diagnosis is crucial for spinal muscular atrophy because early diagnosis may lead to early supportive care and reduction in patient and caregiver stress. The purpose of this study was to examine the published literature for diagnostic delay in spinal muscular atrophy. A systematic literature search was conducted in the PubMed and Web of Science databases for studies published between 2000 and 2014 that listed any type of spinal muscular atrophy and without molecular, mouse, or pathology in the keywords. Mean and/or median age of onset and diagnosis and delay in diagnosis was extracted or calculated. All estimates were weighted by the number of patients and descriptive statistics are reported. A total of 21 studies were included in the final analysis. The weighted mean (standard deviation) ages of onset were 2.5 (0.6), 8.3 (1.6), and 39.0 (32.6) months for spinal muscular atrophy types I, II, and III, respectively, and the weighted mean (standard deviation) ages of confirmed spinal muscular atrophy genetic diagnosis were 6.3 (2.2), 20.7 (2.6), and 50.3 (12.9) months, respectively, for types I, II, and III. For studies reporting both age of onset and diagnosis, the weighted diagnostic delay was 3.6, 14.3, and 43.6 months for types I, II, and III, respectively. Diagnostic delay is common in spinal muscular atrophy. The length of delay varied by severity (type) of spinal muscular atrophy. Further studies evaluating this delay and tools such as newborn screening are warranted to end the diagnostic delay in spinal muscular atrophy. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  18. The PedsQL™ in Pediatric Patients with Spinal Muscular Atrophy: Feasibility, Reliability, and Validity of the Pediatric Quality of Life Inventory™ Generic Core Scales and Neuromuscular Module

    PubMed Central

    Iannaccone, Susan T.; Hynan, Linda S.; Morton, Anne; Buchanan, Renee; Limbers, Christine A.; Varni, James W.

    2009-01-01

    For Phase II and III clinical trials in children with Spinal Muscular Atrophy (SMA), reliable and valid outcome measures are necessary. Since 2000, the American Spinal Muscular Atrophy Randomized Trials (AmSMART) group has established reliability and validity for measures of strength, lung function, and motor function in the population from age 2 years to 18 years. The PedsQL™ (Pediatric Quality of Life Inventory™) Measurement Model was designed to integrate the relative merits of generic and disease-specific approaches, with disease-specific modules. The PedsQL™ 3.0 Neuromuscular Module was designed to measure HRQOL dimensions specific to children ages 2 to 18 years with neuromuscular disorders, including SMA. One hundred seventy-six children with SMA and their parents completed the PedsQL™ 4.0 Generic Core Scales and PedsQL™ 3.0 Neuromuscular Module. The PedsQL™ demonstrated feasibility, reliability and validity in the SMA population. Consistent with the conceptualization of disease-specific symptoms as causal indicators of generic HRQOL, the majority of intercorrelations among the Neuromuscular Module Scales and the Generic Core Scales were in the medium to large range, supporting construct validity. For the purposes of a clinical trial, the PedsQL™ Neuromuscular Module and Generic Core Scales provide an integrated measurement model with the advantages of both generic and condition-specific instruments. PMID:19846309

  19. Rasch analysis of the Pediatric Evaluation of Disability Inventory-computer adaptive test (PEDI-CAT) item bank for children and young adults with spinal muscular atrophy.

    PubMed

    Pasternak, Amy; Sideridis, Georgios; Fragala-Pinkham, Maria; Glanzman, Allan M; Montes, Jacqueline; Dunaway, Sally; Salazar, Rachel; Quigley, Janet; Pandya, Shree; O'Riley, Susan; Greenwood, Jonathan; Chiriboga, Claudia; Finkel, Richard; Tennekoon, Gihan; Martens, William B; McDermott, Michael P; Fournier, Heather Szelag; Madabusi, Lavanya; Harrington, Timothy; Cruz, Rosangel E; LaMarca, Nicole M; Videon, Nancy M; Vivo, Darryl C De; Darras, Basil T

    2016-12-01

    In this study we evaluated the suitability of a caregiver-reported functional measure, the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT), for children and young adults with spinal muscular atrophy (SMA). PEDI-CAT Mobility and Daily Activities domain item banks were administered to 58 caregivers of children and young adults with SMA. Rasch analysis was used to evaluate test properties across SMA types. Unidimensional content for each domain was confirmed. The PEDI-CAT was most informative for type III SMA, with ability levels distributed close to 0.0 logits in both domains. It was less informative for types I and II SMA, especially for mobility skills. Item and person abilities were not distributed evenly across all types. The PEDI-CAT may be used to measure functional performance in SMA, but additional items are needed to identify small changes in function and best represent the abilities of all types of SMA. Muscle Nerve 54: 1097-1107, 2016. © 2016 Wiley Periodicals, Inc.

  20. Identification of strong allele association and candidate cDNAs for the Spinal Muscular Atrophy gene

    SciTech Connect

    DiDonato, C.J.; Carpten, J.; Fuerst, P.

    1994-09-01

    The gene responsible for Spinal Muscular Atrophy (SMA) has been localized to a 850kb region on chromosome 5q11.2-q13.3 between the loci D5S823 and K5S557. This region is extremely complex and consequently the isolation of candidate cDNAs has been difficult. We have isolated a unique dinucleotide repeat marker, Ag1-CA, that maps to this interval and identifies 1, 2 or rarely 3 alleles per chromosome. We have conducted allelic association studies to identify the minimal region that should be searched for candidate cDNAs. Ag1-CA demonstrates the strongest allelic association observed to date with SMA (p<10{sup -4}) in at least 3 populations: French Canadian (HSJ), German and American (OSU) and acts to core two consensus haplotypes observed in the French Canadian population. Class 1 (single Ag1-CA allele) and Class II (2 or 3 alleles) chromosomes were found to be significantly different in Type 1 (p=.0003 OSU; .0012 HSJ) and Type II (p=.001 OSU; .001 HSJ) patients and there was no difference between Type III and normals (p=.5 OSU; .25 HSJ). 72% of Type I patients are Class I homozygotes while 78% of Type II patients are Class I/Class II heterozygotes indicating that the allele class marks the clinical severity of this disease. In addition, deletions may be responsible for the allele loss seen in 9% of German Type I SMA families where one parent fails to contribute any alleles of this locus to the affected child. Given the above results and the fact that we have shown this region to be unstable and frequently deleted in YACs, we have cloned greater than 500 kb surrounding the Ag1-CA locus in cosmids and P1 clones with maximum redundancy. Partial sequence data from one clone has revealed an ORF and no strong similarities to known sequences. In order to isolate the full length transcript we have used this clone in cDNA hybridizations and isolated an additional 8 cDNAs. Currently we are analyzing this cDNA in our patient population to determine if it is the SMA gene.

  1. New insights into SMA pathogenesis: immune dysfunction and neuroinflammation.

    PubMed

    Deguise, Marc-Olivier; Kothary, Rashmi

    2017-07-01

    Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by motor neuron degeneration, although defects in multiple cell types and tissues have also been implicated. Three independent laboratories recently identified immune organ defects in SMA. We therefore propose a novel pathogenic mechanism contributory to SMA, resulting in higher susceptibility to infection and exacerbated disease progression caused by neuroinflammation. Overall, compromised immune function could significantly affect survival and quality of life of SMA patients. We highlight the recent findings in immune organ defects, their potential consequences on patients, our understanding of neuroinflammation in SMA, and new research hypotheses in SMA pathogenesis.

  2. Spinal muscular atrophy type II (intermediary) and III (Kugelberg-Welander). Evolution of 50 patients with physiotherapy and hydrotherapy in a swimming pool.

    PubMed

    Cunha, M C; Oliveira, A S; Labronici, R H; Gabbai, A A

    1996-09-01

    We added hydrotherapy to 50 patients with spinal muscular atrophy (SMA) who were being treated with individual conventional physiotherapy. Hydrotherapy performed at an approximate temperature of 30 degrees Celsius, twice a week, for thirty minutes in children and forty-five minutes in adults during a 2-year period. The outcome derived from this combined modality of treatment was rated according to physiotherapeutic evaluations, the MMT (Manual Muscular Test), and the Barthel Ladder. Patients were reevaluated at 2-month intervals. After two years of ongoing treatment, we were able to observe that the deformities in hip, knee and foot were progressive in all SMA Type II patients, and in some Type III. Muscle strength stabilized in most SMA Type III patients, and improved in some. MMT was not done in SMA Type II. In all patients we were able to detect an improvement in the Barthel Ladder scale. This study suggests that a measurable improvement in the quality of daily living may be obtained in patients with SMA Types II and III subjected to conventional physiotherapy when associated with hydrotherapy.

  3. The contribution of mouse models to understanding the pathogenesis of spinal muscular atrophy.

    PubMed

    Sleigh, James N; Gillingwater, Thomas H; Talbot, Kevin

    2011-07-01

    Spinal muscular atrophy (SMA), which is caused by inactivating mutations in the survival motor neuron 1 (SMN1) gene, is characterized by loss of lower motor neurons in the spinal cord. The gene encoding SMN is very highly conserved in evolution, allowing the disease to be modeled in a range of species. The similarities in anatomy and physiology to the human neuromuscular system, coupled with the ease of genetic manipulation, make the mouse the most suitable model for exploring the basic pathogenesis of motor neuron loss and for testing potential treatments. Therapies that increase SMN levels, either through direct viral delivery or by enhancing full-length SMN protein expression from the SMN1 paralog, SMN2, are approaching the translational stage of development. It is therefore timely to consider the role of mouse models in addressing aspects of disease pathogenesis that are most relevant to SMA therapy. Here, we review evidence suggesting that the apparent selective vulnerability of motor neurons to SMN deficiency is relative rather than absolute, signifying that therapies will need to be delivered systemically. We also consider evidence from mouse models suggesting that SMN has its predominant action on the neuromuscular system in early postnatal life, during a discrete phase of development. Data from these experiments suggest that the timing of therapy to increase SMN levels might be crucial. The extent to which SMN is required for the maintenance of motor neurons in later life and whether augmenting its levels could treat degenerative motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), requires further exploration.

  4. Recapitulation of spinal motor neuron-specific disease phenotypes in a human cell model of spinal muscular atrophy

    PubMed Central

    Wang, Zhi-Bo; Zhang, Xiaoqing; Li, Xue-Jun

    2013-01-01

    Establishing human cell models of spinal muscular atrophy (SMA) to mimic motor neuron-specific phenotypes holds the key to understanding the pathogenesis of this devastating disease. Here, we developed a closely representative cell model of SMA by knocking down the disease-determining gene, survival motor neuron (SMN), in human embryonic stem cells (hESCs). Our study with this cell model demonstrated that knocking down of SMN does not interfere with neural induction or the initial specification of spinal motor neurons. Notably, the axonal outgrowth of spinal motor neurons was significantly impaired and these disease-mimicking neurons subsequently degenerated. Furthermore, these disease phenotypes were caused by SMN-full length (SMN-FL) but not SMN-Δ7 (lacking exon 7) knockdown, and were specific to spinal motor neurons. Restoring the expression of SMN-FL completely ameliorated all of the disease phenotypes, including specific axonal defects and motor neuron loss. Finally, knockdown of SMN-FL led to excessive mitochondrial oxidative stress in human motor neuron progenitors. The involvement of oxidative stress in the degeneration of spinal motor neurons in the SMA cell model was further confirmed by the administration of N-acetylcysteine, a potent antioxidant, which prevented disease-related apoptosis and subsequent motor neuron death. Thus, we report here the successful establishment of an hESC-based SMA model, which exhibits disease gene isoform specificity, cell type specificity, and phenotype reversibility. Our model provides a unique paradigm for studying how motor neurons specifically degenerate and highlights the potential importance of antioxidants for the treatment of SMA. PMID:23208423

  5. Recapitulation of spinal motor neuron-specific disease phenotypes in a human cell model of spinal muscular atrophy.

    PubMed

    Wang, Zhi-Bo; Zhang, Xiaoqing; Li, Xue-Jun

    2013-03-01

    Establishing human cell models of spinal muscular atrophy (SMA) to mimic motor neuron-specific phenotypes holds the key to understanding the pathogenesis of this devastating disease. Here, we developed a closely representative cell model of SMA by knocking down the disease-determining gene, survival motor neuron (SMN), in human embryonic stem cells (hESCs). Our study with this cell model demonstrated that knocking down of SMN does not interfere with neural induction or the initial specification of spinal motor neurons. Notably, the axonal outgrowth of spinal motor neurons was significantly impaired and these disease-mimicking neurons subsequently degenerated. Furthermore, these disease phenotypes were caused by SMN-full length (SMN-FL) but not SMN-Δ7 (lacking exon 7) knockdown, and were specific to spinal motor neurons. Restoring the expression of SMN-FL completely ameliorated all of the disease phenotypes, including specific axonal defects and motor neuron loss. Finally, knockdown of SMN-FL led to excessive mitochondrial oxidative stress in human motor neuron progenitors. The involvement of oxidative stress in the degeneration of spinal motor neurons in the SMA cell model was further confirmed by the administration of N-acetylcysteine, a potent antioxidant, which prevented disease-related apoptosis and subsequent motor neuron death. Thus, we report here the successful establishment of an hESC-based SMA model, which exhibits disease gene isoform specificity, cell type specificity, and phenotype reversibility. Our model provides a unique paradigm for studying how motor neurons specifically degenerate and highlights the potential importance of antioxidants for the treatment of SMA.

  6. TIA1 prevents skipping of a critical exon associated with spinal muscular atrophy.

    PubMed

    Singh, Natalia N; Seo, Joonbae; Ottesen, Eric W; Shishimorova, Maria; Bhattacharya, Dhruva; Singh, Ravindra N

    2011-03-01

    Prevention of skipping of exon 7 during pre-mRNA splicing of Survival Motor Neuron 2 (SMN2) holds the promise for cure of spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. Here, we report T-cell-restricted intracellular antigen 1 (TIA1) and TIA1-related (TIAR) proteins as intron-associated positive regulators of SMN2 exon 7 splicing. We show that TIA1/TIAR stimulate exon recognition in an entirely novel context in which intronic U-rich motifs are separated from the 5' splice site by overlapping inhibitory elements. TIA1 and TIAR are modular proteins with three N-terminal RNA recognition motifs (RRMs) and a C-terminal glutamine-rich (Q-rich) domain. Our results reveal that any one RRM in combination with a Q domain is necessary and sufficient for TIA1-associated regulation of SMN2 exon 7 splicing in vivo. We also show that increased expression of TIA1 counteracts the inhibitory effect of polypyrimidine tract binding protein, a ubiquitously expressed factor recently implicated in regulation of SMN exon 7 splicing. Our findings expand the scope of TIA1/TIAR in genome-wide regulation of alternative splicing under normal and pathological conditions.

  7. [Clinical features of a genetically identified spinal and 
bulbar muscular atrophy pedigree].

    PubMed

    Wang, Zhe; Chen, Qihua; Li, Qiuxiang; Bi, Fangfang

    2016-10-28

    Spinal and bulbar muscular atrophy (SBMA) is a rare X-linked motor neuron disease with significant phenotypic viability. Here, we present a genetically identified SBMA family without bulbar paralysis or androgen insensitivity. All four male patients presented with progressive lower motor neuron paralysis in all limbs, with distal extremities more dominant. None of them had bulbar palsy or androgen insensitivity. A consistently mild elevated blood creatine phosphokinase (CPK) levels were detected in all patients and the EMG showed a chronic neurogenic damage. Muscle biopsy of propositus indicated a typical neurogenic amyotrophy. Genetic testing for SMA of mutation in SMN1 was negative, while for SBMA of androgen receptor showed the increased CAG repeat in exon 1, suggesting that although bulbar symptoms and androgen insensitivity are characteristic symptoms of SBMA, they are not obligatory for the diagnosis. In adult males with a chronic motor neuron syndrome without upper motor neuron signs, even in absence of the classical features of androgen insensitivity or bulbar findings, genetic testing for SBMA should be strongly considered.

  8. Population Pharmacokinetics of Valproic Acid in Pediatric Patients With Epilepsy: Considerations for Dosing Spinal Muscular Atrophy Patients

    PubMed Central

    Williams, Jason H.; Jayaraman, Bhuvaneswari; Swoboda, Kathryn J.; Barrett, Jeffrey S.

    2012-01-01

    Valproic acid (VPA) dosing strategies used in recent clinical trials in patients with spinal muscular atrophy (SMA) have utilized a paradigm of monitoring trough levels to estimate drug exposure with subsequent dose titration. The validity of this approach remains uncertain and could be improved by understanding sources of pharmacokinetic variability. A population pharmacokinetic analysis of VPA in pediatric patients with epilepsy was recently performed. The pooled data set included 52 subjects with epilepsy, ages 1 to 17 years, who received intravenous and/or various oral formulations. The data was best fit by a 2-compartment model; inclusion of age and weight reduced intersubject variability for clearance (41%), central volume (70%), and peripheral volume (42%) over the base model. The final model for clearance and volume parameters was clearance = 0.854 · (weight/70)0.75; central volume of distribution = 10.3 · (weight/70)1.0 · (age/8.5)−0.267; peripheral volume of distribution = 4.08 · (weight/70)1.0; and intercompartmental clearance = 5.34 · (weight/70)0.75. Application of the model to data from a clinical trial in SMA patients suggests altered kinetics, perhaps based on underlying physiologic differences such as alterations in lean body mass. Future studies in SMA should incorporate modeling and simulation techniques to support individualized dosing and further assess if additional patient-specific factors necessitate alternative dosing strategies. PMID:22167565

  9. Apparent gene conversions involving the SMN gene in the region of the spinal muscular atrophy locus on chromosome 5

    SciTech Connect

    Steege, G. van der; Grootscholten, P.M.; Cobben, J.M.; Scheffer, H.; Buys, C.H.C.M.

    1996-10-01

    The survival motor neuron (SMN) gene has been described as a determining gene for spinal muscular atrophy (SMA). SMN has a closely flanking, nearly identical copy ({sup C}BCD541). Gene and copy gene can be discriminated by sequence differences in exons 7 and 8. The large majority of SMA patients show homozygous deletions of at least exons 7 and 8 of the SMN gene. A minority of patients show absence of SMN exon 7 but retention of exon 8. This is explained by results of our present analysis of 13 such patients providing evidence for apparent gene-conversion events between SMN and the centromeric copy gene. Instead of applying a separate analysis for absence or presence of SMN exons 7 and 8, we used a contiguous PCR from intron 6 to exon 8. In every case we found a chimeric gene with a fusion of exon 7 of the copy gene and exon 8 of SMN and absence of a normal SMN gene. Similar events, including the fusion counterpart, were observed in a group of controls, although in the presence of a normal SMN gene. Chimeric genes as the result of fusions of parts of SMN and {sup C}BCD541 apparently are far from rare and may partly explain the frequently observed SMN deletions in SMA patients. 23 refs., 4 figs.

  10. Severe impairment of male reproductive organ development in a low SMN expressing mouse model of spinal muscular atrophy

    PubMed Central

    Ottesen, Eric W.; Howell, Matthew D.; Singh, Natalia N.; Seo, Joonbae; Whitley, Elizabeth M.; Singh, Ravindra N.

    2016-01-01

    Spinal muscular atrophy (SMA) is caused by low levels of survival motor neuron (SMN), a multifunctional protein essential for higher eukaryotes. While SMN is one of the most scrutinized proteins associated with neurodegeneration, its gender-specific role in vertebrates remains unknown. We utilized a mild SMA model (C/C model) to examine the impact of low SMN on growth and development of mammalian sex organs. We show impaired testis development, degenerated seminiferous tubules, reduced sperm count and low fertility in C/C males, but no overt sex organ phenotype in C/C females. Underscoring an increased requirement for SMN expression, wild type testis showed extremely high levels of SMN protein compared to other tissues. Our results revealed severe perturbations in pathways critical to C/C male reproductive organ development and function, including steroid biosynthesis, apoptosis, and spermatogenesis. Consistent with enhanced apoptosis in seminiferous tubules of C/C testes, we recorded a drastic increase in cells with DNA fragmentation. SMN was expressed at high levels in adult C/C testis due to an adult-specific splicing switch, but could not compensate for low levels during early testicular development. Our findings uncover novel hallmarks of SMA disease progression and link SMN to general male infertility. PMID:26830971

  11. [Sanger sequencing for the diagnosis of spinal muscular atrophy patients with survival motor neuron gene 1 compound heterozygous mutation].

    PubMed

    Yang, L; Cao, Y Y; Qu, Y J; Bai, J L; Wang, H; Jin, Y W; Han, Y L; Song, F

    2017-02-14

    Objective: To detect the subtle variant of survival motor neuron gene 1(SMN1) by Sanger sequencing, and to assess the