The identification of HESX1 mutations in Kallmann syndrome

PubMed Central

Newbern, Kayce; Natrajan, Nithya; Kim, Hyung-Goo; Chorich, Lynn .P.; Halvorson, Lisa; Cameron, Richard S.; Layman, Lawrence C.

2013-01-01

Objective To determine if HESX1 mutations are present in patients with idiopathic hypogonadotropic hypogonadism (IHH)/Kallmann syndrome (KS). HESX1 mutations have previously been characterized in patients with septo-optic dysplasia (SOD), isolated growth hormone deficiency (IGHD), and combined pituitary hormone deficiency (CPHD). We hypothesized that IHH/KS represents a milder phenotypic variant of SOD. Design PCR-based DNA sequencing was performed on 217 well-characterized IHH/KS patients. Putative missense mutations were analyzed by sorting intolerant from tolerant (SIFT) and Clustal Ω. Setting An academic medical center Patients 217 IHH/KS and 192 controls Interventions DNA was extracted from patients and controls; genotype/phenotype comparisons were made Main Outcome Measures DNA sequence of HESX1, SIFT analysis, and ortholog alignment Results Two novel heterozygous missense mutations (p.H42Y and p.V75L) and previously reported heterozygous missense mutation p.Q6H in HESX1 were identified in 3/217 (1.4%) patients. All were males with KS. Both p.Q6H and p.H42Y were predicted to be deleterious by SIFT, while p.V75L was conserved in 8/9 species. No other IHH/KS gene mutations were present. Conclusions HESX1 mutations may cause KS in addition to more severe phenotypes. Our findings expand the phenotypic spectrum of HESX1 mutations in humans, thereby broadening its role in development. PMID:23465708

Non-syndromic posterior lenticonus a cause of childhood cataract: evidence for X-linked inheritance.

PubMed

Russell-Eggitt, I M

2000-12-01

When an X-linked pedigree of posterior lenticonus with cataract was identified further evidence for X-linked inheritance of this condition was sought. Forty-three cases of posterior lenticonus were identified from a database of 354 children with cataract. Two children with the X-linked syndromes of Lowe and Nance-Horan and 3 children with Fanconi syndrome have been excluded from further analysis. None of the children was deaf. None of the non-syndromic cases had microcornea. There were 38 cases of non-syndromic posterior lenticonus (approximately 11%). There were 15 children from 13 pedigrees and 23 apparently sporadic cases. Of the 106 cases on the database with unilateral cataract 15 had posterior lenticonus (approximately 14%). Eleven of 13 pedigrees were compatible with X-linked inheritance or autosomal dominant inheritance with variable expression. However, in 2 pedigrees there was father to son transmission. Posterior lenticonus is a common cause of unilateral infantile cataract, but is thought to be a rare cause of bilateral cataracts. This study suggests that posterior lenticonus is responsible for a significant proportion of childhood cataracts (approximately 14% of unilateral and approximately 9% of bilateral cases). Posterior lenticonus is generally thought to occur as a sporadic condition. This study demonstrates that there is a family history of early-onset cataract in a significant number of bilateral cases (approximately 58%).

X-linked Acrogigantism (X-LAG) Syndrome: Clinical Profile and Therapeutic Responses

PubMed Central

Beckers, Albert; Lodish, Maya Beth; Trivellin, Giampaolo; Rostomyan, Liliya; Lee, Misu; Faucz, Fabio R; Yuan, Bo; Choong, Catherine S; Caberg, Jean-Hubert; Verrua, Elisa; Naves, Luciana Ansaneli; Cheetham, Tim D; Young, Jacques; Lysy, Philippe A; Petrossians, Patrick; Cotterill, Andrew; Shah, Nalini Samir; Metzger, Daniel; Castermans, Emilie; Ambrosio, Maria Rosaria; Villa, Chiara; Strebkova, Natalia; Mazerkina, Nadia; Gaillard, Stéphan; Barra, Gustavo Barcelos; Casulari, Luis Augusto; Neggers, Sebastian J.; Salvatori, Roberto; Jaffrain-Rea, Marie-Lise; Zacharin, Margaret; Santamaria, Beatriz Lecumberri; Zacharieva, Sabina; Lim, Ee Mun; Mantovani, Giovanna; Zatelli, Maria Chaira; Collins, Michael T; Bonneville, Jean-François; Quezado, Martha; Chittiboina, Prashant; Oldfield, Edward H.; Bours, Vincent; Liu, Pengfei; De Herder, Wouter; Pellegata, Natalia; Lupski, James R.; Daly, Adrian F.; Stratakis, Constantine A.

2015-01-01

X-linked acro-gigantism (X-LAG) is a new syndrome of pituitary gigantism, caused by microduplications on chromosome Xq26.3, encompassing the gene GPR101, which is highly upregulated in pituitary tumors. We conducted this study to explore the clinical, radiological and hormonal phenotype and responses to therapy in patients with X-LAG syndrome. The study included 18 patients (13 sporadic) with X-LAG and a microduplication in chromosome Xq26.3. All sporadic cases had unique duplications and the inheritance pattern in 2 families was dominant with all Xq26.3 duplication carriers being affected. Patients began to grow rapidly as early as 2–3 months of age (median 12 months). At diagnosis (median delay 27 months), patients had a median height and weight SDS score of >+3.9 SDS. Apart from the increased overall body size, the children had acromegalic symptoms including acral enlargement and facial coarsening. More than a third of cases had increased appetite. Patients had marked hypersecretion of GH/IGF-1 and prolactin, usually due to a pituitary macroadenoma or hyperplasia. Primary neurosurgical control was achieved with extensive anterior pituitary resection but postoperative hypopituitarism was frequent. Control with somatostatin analogs was not readily achieved despite moderate to high somatostatin receptor subtype-2 expression in tumor tissue. Postoperative adjuvant pegvisomant achieved control of IGF-1 all 5 cases in which it was employed. X-LAG is a new infant-onset gigantism syndrome that has a severe clinical phenotype leading to challenging disease management. PMID:25712922

X-linked cataract and Nance-Horan syndrome are allelic disorders.

PubMed

Coccia, Margherita; Brooks, Simon P; Webb, Tom R; Christodoulou, Katja; Wozniak, Izabella O; Murday, Victoria; Balicki, Martha; Yee, Harris A; Wangensteen, Teresia; Riise, Ruth; Saggar, Anand K; Park, Soo-Mi; Kanuga, Naheed; Francis, Peter J; Maher, Eamonn R; Moore, Anthony T; Russell-Eggitt, Isabelle M; Hardcastle, Alison J

2009-07-15

Nance-Horan syndrome (NHS) is an X-linked developmental disorder characterized by congenital cataract, dental anomalies, facial dysmorphism and, in some cases, mental retardation. Protein truncation mutations in a novel gene (NHS) have been identified in patients with this syndrome. We previously mapped X-linked congenital cataract (CXN) in one family to an interval on chromosome Xp22.13 which encompasses the NHS locus; however, no mutations were identified in the NHS gene. In this study, we show that NHS and X-linked cataract are allelic diseases. Two CXN families, which were negative for mutations in the NHS gene, were further analysed using array comparative genomic hybridization. CXN was found to be caused by novel copy number variations: a complex duplication-triplication re-arrangement and an intragenic deletion, predicted to result in altered transcriptional regulation of the NHS gene. Furthermore, we also describe the clinical and molecular analysis of seven families diagnosed with NHS, identifying four novel protein truncation mutations and a novel large deletion encompassing the majority of the NHS gene, all leading to no functional protein. We therefore show that different mechanisms, aberrant transcription of the NHS gene or no functional NHS protein, lead to different diseases. Our data highlight the importance of copy number variation and non-recurrent re-arrangements leading to different severity of disease and describe the potential mechanisms involved.

X-linked cataract and Nance-Horan syndrome are allelic disorders

PubMed Central

Coccia, Margherita; Brooks, Simon P.; Webb, Tom R.; Christodoulou, Katja; Wozniak, Izabella O.; Murday, Victoria; Balicki, Martha; Yee, Harris A.; Wangensteen, Teresia; Riise, Ruth; Saggar, Anand K.; Park, Soo-Mi; Kanuga, Naheed; Francis, Peter J.; Maher, Eamonn R.; Moore, Anthony T.; Russell-Eggitt, Isabelle M.; Hardcastle, Alison J.

2009-01-01

Nance-Horan syndrome (NHS) is an X-linked developmental disorder characterized by congenital cataract, dental anomalies, facial dysmorphism and, in some cases, mental retardation. Protein truncation mutations in a novel gene (NHS) have been identified in patients with this syndrome. We previously mapped X-linked congenital cataract (CXN) in one family to an interval on chromosome Xp22.13 which encompasses the NHS locus; however, no mutations were identified in the NHS gene. In this study, we show that NHS and X-linked cataract are allelic diseases. Two CXN families, which were negative for mutations in the NHS gene, were further analysed using array comparative genomic hybridization. CXN was found to be caused by novel copy number variations: a complex duplication–triplication re-arrangement and an intragenic deletion, predicted to result in altered transcriptional regulation of the NHS gene. Furthermore, we also describe the clinical and molecular analysis of seven families diagnosed with NHS, identifying four novel protein truncation mutations and a novel large deletion encompassing the majority of the NHS gene, all leading to no functional protein. We therefore show that different mechanisms, aberrant transcription of the NHS gene or no functional NHS protein, lead to different diseases. Our data highlight the importance of copy number variation and non-recurrent re-arrangements leading to different severity of disease and describe the potential mechanisms involved. PMID:19414485

A Novel Mutation in a Kazakh Family with X-Linked Alport Syndrome

PubMed Central

Rakhimova, Saule E.; Nigmatullina, Nazym B.; Momynaliev, Kuvat T.; Ramanculov, Yerlan M.

2015-01-01

Alport syndrome is a genetic condition that results in hematuria, progressive renal impairment, hearing loss, and occasionally lenticonus and retinopathy. Approximately 80% of Alport syndrome cases are caused by X-linked mutations in the COL4A5 gene encoding type IV collagen. The objective of this study was to define the SNP profiles for COL4A5 in patients with hereditary nephritis and hematuria. For this, we examined four subjects from one Kazakh family clinically affected with X-linked Alport syndrome due to COL4A5 gene mutations. All 51 exons of the COL4A5 gene were screened by linkage analysis and direct DNA sequencing, resulting in the identification of a novel mutation (G641E) in exon 25. The mutation was found only in two affected family individuals but was not present in healthy family members or 200 unrelated healthy controls. This result demonstrates that this novel mutation is pathogenic and has meaningful implications for the diagnosis of patients with Alport syndrome. PMID:26168235

A Novel Mutation in a Kazakh Family with X-Linked Alport Syndrome.

PubMed

Baikara, Barshagul T; Zholdybayeva, Elena V; Rakhimova, Saule E; Nigmatullina, Nazym B; Momynaliev, Kuvat T; Ramanculov, Yerlan M

2015-01-01

Alport syndrome is a genetic condition that results in hematuria, progressive renal impairment, hearing loss, and occasionally lenticonus and retinopathy. Approximately 80% of Alport syndrome cases are caused by X-linked mutations in the COL4A5 gene encoding type IV collagen. The objective of this study was to define the SNP profiles for COL4A5 in patients with hereditary nephritis and hematuria. For this, we examined four subjects from one Kazakh family clinically affected with X-linked Alport syndrome due to COL4A5 gene mutations. All 51 exons of the COL4A5 gene were screened by linkage analysis and direct DNA sequencing, resulting in the identification of a novel mutation (G641E) in exon 25. The mutation was found only in two affected family individuals but was not present in healthy family members or 200 unrelated healthy controls. This result demonstrates that this novel mutation is pathogenic and has meaningful implications for the diagnosis of patients with Alport syndrome.

Molecular characterization of a novel X-linked syndrome involving developmental delay and deafness.

PubMed

Hildebrand, Michael S; de Silva, Michelle G; Tan, Tiong Yang; Rose, Elizabeth; Nishimura, Carla; Tolmachova, Tanya; Hulett, Joanne M; White, Susan M; Silver, Jeremy; Bahlo, Melanie; Smith, Richard J H; Dahl, Hans-Henrik M

2007-11-01

X-linked syndromes associated with developmental delay and sensorineural hearing loss (SNHL) have been characterized at the molecular level, including Mohr-Tranebjaerg syndrome and Norrie disease. In this study we report on a novel X-linked recessive, congenital syndrome in a family with developmental delay and SNHL that maps to a locus associated with mental retardation (MR) for which no causative gene has been identified. The X-linked recessive inheritance and congenital nature of the syndrome was confirmed by detailed clinical investigation and the family history. Linkage mapping of the X-chromosome was conducted to ascertain the disease locus and candidate genes were screened by direct sequencing and STRP analysis. The recessive syndrome was mapped to Xp11.3-q21.32 and a deletion was identified in a regulatory region upstream of the POU3F4 gene in affected family members. Since mutations in POU3F4 cause deafness at the DFN3 locus, the deletion is the likely cause of the SNHL in this family. The choroideremia (CHM) gene was also screened and a novel missense change was identified. The alteration changes the serine residue at position 89 in the Rab escort 1 protein (REP-1) to a cysteine (S89C). Prenylation of Rab proteins was investigated in patients and the location of REP-1 expression in the brain determined. However, subsequent analysis revealed that this change in CHM was polymorphic having no effect on REP-1 function. Although the causative gene at the MR locus in this family has not been identified, there are a number of genes involved in syndromic and nonsyndromic forms of MR that are potential candidates. Copyright 2007 Wiley-Liss, Inc.

A heterozygous mutation in RPGR associated with X-linked retinitis pigmentosa in a patient with Turner syndrome mosaicism (45,X/46,XX).

PubMed

Zhou, Qi; Yao, Fengxia; Wang, Feng; Li, Hui; Chen, Rui; Sui, Ruifang

2018-01-01

Turner syndrome with retinitis pigmentosa (RP) is rare, with only three cases reported based on clinical examination alone. We summarized the 4-year follow-up and molecular findings in a 28-year-old patient with Turner syndrome and the typical features of short stature and neck webbing, who also had X-linked RP. Her main complaints were night blindness and progressive loss of vision since the age of 9 years. Ophthalmologic examination, optical coherent tomographic imaging, and visual electrophysiology tests showed classic manifestations of RP. The karyotype of peripheral blood showed mosaicism (45,X [72%]/46,XX[28%]). A novel heterozygous frameshift mutation (c.2403_2406delAGAG, p.T801fsX812) in the RP GTPase regulator (RPGR) gene was detected using next generation sequencing and validated by Sanger sequencing. We believe that this is the first report of X-linked RP in a patient with Turner syndrome associated with mosaicism, and an RPGR heterozygous mutation. We hypothesize that X-linked RP in this woman is not related to Turner syndrome, but may be a manifestation of the lack of a normal paternal X chromosome with intact but mutated RPGR. © 2017 Wiley Periodicals, Inc.

X-linked acrogigantism syndrome: clinical profile and therapeutic responses.

PubMed

Beckers, Albert; Lodish, Maya Beth; Trivellin, Giampaolo; Rostomyan, Liliya; Lee, Misu; Faucz, Fabio R; Yuan, Bo; Choong, Catherine S; Caberg, Jean-Hubert; Verrua, Elisa; Naves, Luciana Ansaneli; Cheetham, Tim D; Young, Jacques; Lysy, Philippe A; Petrossians, Patrick; Cotterill, Andrew; Shah, Nalini Samir; Metzger, Daniel; Castermans, Emilie; Ambrosio, Maria Rosaria; Villa, Chiara; Strebkova, Natalia; Mazerkina, Nadia; Gaillard, Stéphan; Barra, Gustavo Barcelos; Casulari, Luis Augusto; Neggers, Sebastian J; Salvatori, Roberto; Jaffrain-Rea, Marie-Lise; Zacharin, Margaret; Santamaria, Beatriz Lecumberri; Zacharieva, Sabina; Lim, Ee Mun; Mantovani, Giovanna; Zatelli, Maria Chaira; Collins, Michael T; Bonneville, Jean-François; Quezado, Martha; Chittiboina, Prashant; Oldfield, Edward H; Bours, Vincent; Liu, Pengfei; W de Herder, Wouter; Pellegata, Natalia; Lupski, James R; Daly, Adrian F; Stratakis, Constantine A

2015-06-01

X-linked acrogigantism (X-LAG) is a new syndrome of pituitary gigantism, caused by microduplications on chromosome Xq26.3, encompassing the gene GPR101, which is highly upregulated in pituitary tumors. We conducted this study to explore the clinical, radiological, and hormonal phenotype and responses to therapy in patients with X-LAG syndrome. The study included 18 patients (13 sporadic) with X-LAG and microduplication of chromosome Xq26.3. All sporadic cases had unique duplications and the inheritance pattern in two families was dominant, with all Xq26.3 duplication carriers being affected. Patients began to grow rapidly as early as 2-3 months of age (median 12 months). At diagnosis (median delay 27 months), patients had a median height and weight standard deviation scores (SDS) of >+3.9 SDS. Apart from the increased overall body size, the children had acromegalic symptoms including acral enlargement and facial coarsening. More than a third of cases had increased appetite. Patients had marked hypersecretion of GH/IGF1 and usually prolactin, due to a pituitary macroadenoma or hyperplasia. Primary neurosurgical control was achieved with extensive anterior pituitary resection, but postoperative hypopituitarism was frequent. Control with somatostatin analogs was not readily achieved despite moderate to high levels of expression of somatostatin receptor subtype-2 in tumor tissue. Postoperative use of adjuvant pegvisomant resulted in control of IGF1 in all five cases where it was employed. X-LAG is a new infant-onset gigantism syndrome that has a severe clinical phenotype leading to challenging disease management. © 2015 Society for Endocrinology.

Congenital hypogonadotropic hypogonadism and Kallmann syndrome as models for studying hormonal regulation of human testicular endocrine functions.

PubMed

Trabado, Séverine; Lamothe, Sophie; Maione, Luigi; Bouvattier, Claire; Sarfati, Julie; Brailly-Tabard, Sylvie; Young, Jacques

2014-05-01

Men with Kallmann syndrome (KS) and those with congenital isolated hypogonadotropic hypogonadism with normal olfaction share a chronic, usually profound deficit, in FSH and LH, the two pituitary gonadotropins. Many studies indicate that this gonadotropin deficiency is already present during fetal life, thus explaining the micropenis, cryptorchidism and marked testicular hypotrophy already present at birth. In addition, neonatal activation of gonadotropin secretion is compromised in boys with severe CHH/Kallmann, preventing the first phase of postnatal testicular activation. Finally, CHH is characterized by the persistence, in the vast majority of cases, of gonadotropin deficiency at the time of puberty and during adulthood. This prevents the normal pubertal testicular reactivation required for physiological sex steroid and testicular peptide production, and for spermatogenesis. CHH/KS thus represents a pathological paradigm that can help to unravel, in vivo, the role of each gonadotropin in human testicular exocrine and endocrine functions at different stages of development. Recombinant gonadotropins with pure LH or FSH activity have been used to stimulate Leydig's cells and Sertoli's cells, respectively, and thereby to clarify their paracrine interaction in vivo. The effects of these pharmacological probes can be assessed by measuring the changes they provoke in circulating testicular hormone concentrations. This review discusses the impact of chronic gonadotropin deficiency on the endocrine functions of the interstitial compartment, which contains testosterone-, estradiol- and INSL3-secreting Leydig's cells. It also examines the regulation of inhibin B and anti-Mullerian hormone (AMH) secretion in the seminiferous tubules, and the insights provided by studies of human testicular stimulation with recombinant gonadotropins, used either individually or in combination. Copyright © 2014. Published by Elsevier Masson SAS.

Sniffin' Sticks and olfactory system imaging in patients with Kallmann syndrome.

PubMed

Ottaviano, Giancarlo; Cantone, Elena; D'Errico, Arianna; Salvalaggio, Alessandro; Citton, Valentina; Scarpa, Bruno; Favaro, Angela; Sinisi, Antonio Agostino; Liuzzi, Raffaele; Bonanni, Guglielmo; Di Salle, Francesco; Elefante, Andrea; Manara, Renzo; Staffieri, Alberto; Martini, Alessandro; Brunetti, Arturo

2015-09-01

The relationship between olfactory function, rhinencephalon and forebrain changes in Kallmann syndrome (KS) have not been adequately investigated. We evaluated a large cohort of male KS patients using Sniffin' Sticks and MRI in order to study olfactory bulb (OB) volume, olfactory sulcus (OS) depth, cortical thickness close to the OS, and olfactory phenotype. Olfaction was assessed administering Sniffin' Sticks®, in 38 KS patients and 17 controls (by means of Screening 12 test®). All subjects underwent magnetic resonance imaging (MRI) to study OB volume, sulcus depth, and cortical thickness. Compared to controls, KS patients showed smaller OB volume (p<0.0001), reduced sulcus depth (p<0.0001), and thicker cortex in the region close to the OS (p<0.0001). Anosmic KS patients had smaller OB than controls and hyposmic KS patients; there was no difference between hyposmic KS patients and controls. OB volume correlated with Sniffin' Sticks score (r = 0.64; p < 0.001), OS depth (p<0.0001) and, inversely, with cortical thickness changes (p<0.0001). Sniffin' Sticks showed an inverse correlation with cortical thickness (r = -0.5; p<0.0001) and a trend toward a statistically significant correlation with OS depth. The present study provides further evidence of the strict relationship between olfaction and OB volume. The strong correlation between OB volume and the overlying cortical changes highlights the key role of rhinencephalon in forebrain embryogenesis. © 2015 ARS-AAOA, LLC.

SEMA3A, a Gene Involved in Axonal Pathfinding, Is Mutated in Patients with Kallmann Syndrome

PubMed Central

Parkash, Jyoti; Espy, Cécile; Fouveaut, Corinne; Leroy, Chrystel; Baron, Stéphanie; Campagne, Céline; Vanacker, Charlotte; Collier, Francis; Cruaud, Corinne; Meyer, Vincent; García-Piñero, Alfons; Dewailly, Didier; Cortet-Rudelli, Christine; Gersak, Ksenija; Metz, Chantal; Chabrier, Gérard; Pugeat, Michel; Young, Jacques; Hardelin, Jean-Pierre; Prevot, Vincent; Dodé, Catherine

2012-01-01

Kallmann syndrome (KS) associates congenital hypogonadism due to gonadotropin-releasing hormone (GnRH) deficiency and anosmia. The genetics of KS involves various modes of transmission, including oligogenic inheritance. Here, we report that Nrp1 sema/sema mutant mice that lack a functional semaphorin-binding domain in neuropilin-1, an obligatory coreceptor of semaphorin-3A, have a KS–like phenotype. Pathohistological analysis of these mice indeed showed abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the basal forebrain, which results in increased mortality of newborn mice and reduced fertility in adults. We thus screened 386 KS patients for the presence of mutations in SEMA3A (by Sanger sequencing of all 17 coding exons and flanking splice sites) and identified nonsynonymous mutations in 24 patients, specifically, a frameshifting small deletion (D538fsX31) and seven different missense mutations (R66W, N153S, I400V, V435I, T688A, R730Q, R733H). All the mutations were found in heterozygous state. Seven mutations resulted in impaired secretion of semaphorin-3A by transfected COS-7 cells (D538fsX31, R66W, V435I) or reduced signaling activity of the secreted protein in the GN11 cell line derived from embryonic GnRH cells (N153S, I400V, T688A, R733H), which strongly suggests that these mutations have a pathogenic effect. Notably, mutations in other KS genes had already been identified, in heterozygous state, in five of these patients. Our findings indicate that semaphorin-3A signaling insufficiency contributes to the pathogenesis of KS and further substantiate the oligogenic pattern of inheritance in this developmental disorder. PMID:22927827

SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome.

PubMed

Hanchate, Naresh Kumar; Giacobini, Paolo; Lhuillier, Pierre; Parkash, Jyoti; Espy, Cécile; Fouveaut, Corinne; Leroy, Chrystel; Baron, Stéphanie; Campagne, Céline; Vanacker, Charlotte; Collier, Francis; Cruaud, Corinne; Meyer, Vincent; García-Piñero, Alfons; Dewailly, Didier; Cortet-Rudelli, Christine; Gersak, Ksenija; Metz, Chantal; Chabrier, Gérard; Pugeat, Michel; Young, Jacques; Hardelin, Jean-Pierre; Prevot, Vincent; Dodé, Catherine

2012-08-01

Kallmann syndrome (KS) associates congenital hypogonadism due to gonadotropin-releasing hormone (GnRH) deficiency and anosmia. The genetics of KS involves various modes of transmission, including oligogenic inheritance. Here, we report that Nrp1(sema/sema) mutant mice that lack a functional semaphorin-binding domain in neuropilin-1, an obligatory coreceptor of semaphorin-3A, have a KS-like phenotype. Pathohistological analysis of these mice indeed showed abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the basal forebrain, which results in increased mortality of newborn mice and reduced fertility in adults. We thus screened 386 KS patients for the presence of mutations in SEMA3A (by Sanger sequencing of all 17 coding exons and flanking splice sites) and identified nonsynonymous mutations in 24 patients, specifically, a frameshifting small deletion (D538fsX31) and seven different missense mutations (R66W, N153S, I400V, V435I, T688A, R730Q, R733H). All the mutations were found in heterozygous state. Seven mutations resulted in impaired secretion of semaphorin-3A by transfected COS-7 cells (D538fsX31, R66W, V435I) or reduced signaling activity of the secreted protein in the GN11 cell line derived from embryonic GnRH cells (N153S, I400V, T688A, R733H), which strongly suggests that these mutations have a pathogenic effect. Notably, mutations in other KS genes had already been identified, in heterozygous state, in five of these patients. Our findings indicate that semaphorin-3A signaling insufficiency contributes to the pathogenesis of KS and further substantiate the oligogenic pattern of inheritance in this developmental disorder.

A Trial of Metformin in Individuals With Fragile X Syndrome

ClinicalTrials.gov

2018-06-05

Fragile X Syndrome; Fragile X Mental Retardation Syndrome; Mental Retardation, X Linked; Genetic Diseases, X-Linked; Trinucleotide Repeat Expansion; Fra(X) Syndrome; Intellectual Disability; FXS; Neurobehavioral Manifestations; Sex Chromosome Disorders

A previously unreported, dominantly inherited syndrome of shortness of stature, ear malformations, and hip dislocation: the coxoauricular syndrome--autosomal or X-linked male-lethal.

PubMed

Duca, D; Pană, I; Ciovirnache, M; Simionesu, L; Ispas, I; Maxililian, C

1981-01-01

We reported an apparently previously undescribed syndrome, designated the coxoauricular syndrome, in a mother and her 3 daughters, all of whom shared in variable manner shortness of stature, minor vertebral and pelvic changes, dislocated hip(s), and microtia with corresponding hearing loss. The oldest daughter had coincidental Ullrich-Turner syndrome with 46, Xdel(X)(q 13) chromosome constitution. Inheritance of the trait in this family is dominant, either autosomal or X-linked, with hemizygote lethality.

Spectrum of X-linked hydrocephalus (HSAS), MASA syndrome, and complicated spastic paraplegia (SPG1): Clincal review with six additional families

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schrander-Stumpel, C.; Hoeweler, C.; Jones, M.

X-linked hydrocephalus (HSAS) (MIM{sup *}307000), MASA syndrome (MIM {sup *}303350), and complicated spastic paraplegia (SPG1) (MIM {sup *}3129000) are closely related. Soon after delineation, SPG1 was incorporated into the spectrum of MASA syndrome. HSAS and MASA syndrome show great clinical overlap; DNA linkage analysis places the loci at Xq28. In an increasing number of families with MASA syndrome or HSAS, mutations in L1CAM, a gene located at Xq28, have been reported. In order to further delineate the clinical spectrum, we studied 6 families with male patients presenting with MASA syndrome, HSAS, or a mixed phenotype. We summarized data from previousmore » reports and compared them with our data. Clinical variability appears to be great, even within families. Problems in genetic counseling and prenatal diagnosis, the possible overlap with X-linked corpus callosum agenesis and FG syndrome, and the different forms of X-linked complicated spastic paraplegia are discussed. Since adducted thumbs and spastic paraplegia are found in 90% of the patients, the condition may be present in males with nonspecific mental retardation. We propose to abandon the designation MASA syndrome and use the term HSAS/MASA spectrum, incorporating SPG1. 79 refs., 6 figs., 2 tabs.« less

Biochemical and molecular analysis of an X-linked case of Leigh syndrome associated with thiamin-responsive pyruvate dehydrogenase deficiency.

PubMed

Naito, E; Ito, M; Yokota, I; Saijo, T; Matsuda, J; Osaka, H; Kimura, S; Kuroda, Y

1997-08-01

We report molecular analysis of thiamin-responsive pyruvate dehydrogenase complex (PDHC) deficiency in a patient with an X-linked form of Leigh syndrome. PDHC activity in cultured lymphoblastoid cells of this patient and his asymptomatic mother were normal in the presence of a high thiamin pyrophosphate (TPP) concentration (0.4 mmol/L). However, in the presence of a low concentration (1 x 10(-4) mmol/L) of TPP, the activity was significantly decreased, indicating that PDHC deficiency in this patient was due to decreased affinity of PDHC for TPP. The patient's older brother also was diagnosed as PDHC deficiency with Leigh syndrome, suggesting that PDHC deficiency in these two brothers was not a de novo mutation. Sequencing of the X-linked PDHC E1 alpha subunit revealed a C-->G point mutation at nucleotide 787, resulting in a substitution of glycine for arginine 263. Restriction enzyme analysis of the E1 alpha gene revealed that the mother was a heterozygote, indicating that thiamin-responsive PDHC deficiency associated with Leigh syndrome due to this mutation is transmitted by X-linked inheritance.

Delayed puberty, eroticism, and sense of smell: A psychological study of hypogonadotropinism, osmatic and anosmatic (Kallmann's syndrome).

PubMed

Bobrow, N A; Money, J; Lewis, V G

1971-12-01

In 13 male patients with a diagnosis of hypogonadotropic hypogonadism, associated in five cases with verified hyposmia (Kallmann's syndrome), social development and participation were delayed. The patients associated the lack of visible signs of male puberty with their delayed sociosexual maturation. However, the evidence of physical maturation after treatment did not have the ameliorative effect on their social behavior one would have liked to predict. Dating behavior was limited before and after treatment for all the patients, and sexual interest was low even for the three married ones. The experience of falling in love was notably absent in the relationships described. Two characteristic social reaction patterns were social introversion and hostile rejection of agemates. Intellectual functioning and the incidence of personality pathology were not diagnostically noteworthy. None of the patients had any problems with gender identity except for erotic apathy which extended to masturbation. There was an absence of homosexuality. Possibly hypogonadotropic patients have a primary defect of the hypothalamus, manifesting itself as a dysfunction of the behavioral concomitants of puberty as well as a failure of hormonal puberty.

Genetic Overlap in Kallmann Syndrome, Combined Pituitary Hormone Deficiency, and Septo-Optic Dysplasia

PubMed Central

Raivio, Taneli; Avbelj, Magdalena; McCabe, Mark J.; Romero, Christopher J.; Dwyer, Andrew A.; Tommiska, Johanna; Sykiotis, Gerasimos P.; Gregory, Louise C.; Diaczok, Daniel; Tziaferi, Vaitsa; Elting, Mariet W.; Padidela, Raja; Plummer, Lacey; Martin, Cecilia; Feng, Bihua; Zhang, Chengkang; Zhou, Qun-Yong; Chen, Huaibin; Mohammadi, Moosa; Quinton, Richard; Sidis, Yisrael; Radovick, Sally; Dattani, Mehul T.

2012-01-01

Context: Kallmann syndrome (KS), combined pituitary hormone deficiency (CPHD), and septo-optic dysplasia (SOD) all result from development defects of the anterior midline in the human forebrain. Objective: The objective of the study was to investigate whether KS, CPHD, and SOD have shared genetic origins. Design and Participants: A total of 103 patients with either CPHD (n = 35) or SOD (n = 68) were investigated for mutations in genes implicated in the etiology of KS (FGFR1, FGF8, PROKR2, PROK2, and KAL1). Consequences of identified FGFR1, FGF8, and PROKR2 mutations were investigated in vitro. Results: Three patients with SOD had heterozygous mutations in FGFR1; these were either shown to alter receptor signaling (p.S450F, p.P483S) or predicted to affect splicing (c.336C>T, p.T112T). One patient had a synonymous change in FGF8 (c.216G>A, p.T72T) that was shown to affect splicing and ligand signaling activity. Four patients with CPHD/SOD were found to harbor heterozygous rare loss-of-function variants in PROKR2 (p.R85G, p.R85H, p.R268C). Conclusions: Mutations in FGFR1/FGF8/PROKR2 contributed to 7.8% of our patients with CPHD/SOD. These data suggest a significant genetic overlap between conditions affecting the development of anterior midline in the human forebrain. PMID:22319038

Prioritizing Genetic Testing in Patients With Kallmann Syndrome Using Clinical Phenotypes

PubMed Central

Costa-Barbosa, Flavia Amanda; Balasubramanian, Ravikumar; Keefe, Kimberly W.; Shaw, Natalie D.; Al-Tassan, Nada; Plummer, Lacey; Dwyer, Andrew A.; Buck, Cassandra L.; Choi, Jin-Ho; Seminara, Stephanie B.; Quinton, Richard; Monies, Dorota; Meyer, Brian; Hall, Janet E.; Pitteloud, Nelly

2013-01-01

Context: The complexity of genetic testing in Kallmann syndrome (KS) is growing and costly. Thus, it is important to leverage the clinical evaluations of KS patients to prioritize genetic screening. Objective: The objective of the study was to determine which reproductive and nonreproductive phenotypes of KS subjects have implications for specific gene mutations. Subjects: Two hundred nineteen KS patients were studied: 151 with identified rare sequence variants (RSVs) in 8 genes known to cause KS (KAL1, NELF, CHD7, HS6ST1, FGF8/FGFR1, or PROK2/PROKR2) and 68 KS subjects who remain RSV negative for all 8 genes. Main Outcome Measures: Reproductive and nonreproductive phenotypes within each genetic group were measured. Results: Male KS subjects with KAL1 RSVs displayed the most severe reproductive phenotype with testicular volumes (TVs) at presentation of 1.5 ± 0.1 mL vs 3.7 ± 0.3 mL, P < .05 vs all non-KAL1 probands. In both sexes, synkinesia was enriched but not unique to patients with KAL1 RSVs compared with KAL1-negative probands (43% vs 12%; P < .05). Similarly, dental agenesis and digital bone abnormalities were enriched in patients with RSVs in the FGF8/FGFR1 signaling pathway compared with all other gene groups combined (39% vs 4% and 23% vs 0%; P < .05, respectively). Hearing loss marked the probands with CHD7 RSVs (40% vs 13% in non-CHD7 probands; P < .05). Renal agenesis and cleft lip/palate did not emerge as statistically significant phenotypic predictors. Conclusions: Certain clinical features in men and women are highly associated with genetic causes of KS. Synkinesia (KAL1), dental agenesis (FGF8/FGFR1), digital bony abnormalities (FGF8/FGFR1), and hearing loss (CHD7) can be useful for prioritizing genetic screening. PMID:23533228

Genetics Home Reference: X-linked dystonia-parkinsonism

MedlinePlus

... X-linked dystonia-parkinsonism syndrome (XDP): clinical and molecular genetic analysis. Brain Pathol. 1992 Oct;2(4):287-95. Review. Citation on PubMed Kaji R, Goto S, Tamiya G, Ando S, Makino S, Lee LV. Molecular dissection and anatomical basis of dystonia: X-linked ...

Unique Variants in OPN1LW Cause Both Syndromic and Nonsyndromic X-Linked High Myopia Mapped to MYP1.

PubMed

Li, Jiali; Gao, Bei; Guan, Liping; Xiao, Xueshan; Zhang, Jianguo; Li, Shiqiang; Jiang, Hui; Jia, Xiaoyun; Yang, Jianhua; Guo, Xiangming; Yin, Ye; Wang, Jun; Zhang, Qingjiong

2015-06-01

MYP1 is a locus for X-linked syndromic and nonsyndromic high myopia. Recently, unique haplotypes in OPN1LW were found to be responsible for X-linked syndromic high myopia mapped to MYP1. The current study is to test if such variants in OPN1LW are also responsible for X-linked nonsyndromic high myopia mapped to MYP1. The proband of the family previously mapped to MYP1 was initially analyzed using whole-exome sequencing and whole-genome sequencing. Additional probands with early-onset high myopia were analyzed using whole-exome sequencing. Variants in OPN1LW were selected and confirmed by Sanger sequencing. Long-range and second PCR were used to determine the haplotype and the first gene of the red-green gene array. Candidate variants were further validated in family members and controls. The unique LVAVA haplotype in OPN1LW was detected in the family with X-linked nonsyndromic high myopia mapped to MYP1. In addition, this haplotype and a novel frameshift mutation (c.617_620dup, p.Phe208Argfs*51) in OPN1LW were detected in two other families with X-linked high myopia. The unique haplotype cosegregated with high myopia in the two families, with a maximum LOD score of 3.34 and 2.31 at θ = 0. OPN1LW with the variants in these families was the first gene in the red-green gene array and was not present in 247 male controls. Reevaluation of the clinical data in both families with the unique haplotype suggested nonsyndromic high myopia. Our study confirms the findings that unique variants in OPN1LW are responsible for both syndromic and nonsyndromic X-linked high myopia mapped to MYP1.

Whole-brain voxel-based morphometry in Kallmann syndrome associated with mirror movements.

PubMed

Koenigkam-Santos, M; Santos, A C; Borduqui, T; Versiani, B R; Hallak, J E C; Crippa, J A S; Castro, M

2008-10-01

There are 2 main hypotheses concerning the cause of mirror movements (MM) in Kallmann syndrome (KS): abnormal development of the primary motor system, involving the ipsilateral corticospinal tract; and lack of contralateral motor cortex inhibitory mechanisms, mainly through the corpus callosum. The purpose of our study was to determine white and gray matter volume changes in a KS population by using optimized voxel-based morphometry (VBM) and to investigate the relationship between the abnormalities and the presence of MM, addressing the 2 mentioned hypotheses. T1-weighted volumetric images from 21 patients with KS and 16 matched control subjects were analyzed with optimized VBM. Images were segmented and spatially normalized, and these deformation parameters were then applied to the original images before the second segmentation. Patients were divided into groups with and without MM, and a t test statistic was then applied on a voxel-by-voxel basis between the groups and controls to evaluate significant differences. When considering our hypothesis a priori, we found that 2 areas of increased gray matter volume, in the left primary motor and sensorimotor cortex, were demonstrated only in patients with MM, when compared with healthy controls. Regarding white matter alterations, no areas of altered volume involving the corpus callosum or the projection of the corticospinal tract were demonstrated. The VBM study did not show significant white matter changes in patients with KS but showed gray matter alterations in keeping with a hypertrophic response to a deficient pyramidal decussation in patients with MM. In addition, gray matter alterations were observed in patients without MM, which can represent more complex mechanisms determining the presence or absence of this symptom.

[Detection of large deletions in X linked Alport syndrome using competitive multiplex fluorescence polymerase chain reaction].

PubMed

Wang, F; Zhang, Y Q; Ding, J; Yu, L X

2017-10-18

To evaluate the ability of multiplex competitive fluorescence polymerase chain reaction in detection of large deletion and duplication genotypes of X-linked Alport syndrome. Clinical diagnosis of X-linked Alport syndrome was based on either abnormal staining of type IV collagen α5 chain in the epidermal basement membrane alone or with abnormal staining of type IV collagen α5 chain in the glomerular basement membrane and Bowman's capsule/ultrastructural changes in the glomerular basement membrane typical of Alport syndrome. A total of 20 unrelated Chinese patients (13 males and 7 females) clinically diagnosed as X-linked Alport syndrome were included in the study. Their genotypes were unknown. Control subjects included a male patient with other renal disease and two patients who had large deletions in COL4A5 gene detected by multiplex ligation-dependent probe amplification. Genomic DNA was isolated from peripheral blood leukocytes in all the participants. Multiplex competitive fluorescence polymerase chain reaction was used to coamplify 53 exons of COL4A5 gene and four reference genes in a single reaction. When a deletion removed exon 1 of COL4A5 gene was identified, the same method was used to coamplify the first 4 exons of COL4A5 and COL4A6 genes, a promoter shared by COL4A5 and COL4A6 genes, and three reference genes in a single reaction. Any copy number loss suggested by this method was verified by electrophoresis of corresponding polymerase chain reaction amplified products or DNA sequencing to exclude possible DNA variations in the primer regions. Genotypes of two positive controls identified by multiplex competitive fluorescence polymerase chain reaction were consistent with those detected by multiplex ligation-dependent probe amplification. Deletions were identified in 6 of the 20 patients, including two large deletions removing the 5' part of both COL4A5 and COL4A6 genes with the breakpoint located in the second intron of COL4A6, two large deletions

Dysfunctional SEMA3E signaling underlies gonadotropin-releasing hormone neuron deficiency in Kallmann syndrome.

PubMed

Cariboni, Anna; André, Valentina; Chauvet, Sophie; Cassatella, Daniele; Davidson, Kathryn; Caramello, Alessia; Fantin, Alessandro; Bouloux, Pierre; Mann, Fanny; Ruhrberg, Christiana

2015-06-01

Individuals with an inherited deficiency in gonadotropin-releasing hormone (GnRH) have impaired sexual reproduction. Previous genetic linkage studies and sequencing of plausible gene candidates have identified mutations associated with inherited GnRH deficiency, but the small number of affected families and limited success in validating candidates have impeded genetic diagnoses for most patients. Using a combination of exome sequencing and computational modeling, we have identified a shared point mutation in semaphorin 3E (SEMA3E) in 2 brothers with Kallmann syndrome (KS), which causes inherited GnRH deficiency. Recombinant wild-type SEMA3E protected maturing GnRH neurons from cell death by triggering a plexin D1-dependent (PLXND1-dependent) activation of PI3K-mediated survival signaling. In contrast, recombinant SEMA3E carrying the KS-associated mutation did not protect GnRH neurons from death. In murine models, lack of either SEMA3E or PLXND1 increased apoptosis of GnRH neurons in the developing brain, reducing innervation of the adult median eminence by GnRH-positive neurites. GnRH neuron deficiency in male mice was accompanied by impaired testes growth, a characteristic feature of KS. Together, these results identify SEMA3E as an essential gene for GnRH neuron development, uncover a neurotrophic function for SEMA3E in the developing brain, and elucidate SEMA3E/PLXND1/PI3K signaling as a mechanism that prevents GnRH neuron deficiency.

X linked mental retardation: a clinical guide.

PubMed

Raymond, F L

2006-03-01

Mental retardation is more common in males than females in the population, assumed to be due to mutations on the X chromosome. The prevalence of the 24 genes identified to date is low and less common than expansions in FMR1, which cause Fragile X syndrome. Systematic screening of all other X linked genes in X linked families with mental retardation is currently not feasible in a clinical setting. The phenotypes of genes causing syndromic and non-syndromic mental retardation (NLGN3, NLGN4, RPS6KA3(RSK2), OPHN1, ATRX, SLC6A8, ARX, SYN1, AGTR2, MECP2, PQBP1, SMCX, and SLC16A2) are first discussed, as these may be the focus of more targeted mutation analysis. Secondly, the relative prevalence of genes causing only non-syndromic mental retardation (IL1RAPL1, TM4SF2, ZNF41, FTSJ1, DLG3, FACL4, PAK3, ARHGEF6, FMR2, and GDI) is summarised. Thirdly, the problem of recurrence risk where a molecular genetics diagnosis has not been made and what proportion of the male excess of mental retardation is due to monogenic disorders of the X chromosome are discussed.

Physiological Arousal in Autism and Fragile X Syndrome: Group Comparisons and Links with Pragmatic Language

ERIC Educational Resources Information Center

Klusek, Jessica; Martin, Gary E.; Losh, Molly

2013-01-01

This study tested the hypothesis that pragmatic (i.e., social) language impairment is linked to arousal dysregulation in autism spectrum disorder (ASD) and fragile X syndrome (FXS). Forty boys with ASD, 39 with FXS, and 27 with typical development (TD), aged 4-15 years, participated. Boys with FXS were hyperaroused compared to boys with TD but did…

Aggressive tumor growth and clinical evolution in a patient with X-linked acro-gigantism syndrome.

PubMed

Naves, Luciana A; Daly, Adrian F; Dias, Luiz Augusto; Yuan, Bo; Zakir, Juliano Coelho Oliveira; Barra, Gustavo Barcellos; Palmeira, Leonor; Villa, Chiara; Trivellin, Giampaolo; Júnior, Armindo Jreige; Neto, Florêncio Figueiredo Cavalcante; Liu, Pengfei; Pellegata, Natalia S; Stratakis, Constantine A; Lupski, James R; Beckers, Albert

2016-02-01

X-linked acro-gigantism (X-LAG) syndrome is a newly described disease caused by microduplications on chromosome Xq26.3 leading to copy number gain of GPR101. We describe the clinical progress of a sporadic male X-LAG syndrome patient with an Xq26.3 microduplication, highlighting the aggressive natural history of pituitary tumor growth in the absence of treatment. The patient first presented elsewhere aged 5 years 8 months with a history of excessive growth for >2 years. His height was 163 cm, his weight was 36 kg, and he had markedly elevated GH and IGF-1. MRI showed a non-invasive sellar mass measuring 32.5 × 23.9 × 29.1 mm. Treatment was declined and the family was lost to follow-up. At the age of 10 years and 7 months, he presented again with headaches, seizures, and visual disturbance. His height had increased to 197 cm. MRI showed an invasive mass measuring 56.2 × 58.1 × 45.0 mm, with compression of optic chiasma, bilateral cavernous sinus invasion, and hydrocephalus. His thyrotrope, corticotrope, and gonadotrope axes were deficient. Surgery, somatostatin analogs, and cabergoline did not control vertical growth and pegvisomant was added, although vertical growth continues (currently 207 cm at 11 years 7 months of age). X-LAG syndrome is a new genomic disorder in which early-onset pituitary tumorigenesis can lead to marked overgrowth and gigantism. This case illustrates the aggressive nature of tumor evolution and the challenging clinical management in X-LAG syndrome.

Aggressive tumor growth and clinical evolution in a patient with X-linked acro-gigantism syndrome

PubMed Central

Naves, Luciana A.; Daly, Adrian F.; Dias, Luiz Augusto; Yuan, Bo; Zakir, Juliano Coelho Oliveira; Barra, Gustavo Barcellos; Palmeira, Leonor; Villa, Chiara; Trivellin, Giampaolo; Jreige, Armindo; Neto, Florêncio Figueiredo Cavalcante; Liu, Pengfei; Pellegata, Natalia S.; Stratakis, Constantine A.; Lupski, James R.

2017-01-01

X-linked acro-gigantism (X-LAG) syndrome is a newly described disease caused by microduplications on chromosome Xq26.3 leading to copy number gain of GPR101. We describe the clinical progress of a sporadic male X-LAG syndrome patient with an Xq26.3 microduplication, highlighting the aggressive natural history of pituitary tumor growth in the absence of treatment. The patient first presented elsewhere aged 5 years 8 months with a history of excessive growth for >2 years. His height was 163 cm, his weight was 36 kg, and he had markedly elevated GH and IGF-1. MRI showed a non-invasive sellar mass measuring 32.5 × 23.9 × 29.1 mm. Treatment was declined and the family was lost to follow-up. At the age of 10 years and 7 months, he presented again with headaches, seizures, and visual disturbance. His height had increased to 197 cm. MRI showed an invasive mass measuring 56.2 × 58.1 × 45.0 mm, with compression of optic chiasma, bilateral cavernous sinus invasion, and hydrocephalus. His thyrotrope, corticotrope, and gonadotrope axes were deficient. Surgery, somatostatin analogs, and cabergoline did not control vertical growth and pegvisomant was added, although vertical growth continues (currently 207 cm at 11 years 7 months of age). X-LAG syndrome is a new genomic disorder in which early-onset pituitary tumorigenesis can lead to marked overgrowth and gigantism. This case illustrates the aggressive nature of tumor evolution and the challenging clinical management in X-LAG syndrome. PMID:26607152

New domains of neural cell-adhesion molecule L1 implicated in X-linked hydrocephalus and MASA syndrome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jouet, M.; Kenwick, S.; Moncla, A.

1995-06-01

The neural cell-adhesion molecule L1 is involved in intercellular recognition and neuronal migration in the CNS. Recently, we have shown that mutations in the gene encoding L1 are responsible for three related disorders; X-linked hydrocephalus, MASA (mental retardation, aphasia, shuffling gait, and adducted thumbs) syndrome, and spastic paraplegia type I (SPG1). These three disorders represent a clinical spectrum that varies not only between families but sometimes also within families. To date, 14 independent L1 mutations have been reported and shown to be disease causing. Here we report nine novel L1 mutations in X-linked hydrocephalus and MASA-syndrome families, including the firstmore » examples of mutations affecting the fibronectin type III domains of the molecule. They are discussed in relation both to phenotypes and to the insights that they provide into L1 function. 39 refs., 5 figs., 3 tabs.« less

A novel intronic mutation in the DDP1 gene in a family with X-linked dystonia-deafness syndrome.

PubMed

Ezquerra, Mario; Campdelacreu, Jaume; Muñoz, Esteban; Tolosa, Eduardo; Martí, María J

2005-02-01

X-linked dystonia-deafness syndrome (Mohr-Tranebjaerg syndrome) is a rare neurodegenerative disease characterized by hearing loss and dystonia. So far, 7 mutations in the coding region of the DDP1 gene have been described. They consist of frameshift, nonsense, missense mutations or deletions. To investigate the presence of mutations in the DDP1 gene in a family with dystonia-deafness syndrome. Seven members belonging to 2 generations of a family with 2 affected subjects underwent genetic analysis. Mutational screening in the DDP1 gene was made through DNA direct sequencing. We found an intronic mutation in the DDP1 gene. It consists of an A-to-C substitution in the position -23 in reference to the first nucleotide of exon 2 (IVS1-23A>C). The mutation was present in 2 affected men and their respective unaffected mothers, whereas it was absent in the healthy men from this family and in 90 healthy controls. Intronic mutations in the DDP1 gene can also cause X-linked dystonia-deafness syndrome. In our case, the effect of the mutation could be due to a splicing alteration.

Somatic mosaicism underlies X-linked acrogigantism syndrome in sporadic male subjects.

PubMed

Daly, Adrian F; Yuan, Bo; Fina, Frederic; Caberg, Jean-Hubert; Trivellin, Giampaolo; Rostomyan, Liliya; de Herder, Wouter W; Naves, Luciana A; Metzger, Daniel; Cuny, Thomas; Rabl, Wolfgang; Shah, Nalini; Jaffrain-Rea, Marie-Lise; Zatelli, Maria Chiara; Faucz, Fabio R; Castermans, Emilie; Nanni-Metellus, Isabelle; Lodish, Maya; Muhammad, Ammar; Palmeira, Leonor; Potorac, Iulia; Mantovani, Giovanna; Neggers, Sebastian J; Klein, Marc; Barlier, Anne; Liu, Pengfei; Ouafik, L'Houcine; Bours, Vincent; Lupski, James R; Stratakis, Constantine A; Beckers, Albert

2016-04-01

Somatic mosaicism has been implicated as a causative mechanism in a number of genetic and genomic disorders. X-linked acrogigantism (XLAG) syndrome is a recently characterized genomic form of pediatric gigantism due to aggressive pituitary tumors that is caused by submicroscopic chromosome Xq26.3 duplications that include GPR101 We studied XLAG syndrome patients (n= 18) to determine if somatic mosaicism contributed to the genomic pathophysiology. Eighteen subjects with XLAG syndrome caused by Xq26.3 duplications were identified using high-definition array comparative genomic hybridization (HD-aCGH). We noted that males with XLAG had a decreased log2ratio (LR) compared with expected values, suggesting potential mosaicism, whereas females showed no such decrease. Compared with familial male XLAG cases, sporadic males had more marked evidence for mosaicism, with levels of Xq26.3 duplication between 16.1 and 53.8%. These characteristics were replicated using a novel, personalized breakpoint junction-specific quantification droplet digital polymerase chain reaction (ddPCR) technique. Using a separate ddPCR technique, we studied the feasibility of identifying XLAG syndrome cases in a distinct patient population of 64 unrelated subjects with acromegaly/gigantism, and identified one female gigantism patient who had had increased copy number variation (CNV) threshold for GPR101 that was subsequently diagnosed as having XLAG syndrome on HD-aCGH. Employing a combination of HD-aCGH and novel ddPCR approaches, we have demonstrated, for the first time, that XLAG syndrome can be caused by variable degrees of somatic mosaicism for duplications at chromosome Xq26.3. Somatic mosaicism was shown to occur in sporadic males but not in females with XLAG syndrome, although the clinical characteristics of the disease were similarly severe in both sexes. © 2016 Society for Endocrinology.

Mapping of the X-linked cataract (Xcat) mutation, the gene implicated in the Nance Horan syndrome, on the mouse X chromosome.

PubMed

Stambolian, D; Favor, J; Silvers, W; Avner, P; Chapman, V; Zhou, E

1994-07-15

The Xcat mutation in the mouse, an X-linked inherited disorder, is characterized by the congenital onset of cataracts. The cataracts have morphologies similar to those of cataracts found in the human Nance Horan (X-linked cataract dental) syndrome, suggesting that Xcat is an animal model for Nance Horan. The Xcat mutation provides an opportunity to investigate, at the molecular level, the pathogenesis of cataract. As a first step to cloning the Xcat gene, we report the localization of the Xcat mutation with respect to known molecular markers on the mouse X chromosome. Back-cross progeny carrying the Xcat mutation were obtained from an interspecific cross. Genomic DNA from each mouse was subjected to Southern and PCR analysis to identify restriction fragment length polymorphisms and simple sequence length polymorphisms, respectively. Our results refine the location of Xcat to a 2-cM region, eliminate several genes from consideration as the Xcat mutation, identify molecular probes tightly linked with Xcat, and suggest candidate genes responsible for the Xcat phenotype.

HDR syndrome with a novel mutation in GATA3 mimicking a congenital X-linked stapes gusher: a case report.

PubMed

Yang, Aram; Kim, Jinsup; Ki, Chang-Seok; Hong, Sung Hwa; Cho, Sung Yoon; Jin, Dong-Kyu

2017-10-26

Hypoparathyroidism, sensorineural hearing loss, and renal disease (HDR) syndrome, also known as Barakat syndrome, is a rare genetic disorder with high phenotypic heterogeneity caused by haploinsufficiency of the GATA3 gene on chromosome 10p14-p15. For these reasons, the diagnosis of HDR syndrome is challenging and requires a high index of suspicion as well as genetic analysis. A 14-month-old boy, with sensorineural hearing loss in both ears, showed typical radiological features of X-linked stapes gusher on preoperative temporal bone computed tomography (CT) for cochlear implantations. Then after his discharge from hospital, he suffered a hypocalcemic seizure and we discovered a renal cyst during investigation of hypocalcemia. He was finally diagnosed with HDR syndrome by clinical findings, which were confirmed by molecular genetic testing. Direct sequencing of the GATA3 gene showed a heterozygous 2-bp deletion (c.1201_1202delAT), which is predicted to cause a frameshift of the reading frame (p.Met401Valfs*106). To our knowledge, this is the first case of HDR syndrome with a novel de novo variant mimicking a congenital X-linked stapes gusher syndrome. Novel mutations and the diversity of clinical manifestations expand the genotypic and phenotypic spectrum of HDR syndrome. Diagnosis of HDR syndrome is still challenging, but clinicians should consider it in their differential diagnosis for children with a wide range of clinical manifestations including hypocalcemia induced seizures and deafness. We hope that this case will contribute to further understanding and studies of HDR-associated GATA3 mutations.

Genetics Home Reference: X-linked lymphoproliferative disease

MedlinePlus

... infects most humans. In some people it causes infectious mononucleosis (commonly known as "mono"). Normally, after initial infection, ... severe susceptibility to EBV infection severe susceptibility to infectious mononucleosis X-linked lymphoproliferative syndrome XLP Related Information How ...

Somatic Mosaicism Underlies X-linked Acrogigantism (XLAG) Syndrome in Sporadic Male Subjects

PubMed Central

Daly, Adrian F.; Yuan, Bo; Fina, Frederic; Caberg, Jean-Hubert; Trivellin, Giampaolo; Rostomyan, Liliya; de Herder, Wouter W.; Naves, Luciana A.; Metzger, Daniel; Cuny, Thomas; Rabl, Wolfgang; Shah, Nalini; Jaffrain-Rea, Marie-Lise; Zatelli, Maria Chiara; Faucz, Fabio R; Castermans, Emilie; Nanni-Metellus, Isabelle; Lodish, Maya; Muhammad, Ammar; Palmeira, Leonor; Potorac, Iulia; Mantovani, Giovanna; Neggers, Sebastian J.; Klein, Marc; Barlier, Anne; Liu, Pengfei; Ouafik, L'Houcine; Bours, Vincent; Lupski, James R.; Stratakis, Constantine A.; Beckers., Albert

2016-01-01

Somatic mosaicism has been implicated as a causative mechanism in a number of genetic and genomic disorders. X-linked acrogigantism (XLAG) syndrome is a recently characterized genomic form of pediatric gigantism due to aggressive pituitary tumors that is caused by submicroscopic chromosome Xq26.3 duplications that include GPR101. We studied XLAG syndrome patients (N=18) to determine if somatic mosaicism contributed to the genomic pathophysiology. Eighteen subjects with XLAG syndrome were identified with Xq26.3 duplications using high definition array comparative genome hybridization (HD-aCGH). We noted males with XLAG had a decreased log2 ratio compared with expected values, suggesting potential mosaicism, while females showed no such decrease. As compared with familial male XLAG cases, sporadic males had more marked evidence for mosaicism, with levels of Xq26.3 duplication between 16.1-53.8%. These characteristics were replicated using a novel, personalized breakpoint-junction specific quantification droplet digital PCR (ddPCR) technique. Using a separate ddPCR technique we studied the feasibility of identifying XLAG syndrome cases in a distinct patient population of 64 unrelated subjects with acromegaly/gigantism and identified one female gigantism patient that had increased copy number variation (CNV) threshold for GPR101 that was subsequently diagnosed as having XLAG syndrome on HD-aCGH. Employing a combination of HD-aCGH and novel ddPCR approaches, we have demonstrated, for the first time, that XLAG syndrome can be caused by variable degrees of somatic mosaicism for duplications at chromosome Xq26.3. Somatic mosaicism was shown to occur in sporadic males but not in females with XLAG syndrome, although the clinical characteristics of the disease were similarly severe in both sexes. PMID:26935837

Transcription map of Xq27: candidates for several X-linked diseases.

PubMed

Zucchi, I; Jones, J; Affer, M; Montagna, C; Redolfi, E; Susani, L; Vezzoni, P; Parvari, R; Schlessinger, D; Whyte, M P; Mumm, S

1999-04-15

Human Xq27 contains candidate regions for several disorders, yet is predicted to be a gene-poor cytogenetic band. We have developed a transcription map for the entire cytogenetic band to facilitate the identification of the relatively small number of expected candidate genes. Two approaches were taken to identify genes: (1) a group of 64 unique STSs that were generated during the physical mapping of the region were used in RT-PCR with RNA from human adult and fetal brain and (2) ESTs that have been broadly mapped to this region of the chromosome were finely mapped using a high-resolution yeast artificial chromosome contig. This combined approach identified four distinct regions of transcriptional activity within the Xq27 band. Among them is a region at the centromeric boundary that contains candidate regions for several rare developmental disorders (X-linked recessive hypoparathyroidism, thoracoabdominal syndrome, albinism-deafness syndrome, and Borjeson-Forssman-Lehman syndrome). Two transcriptionally active regions were identified in the center of Xq27 and include candidate regions for X-linked mental retardation syndrome 6, X-linked progressive cone dystrophy, X-linked retinitis pigmentosa 24, and a prostate cancer susceptibility locus. The fourth region of transcriptional activity encompasses the FMR1 (FRAXA) and FMR2 (FRAXE) genes. The analysis thus suggests clustered transcription in Xq27 and provides candidates for several heritable disorders for which the causative genes have not yet been found. Copyright 1999 Academic Press.

Eugenics ideals, racial hygiene, and the emigration process of German-American neurogeneticist Franz Josef Kallmann (1897-1965).

PubMed

Pow, Stephen; Stahnisch, Frank W

2016-01-01

Biological psychiatry in the early twentieth century was based on interrelated disciplines, such as neurology and experimental biology. Neuropsychiatrist Franz Josef Kallmann (1897-1965) was a product of this interdisciplinary background who showed an ability to adapt to different scientific contexts, first in the field of neuromorphology in Berlin, and later in New York. Nonetheless, having innovative ideas, as Kallmann did, could be an ambiguous advantage, since they could lead to incommensurable scientific views and marginalization in existing research programs. Kallmann followed his Dr. Med. degree (1919) with training periods at the Charité Medical School in Berlin under psychiatrist Karl Bonhoeffer (1868-1948). Subsequently, he collaborated with Ernst Ruedin (1874-1952), investigating sibling inheritance of schizophrenia and becoming a protagonist of genetic research on psychiatric conditions. In 1936, Kallmann was forced to immigrate to the USA where he published The Genetics of Schizophrenia (1938), based on data he had gathered from the district pathological institutes of Berlin's public health department. Kallmann resumed his role as an international player in biological psychiatry and genetics, becoming president (1952) of the American Society of Human Genetics and Director of the New York State Psychiatric Institute in 1955. While his work was well received by geneticists, the idea of genetic differences barely took hold in American psychiatry, largely because of émigré psychoanalysts who dominated American clinical psychiatry until the 1960s and established a philosophical direction in which genetics played no significant role, being regarded as dangerous in light of Nazi medical atrocities. After all, medical scientists in Nazi Germany had been among the social protagonists of racial hygiene which, under the aegis of Nazi philosophies, replaced medical genetics as the basis for the ideals and application of eugenics.

CD40 agonist antibody mediated improvement of chronic Cryptosporidium infection in patients with X-linked hyper IgM syndrome

USDA-ARS?s Scientific Manuscript database

X-linked hyper-IgM syndrome (XHM) is a combined immune deficiency disorder caused by mutations in CD40 ligand. We tested CP-870,893, a human CD40 agonist monoclonal antibody, in the treatment of two XHM patients with biliary Cryptosporidiosis. CP-870,893 activated B cells and APCs in vitro, restori...

Hungry bone syndrome and normalisation of renal phosphorus threshold after total parathyroidectomy for tertiary hyperparathyroidism in X-linked hypophosphataemia: a case report.

PubMed

Crowley, Rachel K; Kilbane, Mark; King, Thomas Fj; Morrin, Michelle; O'Keane, Myra; McKenna, Malachi J

2014-03-04

This is the first report of which the authors are aware to describe this c.2166delinsGG mutation in X-linked hypophosphataemia and to describe normalisation of renal threshold for phosphate excretion after parathyroidectomy for tertiary hyperparathyroidism in X-linked hypophosphataemia. We present the case of a 34-year-old Caucasian woman with X-linked hypophosphataemia. She developed tertiary hyperparathyroidism with markedly high bone turnover requiring total parathyroidectomy and had prolonged requirement for intravenous calcium infusion after surgery. She had a novel mutation in her phosphate-regulating gene with homologies to endopeptidases on the X-chromosome and had an unusual degree of dependence on phosphate supplementation. Prior to operative intervention she had a trial of cinacalcet that improved bone turnover markers when used in isolation but which led to a paradoxical rise in parathyroid hormone levels when given with phosphate supplementation. After correction of hungry bone syndrome, the renal phosphorus threshold normalised as a manifestation of hypoparathyroid state despite marked elevation in level of fibroblast growth factor 23. This case illustrates the risk of tertiary hyperparathyroidism as a complication of treatment for hypophosphataemia; it highlights the morbidity associated with hungry bone syndrome and provides novel insight into renal handling of phosphorus.

Dysregulation of X-linked gene expression in Klinefelter's syndrome and association with verbal cognition.

PubMed

Vawter, Marquis P; Harvey, Philip D; DeLisi, Lynn E

2007-09-05

Klinefelter's Syndrome (KS) is a chromosomal karyotype with one or more extra X chromosomes. KS individuals often show language impairment and the phenotype might be due to overexpression of genes on the extra X chromosome(s). We profiled mRNA derived from lymphoblastoid cell lines from males with documented KS and control males using the Affymetrix U133P microarray platform. There were 129 differentially expressed genes (DEGs) in KS group compared with controls after Benjamini-Hochberg false discovery adjustment. The DEGs included 14 X chromosome genes which were significantly over-represented. The Y chromosome had zero DEGs. In exploratory analysis of gene expression-cognition relationships, 12 DEGs showed significant correlation of expression with measures of verbal cognition in KS. Overexpression of one pseudoautosomal gene, GTPBP6 (GTP binding protein 6, putative) was inversely correlated with verbal IQ (r = -0.86, P < 0.001) and four other measures of verbal ability. Overexpression of XIST was found in KS compared to XY controls suggesting that silencing of many genes on the X chromosome might occur in KS similar to XX females. The microarray findings for eight DEGs were validated by quantitative PCR. The 14 X chromosome DEGs were not differentially expressed in prior studies comparing female and male brains suggesting a dysregulation profile unique to KS. Examination of X-linked DEGs, such as GTPBP6, TAF9L, and CXORF21, that show verbal cognition-gene expression correlations may establish a causal link between these genes, neurodevelopment, and language function. A screen of candidate genes may serve as biomarkers of KS for early diagnosis. Copyright 2007 Wiley-Liss, Inc.

X-linked cardiomyopathy is heterogeneous

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wilson, M.J.; Sillence, D.O.; Mulley, J.C.

Two major loci of X-linked cardiomyopathy have been mapped by linkage analysis. The gene for X-linked dilated cardiomyopathy (XLCM) is mapped to the dystrophin locus at Xp21, while Barth syndrome has been localised to distal Xq28. XLCM usually presents in juvenile males with no skeletal disease but decreased dystrophin in cardiac muscle. Barth syndrome most often presents in infants and is characterized by skeletal myopathy, short stature and neutropenia in association with cardiomyopathy of variable severity. Prior to carrier or prenatal diagnosis in a family, delineation of the cardiomyopathy locus involved is essential. We report the linkage mapping of amore » large kindred in which several male infants have died with hypertrophic cardiomyopathy. There is a family history of unexplained death of infant males less than 6 months old over 4 generations. Features of Barth syndrome such as short stature, skeletal myopathy and neutropenia have not been observed. Genotyping at 10 marker loci in Xq28 has revealed significant pairwise lod scores with the cardiomyopathy phenotype at DXS52 (Z=2.21 at {theta}=0.0), at markers p26 and p39 near DXS15 (Z=2.30 at {theta}=0.0) and at F8C (Z=2.24 at {theta}=0.0). A recombinant detected with DXS296 defines the proximal limit to the localization. No recombinants were detected at any of the loci distal to DXS296. The most distal marker in Xq28, DXS1108, is within 500 kb of the telomere. As the gene in this family is localized to Xq28, it is possible that this disorder is an allelic variant at the Barth syndrome locus.« less

X-Linked Congenital Hypertrichosis Syndrome Is Associated with Interchromosomal Insertions Mediated by a Human-Specific Palindrome near SOX3

PubMed Central

Zhu, Hongwen; Shang, Dandan; Sun, Miao; Choi, Sunju; Liu, Qing; Hao, Jiajie; Figuera, Luis E.; Zhang, Feng; Choy, Kwong Wai; Ao, Yang; Liu, Yang; Zhang, Xiao-Lin; Yue, Fengzhen; Wang, Ming-Rong; Jin, Li; Patel, Pragna I.; Jing, Tao; Zhang, Xue

2011-01-01

X-linked congenital generalized hypertrichosis (CGH), an extremely rare condition characterized by universal overgrowth of terminal hair, was first mapped to chromosome Xq24-q27.1 in a Mexican family. However, the underlying genetic defect remains unknown. We ascertained a large Chinese family with an X-linked congenital hypertrichosis syndrome combining CGH, scoliosis, and spina bifida and mapped the disease locus to a 5.6 Mb critical region within the interval defined by the previously reported Mexican family. Through the combination of a high-resolution copy-number variation (CNV) scan and targeted genomic sequencing, we identified an interchromosomal insertion at Xq27.1 of a 125,577 bp intragenic fragment of COL23A1 on 5q35.3, with one X breakpoint within and the other very close to a human-specific short palindromic sequence located 82 kb downstream of SOX3. In the Mexican family, we found an interchromosomal insertion at the same Xq27.1 site of a 300,036 bp genomic fragment on 4q31.2, encompassing PRMT10 and TMEM184C and involving parts of ARHGAP10 and EDNRA. Notably, both of the two X breakpoints were within the short palindrome. The two palindrome-mediated insertions fully segregate with the CGH phenotype in each of the families, and the CNV gains of the respective autosomal genomic segments are not present in the public database and were not found in 1274 control individuals. Analysis of control individuals revealed deletions ranging from 173 bp to 9104 bp at the site of the insertions with no phenotypic consequence. Taken together, our results strongly support the pathogenicity of the identified insertions and establish X-linked congenital hypertrichosis syndrome as a genomic disorder. PMID:21636067

Physiological Arousal in Autism and Fragile X Syndrome: Group Comparisons and Links With Pragmatic Language

PubMed Central

Klusek, Jessica; Martin, Gary E.; Losh, Molly

2014-01-01

This study tested the hypothesis that pragmatic (i.e., social) language impairment is linked to arousal dysregulation in autism spectrum disorder (ASD) and fragile X syndrome (FXS). Forty boys with ASD, 39 with FXS, and 28 with typical development (TD), aged 4–15 years, participated. Boys with FXS were hyperaroused compared to boys with TD but did not differ from boys with ASD. Dampened vagal tone predicted pragmatic impairment in ASD, and associations emerged between cardiac activity and receptive/expressive vocabulary across groups. Findings support autonomic dysfunction as a mechanism underlying pragmatic impairment in ASD and suggest that biophysiological profiles are shared in ASD and FXS, which has implications for understanding the role of fragile X mental retardation-1 (FMR1, the FXS gene) in the pathophysiology of ASD. PMID:24432860

Macular hole in juvenile X-linked retinoschisis.

PubMed

Al-Swaina, Nayef; Nowilaty, Sawsan R

2013-10-01

An 18 year-old male with no antecedent of trauma, systemic syndrome or myopia was referred for surgical treatment of a full thickness macular hole in the left eye. A more careful inspection revealed discrete foveal cystic changes in the fellow eye and subtle peripheral depigmented retinal pigment epithelial changes in both eyes. A spectral-domain optical coherence tomography (SD-OCT) scan confirmed, in addition to the full thickness macular hole in the left eye, microcystic spaces in the nuclear layers of both retinae. The diagnosis of X-linked retinoschisis was confirmed with a full field electroretinogram displaying the typical negative ERG. Macular holes are uncommon in the young and those complicating X-linked retinoschisis are rare. This report highlights the importance of investigating the presence of a macular hole in a young patient and illustrates the clinical and SD-OCT clues beyond the foveal center which led to the correct diagnosis of X-linked juvenile retinoschisis.

A Mutation in the Rett Syndrome Gene, MECP2, Causes X-Linked Mental Retardation and Progressive Spasticity in Males

PubMed Central

Meloni, Ilaria; Bruttini, Mirella; Longo, Ilaria; Mari, Francesca; Rizzolio, Flavio; D’Adamo, Patrizia; Denvriendt, Koenraad; Fryns, Jean-Pierre; Toniolo, Daniela; Renieri, Alessandra

2000-01-01

Heterozygous mutations in the X-linked MECP2 gene cause Rett syndrome, a severe neurodevelopmental disorder of young females. Only one male presenting an MECP2 mutation has been reported; he survived only to age 1 year, suggesting that mutations in MECP2 are male lethal. Here we report a three-generation family in which two affected males showed severe mental retardation and progressive spasticity, previously mapped in Xq27.2-qter. Two obligate carrier females showed either normal or borderline intelligence, simulating an X-linked recessive trait. The two males and the two obligate carrier females presented a mutation in the MECP2 gene, demonstrating that, in males, MECP2 can be responsible for severe mental retardation associated with neurological disorders. PMID:10986043

The Nance-Horan syndrome: a rare X-linked ocular-dental trait with expression in heterozygous females.

PubMed

Bixler, D; Higgins, M; Hartsfield, J

1984-07-01

This report describes two families with the Nance-Horan syndrome, an X-linked trait featuring lenticular cataracts and anomalies of tooth shape and number. Previous reports have described blindness in affected males but posterior sutural cataracts with normal vision as the primary ocular expression in heterozygous females. In one of these two families, the affected female is not only blind in one eye but reportedly had supernumerary central incisors (mesiodens) removed. This constitutes the most severe ocular and dental expression of this gene in heterozygous females yet reported.

Fragile X syndrome

MedlinePlus

Martin-Bell syndrome; Marker X syndrome ... Fragile X syndrome is caused by a change in a gene called FMR1 . A small part of the gene ... repeated several times in one area of the X chromosome. The more repeats, the more likely the ...

AP1S2 is mutated in X-linked Dandy-Walker malformation with intellectual disability, basal ganglia disease and seizures (Pettigrew syndrome).

PubMed

Cacciagli, Pierre; Desvignes, Jean-Pierre; Girard, Nadine; Delepine, Marc; Zelenika, Diana; Lathrop, Mark; Lévy, Nicolas; Ledbetter, David H; Dobyns, William B; Villard, Laurent

2014-03-01

MRXS5 or Pettigrew syndrome was described 20 years ago in a four generation family including nine affected individuals presenting with facial dysmorphism, intellectual disability, Dandy-Walker malformation and inconstant choreoathetosis. Four individuals had iron deposition in the basal ganglia seen on MRI or at autopsy. The mutation causing Pettigrew has remained elusive since the initial description of the condition. We report the identification of a mutation in the X-linked AP1S2 gene in the original Pettigrew syndrome family using X-chromosome exome sequencing. We report additional phenotype details for several of the affected individuals, allowing us to further refine the phenotype corresponding to this X-linked intellectual disability syndrome. The AP1S2 c.426+1 G>T mutation segregates with the disease in the Pettigrew syndrome family and results in loss of 46 amino acids in the clathrin adaptor complex small chain domain that spans most of the AP1S2 protein sequence. The mutation reported here in AP1S2 is the first mutation that is not predicted to cause a premature termination of the coding sequence or absence of the AP1S2 protein. Although most of the families affected by a mutation in AP1S2 were initially described as having different disorders assigned to at least three different OMIM numbers (MIM 300629, 300630 and 304340), our analysis of the phenotype shows that they are all the same syndrome with recognition complicated by highly variable expressivity that is seen within as well as between families and is probably not explained by differences in mutation severity.

AP1S2 is mutated in X-linked Dandy–Walker malformation with intellectual disability, basal ganglia disease and seizures (Pettigrew syndrome)

PubMed Central

Cacciagli, Pierre; Desvignes, Jean-Pierre; Girard, Nadine; Delepine, Marc; Zelenika, Diana; Lathrop, Mark; Lévy, Nicolas; Ledbetter, David H; Dobyns, William B; Villard, Laurent

2014-01-01

MRXS5 or Pettigrew syndrome was described 20 years ago in a four generation family including nine affected individuals presenting with facial dysmorphism, intellectual disability, Dandy–Walker malformation and inconstant choreoathetosis. Four individuals had iron deposition in the basal ganglia seen on MRI or at autopsy. The mutation causing Pettigrew has remained elusive since the initial description of the condition. We report the identification of a mutation in the X-linked AP1S2 gene in the original Pettigrew syndrome family using X-chromosome exome sequencing. We report additional phenotype details for several of the affected individuals, allowing us to further refine the phenotype corresponding to this X-linked intellectual disability syndrome. The AP1S2 c.426+1 G>T mutation segregates with the disease in the Pettigrew syndrome family and results in loss of 46 amino acids in the clathrin adaptor complex small chain domain that spans most of the AP1S2 protein sequence. The mutation reported here in AP1S2 is the first mutation that is not predicted to cause a premature termination of the coding sequence or absence of the AP1S2 protein. Although most of the families affected by a mutation in AP1S2 were initially described as having different disorders assigned to at least three different OMIM numbers (MIM 300629, 300630 and 304340), our analysis of the phenotype shows that they are all the same syndrome with recognition complicated by highly variable expressivity that is seen within as well as between families and is probably not explained by differences in mutation severity. PMID:23756445

Dysregulation of X-Linked Gene Expression in Klinefelter’s Syndrome and Association With Verbal Cognition

PubMed Central

Vawter, Marquis P.; Harvey, Philip D.; DeLisi, Lynn E.

2007-01-01

Klinefelter’s Syndrome (KS) is a chromosomal karyotype with one or more extra X chromosomes. KS individuals often show language impairment and the phenotype might be due to overexpression of genes on the extra X chromosome(s). We profiled mRNA derived from lymphoblastoid cell lines from males with documented KS and control males using the Affymetrix U133P microarray platform. There were 129 differentially expressed genes (DEGs) in KS group compared with controls after Benjamini–Hochberg false discovery adjustment. The DEGs included 14 X chromosome genes which were significantly over-represented. The Y chromosome had zero DEGs. In exploratory analysis of gene expression–cognition relationships, 12 DEGs showed significant correlation of expression with measures of verbal cognition in KS. Overexpression of one pseudoautosomal gene, GTPBP6 (GTP binding protein 6, putative) was inversely correlated with verbal IQ (r = −0.86, P < 0.001) and four other measures of verbal ability. Overexpression of XIST was found in KS compared to XY controls suggesting that silencing of many genes on the X chromosome might occur in KS similar to XX females. The microarray findings for eight DEGs were validated by quantitative PCR. The 14 X chromosome DEGs were not differentially expressed in prior studies comparing female and male brains suggesting a dysregulation profile unique to KS. Examination of X-linked DEGs, such as GTPBP6, TAF9L, and CXORF21, that show verbal cognition–gene expression correlations may establish a causal link between these genes, neurodevelopment, and language function. A screen of candidate genes may serve as biomarkers of KS for early diagnosis. PMID:17347996

Brief report: linkage between G6PD and fragile-X syndrome.

PubMed

Filippi, G; Rinaldi, A; Archidiacono, N; Rocchi, M; Balazs, I; Siniscalco, M

1983-05-01

Eighteen Sardinian pedigrees segregating for the X-fragile site syndrome were studied with respect to the segregation of the fragile site (FS) at Xq28, mental retardation, and macro-orchidism. No exception was found in the association of this symptomatic triad (MOM-X) in 41 out of 42 patients examined. The exceptional individual had micro- rather than macro-orchidism and was found to have a 47, XXY sex chromosome complement. In six informative sibships, the MOM-X syndrome was found to segregate in close linkage association with G6PD-deficiency or protan colorblindness. The maximum likelihood estimate of recombination if 6% with 90% fiducial limits between 2.5 and 19.5% and an odds ratio in favor of measurable linkage of 428:1. However, no hint of measurable linkage was found in six pedigrees segregating for G6PD and the Renpenning syndrome or other unspecified types of X-linked mental retardation. These data give strong support to the generally held hypothesis that the FS at Zq28, characteristic of the MOM-X syndrome, is a direct expression of a genetic change in the same chromosomal region. They also clearly suggest that X-linked MR without FS may be the result of different allelic mutations at the same locus.

Genetic localization and phenotypic expression of X-linked cataract (Xcat) in Mus musculus.

PubMed

Favor, J; Pretsch, W

1990-01-01

Linkage data relative to the markers tabby and glucose-6-phosphate dehydrogenase are presented to locate X-linked cataract (Xcat) in the distal portion of the mouse X-chromosome between jimpy and hypophosphatemia. The human X-linked cataract-dental syndrome, Nance-Horan Syndrome, also maps closely to human hypophosphatemia and would suggest homology between mouse Xcat and human Nance-Horan Syndrome genes. In hemizygous males and homozygous females penetrance is complete with only slight variation in the degree of expression. Phenotypic expression in Xcat heterozygous females ranges from totally clear to totally opaque lenses. The phenotypic expression between the two lenses of a heterozygous individual could also vary between totally clear and totally opaque lenses. However, a correlation in the degree of expression between the eyes of an individual was observed. A variegated pattern of lens opacity was evident in female heterozygotes. Based on these observations, the site of gene action for the Xcat locus is suggested to be endogenous to the lens cells and the precursor cell population of the lens is concluded to be small. The identification of an X-linked cataract locus is an important contribution to the estimate of the number of mutable loci resulting in cataract, an estimate required so that dominant cataract mutagenesis results may be expressed on a per locus basis. The Xcat mutation may be a useful marker for a distal region of the mouse X-chromosome which is relatively sparsely marked and the X-linked cataract mutation may be employed in gene expression and lens development studies.

GHRH excess and blockade in X-LAG syndrome.

PubMed

Daly, Adrian F; Lysy, Philippe A; Desfilles, Céline; Rostomyan, Liliya; Mohamed, Amira; Caberg, Jean-Hubert; Raverot, Veronique; Castermans, Emilie; Marbaix, Etienne; Maiter, Dominique; Brunelle, Chloe; Trivellin, Giampaolo; Stratakis, Constantine A; Bours, Vincent; Raftopoulos, Christian; Beauloye, Veronique; Barlier, Anne; Beckers, Albert

2016-03-01

X-linked acrogigantism (X-LAG) syndrome is a newly described form of inheritable pituitary gigantism that begins in early childhood and is usually associated with markedly elevated GH and prolactin secretion by mixed pituitary adenomas/hyperplasia. Microduplications on chromosome Xq26.3 including the GPR101 gene cause X-LAG syndrome. In individual cases random GHRH levels have been elevated. We performed a series of hormonal profiles in a young female sporadic X-LAG syndrome patient and subsequently undertook in vitro studies of primary pituitary tumor culture following neurosurgical resection. The patient demonstrated consistently elevated circulating GHRH levels throughout preoperative testing, which was accompanied by marked GH and prolactin hypersecretion; GH demonstrated a paradoxical increase following TRH administration. In vitro, the pituitary cells showed baseline GH and prolactin release that was further stimulated by GHRH administration. Co-incubation with GHRH and the GHRH receptor antagonist, acetyl-(d-Arg(2))-GHRH (1-29) amide, blocked the GHRH-induced GH stimulation; the GHRH receptor antagonist alone significantly reduced GH release. Pasireotide, but not octreotide, inhibited GH secretion. A ghrelin receptor agonist and an inverse agonist led to modest, statistically significant increases and decreases in GH secretion, respectively. GHRH hypersecretion can accompany the pituitary abnormalities seen in X-LAG syndrome. These data suggest that the pathology of X-LAG syndrome may include hypothalamic dysregulation of GHRH secretion, which is in keeping with localization of GPR101 in the hypothalamus. Therapeutic blockade of GHRH secretion could represent a way to target the marked hormonal hypersecretion and overgrowth that characterizes X-LAG syndrome. © 2016 Society for Endocrinology.

Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome: A Paradigm of Immunodeficiency with Autoimmunity

PubMed Central

Barzaghi, Federica; Passerini, Laura; Bacchetta, Rosa

2012-01-01

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare monogenic primary immunodeficiency (PID) due to mutations of FOXP3, a key transcription factor for naturally occurring (n) regulatory T (Treg) cells. The dysfunction of Treg cells is the main pathogenic event leading to the multi-organ autoimmunity that characterizes IPEX syndrome, a paradigm of genetically determined PID with autoimmunity. IPEX has a severe early onset and can become rapidly fatal within the first year of life regardless of the type and site of the mutation. The initial presenting symptoms are severe enteritis and/or type-1 diabetes mellitus, alone or in combination with eczema and elevated serum IgE. Other autoimmune symptoms, such as hypothyroidism, cytopenia, hepatitis, nephropathy, arthritis, and alopecia can develop in patients who survive the initial acute phase. The current therapeutic options for IPEX patients are limited. Supportive and replacement therapies combined with pharmacological immunosuppression are required to control symptoms at onset. However, these procedures can allow only a reduction of the clinical manifestations without a permanent control of the disease. The only known effective cure for IPEX syndrome is hematopoietic stem cell transplantation, but it is always limited by the availability of a suitable donor and the lack of specific guidelines for bone marrow transplant in the context of this disease. This review aims to summarize the clinical histories and genomic mutations of the IPEX patients described in the literature to date. We will focus on the clinical and immunological features that allow differential diagnosis of IPEX syndrome and distinguish it from other PID with autoimmunity. The efficacy of the current therapies will be reviewed, and possible innovative approaches, based on the latest highlights of the pathogenesis to treat this severe primary autoimmune disease of childhood, will be discussed. PMID:23060872

Conceptualizing neurodevelopmental disorders through a mechanistic understanding of fragile X syndrome and Williams syndrome.

PubMed

Fung, Lawrence K; Quintin, Eve-Marie; Haas, Brian W; Reiss, Allan L

2012-04-01

The overarching goal of this review is to compare and contrast the cognitive-behavioral features of fragile X syndrome (FraX) and Williams syndrome and to review the putative neural and molecular underpinnings of these features. Information is presented in a framework that provides guiding principles for conceptualizing gene-brain-behavior associations in neurodevelopmental disorders. Abnormalities, in particular cognitive-behavioral domains with similarities in underlying neurodevelopmental correlates, occur in both FraX and Williams syndrome including aberrant frontostriatal pathways leading to executive function deficits, and magnocellular/dorsal visual stream, superior parietal lobe, inferior parietal lobe, and postcentral gyrus abnormalities contributing to deficits in visuospatial function. Compelling cognitive-behavioral and neurodevelopmental contrasts also exist in these two disorders, for example, aberrant amygdala and fusiform cortex structure and function occurring in the context of contrasting social behavioral phenotypes, and temporal cortical and cerebellar abnormalities potentially underlying differences in language function. Abnormal dendritic development is a shared neurodevelopmental morphologic feature between FraX and Williams syndrome. Commonalities in molecular machinery and processes across FraX and Williams syndrome occur as well - microRNAs involved in translational regulation of major synaptic proteins; scaffolding proteins in excitatory synapses; and proteins involved in axonal development. Although the genetic variations leading to FraX and Williams syndrome are different, important similarities and contrasts in the phenotype, neurocircuitry, molecular machinery, and cellular processes in these two disorders allow for a unique approach to conceptualizing gene-brain-behavior links occurring in neurodevelopmental disorders.

The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism

PubMed Central

Bianco, Suzy D. C.; Kaiser, Ursula B.

2010-01-01

Idiopathic hypogonadotropic hypogonadism (IHH) has an incidence of 1–10 cases per 100,000 births. About 60% of patients with IHH present with associated anosmia, also known as Kallmann syndrome, characterized by total or partial loss of olfaction. Many of the gene mutations associated with Kallmann syndrome have been mapped to KAL1 or FGFR1. However, together, these mutations account for only about 15% of Kallmann syndrome cases. More recently, mutations in PROK2 and PROKR2 have been linked to the syndrome and may account for an additional 5–10% of cases. The remaining 40% of patients with IHH have a normal sense of smell. Prior to 2003, the only gene linked to normosmic IHH was the gonadotropin-releasing hormone receptor gene. However, mutations in this receptor are believed to account for only 10% of cases. Subsequently, mutations in KISS1R, TAC3 and TACR3 were identified as causes of normosmic IHH. Certain genes, including PROK2 and FGFR1, are associated with both anosmic and normosmic IHH. Despite recent advances in the field, the genetic causes of the majority of cases of IHH remain unknown. This Review discusses genes associated with hypogonadotropic disorders and the molecular mechanisms by which mutations in these genes may result in IHH. PMID:19707180

Molecular and clinical studies of X-linked deafness among Pakistani families.

PubMed

Waryah, Ali M; Ahmed, Zubair M; Bhinder, Munir A; Binder, Munir A; Choo, Daniel I; Sisk, Robert A; Shahzad, Mohsin; Khan, Shaheen N; Friedman, Thomas B; Riazuddin, Sheikh; Riazuddin, Saima

2011-07-01

There are 68 sex-linked syndromes that include hearing loss as one feature and five sex-linked nonsyndromic deafness loci listed in the OMIM database. The possibility of additional such sex-linked loci was explored by ascertaining three unrelated Pakistani families (PKDF536, PKDF1132 and PKDF740) segregating X-linked recessive deafness. Sequence analysis of POU3F4 (DFN3) in affected members of families PKDF536 and PKDF1132 revealed two novel nonsense mutations, p.Q136X and p.W114X, respectively. Family PKDF740 is segregating congenital blindness, mild-to-profound progressive hearing loss that is characteristic of Norrie disease (MIM#310600). Sequence analysis of NDP among affected members of this family revealed a novel single nucleotide deletion c.49delG causing a frameshift and premature truncation (p.V17fsX1) of the encoded protein. These mutations were not found in 150 normal DNA samples. Identification of pathogenic alleles causing X-linked recessive deafness will improve molecular diagnosis, genetic counseling and molecular epidemiology of hearing loss among Pakistanis.

Molecular and Clinical Studies of X-linked Deafness Among Pakistani Families

PubMed Central

Waryah, Ali M.; Ahmed, Zubair M.; Choo, Daniel I.; Sisk, Robert A.; Binder, Munir A.; Shahzad, Mohsin; Khan, Shaheen N.; Friedman, Thomas B.; Riazuddin, Sheikh; Riazuddin, Saima

2011-01-01

There are 68 sex-linked syndromes that include hearing loss as one feature and five sex-linked nonsyndromic deafness loci listed in the OMIM database. The possibility of additional such sex-linked loci was explored by ascertaining three unrelated Pakistani families (PKDF536, PKDF1132, PKDF740) segregating X-linked recessive deafness. Sequence analysis of POU3F4 (DFN3) in affected members of families PKDF536 and PKDF1132 revealed two novel nonsense mutations, p.Q136X and p.W114X, respectively. Family PKDF740 is segregating congenital blindness, mild to profound progressive hearing loss that is characteristic of Norrie disease (MIM#310600). Sequence analysis of NDP among affected members of this family revealed a novel single nucleotide deletion c.49delG causing a frameshift and premature truncation (p.V17fsX1) of the encoded protein. These mutations were not found in 150 normal DNA samples. Identification of pathogenic alleles causing X-linked recessive deafness will improve molecular diagnosis, genetic counseling, and molecular epidemiology of hearing loss among Pakistanis. PMID:21633365

Mapping X-linked ophthalmic diseases. IV. Provisional assignment of the locus for X-linked congenital cataracts and microcornea (the Nance-Horan syndrome) to Xp22.2-p22.3.

PubMed

Lewis, R A; Nussbaum, R L; Stambolian, D

1990-01-01

The Nance-Horan syndrome (NHS) is an infrequent X-linked disorder typified by dense congenital central cataracts, microcornea, anteverted and simplex pinnae, brachymetacarpalia, and numerous dental anomalies. The regional location of the genetic mutation causing NHS is unknown. The authors applied the modern molecular techniques of analysis of restriction fragment length polymorphisms to five multigenerational kindreds in which NHS segregated. Provisional linkage is established to two DNA markers--DXS143 at Xp22.3-p22.2 and DXS43 at Xp22.2. Regional localization of NHS will provide potential antenatal diagnosis in families at risk for the disease and will enhance understanding of the multifaceted genetic defects.

Fragile X syndrome and fragile X-associated tremor ataxia syndrome.

PubMed

Hall, Deborah A; Berry-Kravis, Elizabeth

2018-01-01

Fragile X-associated disorders encompass several conditions, which are caused by expansion mutations in the fragile X mental retardation 1 (FMR1) gene. Fragile X syndrome is the most common inherited etiology of intellectual disability and results from a full mutation or >200 CGG repeats in FMR1. It is associated with developmental delay, autism spectrum disorder, and seizures. Fragile X-associated tremor/ataxia syndrome is a progressive neurodegenerative disease that occurs in premutation carriers of 55-200 CGG repeats in FMR1 and is characterized by kinetic tremor, gait ataxia, parkinsonism, executive dysfunction, and neuropathy. Fragile X-associated primary ovarian insufficiency also occurs in premutation carrier women and manifests with infertility and early menopause. The diseases constituting fragile X-associated disorders differ mechanistically, due to the distinct molecular properties of premutation versus full mutations. Fragile X syndrome occurs when there is a lack of fragile X mental retardation protein (FMRP) due to FMR1 methylation and silencing. In fragile X-associated tremor ataxia syndrome, a toxic gain of function is postulated with the production of excess CGG repeat-containing FMR1 mRNA, abnormal translation of the repeat sequence leading to production of polyglycine, polyalanine, and other polypeptides and to outright deficits in translation leading to reduced FMRP at larger premutation sizes. The changes in underlying brain chemistry due to FMR1 mutations have led to therapeutic studies in these disorders, with some progress being made in fragile X syndrome. This paper also summarizes indications for testing, genetic counseling issues, and what the future holds for these disorders. Copyright © 2018 Elsevier B.V. All rights reserved.

[Fragile X syndrome and white matter abnormalities: Case study of two brothers].

PubMed

Wallach, E; Bieth, E; Sevely, A; Cances, C

2017-03-01

Fragile X syndrome is the most usual cause of hereditary intellectual deficiency. Typical symptoms combine intellectual deficiency, social anxiety, intense emotional vigilance, and a characteristic facial dysmorphy. This is subsequent to a complete mutation of the FMR1 gene, considering a semidominant transmission linked to the unstable X. The expansion of the CGG triplet greater than 200 units combined with a high methylation pattern lead to a transcriptional silence of the FMR1 gene, and the protein product, the FMRP, is not synthesized. This protein is involved in synaptic plasticity. Brain MRI can show an increased volume of the caudate nucleus and hippocampus, combined with hypoplasia of the cerebellar vermis. Fragile X Associated Tremor Ataxia Syndrome (FXTAS) syndrome is a neurodegenerative disorder occurring in carriers of the premutation in FMR1. Brain MRI shows an increased T2 signal in the middle cerebellar peduncles. This syndrome is linked to a premutation in the FMR1 gene. We report here the case of two brothers presenting a typical fragile X symptomatology. Brain MRI showed hyperintensities of the middle cerebellar peduncles. Such MRI findings support the assumption of a genetic mosaicism. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Conceptualizing neurodevelopmental disorders through a mechanistic understanding of fragile X syndrome and Williams syndrome

PubMed Central

Fung, Lawrence K.; Quintin, Eve-Marie; Haas, Brian W.

2013-01-01

Purpose of review The overarching goal of this review is to compare and contrast the cognitive-behavioral features of fragile X syndrome (FraX) and Williams syndrome and to review the putative neural and molecular underpinnings of these features. Information is presented in a framework that provides guiding principles for conceptualizing gene-brain-behavior associations in neurodevelopmental disorders. Recent findings Abnormalities, in particular cognitive-behavioral domains with similarities in underlying neurodevelopmental correlates, occur in both FraX and Williams syndrome including aberrant frontostriatal pathways leading to executive function deficits, and magnocellular/dorsal visual stream, superior parietal lobe, inferior parietal lobe, and postcentral gyrus abnormalities contributing to deficits in visuospatial function. Compelling cognitive–behavioral and neurodevelopmental contrasts also exist in these two disorders, for example, aberrant amygdala and fusiform cortex structure and function occurring in the context of contrasting social behavioral phenotypes, and temporal cortical and cerebellar abnormalities potentially underlying differences in language function. Abnormal dendritic development is a shared neurodevelopmental morphologic feature between FraX and Williams syndrome. Commonalities in molecular machinery and processes across FraX and Williams syndrome occur as well – microRNAs involved in translational regulation of major synaptic proteins; scaffolding proteins in excitatory synapses; and proteins involved in axonal development. Summary Although the genetic variations leading to FraX and Williams syndrome are different, important similarities and contrasts in the phenotype, neurocircuitry, molecular machinery, and cellular processes in these two disorders allow for a unique approach to conceptualizing gene–brain–behavior links occurring in neurodevelopmental disorders. PMID:22395002

FMR1 CGG repeat expansion mutation detection and linked haplotype analysis for reliable and accurate preimplantation genetic diagnosis of fragile X syndrome.

PubMed

Rajan-Babu, Indhu-Shree; Lian, Mulias; Cheah, Felicia S H; Chen, Min; Tan, Arnold S C; Prasath, Ethiraj B; Loh, Seong Feei; Chong, Samuel S

2017-07-19

Fragile X mental retardation 1 (FMR1) full-mutation expansion causes fragile X syndrome. Trans-generational fragile X syndrome transmission can be avoided by preimplantation genetic diagnosis (PGD). We describe a robust PGD strategy that can be applied to virtually any couple at risk of transmitting fragile X syndrome. This novel strategy utilises whole-genome amplification, followed by triplet-primed polymerase chain reaction (TP-PCR) for robust detection of expanded FMR1 alleles, in parallel with linked multi-marker haplotype analysis of 13 highly polymorphic microsatellite markers located within 1 Mb of the FMR1 CGG repeat, and the AMELX/Y dimorphism for gender identification. The assay was optimised and validated on single lymphoblasts isolated from fragile X reference cell lines, and applied to a simulated PGD case and a clinical in vitro fertilisation (IVF)-PGD case. In the simulated PGD case, definitive diagnosis of the expected results was achieved for all 'embryos'. In the clinical IVF-PGD case, delivery of a healthy baby girl was achieved after transfer of an expansion-negative blastocyst. FMR1 TP-PCR reliably detects presence of expansion mutations and obviates reliance on informative normal alleles for determining expansion status in female embryos. Together with multi-marker haplotyping and gender determination, misdiagnosis and diagnostic ambiguity due to allele dropout is minimised, and couple-specific assay customisation can be avoided.

Does Attention Constrain Developmental Trajectories in Fragile X Syndrome? A 3-Year Prospective Longitudinal Study

ERIC Educational Resources Information Center

Cornish, Kim; Cole, Victoria; Longhi, Elena; Karmiloff-Smith, Annette; Scerif, Gaia

2012-01-01

Basic attentional processes and their impact on developmental trajectories in fragile X syndrome were assessed in a 3-year prospective study. Although fragile X syndrome is a monogenic X-linked disorder, there is striking variability in outcomes even in young boys with the condition. Attention is a key factor constraining interactions with the…

Congenital cataracts and other abnormalities in a female with 46.X, del(X)(q26q28)mat: A new locus for X-linked congenital cataract?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Babul, R.; Chitayat, D.; Teshima, I.

1994-09-01

Three forms of X-linked congenital cataracts have been delineated: congenital cataract with posterior Y-sutural opacities in heterozygotes, congenital cataract and microcornea or microphthalmia and congenital cataract-dental syndrome (Nance-Horan syndrome). Of these, only the Nance-Horan syndrome has been mapped to Xp22.3-p21.1. However, Warburg has suggested that these different forms of X-linked congenital cataracts are due to deletions of varying sizes, placing them in the vicinity of the Nance-Horan syndrome region. We report on a female patient born to a 29-year-old primigravida woman who at birth was found to have hypotonia, dysmorphic facial features, hydrocephalus and dense white congenital bilateral cataracts. Othermore » ophthalmological findings included bilateral nystagmus and shallow orbits. Chromosome analysis revealed 46,X,del(X)(q26q28)mat. The mother, however, is phenotypically normal. Brain CT scan on the female infant revealed communicating hydrocephalus and a muscle biopsy showed congenital muscle fiber disproportion. An EMG and NCV were normal. At 4 years of age, her height and weight were below -3SD and her OFC was +2SD. Molecular studies using DNA markers located in Xq26-qter have revealed that the proximal breakpoint in the patient and her mother is defined by the HPRT locus while the distal breakpoint is defined by the locus DXS1108. This indicates that the deletion is not terminal but rather interstitial, retaining sequences proximal to the telomeric region. Other molecular studies are in progress to determine the X-inactivation status of the deleted chromosome in our patient and her mother as a possible explanation for the variation in the phenotype. These clinical and molecular findings suggest that another locus for X-linked congenital cataract exists at Xq26-28.« less

PPM-X: a new X-linked mental retardation syndrome with psychosis, pyramidal signs, and macroorchidism maps to Xq28.

PubMed Central

Lindsay, S.; Splitt, M.; Edney, S.; Berney, T. P.; Knight, S. J.; Davies, K. E.; O'Brien, O.; Gale, M.; Burn, J.

1996-01-01

We report a three-generation family manifesting a previously undescribed X-linked mental retardation syndrome. Four of the six moderately retarded males have had episodes of manic-depressive psychosis. The phenotype also includes pyramidal signs, Parkinsonian features, and macroorchidism, but there are no characteristic dysmorphic facial features. Affected males do not show fragile sites at distal Xq on cytogenetic analysis, nor do they have expansions of the CGG repeats at the FRAXA, FRAXE, or FRAXF loci. Linkage analyses were undertaken, and a maximal LOD score of 3.311 at theta = .0 was observed with the microsatellite marker DXS1123 in Xq28. A recombination was detected in one of the affected males with DXS1691 (Xq28), which gives the proximal boundary of the localization. No distal recombination has been detected at any of the loci tested. Images Figure 2 PMID:8651288

X-Linked Syndrome of Polyendocrinopathy, Immune Dysfunction, and Diarrhea Maps to Xp11.23-Xq13.3

PubMed Central

Bennett, Craig L.; Yoshioka, Ritsuko; Kiyosawa, Hidenori; Barker, David F.; Fain, Pamela R.; Shigeoka, Ann O.; Chance, Phillip F.

2000-01-01

Summary We describe genetic analysis of a large pedigree with an X-linked syndrome of polyendocrinopathy, immune dysfunction, and diarrhea (XPID), which frequently results in death during infancy or childhood. Linkage analysis mapped the XPID gene to a 17-cM interval defined by markers DXS8083 and DXS8107 on the X chromosome, at Xp11.23-Xq13.3. The maximum LOD score was 3.99 (recombination fraction0) at DXS1235. Because this interval also harbors the gene for Wiskott-Aldrich syndrome (WAS), we investigated mutations in the WASP gene, as the molecular basis of XPID. Northern blot analysis detected the same relative amount and the same-sized WASP message in patients with XPID and in a control. Analysis of the WASP coding sequence, an alternate promoter, and an untranslated upstream first exon was carried out, and no mutations were found in patients with XPID. A C→T transition within the alternate translation start site cosegregated with the XPID phenotype in this family; however, the same transition site was detected in a normal control male. We conclude that XPID maps to Xp11.23-Xq13.3 and that mutations of WASP are not associated with XPID. PMID:10677306

X-linked Alport syndrome: An SSCP-based mutation survey over all 51 exons of the COL4A5 gene

DOE Office of Scientific and Technical Information (OSTI.GOV)

Renieri, A.; Bruttini, M.; Galli, L.

1996-06-01

The COL4A5 gene encodes the {alpha}5 (type IV) collagen chain and is defective in X-linked Alport syndrome (AS). Here, we report the first systematic analysis of all 51 exons of COL4A5 gene in a series of 201 Italian AS patients. We have previously reported nine major rearrangements, as well as 18 small mutations identified in the same patient series by SSCP analysis of several exons. After systematic analysis of all 51 exons of COL4A5, we have now identified 30 different mutations: 10 glycine substitutions in the triple helical domain of the protein, 9 frameshift mutations, 4 in-frame deletions, 1 startmore » codon, 1 nonsense, and 5 splice-site mutations. These mutations were either unique or found in two unrelated families, thus excluding the presence of a common mutation in the coding part of the gene. Overall, mutations were detected in only 45% of individuals with a certain or likely diagnosis of X-linked AS. This finding suggests that mutations in noncoding segments of COL4A5 account for a high number of X-linked AS cases. An alternative hypothesis is the presence of locus heterogeneity, even within the X-linked form of the disease. A genotype/phenotype comparison enabled us to better substantiate a significant correlation between the degree of predicted disruption of the {alpha}5 chain and the severity of phenotype in affected male individuals. Our study has significant implications in the diagnosis and follow-up of AS patients. 44 refs., 3 figs., 4 tabs.« less

X-linked CHARGE-like Abruzzo-Erickson syndrome and classic cleft palate with ankyloglossia result from TBX22 splicing mutations.

PubMed

Pauws, E; Peskett, E; Boissin, C; Hoshino, A; Mengrelis, K; Carta, E; Abruzzo, M A; Lees, M; Moore, G E; Erickson, R P; Stanier, P

2013-04-01

X-linked cleft palate (CPX) is caused by mutations in the gene encoding the TBX22 transcription factor and is known to exhibit phenotypic variability, usually involving either a complete, partial or submucous cleft palate, with or without ankyloglossia. This study hypothesized a possible involvement of TBX22 in a family with X-linked, CHARGE-like Abruzzo-Erickson syndrome, of unknown etiology. The phenotype extends to additional features including sensorineural deafness and coloboma, which are suggested by the Tbx22 developmental expression pattern but not previously associated in CPX patients. A novel TBX22 splice acceptor mutation (c.593-5T>A) was identified that tracked with the phenotype in this family. A novel splice donor variant (c.767+5G>A) and a known canonical splice donor mutation (c.767+1G>A) affecting the same exon were identified in patients with classic CPX phenotypes and were comparatively analyzed using both in silico and in vitro splicing studies. All three variants were predicted to abolish normal mRNA splicing and an in vitro assay indicated that use of alternative splice sites was a likely outcome. Collectively, the data showed the functional effect of several novel intronic splice site variants but most importantly confirms that TBX22 is the gene underlying Abruzzo-Erickson syndrome, expanding the phenotypic spectrum of TBX22 mutations. © 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.

TARGETED TREATMENTS IN AUTISM AND FRAGILE X SYNDROME

PubMed Central

Gürkan, C. Kağan; Hagerman, Randi J.

2012-01-01

Autism is a neurodevelopmental disorder consisting of a constellation of symptoms that sometimes occur as part of a complex disorder characterized by impairments in social interaction, communication and behavioral domains. It is a highly disabling disorder and there is a need for treatment targeting the core symptoms. Although autism is accepted as highly heritable, there is no genetic cure at this time. Autism is shown to be linked to several genes and is a feature of some complex genetic disorders, including fragile X syndrome (FXS), fragile X premutation involvement, tuberous sclerosis and Rett syndrome. The term autism spectrum disorders (ASDs) covers autism, Asperger syndrome and pervasive developmental disorders (PDD-NOS) and the etiologies are heterogeneous. In recent years, targeted treatments have been developed for several disorders that have a known specific genetic cause leading to autism. Since there are significant molecular and neurobiological overlaps among disorders, targeted treatments developed for a specific disorder may be helpful in ASD of unknown etiology. Examples of this are two drug classes developed to treat FXS, Arbaclofen, a GABAB agonist, and mGluR5 antagonists, and both may be helpful in autism without FXS. The mGluR5 antagonists are also likely to have a benefit in the aging problems of fragile X premutation carriers, the fragile X –associated tremor ataxia syndrome (FXTAS) and the Parkinsonism that can occur in aging patients with fragile X syndrome. Targeted treatments in FXS which has a well known genetic etiology may lead to new targeted treatments in autism. PMID:23162607

Generation of integration-free induced pluripotent stem cell lines derived from two patients with X-linked Alport syndrome (XLAS).

PubMed

Kuebler, Bernd; Aran, Begoña; Miquel-Serra, Laia; Muñoz, Yolanda; Ars, Elisabet; Bullich, Gemma; Furlano, Monica; Torra, Roser; Marti, Merce; Veiga, Anna; Raya, Angel

2017-12-01

Skin biopsies were obtained from two male patients with X-linked Alport syndrome (XLAS) with hemizygous COL4A5 mutations in exon 41 or exon 46. Dermal fibroblasts were extracted and reprogrammed by nucleofection with episomal plasmids carrying OCT3/4, SOX2, KLF4 LIN28, L-MYC and p53 shRNA. The generated induced Pluripotent Stem Cell (iPSC) lines AS-FiPS2-Ep6F-28 and AS-FiPS3-Ep6F-9 were free of genomically integrated reprogramming genes, had the specific mutations, a stable karyotype, expressed pluripotency markers and generated embryoid bodies which were differentiated towards the three germ layers in vitro. These iPSC lines offer a useful resource to study Alport syndrome pathomechanisms and drug testing. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Genetics Home Reference: triple X syndrome

MedlinePlus

... Twitter Home Health Conditions Triple X syndrome Triple X syndrome Printable PDF Open All Close All Enable ... to view the expand/collapse boxes. Description Triple X syndrome , also called trisomy X or 47,XXX, ...

Modeling Family Dynamics in Children with Fragile X Syndrome

ERIC Educational Resources Information Center

Hall, Scott S.; Burns, David D.; Reiss, Allan L.

2007-01-01

Few studies have examined the impact of children with genetic disorders and their unaffected siblings on family functioning. In this study, the reciprocal causal links between problem behaviors and maternal distress were investigated in 150 families containing a child with fragile X syndrome (FXS) and an unaffected sibling. Both children's…

Implicit Procedural Learning in Fragile X and Down Syndrome

ERIC Educational Resources Information Center

Bussy, G.; Charrin, E.; Brun, A.; Curie, A.; des Portes, V.

2011-01-01

Background: Procedural learning refers to rule-based motor skill learning and storage. It involves the cerebellum, striatum and motor areas of the frontal lobe network. Fragile X syndrome, which has been linked with anatomical abnormalities within the striatum, may result in implicit procedural learning deficit. Methods: To address this issue, a…

Arch fingerprints, hypotonia, and areflexia associated with X linked mental retardation.

PubMed Central

Stevenson, R E; Häne, B; Arena, J F; May, M; Lawrence, L; Lubs, H A; Schwartz, C E

1997-01-01

A syndrome with distinctive facies, poor muscle tone, absent deep tendon reflexes, tapered fingers, excessive fingerprint arches, genu valgum and mild-moderate mental retardation has occurred in four males in two generations of a white family of European ancestry. The facies are characterised by square configuration, tented upper lip, and thickening of the helices, upper eyelids, and alae nasi. At birth and at maturity, growth (head circumference, height, weight) of affected males is comparable to or greater than unaffected male sibs. Moderate impairment of cognitive function was documented (IQ scores between 40-51). Carriers show no heterozygote manifestations. This X linked condition appears to be different from other syndromes with mental retardation, although there are certain similarities with the alpha thalassaemia-mental retardation syndrome (ATR-X). Linkage analysis found tight linkage to DXS1166 and DXS995 in Xq13 and Xq21 respectively. Images PMID:9192265

Arch fingerprints, hypotonia, and areflexia associated with X linked mental retardation.

PubMed

Stevenson, R E; Häne, B; Arena, J F; May, M; Lawrence, L; Lubs, H A; Schwartz, C E

1997-06-01

A syndrome with distinctive facies, poor muscle tone, absent deep tendon reflexes, tapered fingers, excessive fingerprint arches, genu valgum and mild-moderate mental retardation has occurred in four males in two generations of a white family of European ancestry. The facies are characterised by square configuration, tented upper lip, and thickening of the helices, upper eyelids, and alae nasi. At birth and at maturity, growth (head circumference, height, weight) of affected males is comparable to or greater than unaffected male sibs. Moderate impairment of cognitive function was documented (IQ scores between 40-51). Carriers show no heterozygote manifestations. This X linked condition appears to be different from other syndromes with mental retardation, although there are certain similarities with the alpha thalassaemia-mental retardation syndrome (ATR-X). Linkage analysis found tight linkage to DXS1166 and DXS995 in Xq13 and Xq21 respectively.

Dysregulation of mTOR signaling in fragile X syndrome.

PubMed

Sharma, Ali; Hoeffer, Charles A; Takayasu, Yukihiro; Miyawaki, Takahiro; McBride, Sean M; Klann, Eric; Zukin, R Suzanne

2010-01-13

Fragile X syndrome, the most common form of inherited mental retardation and leading genetic cause of autism, is caused by transcriptional silencing of the Fmr1 gene. The fragile X mental retardation protein (FMRP), the gene product of Fmr1, is an RNA binding protein that negatively regulates translation in neurons. The Fmr1 knock-out mouse, a model of fragile X syndrome, exhibits cognitive deficits and exaggerated metabotropic glutamate receptor (mGluR)-dependent long-term depression at CA1 synapses. However, the molecular mechanisms that link loss of function of FMRP to aberrant synaptic plasticity remain unclear. The mammalian target of rapamycin (mTOR) signaling cascade controls initiation of cap-dependent translation and is under control of mGluRs. Here we show that mTOR phosphorylation and activity are elevated in hippocampus of juvenile Fmr1 knock-out mice by four functional readouts: (1) association of mTOR with regulatory associated protein of mTOR; (2) mTOR kinase activity; (3) phosphorylation of mTOR downstream targets S6 kinase and 4E-binding protein; and (4) formation of eukaryotic initiation factor complex 4F, a critical first step in cap-dependent translation. Consistent with this, mGluR long-term depression at CA1 synapses of FMRP-deficient mice is exaggerated and rapamycin insensitive. We further show that the p110 subunit of the upstream kinase phosphatidylinositol 3-kinase (PI3K) and its upstream activator PI3K enhancer PIKE, predicted targets of FMRP, are upregulated in knock-out mice. Elevated mTOR signaling may provide a functional link between overactivation of group I mGluRs and aberrant synaptic plasticity in the fragile X mouse, mechanisms relevant to impaired cognition in fragile X syndrome.

DXS106 and DXSW559 flank the X-linked dystonia-parkisonism syndrome locus (DYT3)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mueller, U.; Haberhausen, G.; Wagner, T.

1994-09-01

The locus (DYT3) underlying the X-linked dystonia-parkinsonism syndrome (XDP) was delineated within proximal Xq12-Xq13.1 by analysis of linkage, allelic association, and haplotypes. Short tandem repeat polymorphism at loci DXS227, DXS559, DXS453, DXS106, DXS339, and DXS135 were studied. The occurrence of a recombination within a three-generation family established DXS559 as the distal flanking marker of DYT3. /{phi}/and /{Delta}/ values were determined as indicators of the degree of allelic association between DYT3 and the six marker loci. In addition, haplotype analysis was performed at the loci studied. The findings establish DXS106 as the proximal flanking marker of DYT3. Given an approximate distancemore » between DXS106 and DXS559 of 3.0 Mb, isolation of DYT3 is now feasible by positional cloning techniques. 21 refs., 2 figs., 3 tabs.« less

Submicroscopic interstitial deletion of the X chromosome explains a complex genetic syndrome dominated by Norrie disease.

PubMed

Gal, A; Wieringa, B; Smeets, D F; Bleeker-Wagemakers, L; Ropers, H H

1986-01-01

Norrie disease (ND), an X-linked recessive disorder, is characterized by congenital blindness followed by bulbar atrophy. We have examined a three-generation family in which ND is part of a complex X-linked syndrome with severe mental retardation, hypogonadism, growth disturbances, and increased susceptibility to infections as additional features. This syndrome is apparently due to an interstitial deletion, as evidenced by the failure of the L1.28 DNA probe (DXS7 locus, Xp11.3) to detect complementary DNA sequences on the defective X chromosome of an affected male and of several obligatory heterozygotes. Attempts to further define this deletion with other DNA probes from the proximal short arm of the X chromosome or by prometaphase chromosome analysis were unsuccessful.

A distinct X-linked syndrome involving joint contractures, keloids, large optic cup-to-disc ratio, and renal stones results from a filamin A (FLNA) mutation.

PubMed

Lah, Melissa; Niranjan, Tejasvi; Srikanth, Sujata; Holloway, Lynda; Schwartz, Charles E; Wang, Tao; Weaver, David D

2016-04-01

We further evaluated a previously reported family with an apparently undescribed X-linked syndrome involving joint contractures, keloids, an increased optic cup-to-disc ratio, and renal stones to elucidate the genetic cause. To do this, we obtained medical histories and performed physical examination on 14 individuals in the family, five of whom are affected males and three are obligate carrier females. Linkage analysis was performed on all but one individual and chromosome X-exome sequencing was done on two affected males. The analysis localized the putative gene to Xq27-qter and chromosome X-exome sequencing revealed a mutation in exon 28 (c.4726G>A) of the filamin A (FLNA) gene, predicting that a conserved glycine had been replaced by arginine at amino acid 1576 (p.G1576R). Segregation analysis demonstrated that all known carrier females tested were heterozygous (G/A), all affected males were hemizygous for the mutation (A allele) and all normal males were hemizygous for the normal G allele. The data and the bioinformatic analysis indicate that the G1576R mutation in the FLNA gene is very likely pathogenic in this family. The syndrome affecting the family shares phenotypic overlap with other syndromes caused by FLNA mutations, but appears to be a distinct phenotype, likely representing a unique genetic syndrome. © 2016 Wiley Periodicals, Inc.

GENETICS IN ENDOCRINOLOGY: Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing.

PubMed

Maione, Luigi; Dwyer, Andrew A; Francou, Bruno; Guiochon-Mantel, Anne; Binart, Nadine; Bouligand, Jérôme; Young, Jacques

2018-03-01

Congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS) are rare, related diseases that prevent normal pubertal development and cause infertility in affected men and women. However, the infertility carries a good prognosis as increasing numbers of patients with CHH/KS are now able to have children through medically assisted procreation. These are genetic diseases that can be transmitted to patients' offspring. Importantly, patients and their families should be informed of this risk and given genetic counseling. CHH and KS are phenotypically and genetically heterogeneous diseases in which the risk of transmission largely depends on the gene(s) responsible(s). Inheritance may be classically Mendelian yet more complex; oligogenic modes of transmission have also been described. The prevalence of oligogenicity has risen dramatically since the advent of massively parallel next-generation sequencing (NGS) in which tens, hundreds or thousands of genes are sequenced at the same time. NGS is medically and economically more efficient and more rapid than traditional Sanger sequencing and is increasingly being used in medical practice. Thus, it seems plausible that oligogenic forms of CHH/KS will be increasingly identified making genetic counseling even more complex. In this context, the main challenge will be to differentiate true oligogenism from situations when several rare variants that do not have a clear phenotypic effect are identified by chance. This review aims to summarize the genetics of CHH/KS and to discuss the challenges of oligogenic transmission and also its role in incomplete penetrance and variable expressivity in a perspective of genetic counseling. © 2018 European Society of Endocrinology.

A novel UBE2A mutation causes X-linked intellectual disability type Nascimento.

PubMed

Tsurusaki, Yoshinori; Ohashi, Ikuko; Enomoto, Yumi; Naruto, Takuya; Mitsui, Jun; Aida, Noriko; Kurosawa, Kenji

2017-01-01

X-linked intellectual disability (ID) type Nascimento (MIM #300860), also known as ubiquitin-conjugating enzyme E2 A (UBE2A) deficiency syndrome, is a congenital malformation syndrome characterized by moderate to severe ID, speech impairment, dysmorphic facial features, genital anomalies and skin abnormalities. Here, we report a Japanese patient with severe ID and congenital cataract. We identified a novel hemizygous mutation (c.76G>A, p.Gly26Arg) in UBE2A by whole-exome sequencing.

Novel FGFR1 mutations in Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism: evidence for the involvement of an alternatively spliced isoform.

PubMed

Gonçalves, Catarina; Bastos, Margarida; Pignatelli, Duarte; Borges, Teresa; Aragüés, José M; Fonseca, Fernando; Pereira, Bernardo D; Socorro, Sílvia; Lemos, Manuel C

2015-11-01

To determine the prevalence of fibroblast growth factor receptor 1 (FGFR1) mutations and their predicted functional consequences in patients with idiopathic hypogonadotropic hypogonadism (IHH). Cross-sectional study. Multicentric. Fifty unrelated patients with IHH (21 with Kallmann syndrome and 29 with normosmic IHH). None. Patients were screened for mutations in FGFR1. The functional consequences of mutations were predicted by in silico structural and conservation analysis. Heterozygous FGFR1 mutations were identified in six (12%) kindreds. These consisted of frameshift mutations (p.Pro33-Alafs*17 and p.Tyr654*) and missense mutations in the signal peptide (p.Trp4Cys), in the D1 extracellular domain (p.Ser96Cys) and in the cytoplasmic tyrosine kinase domain (p.Met719Val). A missense mutation was identified in the alternatively spliced exon 8A (p.Ala353Thr) that exclusively affects the D3 extracellular domain of FGFR1 isoform IIIb. Structure-based and sequence-based prediction methods and the absence of these variants in 200 normal controls were all consistent with a critical role for the mutations in the activity of the receptor. Oligogenic inheritance (FGFR1/CHD7/PROKR2) was found in one patient. Two FGFR1 isoforms, IIIb and IIIc, result from alternative splicing of exons 8A and 8B, respectively. Loss-of-function of isoform IIIc is a cause of IHH, whereas isoform IIIb is thought to be redundant. Ours is the first report of normosmic IHH associated with a mutation in the alternatively spliced exon 8A and suggests that this disorder can be caused by defects in either of the two alternatively spliced FGFR1 isoforms. Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Juvenile muscular atrophy of the distal upper extremities associated with x-linked periventricular heterotopia with features of Ehlers-Danlos syndrome.

PubMed

Hommel, Alyson L; Jewett, Tamison; Mortenson, Megan; Caress, James B

2016-10-01

Juvenile muscular atrophy of the distal upper extremities (JMADUE) is a rare, sporadic disorder that affects adolescent males and is characterized by progressive but self-limited weakness of the distal upper extremities. The etiology is unknown, but cervical hyperflexion has been hypothesized. We report a case of an adolescent male who presented with typical JMADUE but also had joint hypermobility and multiple congenital anomalies, including periventricular heterotopias, suggesting a multisystem syndrome. Subsequent diagnostic testing confirmed a diagnosis of JMADUE, and sequencing of the filamin-A gene showed a novel, pathogenic mutation that confirmed an additional diagnosis of X-linked periventricular heterotopias with features of Ehlers-Danlos syndrome (XLPH-EDS). The concurrent diagnosis of these 2 rare conditions suggests a pathogenic connection. It is likely that the joint hypermobility from XLPH-EDS predisposed this patient to developing JMADUE. This supports the cervical hyperflexion theory of pathogenesis. This case also expands the phenotype associated with FLNA mutations. Muscle Nerve 54: 794-797, 2016. © 2016 Wiley Periodicals, Inc.

Genetics Home Reference: X-linked thrombocytopenia

MedlinePlus

... Facebook Twitter Home Health Conditions X-linked thrombocytopenia X-linked thrombocytopenia Printable PDF Open All Close All ... Javascript to view the expand/collapse boxes. Description X-linked thrombocytopenia is a bleeding disorder that primarily ...

Fragile X Syndrome

MedlinePlus

Fragile X syndrome is the most common form of inherited developmental disability. A problem with a specific gene causes ... the protein. This causes the symptoms of Fragile X. People with only a small change in the ...

Successful bone marrow transplantation in a boy with X-linked lymphoproliferative syndrome and acute severe infectious mononucleosis.

PubMed

Pracher, E; Panzer-Grümayer, E R; Zoubek, A; Peters, C; Gadner, H

1994-05-01

We report a 5.9-year-old boy with X-linked lymphoproliferative syndrome (XLP) who presented with acute severe infectious mononucleosis. Clinical symptoms rapidly improved after chemotherapy with etoposide. Allogeneic bone marrow transplantation (BMT) was performed after conditioning with etoposide, busulfan and cyclophosphamide. After successful hematopoietic recovery we were able to demonstrate seroconversion from an impaired antibody response to Epstein-Barr virus (EBV) to a normal antibody-producing state in an immunocompetent child. The only post-transplant complication was mild acute graft-versus-host disease (GVHD). Three years after BMT, the boy is healthy and shows no signs of immunodeficiency. This is the first report on successful allogeneic BMT in the severe course of acute infectious mononucleosis in a patient with XLP. We speculate that the application of etoposide contributed to the positive outcome in this patient.

Parents' Decisions to Screen Their Newborn for Fragile X Syndrome. FPG Snapshot #63

ERIC Educational Resources Information Center

FPG Child Development Institute, 2011

2011-01-01

State newborn screening (NBS) programs have expanded in recent years, and more tests may be added in the future. The expansion of neonatal screening raises ethical, legal, and social questions. The questions surrounding NBS for fragile X syndrome (FXS) typify these concerns. FXS is an X-linked genetic condition that is the most common inherited…

A novel UBE2A mutation causes X-linked intellectual disability type Nascimento

PubMed Central

Tsurusaki, Yoshinori; Ohashi, Ikuko; Enomoto, Yumi; Naruto, Takuya; Mitsui, Jun; Aida, Noriko; Kurosawa, Kenji

2017-01-01

X-linked intellectual disability (ID) type Nascimento (MIM #300860), also known as ubiquitin-conjugating enzyme E2 A (UBE2A) deficiency syndrome, is a congenital malformation syndrome characterized by moderate to severe ID, speech impairment, dysmorphic facial features, genital anomalies and skin abnormalities. Here, we report a Japanese patient with severe ID and congenital cataract. We identified a novel hemizygous mutation (c.76G>A, p.Gly26Arg) in UBE2A by whole-exome sequencing. PMID:28611923

Increased skewing of X chromosome inactivation in Rett syndrome patients and their mothers.

PubMed

Knudsen, Gun Peggy S; Neilson, Tracey C S; Pedersen, June; Kerr, Alison; Schwartz, Marianne; Hulten, Maj; Bailey, Mark E S; Orstavik, Karen Helene

2006-11-01

Rett syndrome is a largely sporadic, X-linked neurological disorder with a characteristic phenotype, but which exhibits substantial phenotypic variability. This variability has been partly attributed to an effect of X chromosome inactivation (XCI). There have been conflicting reports regarding incidence of skewed X inactivation in Rett syndrome. In rare familial cases of Rett syndrome, favourably skewed X inactivation has been found in phenotypically normal carrier mothers. We have investigated the X inactivation pattern in DNA from blood and buccal cells of sporadic Rett patients (n=96) and their mothers (n=84). The mean degree of skewing in blood was higher in patients (70.7%) than controls (64.9%). Unexpectedly, the mothers of these patients also had a higher mean degree of skewing in blood (70.8%) than controls. In accordance with these findings, the frequency of skewed (XCI > or =80%) X inactivation in blood was also higher in both patients (25%) and mothers (30%) than in controls (11%). To test whether the Rett patients with skewed X inactivation were daughters of skewed mothers, 49 mother-daughter pairs were analysed. Of 14 patients with skewed X inactivation, only three had a mother with skewed X inactivation. Among patients, mildly affected cases were shown to be more skewed than more severely affected cases, and there was a trend towards preferential inactivation of the paternally inherited X chromosome in skewed cases. These findings, particularly the greater degree of X inactivation skewing in Rett syndrome patients, are of potential significance in the analysis of genotype-phenotype correlations in Rett syndrome.

Volvulus and bowel obstruction in ATR-X syndrome-clinical report and review of literature.

PubMed

Horesh, Nir; Pery, Ron; Amiel, Imri; Shwaartz, Chaya; Speter, Chen; Guranda, Larisa; Gutman, Mordechai; Hoffman, Aviad

2015-11-01

Alpha thalassemia-mental retardation, X-linked (ATR-X) syndrome is a rare genetic disorder with a variety of clinical manifestations. Gastrointestinal symptoms described in this syndrome include difficulties in feeding, regurgitation and vomiting which may lead to aspiration pneumonia, abdominal pain, distention, and constipation. We present a 19-year-old male diagnosed with ATR-X syndrome, who suffered from recurrent colonic volvulus that ultimately led to bowel necrosis with severe septic shock requiring emergent surgical intervention. During 1 year, the patient was readmitted four times due to poor oral intake, dehydration and abdominal distention. Investigation revealed partial small bowel volvulus which resolved with non-operative treatment. Small and large bowel volvulus are uncommon and life-threatening gastrointestinal manifestations of ATR-X patients, which may contribute to the common phenomenon of prolonged food refusal in these patients. © 2015 Wiley Periodicals, Inc.

Male-Female Characteristics of Fragile X Syndrome.

ERIC Educational Resources Information Center

Caron, Jackie

Fragile X syndrome is the most common cause of mental retardation next to Down syndrome. The syndrome is more prevalent in males because they only have one X chromosome, where the gene for fragile X is carried, while women have two X chromosomes and the normal gene can compensate for the affected chromosome. Certain physical features are…

The Juberg-Marsidi syndrome maps to the proximal long arm of the X chromosome (Xq12-q21)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Saugier-Veber, P.; Abadie, V.; Turleau, C.

Juberg-Marsidi syndrome (McKusick 309590) is a rare X-linked recessive condition characterized by severe mental retardation, growth failure, sensorineural deafness, and microgenitalism. Here the authors report on the genetic mapping of the Juberg-Marsidi gene to the proximal long arm of the X chromosome (Xq12-q21) by linkage to probe pRX214H1 at the DXS441 locus (Z = 3.24 at [theta] = .00). Multipoint linkage analysis placed the Juberg-Marsidi gene within the interval defined by the DXS159 and the DXYS1X loci in the Xq12-q21 region. These data provide evidence for the genetic distinction between Juberg-Marsidi syndrome and several other X-linked mental retardation syndromes thatmore » have hypogonadism and hypogenitalism and that have been localized previously. Finally, the mapping of the Juberg-Marsidi gene is of potential interest for reliable genetic counseling of at-risk women. 25 refs., 2 figs., 3 tabs.« less

Fragile x syndrome.

PubMed

McLennan, Yingratana; Polussa, Jonathan; Tassone, Flora; Hagerman, Randi

2011-05-01

Recent data from a national survey highlighted a significant difference in obesity rates in young fragile X males (31%) compared to age matched controls (18%). Fragile X syndrome (FXS) is the most common cause of intellectual disability in males and the most common single gene cause of autism. This X-linked disorder is caused by an expansion of a trinucleotide CGG repeat (>200) on the promotor region of the fragile X mental retardation 1 gene (FMR1). As a result, the promotor region often becomes methylated which leads to a deficiency or absence of the FMR1 protein (FMRP). Common characteristics of FXS include mild to severe cognitive impairments in males but less severe cognitive impairment in females. Physical features of FXS include an elongated face, prominent ears, and post-pubertal macroorchidism. Severe obesity in full mutation males is often associated with the Prader-Willi phenotype (PWP) which includes hyperphagia, lack of satiation after meals, and hypogonadism or delayed puberty; however, there is no deletion at 15q11-q13 nor uniparental maternal disomy. Herein, we discuss the molecular mechanisms leading to FXS and the Prader-Willi phenotype with an emphasis on mouse FMR1 knockout studies that have shown the reversal of weight increase through mGluR antagonists. Finally, we review the current medications used in treatment of FXS including the atypical antipsychotics that can lead to weight gain and the research regarding the use of targeted treatments in FXS that will hopefully have a significantly beneficial effect on cognition and behavior without weight gain.

Genetic Analysis of a Kindred With X-linked Mental Handicap and Retinitis Pigmentosa

PubMed Central

Aldred, M. A.; Dry, K. L.; Knight-Jones, E. B.; Hardwick, L. J.; Teague, P. W.; Lester, D. H.; Brown, J.; Spowart, G.; Carothers, A. D.; Raeburn, J. A.; Bird, A. C.; Fielder, A. R.; Wright, A. F.

1994-01-01

A kindred is described in which X-linked nonspecific mental handicap segregates together with retinitis pigmentosa. Carrier females are mentally normal but may show signs of the X-linked retinitis pigmentosa carrier state and become symptomatic in their later years. Analysis of polymorphic DNA markers at nine loci on the short arm of the X chromosome shows that no crossing-over occurs between the disease and Xp11 markers DXS255, TIMP, DXS426, MAOA, and DXS228. The 90% confidence limits show that the locus is in the Xp21-q21 region. Haplotype analysis is consistent with the causal gene being located proximal to the Xp21 loci DXS538 and 5'-dystrophin on the short arm of the X chromosome. The posterior probability of linkage to the RP2 region of the X chromosome short arm (Xp11.4-p11.23) is .727, suggesting the possibility of a contiguous-gene-deletion syndrome. No cytogenetic abnormality has been identified. PMID:7977353

Variation in the X-Linked EFHC2 Gene Is Associated with Social Cognitive Abilities in Males

PubMed Central

Startin, Carla M.; Fiorentini, Chiara; de Haan, Michelle; Skuse, David H.

2015-01-01

Females outperform males on many social cognitive tasks. X-linked genes may contribute to this sex difference. Males possess one X chromosome, while females possess two X chromosomes. Functional variations in X-linked genes are therefore likely to impact more on males than females. Previous studies of X-monosomic women with Turner syndrome suggest a genetic association with facial fear recognition abilities at Xp11.3, specifically at a single nucleotide polymorphism (SNP rs7055196) within the EFHC2 gene. Based on a strong hypothesis, we investigated an association between variation at SNP rs7055196 and facial fear recognition and theory of mind abilities in males. As predicted, males possessing the G allele had significantly poorer facial fear detection accuracy and theory of mind abilities than males possessing the A allele (with SNP variant accounting for up to 4.6% of variance). Variation in the X-linked EFHC2 gene at SNP rs7055196 is therefore associated with social cognitive abilities in males. PMID:26107779

Biobehavioral Indicators of Social Fear in Young Children with Fragile X Syndrome

ERIC Educational Resources Information Center

Tonnsen, Bridgette L.; Shinkareva, Svetlana V.; Deal, Sara C.; Hatton, Deborah D.; Roberts, Jane E.

2013-01-01

Anxiety is among the most impairing conditions associated with Fragile X syndrome (FXS) and is putatively linked to atypical physiological arousal. However, few studies have examined this association in young children with FXS. The authors examined whether patterns of arousal and behavior during an experimental stranger approach paradigm differ…

The Emergence of Effortful Control in Young Boys with Fragile X Syndrome

ERIC Educational Resources Information Center

Robinson, Marissa; Klusek, Jessica; Poe, Michele D.; Hatton, Deborah D.; Roberts, Jane E.

2018-01-01

Effortful control, or the ability to suppress a dominant response to perform a subdominant response, is an early-emerging temperament trait that is linked with positive social-emotional development. Fragile X syndrome (FXS) is a single-gene disorder characterized by hallmark regulatory impairments, suggesting diminished effortful control. This…

Fragile X Syndrome

ERIC Educational Resources Information Center

Schwarte, Andrea R.

2008-01-01

This article provides an overview of current research on Fragile X Syndrome, and how that knowledge can be used to guide successful intervention. The genetic etiology of Fragile X is reviewed and the physical, cognitive, adaptive, behavioral, and emotional phenotypes of children with the disorder are described, highlighting the differences in…

Genetics Home Reference: fragile X syndrome

MedlinePlus

... Citation on PubMed Koukoui SD, Chaudhuri A. Neuroanatomical, molecular genetic, and behavioral correlates of fragile X syndrome. Brain ... GJ, Dictenberg J. The fragile X syndrome: from molecular genetics to neurobiology. Ment Retard Dev Disabil Res Rev. ...

Genetics Home Reference: X-linked dilated cardiomyopathy

MedlinePlus

... Twitter Home Health Conditions X-linked dilated cardiomyopathy X-linked dilated cardiomyopathy Printable PDF Open All Close ... Javascript to view the expand/collapse boxes. Description X-linked dilated cardiomyopathy is a form of heart ...

Genetics Home Reference: X-linked myotubular myopathy

MedlinePlus

... Twitter Home Health Conditions X-linked myotubular myopathy X-linked myotubular myopathy Printable PDF Open All Close ... Javascript to view the expand/collapse boxes. Description X-linked myotubular myopathy is a condition that primarily ...

Genetics Home Reference: X-linked sideroblastic anemia

MedlinePlus

... Twitter Home Health Conditions X-linked sideroblastic anemia X-linked sideroblastic anemia Printable PDF Open All Close ... Javascript to view the expand/collapse boxes. Description X-linked sideroblastic anemia is an inherited disorder that ...

Severe X-linked chondrodysplasia punctata in nine new female fetuses.

PubMed

Lefebvre, Mathilde; Dufernez, Fabienne; Bruel, Ange-Line; Gonzales, Marie; Aral, Bernard; Saint-Onge, Judith; Gigot, Nadège; Desir, Julie; Daelemans, Caroline; Jossic, Frédérique; Schmitt, Sébastien; Mangione, Raphaele; Pelluard, Fanny; Vincent-Delorme, Catherine; Labaune, Jean-Marc; Bigi, Nicole; D'Olne, Dominique; Delezoide, Anne-Lise; Toutain, Annick; Blesson, Sophie; Cormier-Daire, Valérie; Thevenon, Julien; El Chehadeh, Salima; Masurel-Paulet, Alice; Joyé, Nicole; Vibert-Guigue, Claude; Rigonnot, Luc; Rousseau, Thierry; Vabres, Pierre; Hervé, Philippe; Lamazière, Antonin; Rivière, Jean-Baptiste; Faivre, Laurence; Laurent, Nicole; Thauvin-Robinet, Christel

2015-07-01

Conradi-Hünermann-Happle [X-linked dominant chondrodysplasia punctata 2 (CDPX2)] syndrome is a rare X-linked dominant skeletal dysplasia usually lethal in men while affected women show wide clinical heterogeneity. Different EBP mutations have been reported. Severe female cases have rarely been reported, with only six antenatal presentations. To better characterize the phenotype in female fetuses, we included nine antenatally diagnosed cases of women with EBP mutations. All cases were de novo except for two fetuses with an affected mother and one case of germinal mosaicism. The mean age at diagnosis was 22 weeks of gestation. The ultrasound features mainly included bone abnormalities: shortening (8/9 cases) and bowing of the long bones (5/9), punctuate epiphysis (7/9) and an irregular aspect of the spine (5/9). Postnatal X-rays and examination showed ichthyosis (8/9) and epiphyseal stippling (9/9), with frequent asymmetric short and bowed long bones. The X-inactivation pattern of the familial case revealed skewed X-inactivation in the mildly symptomatic mother and random X-inactivation in the severe fetal case. Differently affected skin samples of the same fetus revealed different patterns of X-inactivation. Prenatal detection of asymmetric shortening and bowing of the long bones and cartilage stippling should raise the possibility of CPDX2 in female fetuses, especially because the majority of such cases involve de novo mutations. © 2015 John Wiley & Sons, Ltd.

A major X-linked locus affects kidney function in mice

PubMed Central

Leduc, Magalie S.; Savage, Holly S.; Stearns, Timothy M.; Cario, Clinton L.; Walsh, Kenneth A.; Paigen, Beverly; Berndt, Annerose

2012-01-01

Chronic kidney disease is a common disease with increasing prevalence in the western population. One common reason for chronic kidney failure is diabetic nephropathy. Diabetic nephropathy and hyperglycemia are characteristics of the mouse inbred strain KK/HlJ, which is predominantly used as a model for metabolic syndrome due to its inherited glucose intolerance and insulin resistance. We used KK/HlJ, an albuminuria-sensitive strain, and C57BL/6J, an albuminuria-resistant strain, to perform a quantitative trait locus (QTL) cross to identify the genetic basis for chronic kidney failure. Albumin-creatinine-ratio (ACR) was measured in 130 F2 male offspring. One significant QTL was identified on chromosome (Chr) X and four suggestive QTLs were found on Chrs 6, 7, 12, and 13. Narrowing of the QTL region was focused on the X-linked QTL and performed by incorporating genotype and expression analyses for genes located in the region. From the 485 genes identified in the X-linked QTL region, a few candidate genes were identified using a combination of bioinformatic evidence based on genomic comparison of the parental strains and known function in urine homeostasis. Finally, this study demonstrates the significance of the X chromosome in the genetic determination of albuminuria. PMID:23011808

Aarskog syndrome

MedlinePlus

Aarskog disease; Aarskog-Scott syndrome; AAS; Faciodigitogenital syndrome; Gaciogenital dysplasia ... Aarskog syndrome is a genetic disorder that is linked to the X chromosome. It affects mainly males, but females ...

Genetics Home Reference: Snyder-Robinson syndrome

MedlinePlus

... syndromic, snyder-robinson type Merck Manual Home Health Handbook for Patients & Caregivers: Osteoporosis Orphanet: X-linked intellectual ... in X-linked intellectual disability (Snyder-Robinson syndrome). Methods Mol Biol. 2011;720:437-45. doi: 10. ...

Mutation Update for Kabuki Syndrome Genes KMT2D and KDM6A and Further Delineation of X-Linked Kabuki Syndrome Subtype 2.

PubMed

Bögershausen, Nina; Gatinois, Vincent; Riehmer, Vera; Kayserili, Hülya; Becker, Jutta; Thoenes, Michaela; Simsek-Kiper, Pelin Özlem; Barat-Houari, Mouna; Elcioglu, Nursel H; Wieczorek, Dagmar; Tinschert, Sigrid; Sarrabay, Guillaume; Strom, Tim M; Fabre, Aurélie; Baynam, Gareth; Sanchez, Elodie; Nürnberg, Gudrun; Altunoglu, Umut; Capri, Yline; Isidor, Bertrand; Lacombe, Didier; Corsini, Carole; Cormier-Daire, Valérie; Sanlaville, Damien; Giuliano, Fabienne; Le Quan Sang, Kim-Hanh; Kayirangwa, Honorine; Nürnberg, Peter; Meitinger, Thomas; Boduroglu, Koray; Zoll, Barbara; Lyonnet, Stanislas; Tzschach, Andreas; Verloes, Alain; Di Donato, Nataliya; Touitou, Isabelle; Netzer, Christian; Li, Yun; Geneviève, David; Yigit, Gökhan; Wollnik, Bernd

2016-09-01

Kabuki syndrome (KS) is a rare but recognizable condition that consists of a characteristic face, short stature, various organ malformations, and a variable degree of intellectual disability. Mutations in KMT2D have been identified as the main cause for KS, whereas mutations in KDM6A are a much less frequent cause. Here, we report a mutation screening in a case series of 347 unpublished patients, in which we identified 12 novel KDM6A mutations (KS type 2) and 208 mutations in KMT2D (KS type 1), 132 of them novel. Two of the KDM6A mutations were maternally inherited and nine were shown to be de novo. We give an up-to-date overview of all published mutations for the two KS genes and point out possible mutation hot spots and strategies for molecular genetic testing. We also report the clinical details for 11 patients with KS type 2, summarize the published clinical information, specifically with a focus on the less well-defined X-linked KS type 2, and comment on phenotype-genotype correlations as well as sex-specific phenotypic differences. Finally, we also discuss a possible role of KDM6A in Kabuki-like Turner syndrome and report a mutation screening of KDM6C (UTY) in male KS patients. © 2016 WILEY PERIODICALS, INC.

Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder.

PubMed

Frints, Suzanna G M; Ozanturk, Aysegul; Rodríguez Criado, Germán; Grasshoff, Ute; de Hoon, Bas; Field, Michael; Manouvrier-Hanu, Sylvie; E Hickey, Scott; Kammoun, Molka; Gripp, Karen W; Bauer, Claudia; Schroeder, Christopher; Toutain, Annick; Mihalic Mosher, Theresa; Kelly, Benjamin J; White, Peter; Dufke, Andreas; Rentmeester, Eveline; Moon, Sungjin; Koboldt, Daniel C; van Roozendaal, Kees E P; Hu, Hao; Haas, Stefan A; Ropers, Hans-Hilger; Murray, Lucinda; Haan, Eric; Shaw, Marie; Carroll, Renee; Friend, Kathryn; Liebelt, Jan; Hobson, Lynne; De Rademaeker, Marjan; Geraedts, Joep; Fryns, Jean-Pierre; Vermeesch, Joris; Raynaud, Martine; Riess, Olaf; Gribnau, Joost; Katsanis, Nicholas; Devriendt, Koen; Bauer, Peter; Gecz, Jozef; Golzio, Christelle; Gontan, Cristina; Kalscheuer, Vera M

2018-05-04

RLIM, also known as RNF12, is an X-linked E3 ubiquitin ligase acting as a negative regulator of LIM-domain containing transcription factors and participates in X-chromosome inactivation (XCI) in mice. We report the genetic and clinical findings of 84 individuals from nine unrelated families, eight of whom who have pathogenic variants in RLIM (RING finger LIM domain-interacting protein). A total of 40 affected males have X-linked intellectual disability (XLID) and variable behavioral anomalies with or without congenital malformations. In contrast, 44 heterozygous female carriers have normal cognition and behavior, but eight showed mild physical features. All RLIM variants identified are missense changes co-segregating with the phenotype and predicted to affect protein function. Eight of the nine altered amino acids are conserved and lie either within a domain essential for binding interacting proteins or in the C-terminal RING finger catalytic domain. In vitro experiments revealed that these amino acid changes in the RLIM RING finger impaired RLIM ubiquitin ligase activity. In vivo experiments in rlim mutant zebrafish showed that wild type RLIM rescued the zebrafish rlim phenotype, whereas the patient-specific missense RLIM variants failed to rescue the phenotype and thus represent likely severe loss-of-function mutations. In summary, we identified a spectrum of RLIM missense variants causing syndromic XLID and affecting the ubiquitin ligase activity of RLIM, suggesting that enzymatic activity of RLIM is required for normal development, cognition and behavior.

Neuroligins Provide Molecular Links Between Syndromic and Non-Syndromic Autism

PubMed Central

Singh, Sandeep K.; Eroglu, Cagla

2014-01-01

Autism is a common and heritable neuropsychiatric disorder that can be categorized into two types: syndromic and non-syndromic, the former of which are associated with other neurological disorders or syndromes. Molecular and functional links between syndromic and non-syndromic autism genes were lacking until studies aimed at understanding role of trans-synaptic adhesion molecule neuroligin, which is associated with non-syndromic autism, provided important connections. Here, we integrate data from these studies into a model of how neuroligin functions to control synaptic connectivity in the central nervous system and how neuroligin dysfunction may participate in the pathophysiology of autism. Understanding the complex functional interactions between neuroligins and other autism-associated proteins at the synapse is crucial to understand the pathology of autism. This understanding might bring us closer to development of therapeutic approaches for autism. PMID:23838185

Alpha Thalassemia/Mental Retardation Syndrome X-linked Gene Product ATRX Is Required for Proper Replication Restart and Cellular Resistance to Replication Stress*

PubMed Central

Leung, Justin Wai-Chung; Ghosal, Gargi; Wang, Wenqi; Shen, Xi; Wang, Jiadong; Li, Lei; Chen, Junjie

2013-01-01

Alpha thalassemia/mental retardation syndrome X-linked (ATRX) is a member of the SWI/SNF protein family of DNA-dependent ATPases. It functions as a chromatin remodeler and is classified as an SNF2-like helicase. Here, we showed somatic knock-out of ATRX displayed perturbed S-phase progression as well as hypersensitivity to replication stress. ATRX is recruited to sites of DNA damage, required for efficient checkpoint activation and faithful replication restart. In addition, we identified ATRX as a binding partner of MRE11-RAD50-NBS1 (MRN) complex. Together, these results suggest a non-canonical function of ATRX in guarding genomic stability. PMID:23329831

Genetic analysis of a kindred with X-linked mental handicap and retinitis pigmentosa

DOE Office of Scientific and Technical Information (OSTI.GOV)

Aldred, M.A.; Dry, K.L.; Hardwick, L.J.

1994-11-01

A kindred is described in which X-linked nonspecific mental handicap segregates together with retinitis pigmentosa. Carrier females are mentally normal but may show signs of the X-linked retinitis pigmentosa carrier state and become symptomatic in their later years. Analysis of polymorphic DNA markers at nine loci on the short arm of the X chromosome shows that no crossing-over occurs between the disease and Xp11 markers DXS255, TIMP, DXS426, MAOA, and DXS228. The 90% confidence limits show that the locus is in the Xp21-q21 region. Haplotype analysis is consistent with the causal gene being located proximal to the Xp21 loci DXS538more » and 5{prime}-dystrophin on the short arm of the X chromosome. The posterior probability of linkage to the RP2 region of the X chromosome short arm (Xp11.4-p11.23) is .727, suggesting the possibility of a contiguous-gene-deletion syndrome. No cytogenetic abnormality has been identified. 33 refs., 2 figs., 2 tabs.« less

Phenotype-genotype correlation in potential female carriers of X-linked developmental cataract (Nance-Horan syndrome).

PubMed

Khan, Arif O; Aldahmesh, Mohammed A; Mohamed, Jawahir Y; Alkuraya, Fowzan S

2012-06-01

To correlate clinical examination with underlying genotype in asymptomatic females who are potential carriers of X-linked developmental cataract (Nance-Horan syndrome). An ophthalmologist blind to the pedigree performed comprehensive ophthalmic examination for 16 available family members (two affected and six asymptomatic females, five affected and three asymptomatic males). Facial features were also noted. Venous blood was collected for sequencing of the gene NHS. All seven affected family members had congenital or infantile cataract and facial dysmorphism (long face, bulbous nose, abnormal dentition). The six asymptomatic females ranged in age from 4-35 years old. Four had posterior Y-suture centered lens opacities; these four also exhibited the facial dysmorphism of the seven affected family members. The fifth asymptomatic girl had scattered fine punctate lens opacities (not centered on the Y-suture) while the sixth had clear lenses, and neither exhibited the facial dysmorphism. A novel NHS mutation (p.Lys744AsnfsX15 [c.2232delG]) was found in the seven patients with congenital or infantile cataract. This mutation was also present in the four asymptomatic girls with Y-centered lens opacities but not in the other two asymptomatic girls or in the three asymptomatic males (who had clear lenses). Lens opacities centered around the posterior Y-suture in the context of certain facial features were sensitive and specific clinical signs of carrier status for NHS mutation in asymptomatic females. Lens opacities that did not have this characteristic morphology in a suspected female carrier were not a carrier sign, even in the context of her affected family members.

Localization to Xq22 and clinical update of a family with X-linked recessive mental retardation with progression sensorineural deafness, progressive tapeto-retinal degeneration and dystonia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tranebjaerg, L.; Schwartz, C.; Huggins, K.

1994-07-15

In a reinvestigation of a six-generation Norwegian family, originally reported with non-syndromic X-linked recessive deafness by Mohr and Mageroy, we have demonstrated several syndromic manifestations. The 10 clinically characterized affected males range in age from 14-61 years, and show progressive mental deterioration and visual disability. Ophthalmological and electrophysiological studies showed myopia, decreased visual acuity, combined cone-rod dystrophy as well as central areolar dystrophy by means of ERG. Brain CT-scans showed cortical and central atrophy without predilection to specific areas. Linkage analysis, using X-chromosomal RFLPs and CA-repeats, yielded a maximum LOD score of 4.37 with linkage to DXS17. DXS17 is localizedmore » to Xq22. One recombinant with COL4A5 (deficient in Alport syndrome) was observed. Results from the studies of this family will be important in reclassification of non-syndromic X-linked deafness since the family now represents syndromic deafness and XLMR with a specific phenotype.« less

Newborn Screening for Fragile X Syndrome

ERIC Educational Resources Information Center

Bailey, Donald B., Jr.

2004-01-01

Newborn screening for fragile X syndrome (FXS) is technically possible, and in the relatively near future accurate and inexpensive screening technologies are likely to be available. When that happens, will America's public health system adopt newborn screening for fragile X syndrome? This article addresses this issue by first placing screening for…

X-Linked Glomerulopathy Due to COL4A5 Founder Variant.

PubMed

Barua, Moumita; John, Rohan; Stella, Lorenzo; Li, Weili; Roslin, Nicole M; Sharif, Bedra; Hack, Saidah; Lajoie-Starkell, Ginette; Schwaderer, Andrew L; Becknell, Brian; Wuttke, Matthias; Köttgen, Anna; Cattran, Daniel; Paterson, Andrew D; Pei, York

2018-03-01

Alport syndrome is a rare hereditary disorder caused by rare variants in 1 of 3 genes encoding for type IV collagen. Rare variants in COL4A5 on chromosome Xq22 cause X-linked Alport syndrome, which accounts for ∼80% of the cases. Alport syndrome has a variable clinical presentation, including progressive kidney failure, hearing loss, and ocular defects. Exome sequencing performed in 2 affected related males with an undefined X-linked glomerulopathy characterized by global and segmental glomerulosclerosis, mesangial hypercellularity, and vague basement membrane immune complex deposition revealed a COL4A5 sequence variant, a substitution of a thymine by a guanine at nucleotide 665 (c.T665G; rs281874761) of the coding DNA predicted to lead to a cysteine to phenylalanine substitution at amino acid 222, which was not seen in databases cataloguing natural human genetic variation, including dbSNP138, 1000 Genomes Project release version 01-11-2004, Exome Sequencing Project 21-06-2014, or ExAC 01-11-2014. Review of the literature identified 2 additional families with the same COL4A5 variant leading to similar atypical histopathologic features, suggesting a unique pathologic mechanism initiated by this specific rare variant. Homology modeling suggests that the substitution alters the structural and dynamic properties of the type IV collagen trimer. Genetic analysis comparing members of the 3 families indicated a distant relationship with a shared haplotype, implying a founder effect. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

Speech Fluency in Fragile X Syndrome

ERIC Educational Resources Information Center

Van Borsel, John; Dor, Orianne; Rondal, Jean

2008-01-01

The present study investigated the dysfluencies in the speech of nine French speaking individuals with fragile X syndrome. Type, number, and loci of dysfluencies were analysed. The study confirms that dysfluencies are a common feature of the speech of individuals with fragile X syndrome but also indicates that the dysfluency pattern displayed is…

Mathematics learning disability in girls with Turner syndrome or fragile X syndrome.

PubMed

Murphy, Melissa M; Mazzocco, Michèle M M; Gerner, Gwendolyn; Henry, Anne E

2006-07-01

Two studies were carried out to examine the persistence (Study 1) and characteristics (Study 2) of mathematics learning disability (MLD) in girls with Turner syndrome or fragile X during the primary school years (ages 5-9 years). In Study 1, the rate of MLD for each syndrome group exceeded the rate observed in a grade-matched comparison group, although the likelihood of MLD persisting through the primary school years was comparable for all three groups. In Study 2, formal and informal math skills were compared across the syndrome groups, a normative group, and children from the normative group who had MLD. Few differences were observed between the Turner syndrome and normative groups. Despite having rote counting and number representation skills comparable to those in the normative group, girls with fragile X had difficulty with counting rules (e.g., cardinality, number constancy). However, this difficulty did not distingush them from the MLD group. Overall, counting skills appear to distinguish the Turner syndrome and fragile X groups, suggesting that the specificity of math deficits emerges earlier for fragile X than Turner syndrome.

Functional assessment of a novel COL4A5 splice region variant and immunostaining of plucked hair follicles as an alternative method of diagnosis in X-linked Alport syndrome.

PubMed

Malone, Andrew F; Funk, Steven D; Alhamad, Tarek; Miner, Jeffrey H

2017-06-01

Many COL4A5 splice region variants have been described in patients with X-linked Alport syndrome, but few have been confirmed by functional analysis to actually cause defective splicing. We sought to demonstrate that a novel COL4A5 splice region variant in a family with Alport syndrome is pathogenic using functional studies. We also describe an alternative method of diagnosis. Targeted next-generation sequencing results of an individual with Alport syndrome were analyzed and the results confirmed by Sanger sequencing in family members. A splicing reporter minigene assay was used to examine the variant's effect on splicing in transfected cells. Plucked hair follicles from patients and controls were examined for collagen IV proteins using immunofluorescence microscopy. A novel splice region mutation in COL4A5, c.1780-6T>G, was identified and segregated with disease in this family. This variant caused frequent skipping of exon 25, resulting in a frameshift and truncation of collagen α5(IV) protein. We also developed and validated a new approach to characterize the expression of collagen α5(IV) protein in the basement membranes of plucked hair follicles. Using this approach we demonstrated reduced collagen α5(IV) protein in affected male and female individuals in this family, supporting frequent failure of normal splicing. Differing normal to abnormal transcript ratios in affected individuals carrying splice region variants may contribute to variable disease severity observed in Alport families. Examination of plucked hair follicles in suspected X-linked Alport syndrome patients may offer a less invasive alternative method of diagnosis and serve as a pathogenicity test for COL4A5 variants of uncertain significance.

Functional assessment of a novel COL4A5 splice region variant and immunostaining of plucked hair follicles as an alternative method of diagnosis in X-linked Alport syndrome

PubMed Central

Malone, Andrew F.; Funk, Steven D.; Alhamad, Tarek; Miner, Jeffrey H.

2016-01-01

Introduction Many COL4A5 splice region variants have been described in patients with X-linked Alport syndrome, but few have been confirmed by functional analysis to actually cause defective splicing. We sought to demonstrate that a novel COL4A5 splice region variant in a family with Alport syndrome is pathogenic using functional studies. We also describe an alternative method of diagnosis. Methods We analyzed targeted next-generation sequencing results of an individual with Alport syndrome and confirmed results by Sanger sequencing in family members. A splicing reporter minigene assay was used to examine the variant’s effect on splicing in transfected cells. Plucked hair follicles from patients and controls were examined for collagen IV proteins using immunofluorescence microscopy. Results A novel splice region mutation in COL4A5, c.1780-6T>G, was identified and segregated with disease in this family. This variant caused frequent skipping of exon 25, resulting in a frameshift and truncation of collagen α5(IV) protein. We also developed and validated a new approach to characterize the expression of collagen α5(IV) protein in the basement membranes of plucked hair follicles. We demonstrated reduced collagen α5(IV) protein in affected male and female individuals in this family, supporting frequent failure of normal splicing. Conclusions Differing normal to abnormal transcript ratios in affected individuals carrying splice region variants may contribute to variable disease severity observed in Alport families. Examination of plucked hair follicles in suspected X-linked Alport syndrome patients may offer a less invasive alternative method of diagnosis and serve as a pathogenicity test for COL4A5 variants of uncertain significance. PMID:28013382

New X-linked mental retardation syndrome with the gene mapped tentatively in Xp22.3

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wittwer, B.; Kircheisen, R.; Leutelt, J.

1996-07-12

X-linked mental retardation (XLMR) is genetically heterogeneous and clinically variable. We describe a new XLMR syndrome of severe mental retardation and multiple congenital anomalies. Two sisters have (with 3 different partners) 3 severely handicapped sons. In 2 cases, oligohydramnios and intrauterine growth retardation were noted. Common anomalies included a square-shaped face, high and broad forehead, frontal bossing, downward slant of palpebral fissures, hypertelorism, epicanthic folds, long philtrum, thin upper lip, and apparently low-set ears. One boy has bilateral microphthalmos and sclerocornea, and his cousin has atrophy of the optic nerve. All 3 patients are blind and have profound statomotor andmore » mental retardation, seizures, and a grossly abnormal electroencephalographic pattern. Additional findings are short stature, delayed bone matuation, hydronephrosis, vesicorenal reflux, cryptorchidism, clinodactyly of the 5th fingers, and transverse palmar creases. The karyotype is normal (46,XY). Segregation analysis showed perfect coinheritance between the clinical phenotype and alleles at several loci in Xp22.3, whereas recombinants were identified with marker loci from Xp22.2-qter. Analysis of multiple informative meioses suggests that the disease locus maps in Xp22.3 distal to DXS16. 9 refs., 5 figs., 2 tabs.« less

Whole exome sequencing confirms the clinical diagnosis of Marfan syndrome combined with X-linked hypophosphatemia.

PubMed

Sheng, Xunlun; Chen, Xue; Lei, Bo; Chen, Rui; Wang, Hui; Zhang, Fangxia; Rong, Weining; Ha, Ruoshui; Liu, Yani; Zhao, Feng; Yang, Peizeng; Zhao, Chen

2015-06-04

To determine the genetic lesions and to modify the clinical diagnosis for a Chinese family with significant intrafamilial phenotypic diversities and unusual presentations. Three affected patients and the asymptomatic father were included and received comprehensive systemic examinations. Whole exome sequencing (WES) was performed for mutation detection. Structural modeling test was applied to analyze the potential structural changes caused by the missense substitution. The proband showed a wide spectrum of systemic anomalies, including bilateral ectopia lentis, atrial septal defect, ventricular septal defect, widening of tibial metaphysis with medial bowing, and dolichostenomelia in digits, while her mother and elder brother only demonstrated similar skeletal changes. A recurrent mutation, PHEX p.R291*, was found in all patients, while a de novo mutation, FBN1 p.C792F, was only detected in the proband. The FBN1 substitution was also predicted to cause significant conformational change in fibrillin-1 protein, thus changing its physical and biological properties. Taken together, we finalized the diagnosis for this family as X-linked hypophosphatemia (XLH), and diagnosed this girl as Marfan syndrome combined with XLH, and congenital heart disease. Our study also emphasizes the importance of WES in assisting the clinical diagnosis for complicated cases when the original diagnoses are challenged.

Behavioral Phenotype of Fragile X Syndrome in Adolescence and Adulthood

PubMed Central

Smith, Leann E.; Barker, Erin T.; Seltzer, Marsha Mailick; Abbeduto, Leonard; Greenberg, Jan S.

2012-01-01

The present study explored the behavioral profile of individuals with fragile X syndrome during adolescence and adulthood. Individuals with both fragile X syndrome and autism (n = 30) were compared with (a) individuals diagnosed with fragile X syndrome (but not autism; n = 106) and (b) individuals diagnosed with autism (but not fragile X syndrome; n = 135) on measures of autism symptoms, adaptive functioning, behavior problems, and psychological symptoms. Results indicated that individuals dually diagnosed with fragile X syndrome and autism displayed greater communication and social reciprocity impairments than individuals with fragile X syndrome only. Individuals in the dually diagnosed group also exhibited higher levels of repetitive and challenging behaviors than either comparison group, suggesting a unique profile of vulnerability for those diagnosed with both fragile X syndrome and autism. PMID:22264109

Epilepsy in fragile-X-syndrome mimicking panayiotopoulos syndrome: Description of three patients.

PubMed

Bonanni, Paolo; Casellato, Susanna; Fabbro, Franco; Negrin, Susanna

2017-10-01

Fragile-X-syndrome is the most common cause of inherited intellectual disability. Epilepsy is reported to occur in 10-20% of individuals with Fragile-X-syndrome. A frequent seizure/electroencephalogram (EEG) pattern resembles that of benign rolandic epilepsy. We describe the clinical features, EEG findings and evolution in three patients affected by Fragile-X-syndrome and epilepsy mimicking Panayiotopoulos syndrome. Age at seizure onset was between 4 and about 7 years. Seizures pattern comprised a constellation of autonomic symptoms with unilateral deviation of the eyes and ictal syncope. Duration of the seizures could be brief or lengthy. Interictal EEGs revealed functional multifocal abnormalities. The evolution was benign in all patients with seizures remission before the age of 14. This observation expands the spectrum of benign epileptic phenotypes present in Fragile-X-syndrome and may be quite helpful in guiding anticonvulsant management and counseling families as to expectations regarding seizure remission. © 2017 Wiley Periodicals, Inc.

Site-Specific Gene Editing of Human Hematopoietic Stem Cells for X-Linked Hyper-IgM Syndrome.

PubMed

Kuo, Caroline Y; Long, Joseph D; Campo-Fernandez, Beatriz; de Oliveira, Satiro; Cooper, Aaron R; Romero, Zulema; Hoban, Megan D; Joglekar, Alok V; Lill, Georgia R; Kaufman, Michael L; Fitz-Gibbon, Sorel; Wang, Xiaoyan; Hollis, Roger P; Kohn, Donald B

2018-05-29

X-linked hyper-immunoglobulin M (hyper-IgM) syndrome (XHIM) is a primary immunodeficiency due to mutations in CD40 ligand that affect immunoglobulin class-switch recombination and somatic hypermutation. The disease is amenable to gene therapy using retroviral vectors, but dysregulated gene expression results in abnormal lymphoproliferation in mouse models, highlighting the need for alternative strategies. Here, we demonstrate the ability of both the transcription activator-like effector nuclease (TALEN) and clustered regularly interspaced short palindromic repeats-associated protein 9 (CRISPR/Cas9) platforms to efficiently drive integration of a normal copy of the CD40L cDNA delivered by Adeno-Associated Virus. Site-specific insertion of the donor sequence downstream of the endogenous CD40L promoter maintained physiologic expression of CD40L while overriding all reported downstream mutations. High levels of gene modification were achieved in primary human hematopoietic stem cells (HSCs), as well as in cell lines and XHIM-patient-derived T cells. Notably, gene-corrected HSCs engrafted in immunodeficient mice at clinically relevant frequencies. These studies provide the foundation for a permanent curative therapy in XHIM. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Genetics Home Reference: X-linked severe combined immunodeficiency

MedlinePlus

... Facebook Twitter Home Health Conditions X-linked SCID X-linked severe combined immunodeficiency Printable PDF Open All ... Javascript to view the expand/collapse boxes. Description X-linked severe combined immunodeficiency (SCID) is an inherited ...

Genetics Home Reference: X-linked adrenal hypoplasia congenita

MedlinePlus

... Home Health Conditions X-linked adrenal hypoplasia congenita X-linked adrenal hypoplasia congenita Printable PDF Open All ... Javascript to view the expand/collapse boxes. Description X-linked adrenal hypoplasia congenita is a disorder that ...

Genetics Home Reference: X-linked chondrodysplasia punctata 1

MedlinePlus

... Home Health Conditions X-linked chondrodysplasia punctata 1 X-linked chondrodysplasia punctata 1 Printable PDF Open All ... Javascript to view the expand/collapse boxes. Description X-linked chondrodysplasia punctata 1 is a disorder of ...

ATRX ADD domain links an atypical histone methylation recognition mechanism to human mental-retardation syndrome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Iwase, Shigeki; Xiang, Bin; Ghosh, Sharmistha

ATR-X (alpha-thalassemia/mental retardation, X-linked) syndrome is a human congenital disorder that causes severe intellectual disabilities. Mutations in the ATRX gene, which encodes an ATP-dependent chromatin-remodeler, are responsible for the syndrome. Approximately 50% of the missense mutations in affected persons are clustered in a cysteine-rich domain termed ADD (ATRX-DNMT3-DNMT3L, ADD{sub ATRX}), whose function has remained elusive. Here we identify ADD{sub ATRX} as a previously unknown histone H3-binding module, whose binding is promoted by lysine 9 trimethylation (H3K9me3) but inhibited by lysine 4 trimethylation (H3K4me3). The cocrystal structure of ADD{sub ATRX} bound to H3{sub 1-15}K9me3 peptide reveals an atypical composite H3K9me3-binding pocket,more » which is distinct from the conventional trimethyllysine-binding aromatic cage. Notably, H3K9me3-pocket mutants and ATR-X syndrome mutants are defective in both H3K9me3 binding and localization at pericentromeric heterochromatin; thus, we have discovered a unique histone-recognition mechanism underlying the ATR-X etiology.« less

ATRX ADD Domain Links an Atypical Histone Methylation Recognition Mechanism to Human Mental-Retardation Syndrome

DOE Office of Scientific and Technical Information (OSTI.GOV)

S Iwase; B Xiang; S Ghosh

ATR-X (alpha-thalassemia/mental retardation, X-linked) syndrome is a human congenital disorder that causes severe intellectual disabilities. Mutations in the ATRX gene, which encodes an ATP-dependent chromatin-remodeler, are responsible for the syndrome. Approximately 50% of the missense mutations in affected persons are clustered in a cysteine-rich domain termed ADD (ATRX-DNMT3-DNMT3L, ADD{sub ATRX}), whose function has remained elusive. Here we identify ADD{sub ATRX} as a previously unknown histone H3-binding module, whose binding is promoted by lysine 9 trimethylation (H3K9me3) but inhibited by lysine 4 trimethylation (H3K4me3). The cocrystal structure of ADD{sub ATRX} bound to H3{sub 1-15}K9me3 peptide reveals an atypical composite H3K9me3-binding pocket,more » which is distinct from the conventional trimethyllysine-binding aromatic cage. Notably, H3K9me3-pocket mutants and ATR-X syndrome mutants are defective in both H3K9me3 binding and localization at pericentromeric heterochromatin; thus, we have discovered a unique histone-recognition mechanism underlying the ATR-X etiology.« less

Behavioral Phenotype of Fragile X Syndrome in Adolescence and Adulthood

ERIC Educational Resources Information Center

Smith, Leann E.; Barker, Erin T.; Seltzer, Marsha Mailick; Abbeduto, Leonard; Greenberg, Jan S.

2012-01-01

The present study explored the behavioral profile of individuals with fragile X syndrome during adolescence and adulthood. Individuals with both fragile X syndrome and autism (n = 30) were compared with (a) individuals diagnosed with fragile X syndrome (but not autism; n = 106) and (b) individuals diagnosed with autism (but not fragile X syndrome;…

Psychiatric and autistic comorbidity in fragile X syndrome across ages.

PubMed

Gabis, Lidia V; Baruch, Yael Kesner; Jokel, Ariela; Raz, Raanan

2011-08-01

Fragile X syndrome is caused by CGG trinucleotide repeat expansion within the fragile X mental retardation 1 gene, when repeat number exceeds 200. The typical psychiatric profile of fragile X syndrome patients includes cognitive and behavioral deficits, psychiatric comorbidity, and autistic characteristics. Specific psychiatric features have not yet been clarified, specifically in relationship to age and genetic characteristics. The objective of this study was to characterize psychiatric comorbidities in subjects with fragile X syndrome at different ages. Subjects with fragile X syndrome and their unaffected siblings were recruited and their parents filled out functional-behavioral and psychiatric comorbidities questionnaires. Adolescents with fragile X syndrome showed decreased prevalence of functional-behavioral deficits. Incidence and severity of most psychiatric comorbidities were lower in older subjects. Incidence of generalized anxiety disorder increased with age in the fragile X syndrome group. The typical profile of patients with fragile X syndrome changes with age. Unaffected siblings exhibit anxiety and motor tics.

Genetics Home Reference: Menkes syndrome

MedlinePlus

... males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons. In about one-third of cases, Menkes syndrome is caused by new ...

Fragile X-associated tremor/ataxia syndrome.

PubMed

Hoem, Gry; Koht, Jeanette

2017-10-31

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a hereditary neurodegenerative disorder caused by a mutation on the X chromosome. The major signs and symptoms are tremor, ataxia and parkinsonism. Up to one in 2 000 persons over 50 years of age will develop the syndrome. There is reason to believe that too few individuals in Norway undergo testing for this condition.

X-exome sequencing identifies a HDAC8 variant in a large pedigree with X-linked intellectual disability, truncal obesity, gynaecomastia, hypogonadism and unusual face.

PubMed

Harakalova, Magdalena; van den Boogaard, Marie-Jose; Sinke, Richard; van Lieshout, Stef; van Tuil, Marc C; Duran, Karen; Renkens, Ivo; Terhal, Paulien A; de Kovel, Carolien; Nijman, Ies J; van Haelst, Mieke; Knoers, Nine V A M; van Haaften, Gijs; Kloosterman, Wigard; Hennekam, Raoul C M; Cuppen, Edwin; Ploos van Amstel, Hans Kristian

2012-08-01

We present a large Dutch family with seven males affected by a novel syndrome of X-linked intellectual disability, hypogonadism, gynaecomastia, truncal obesity, short stature and recognisable craniofacial manifestations resembling but not identical to Wilson-Turner syndrome. Seven female relatives show a much milder expression of the phenotype. We performed X chromosome exome (X-exome) sequencing in five individuals from this family and identified a novel intronic variant in the histone deacetylase 8 gene (HDAC8), c.164+5G>A, which disturbs the normal splicing of exon 2 resulting in exon skipping, and introduces a premature stop at the beginning of the histone deacetylase catalytic domain. The identified variant completely segregates in this family and was absent in 96 Dutch controls and available databases. Affected female carriers showed a notably skewed X-inactivation pattern in lymphocytes in which the mutated X-chromosome was completely inactivated. HDAC8 is a member of the protein family of histone deacetylases that play a major role in epigenetic gene silencing during development. HDAC8 specifically controls the patterning of the skull with the mouse HDAC8 knock-out showing craniofacial deformities of the skull. The present family provides the first evidence for involvement of HDAC8 in a syndromic form of intellectual disability.

A hemizygous GYG2 mutation and Leigh syndrome: a possible link?

PubMed

Imagawa, Eri; Osaka, Hitoshi; Yamashita, Akio; Shiina, Masaaki; Takahashi, Eihiko; Sugie, Hideo; Nakashima, Mitsuko; Tsurusaki, Yoshinori; Saitsu, Hirotomo; Ogata, Kazuhiro; Matsumoto, Naomichi; Miyake, Noriko

2014-02-01

Leigh syndrome (LS) is an early-onset progressive neurodegenerative disorder characterized by unique, bilateral neuropathological findings in brainstem, basal ganglia, cerebellum and spinal cord. LS is genetically heterogeneous, with the majority of the causative genes affecting mitochondrial malfunction, and many cases still remain unsolved. Here, we report male sibs affected with LS showing ketonemia, but no marked elevation of lactate and pyruvate. To identify their genetic cause, we performed whole exome sequencing. Candidate variants were narrowed down based on autosomal recessive and X-linked recessive models. Only one hemizygous missense mutation (c.665G>C, p.W222S) in glycogenin-2 (GYG2) (isoform a: NM_001079855) in both affected sibs and a heterozygous change in their mother were identified, being consistent with the X-linked recessive trait. GYG2 encodes glycogenin-2 (GYG2) protein, which plays an important role in the initiation of glycogen synthesis. Based on the structural modeling, the mutation can destabilize the structure and result in protein malfunctioning. Furthermore, in vitro experiments showed mutant GYG2 was unable to undergo the self-glucosylation, which is observed in wild-type GYG2. This is the first report of GYG2 mutation in human, implying a possible link between GYG2 abnormality and LS.

Psychological Well-Being of Mothers of Youth with Fragile X Syndrome: Syndrome Specificity and within-Syndrome Variability

ERIC Educational Resources Information Center

Lewis, P.; Abbeduto, L.; Murphy, M.; Richmond, E.; Giles, N.; Bruno, L.; Schroeder, S.; Anderson, J.; Orsmond, G.

2006-01-01

Background: Research on parental well-being has focused largely on Down syndrome and autism; however, fragile X syndrome is likely to pose different challenges for parents compared with these other diagnostic conditions. Moreover, there is considerable variability among youth with fragile X syndrome; for example, 25% to 33% of affected youth meet…

Reversing the Effects of Fragile X Syndrome

ERIC Educational Resources Information Center

Ogren, Marilee P.; Lombroso, Paul J.

2008-01-01

A research on how synaptic plasticity is abnormally regulated in fragile X syndrome and how this abnormality can be reversed by therapeutic interventions is presented. Fragile X syndrome is a disorder of synaptic plasticity that contributes to abnormal development and interferes with normal learning and memory.

Advances in the Treatment of Fragile X Syndrome

PubMed Central

Hagerman, Randi J.; Berry-Kravis, Elizabeth; Kaufmann, Walter E.; Ono, Michele Y.; Tartaglia, Nicole; Lachiewicz, Ave; Kronk, Rebecca; Delahunty, Carol; Hessl, David; Visootsak, Jeannie; Picker, Jonathan; Gane, Louise; Tranfaglia, Michael

2010-01-01

The FMR1 mutations can cause a variety of disabilities, including cognitive deficits, attention-deficit/hyperactivity disorder, autism, and other socioemotional problems, in individuals with the full mutation form (fragile X syndrome) and distinct difficulties, including primary ovarian insufficiency, neuropathy and the fragile X-associated tremor/ataxia syndrome, in some older premutation carriers. Therefore, multigenerational family involvement is commonly encountered when a proband is identified with a FMR1 mutation. Studies of metabotropic glutamate receptor 5 pathway antagonists in animal models of fragile X syndrome have demonstrated benefits in reducing seizures, improving behavior, and enhancing cognition. Trials of metabotropic glutamate receptor 5 antagonists are beginning with individuals with fragile X syndrome. Targeted treatments, medical and behavioral interventions, genetic counseling, and family supports are reviewed here. PMID:19117905

Syndromes that Link the Endocrine System and Genitourinary Tract.

PubMed

Özlük, Yasemin; Kılıçaslan, Işın

2015-01-01

The endocrine system and genitourinary tract unite in various syndromes. Genitourinary malignancies may cause paraneoplastic endocrine syndromes by secreting hormonal substances. These entities include Cushing`s syndrome, hypercalcemia, hyperglycemia, polycythemia, hypertension, and inappropriate ADH or HCG production. The most important syndromic scenarios that links these two systems are hereditary renal cancer syndromes with specific genotype/phenotype correlation. There are also some very rare entities in which endocrine and genitourinary systems are involved such as Carney complex, congenital adrenal hyperplasia and Beckwith-Wiedemann syndrome. We will review all the syndromes regarding manifestations present in endocrine and genitourinary organs.

Longitudinal Profiles of Adaptive Behavior in Fragile X Syndrome

PubMed Central

Quintin, Eve-Marie; Jo, Booil; Lightbody, Amy A.; Hazlett, Heather Cody; Piven, Joseph; Hall, Scott S.; Reiss, Allan L.

2014-01-01

OBJECTIVE: To examine longitudinally the adaptive behavior patterns in fragile X syndrome. METHOD: Caregivers of 275 children and adolescents with fragile X syndrome and 225 typically developing children and adolescents (2–18 years) were interviewed with the Vineland Adaptive Behavior Scales every 2 to 4 years as part of a prospective longitudinal study. RESULTS: Standard scores of adaptive behavior in people with fragile X syndrome are marked by a significant decline over time in all domains for males and in communication for females. Socialization skills are a relative strength as compared with the other domains for males with fragile X syndrome. Females with fragile X syndrome did not show a discernible pattern of developmental strengths and weaknesses. CONCLUSIONS: This is the first large-scale longitudinal study to show that the acquisition of adaptive behavior slows as individuals with fragile X syndrome age. It is imperative to ensure that assessments of adaptive behavior skills are part of intervention programs focusing on childhood and adolescence in this condition. PMID:25070318

Sensory Impairment and Head Circumference in Fragile X Syndrome, Down Syndrome and Idiopathic Intellectual Disability.

ERIC Educational Resources Information Center

Turk, Jeremy; Patton, Michael

2000-01-01

Eighteen boys with fragile X syndrome were compared with 42 with idiopathic intellectual disability, and 45 with Down syndrome. Boys with Down syndrome had more sensory problems and smaller head circumferences than normal. Head circumferences of boys with fragile X syndrome and with idiopathic intellectual disability were larger than normal.…

Attentional Set-Shifting in Fragile X Syndrome

ERIC Educational Resources Information Center

Van der Molen, M. J. W.; Van der Molen, M. W.; Ridderinkhof, K. R.; Hamel, B. C. J.; Curfs, L. M. G.; Ramakers, G. J. A.

2012-01-01

The ability to flexibly adapt to the changing demands of the environment is often reported as a core deficit in fragile X syndrome (FXS). However, the cognitive processes that determine this attentional set-shifting deficit remain elusive. The present study investigated attentional set-shifting ability in fragile X syndrome males with the…

X inactivation in Rett syndrome: A preliminary study showing partial preferential inactivation of paternal X with the M27{beta} probe

DOE Office of Scientific and Technical Information (OSTI.GOV)

Camus, P.; Abbadi, N.; Gilgenkrantz, S.

1994-04-15

Rett syndrome (RS) is a severe progressive neurological disorder occurring exclusively in females. Most cases are sporadic. The few familial cases (less than 1%) cannot be explained by a simple mode of inheritance. Several hypotheses have been proposed: X-linked male lethal mutation, maternal uniparental disomy, fresh mutation on the X chromosome, involvement of mitochondrial DNA and differential inactivation with metabolic interference of X-borne alleles. The authors have examined the pattern of X inactivation in 10 affected girls who were selected according to the clinical criteria previously described and accepted by the French Rett Scientific Committee. The X inactivation pattern wasmore » studied by analysis of methylation at the hypervariable locus DXS255 with the M27{beta} probe. The results show a more-or-less skewed inactivation of paternal X in 8 Rett females, and 2 cases of symmetrical inactivation. In control girls, inactivation was symmetrical cases and the maternal X has been preferentially inactivated in the other 2 cases. In no case was a total skewed inactivation observed. Though there was clear evidence for a preferential paternal X inactivation that was statistically significant further studies are necessary to establish a relationship between X inactivation pattern and Rett syndrome.« less

The developmental trajectory of disruptive behavior in Down syndrome, fragile X syndrome, Prader-Willi syndrome and Williams syndrome.

PubMed

Rice, Lauren J; Gray, Kylie M; Howlin, Patricia; Taffe, John; Tonge, Bruce J; Einfeld, Stewart L

2015-06-01

The aim of this study was to investigate the developmental trajectories of verbal aggression, physical aggression, and temper tantrums in four genetic syndrome groups. Participants were part of the Australian Child to Adult Development Study (ACAD), which collected information from a cohort of individuals with an intellectual disability at five time points over 18 years. Data were examined from a total of 248 people with one of the four following syndromes: Down syndrome, Fragile X syndrome, Prader-Willi syndrome, or Williams syndrome. Changes in behaviors were measured using validated items from the Developmental Behavior Checklist (DBC). The results indicate that, while verbal aggression shows no evidence of diminishing with age, physical aggression, and temper tantrums decline with age before 19 years for people with Down syndrome, Fragile X syndrome, and William syndrome; and after 19 years for people with Prader-Willi syndrome. These findings offer a somewhat more optimistic outlook for people with an intellectual disability than has previously been suggested. Research is needed to investigate the mechanisms predisposing people with PWS to persistence of temper tantrums and physical aggression into adulthood. © 2015 Wiley Periodicals, Inc.

Combined pituitary hormone deficiency with unique pituitary dysplasia and morning glory syndrome related to a heterozygous PROKR2 mutation

PubMed Central

Asakura, Yumi; Muroya, Koji; Hanakawa, Junko; Sato, Takeshi; Aida, Noriko; Narumi, Satoshi; Hasegawa, Tomonobu; Adachi, Masanori

2015-01-01

Abstract Recent reports have indicated the role of the prokineticin receptor 2 gene (PROKR2) in the etiology of congenital hypopituitarism, including septo-optic dysplasia and Kallmann syndrome. In the present study, using next-generation targeted sequencing, we identified a novel heterozygous PROKR2 variant (c.742C>T; p.R248W) in a female patient who had combined pituitary hormone deficiency (CPHD), morning glory syndrome and a severely malformed pituitary gland. No other mutation was present in 27 genes related to hypogonadotropic hypogonadism, pituitary hormone deficiency and optic nerve malformation. The substituted amino acid was located on the third intracellular loop of the PROKR2 protein, which is a G protein-coupled receptor. Computational analyses with two programs (SIFT and PolyPhen-2) showed that the substitution was deleterious to PROKR2 function. The p.R248W mutation was transmitted from the patient’s mother, who had a slightly delayed menarche. Collectively, we provide further genetic evidence linking heterozygous PROKR2 mutations and the development of CPHD. PMID:25678757

Combined pituitary hormone deficiency with unique pituitary dysplasia and morning glory syndrome related to a heterozygous PROKR2 mutation.

PubMed

Asakura, Yumi; Muroya, Koji; Hanakawa, Junko; Sato, Takeshi; Aida, Noriko; Narumi, Satoshi; Hasegawa, Tomonobu; Adachi, Masanori

2015-01-01

Recent reports have indicated the role of the prokineticin receptor 2 gene (PROKR2) in the etiology of congenital hypopituitarism, including septo-optic dysplasia and Kallmann syndrome. In the present study, using next-generation targeted sequencing, we identified a novel heterozygous PROKR2 variant (c.742C>T; p.R248W) in a female patient who had combined pituitary hormone deficiency (CPHD), morning glory syndrome and a severely malformed pituitary gland. No other mutation was present in 27 genes related to hypogonadotropic hypogonadism, pituitary hormone deficiency and optic nerve malformation. The substituted amino acid was located on the third intracellular loop of the PROKR2 protein, which is a G protein-coupled receptor. Computational analyses with two programs (SIFT and PolyPhen-2) showed that the substitution was deleterious to PROKR2 function. The p.R248W mutation was transmitted from the patient's mother, who had a slightly delayed menarche. Collectively, we provide further genetic evidence linking heterozygous PROKR2 mutations and the development of CPHD.

Genetics Home Reference: X-linked congenital stationary night blindness

MedlinePlus

... Health Conditions X-linked congenital stationary night blindness X-linked congenital stationary night blindness Printable PDF Open ... Javascript to view the expand/collapse boxes. Description X-linked congenital stationary night blindness is a disorder ...

Genetics Home Reference: X-linked lissencephaly with abnormal genitalia

MedlinePlus

... Health Conditions X-linked lissencephaly with abnormal genitalia X-linked lissencephaly with abnormal genitalia Printable PDF Open ... Javascript to view the expand/collapse boxes. Description X-linked lissencephaly with abnormal genitalia (XLAG) is a ...

Genetics Home Reference: X-linked sideroblastic anemia and ataxia

MedlinePlus

... Health Conditions X-linked sideroblastic anemia and ataxia X-linked sideroblastic anemia and ataxia Printable PDF Open ... Javascript to view the expand/collapse boxes. Description X-linked sideroblastic anemia and ataxia is a rare ...

Genetics Home Reference: X-linked intellectual disability, Siderius type

MedlinePlus

... Health Conditions X-linked intellectual disability, Siderius type X-linked intellectual disability, Siderius type Printable PDF Open ... Javascript to view the expand/collapse boxes. Description X-linked intellectual disability, Siderius type is a condition ...

Fragile X Syndrome

PubMed Central

Tassone, Flora; González-Teshima, Laura Yuriko; Forero-Forero, Jose Vicente; Ayala-Zapata, Sebastián; Hagerman, Randi

2014-01-01

Fragile X Syndrome (FXS) is a genetic disease due to a CGG trinucleotide expansion, named full mutation (greater than 200 CGG repeats), in the fragile X mental retardation 1 gene locus Xq27.3; which leads to an hypermethylated region in the gene promoter therefore silencing it and lowering the expression levels of the fragile X mental retardation 1, a protein involved in synaptic plasticity and maturation. Individuals with FXS present with intellectual disability, autism, hyperactivity, long face, large or prominent ears and macroorchidism at puberty and thereafter. Most of the young children with FXS will present with language delay, sensory hyper arousal and anxiety. Girls are less affected than boys, only 25% have intellectual disability. Given the genomic features of the syndrome, there are patients with a number of triplet repeats between 55 and 200, known as premutation carriers. Most carriers have a normal IQ but some have developmental problems. The diagnosis of FXS has evolved from karyotype with special culture medium, to molecular techniques that are more sensitive and specific including PCR and Southern Blot. During the last decade, the advances in the knowledge of FXS, has led to the development of investigations on pharmaceutical management or targeted treatments for FXS. Minocycline and sertraline have shown efficacy in children. PMID:25767309

Craniofacioskeletal Syndrome: An X-Linked Dominant Disorder With Early Lethality in Males

PubMed Central

Stevenson, Roger E.; Brasington, Cam K.; Skinner, Cindy; Simensen, Richard J.; Spence, J. Edward; Kesler, Shelli; Reiss, Allan L.; Schwartz, Charles E.

2011-01-01

A syndrome with multisystem manifestations has been observed in three generations of a Caucasian family. The findings in seven females provide a composite clinical picture of microcephaly, short stature, small retroverted ears, full tip of the nose overhanging the columella, short philtrum, thin upper lip, soft tissue excrescences at the angle of the mouth, small mandible, small hands and feet with brachydactyly, finger V clinodactyly, flat feet, an excessive number of fingerprint arches, and mild impairment of cognitive function. Two males were more severely affected and died in the initial months of life. They showed intrauterine growth retardation, broad cranium with wide sutures and fontanelles, cardiac defects, small hands and feet with abnormal digital creases and small nails, and genital abnormalities. The affected males had low serum calcium in the neonatal period. Serum calcium, phosphorous, and parathormone levels in the females were normal. Radiographs showed cortical thickening of the long bones, underdevelopment of the frontal sinuses, narrow pelvis and hypoplasia of the middle phalanx of finger five. MRI of the brain showed slightly reduced brain volumes and an extra gyrus of the superior temporal region. X-inactivation studies showed near complete skewing in two affected females, but were not informative in three others. X-linkage as the mode of inheritance is proposed on the basis of different severity in males/females, complete skewing of X-inactivation in informative females, and a lod score (1.5) suggestive of linkage to markers in Xq26-q27. PMID:17853486

Alport Syndrome in Women and Girls.

PubMed

Savige, Judy; Colville, Deb; Rheault, Michelle; Gear, Susie; Lennon, Rachel; Lagas, Sharon; Finlay, Moira; Flinter, Frances

2016-09-07

Alport syndrome is an inherited disease characterized by progressive renal failure, hearing loss, and ocular abnormalities. Inheritance is X-linked (85%) or autosomal recessive (15%). Many renal physicians think of Alport syndrome as primarily affecting men. However, twice as many women are affected by the X-linked diseases. Affected women are commonly undiagnosed, but 15%-30% develop renal failure by 60 years and often hearing loss by middle age. Half of their sons and daughters are also affected. Autosomal recessive Alport syndrome is less common, but is often mistaken for X-linked disease. Recessive inheritance is suspected where women develop early-onset renal failure or lenticonus. Their family may be consanguineous. The prognosis for other family members is very different from X-linked disease. Other generations, including parents and offspring, are not affected, and on average only one in four of their siblings inherit the disease. All women with Alport syndrome should have their diagnosis confirmed with genetic testing, even if their renal function is normal, because of their own risk of renal failure and the risk to their offspring. Their mutations indicate the mode of inheritance and the likelihood of disease transmission to their children, and the mutation type suggests the renal prognosis for both X-linked and recessive disease. Women with X-linked Alport syndrome should be tested at least annually for albuminuria and hypertension. The "Expert guidelines for the diagnosis and management of Alport syndrome" recommend treating those with albuminuria with renin-angiotensin-aldosterone system (RAAS) blockade (and adequate birth control because of the teratogenic risks of angiotensin converting enzyme inhibitors), believing that this will delay renal failure. Current recommendations are that women with autosomal recessive Alport syndrome should be treated with RAAS blockade from the time of diagnosis. In addition, women should be offered genetic counseling

A family with X-linked optic atrophy linked to the OPA2 locus Xp11.4-Xp11.2.

PubMed

Katz, Bradley J; Zhao, Yu; Warner, Judith E A; Tong, Zongzhong; Yang, Zhenglin; Zhang, Kang

2006-10-15

Autosomal dominant optic atrophy (ADOA) is the most common inherited optic atrophy. Clinical features of ADOA include a slowly progressive bilateral loss of visual acuity, constriction of peripheral visual fields, central scotomas, and color vision abnormalities. Although ADOA is the most commonly inherited optic atrophy, autosomal recessive, X-linked, mitochondrial, and sporadic forms have also been reported. Four families with X-linked optic atrophy (XLOA) were previously described. One family was subsequently linked to Xp11.4-Xp11.2 (OPA2). This investigation studied one multi-generation family with an apparently X-linked form of optic atrophy and compared their clinical characteristics with those of the previously described families, and determined whether this family was linked to the same genetic locus. Fifteen individuals in a three-generation Idaho family underwent complete eye examination, color vision testing, automated perimetry, and fundus photography. Polymorphic markers were used to genotype each individual and to determine linkage. Visual acuities ranged from 20/30 to 20/100. All affected subjects had significant optic nerve pallor. Obligate female carriers were clinically unaffected. Preliminary linkage analysis (LOD score = 1.8) revealed that the disease gene localized to the OPA2 locus on Xp11.4-Xp11.2. Four forms of inherited optic neuropathy, ADOA, autosomal recessive optic atrophy (Costeff Syndrome), Leber hereditary optic neuropathy, and Charcot-Marie-Tooth disease with optic atrophy, are associated with mitochondrial dysfunction. Future identification of the XLOA gene will reveal whether this form of optic atrophy is also associated with a mitochondrial defect. Identification of the XLOA gene will advance our understanding of the inherited optic neuropathies and perhaps suggest treatments for these diseases. An improved understanding of inherited optic neuropathies may in turn advance our understanding of acquired optic nerve diseases, such

Defining the cause of skewed X-chromosome inactivation in X-linked mental retardation by use of a mouse model.

PubMed

Muers, Mary R; Sharpe, Jacqueline A; Garrick, David; Sloane-Stanley, Jacqueline; Nolan, Patrick M; Hacker, Terry; Wood, William G; Higgs, Douglas R; Gibbons, Richard J

2007-06-01

Extreme skewing of X-chromosome inactivation (XCI) is rare in the normal female population but is observed frequently in carriers of some X-linked mutations. Recently, it has been shown that various forms of X-linked mental retardation (XLMR) have a strong association with skewed XCI in female carriers, but the mechanisms underlying this skewing are unknown. ATR-X syndrome, caused by mutations in a ubiquitously expressed, chromatin-associated protein, provides a clear example of XLMR in which phenotypically normal female carriers virtually all have highly skewed XCI biased against the X chromosome that harbors the mutant allele. Here, we have used a mouse model to understand the processes causing skewed XCI. In female mice heterozygous for a null Atrx allele, we found that XCI is balanced early in embryogenesis but becomes skewed over the course of development, because of selection favoring cells expressing the wild-type Atrx allele. Unexpectedly, selection does not appear to be the result of general cellular-viability defects in Atrx-deficient cells, since it is restricted to specific stages of development and is not ongoing throughout the life of the animal. Instead, there is evidence that selection results from independent tissue-specific effects. This illustrates an important mechanism by which skewed XCI may occur in carriers of XLMR and provides insight into the normal role of ATRX in regulating cell fate.

A large kindred with X-linked neutropenia with an I294T mutation of the Wiskott-Aldrich syndrome gene.

PubMed

Beel, Karolien; Cotter, Melanie M; Blatny, Jan; Bond, Jonathan; Lucas, Geoff; Green, Frances; Vanduppen, Vik; Leung, Daisy W; Rooney, Sean; Smith, Owen P; Rosen, Michael K; Vandenberghe, Peter

2009-01-01

X-linked neutropenia (XLN, OMIM #300299) is a rare form of severe congenital neutropenia. It was originally described in a three-generation family with five affected members that had an L270P mutation in the GTP-ase binding domain (GBD) of the Wiskott-Aldrich syndrome protein (WASP) [Devriendt et al (2001) Nature Genetics, Vol. 27, 313-317]. Here, we report and describe a large three-generation family with XLN, with 10 affected males and eight female carriers. A c.882T>C mutation was identified in the WAS gene, resulting in an I294T mutation. The infectious course is variable and mild in view of the profound neutropenia. In addition to the original description, low-normal IgA levels, low to low-normal platelet counts and reduced natural killer (NK)-cell counts also appear as consistent XLN features. However, inverted CD4/CD8 ratios were not found in this family, nor were cases identified with myelodysplastic syndrome or acute myeloid leukaemia. Female carriers exhibited a variable attenuated phenotype. Like L270P WASP, I294T WASP is constitutively active towards actin polymerization. In conclusion, this largest XLN kindred identified to date provides new independent genetic evidence that mutations disrupting the auto-inhibitory GBD of WASP are the cause of XLN. Reduced NK cells, low to low normal platelet counts and low to low-normal IgA levels are also features of XLN.

Event-related potential alterations in fragile X syndrome

PubMed Central

Knoth, Inga S.; Lippé, Sarah

2012-01-01

Fragile X Syndrome (FXS) is the most common form of X-linked intellectual disability (ID), associated with a wide range of cognitive and behavioral impairments. FXS is caused by a trinucleotide repeat expansion in the FMR1 gene located on the X-chromosome. FMR1 is expected to prevent the expression of the “fragile X mental retardation protein (FMRP)”, which results in altered structural and functional development of the synapse, including a loss of synaptic plasticity. This review aims to unveil the contribution of electrophysiological signal studies for the understanding of the information processing impairments in FXS patients. We discuss relevant event-related potential (ERP) studies conducted with full mutation FXS patients and clinical populations sharing symptoms with FXS in a developmental perspective. Specific deviances found in FXS ERP profiles are described. Alterations are reported in N1, P2, Mismatch Negativity (MMN), N2, and P3 components in FXS compared to healthy controls. Particularly, deviances in N1 and P2 amplitude seem to be specific to FXS. The presented results suggest a cascade of impaired information processes that are in line with symptoms and anatomical findings in FXS. PMID:23015788

Does ATRX germline variation predispose to osteosarcoma? Three additional cases of osteosarcoma in two ATR-X syndrome patients.

PubMed

Masliah-Planchon, Julien; Lévy, Dominique; Héron, Delphine; Giuliano, Fabienne; Badens, Catherine; Fréneaux, Paul; Galmiche, Louise; Guinebretierre, Jean-Marc; Cellier, Cécile; Waterfall, Joshua J; Aït-Raïs, Khadija; Pierron, Gaëlle; Glorion, Christophe; Desguerre, Isabelle; Soler, Christine; Deville, Anne; Delattre, Olivier; Michon, Jean; Bourdeaut, Franck

2018-04-30

Osteosarcoma is the most common malignant bone tumor in adolescents and young adults. Most osteosarcomas are sporadic but the risk of osteosarcoma is also increased by germline variants in TP53, RB1 and RECQL4 genes. ATRX germline variations are responsible for the rare genetic disorder X-linked alpha-thalassemia mental retardation (ATR-X) syndrome characterized by severe developmental delay and alpha-thalassemia but no obvious increased risk of cancer. Here we report two children with ATR-X syndrome who developed osteosarcoma. Notably, one of the children developed two osteosarcomas separated by 10 years. Those two cases raise the possibility that ATRX germline variant could be associated with an increased risk of osteosarcoma.

Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics

PubMed Central

Bagni, Claudia; Tassone, Flora; Neri, Giovanni; Hagerman, Randi

2012-01-01

Fragile X syndrome (FXS) is the most frequent form of inherited intellectual disability and is also linked to other neurologic and psychiatric disorders. FXS is caused by a triplet expansion that inhibits expression of the FMR1 gene; the gene product, FMRP, regulates mRNA metabolism in the brain and thus controls the expression of key molecules involved in receptor signaling and spine morphology. While there is no definitive cure for FXS, the understanding of FMRP function has paved the way for rational treatment designs that could potentially reverse many of the neurobiological changes observed in FXS. Additionally, behavioral, pharmacological, and cognitive interventions can raise the quality of life for both patients and their families. PMID:23202739

Assignment of the Nance-Horan syndrome to the distal short arm of the X chromosome.

PubMed

Zhu, D; Alcorn, D M; Antonarakis, S E; Levin, L S; Huang, P C; Mitchell, T N; Warren, A C; Maumenee, I H

1990-11-01

There are three types of X-linked cataracts recorded in Mendelian Inheritance in Man (McKusick 1988): congenital total, with posterior sutural opacities in heterozygotes; congenital, with microcornea or slight microphthalmia; and the cataract-dental syndrome or Nance-Horan (NH) syndrome. To identify a DNA marker close to the gene responsible for the NH syndrome, linkage analysis on 36 members in a three-generation pedigree including seven affected males and nine carrier females was performed using 31 DNA markers. A LOD score of 1.662 at theta = 0.16 was obtained with probe 782 from locus DXS85 on Xp22.2-p22.3. Negative LOD scores were found at six loci on the short arm, one distal to DXS85, five proximal, and six probes spanning the long arm were highly negative. These results make the assignment of the locus for NH to the distal end of the short arm of the X chromosome likely.

Alport Syndrome in Women and Girls

PubMed Central

Colville, Deb; Rheault, Michelle; Gear, Susie; Lennon, Rachel; Lagas, Sharon; Finlay, Moira; Flinter, Frances

2016-01-01

Alport syndrome is an inherited disease characterized by progressive renal failure, hearing loss, and ocular abnormalities. Inheritance is X-linked (85%) or autosomal recessive (15%). Many renal physicians think of Alport syndrome as primarily affecting men. However, twice as many women are affected by the X-linked diseases. Affected women are commonly undiagnosed, but 15%–30% develop renal failure by 60 years and often hearing loss by middle age. Half of their sons and daughters are also affected. Autosomal recessive Alport syndrome is less common, but is often mistaken for X-linked disease. Recessive inheritance is suspected where women develop early-onset renal failure or lenticonus. Their family may be consanguineous. The prognosis for other family members is very different from X-linked disease. Other generations, including parents and offspring, are not affected, and on average only one in four of their siblings inherit the disease. All women with Alport syndrome should have their diagnosis confirmed with genetic testing, even if their renal function is normal, because of their own risk of renal failure and the risk to their offspring. Their mutations indicate the mode of inheritance and the likelihood of disease transmission to their children, and the mutation type suggests the renal prognosis for both X-linked and recessive disease. Women with X-linked Alport syndrome should be tested at least annually for albuminuria and hypertension. The “Expert guidelines for the diagnosis and management of Alport syndrome” recommend treating those with albuminuria with renin-angiotensin-aldosterone system (RAAS) blockade (and adequate birth control because of the teratogenic risks of angiotensin converting enzyme inhibitors), believing that this will delay renal failure. Current recommendations are that women with autosomal recessive Alport syndrome should be treated with RAAS blockade from the time of diagnosis. In addition, women should be offered genetic

Cholinergic Dysfunction in Fragile X Syndrome and Potential Intervention

PubMed Central

Kesler, Shelli R; Lightbody, Amy A; Reiss, Allan L

2009-01-01

Males with fragile X syndrome are at risk for significant cognitive and behavioral deficits, particularly those involving executive prefrontal systems. Disruption of the cholinergic system secondary to fragile X mental retardation protein deficiency may contribute to the cognitive-behavioral impairments associated with fragile X. We measured choline in the dorsolateral prefrontal cortex of 9 males with fragile X syndrome and 9 age-matched typically developing controls using 1H magnetic resonance spectroscopy. Right choline/creatine was significantly reduced in the fragile X group compared to controls. In controls, both left and right choline was significantly positively correlated with intelligence and age was significantly negatively correlated with left choline. There were no correlations in the fragile X group. Subjects with fragile X syndrome participating in a pilot open-label trial of donepezil, an acetylcholinesterase inhibitor, demonstrated significantly improved cognitive-behavioral function. Studies utilizing biochemical neuroimaging techniques such as these have the potential to significantly impact the design of treatment strategies for fragile X syndrome and other genetic disorders by helping identify neurochemical targets for intervention as well as serving as metrics for treatment efficacy. PMID:19215057

Language Development in Individuals with Fragile X Syndrome

ERIC Educational Resources Information Center

Finestack, Lizbeth H.; Richmond, Erica K.; Abbeduto, Leonard

2009-01-01

Fragile X syndrome (FXS) is the leading inherited cause of intellectual disability. The syndrome is caused by a single gene mutation on the X chromosome. Although individual differences are large, most individuals with FXS display weaknesses across all language and literacy domains compared with peers of the same chronological age with typical…

Neurosteroids Reverse Tonic Inhibition Deficits in Fragile X Syndrome

DTIC Science & Technology

2017-10-01

AWARD NUMBER: W81XWH-15-1-0190 TITLE: Neurosteroids Reverse Tonic Inhibition Deficits in Fragile X Syndrome PRINCIPAL INVESTIGATOR: Dr...14 July 2017 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Neurosteroids Reverse Tonic Inhibition Deficits in Fragile X Syndrome 5b. GRANT NUMBER...18 9. Appendices……………………………………………………………18 2 1. Introduction Fragile X syndrome (FXS) is the most common form of inherited

Neurosteroids Reverse Tonic Inhibition Deficits in Fragile X Syndrome

DTIC Science & Technology

2016-08-01

AWARD NUMBER: W81XWH-15-1-0190 TITLE: Neurosteroids Reverse Tonic Inhibition Deficits in Fragile X Syndrome PRINCIPAL INVESTIGATOR: Dr. Paul...AND SUBTITLE 5a. CONTRACT NUMBER Neurosteroids Reverse Tonic Inhibition Deficits in Fragile X Syndrome 5b. GRANT NUMBER 5c. PROGRAM ELEMENT...Appendices……………………………………………………………11 2 1. Introduction Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. In addition

Discourse Skills of Boys with Fragile X Syndrome in Comparison to Boys with Down Syndrome

ERIC Educational Resources Information Center

Roberts, Joanne; Martin, Gary E.; Moskowitz, Lauren; Harris, Adrianne A.; Foreman, Jamila; Nelson, Lauren

2007-01-01

Purpose: This study compared the conversational discourse skills of boys who have fragile X syndrome with and without autism spectrum disorder (ASD) with those of boys with Down syndrome and boys who are typically developing. Method: Participants were boys who have fragile X syndrome with (n = 26) and without (n = 28) ASD, boys with Down syndrome…

Mutation in the 5' alternatively spliced region of the XNP/ATR-X gene causes Chudley-Lowry syndrome.

PubMed

Abidi, Fatima E; Cardoso, Carlos; Lossi, Anne-Marie; Lowry, Robert Brian; Depetris, Danielle; Mattéi, Marie-Geneviève; Lubs, Herbert A; Stevenson, Roger E; Fontes, Michel; Chudley, Albert E; Schwartz, Charles E

2005-02-01

The Chudley-Lowry syndrome (ChLS, MIM 309490) is an X-linked recessive condition characterized by moderate to severe mental retardation, short stature, mild obesity, hypogonadism, and distinctive facial features characterized by depressed nasal bridge, anteverted nares, inverted-V-shaped upper lip, and macrostomia. The original Chudley-Lowry family consists of three affected males in two generations. Linkage analysis had localized the gene to a large interval, Xp21-Xq26 and an obligate carrier was demonstrated to have highly skewed X inactivation. The combination of the clinical phenotype, consistent with that of the patients with ATR-X syndrome, the skewed X-inactivation pattern in a carrier female, as well as the mapping interval including band Xq13.3, prompted us to consider the XNP/ATR-X gene being involved in this syndrome. Using RT-PCR analysis, we screened the entire XNP/ATR-X gene and found a mutation in exon 2 (c.109C > T) giving rise to a stop codon at position 37 (p.R37X). Western blot and immunocytochemical analyses using a specific monoclonal antibody directed against XNP/ATR-X showed the protein to be present in lymphoblastoid cells from one affected male, despite the premature stop codon. To explain these discordant results, we further analyzed the 5' region of the XNP/ATR-X gene and found three alternative transcripts, which differ in the presence or absence of exon 2, and the length of exon 1. Our data suggest that ChLS is allelic to the ATR-X syndrome with its less severe phenotype being due to the presence of some XNP/ATR-X protein.

Autoimmune retinopathy with RPE hypersensitivity and 'negative ERG' in X-linked hyper-IgM syndrome.

PubMed

Schuster, Andreas; Apfelstedt-Sylla, Eckart; Pusch, Carsten M; Zrenner, Eberhart; Thirkill, Charles E

2005-01-01

To report the clinical, electrophysiological, and immunological features of a patient with X-linked hyper-IgM immunodeficiency syndrome type 1 (HIGM1) accompanied by a novel type of autoimmune retinopathy, including retinal pigment epithelium (RPE) hypersensitivity. Comprehensive ophthalmological examinations, electrophysiological function testing, and inquiries into the immunological status of a 13-year-old presenting with subacute loss of vision in association with a molecularly confirmed diagnosis of HIGM1 were performed. The patient was genotyped by a PCR-based sequence tag content mapping strategy to define the genetic defect within the causative X-HIM gene TNFSF5. Since conventional allogenic bone marrow transplantation has been reported to cure HIGM1, a peripheral blood stem-cell transplantation was performed. (1) The patient's reduced visual acuity included prolonged dark adaptation and visual field constriction. Electrophysiology revealed a 'negative ERG' indicating post-receptoral dysfunction. (2) Initial immunological examination of the patient's serum identified abnormal antibody activity with components of the photoreceptors and the inner nuclear layer. The patient later developed indications of RPE hypersensitivity. A massively reduced light-peak to dark-trough ratio of the EOG slow oscillations (L/D ratio) corresponded to impaired RPE-photoreceptor complex function. (3) Molecular genetic analyses revealed the patient to be nullizygous for the tumor necrosis factor ligand member 5 gene (TNFSF5; CD40LG). A large chromosomal deletion of approximately 27.6-32.3 kb in size was identified in Xq26. (4) The transplant with its associated immunomodulation appeared to worsen rather than improve the patient's condition. The fundus appearance and electrophysiological function testing revealed indications of atypical retinal degeneration. However, the clinical course and the serological findings were consistent with those of ocular autoimmunity involving both

Aberrant face and gaze habituation in fragile x syndrome.

PubMed

Bruno, Jennifer Lynn; Garrett, Amy S; Quintin, Eve-Marie; Mazaika, Paul K; Reiss, Allan L

2014-10-01

The authors sought to investigate neural system habituation to face and eye gaze in fragile X syndrome, a disorder characterized by eye-gaze aversion, among other social and cognitive deficits. Participants (ages 15-25 years) were 30 individuals with fragile X syndrome (females, N=14) and a comparison group of 25 individuals without fragile X syndrome (females, N=12) matched for general cognitive ability and autism symptoms. Functional MRI (fMRI) was used to assess brain activation during a gaze habituation task. Participants viewed repeated presentations of four unique faces with either direct or averted eye gaze and judged the direction of eye gaze. Four participants (males, N=4/4; fragile X syndrome, N=3) were excluded because of excessive head motion during fMRI scanning. Behavioral performance did not differ between the groups. Less neural habituation (and significant sensitization) in the fragile X syndrome group was found in the cingulate gyrus, fusiform gyrus, and frontal cortex in response to all faces (direct and averted gaze). Left fusiform habituation in female participants was directly correlated with higher, more typical levels of the fragile X mental retardation protein and inversely correlated with autism symptoms. There was no evidence for differential habituation to direct gaze compared with averted gaze within or between groups. Impaired habituation and accentuated sensitization in response to face/eye gaze was distributed across multiple levels of neural processing. These results could help inform interventions, such as desensitization therapy, which may help patients with fragile X syndrome modulate anxiety and arousal associated with eye gaze, thereby improving social functioning.

Mutations of the Mitochondrial Holocytochrome c–Type Synthase in X-Linked Dominant Microphthalmia with Linear Skin Defects Syndrome

PubMed Central

Wimplinger, Isabella; Morleo, Manuela; Rosenberger, Georg; Iaconis, Daniela; Orth, Ulrike; Meinecke, Peter; Lerer, Israela; Ballabio, Andrea; Gal, Andreas; Franco, Brunella; Kutsche, Kerstin

2006-01-01

The microphthalmia with linear skin defects syndrome (MLS, or MIDAS) is an X-linked dominant male-lethal disorder almost invariably associated with segmental monosomy of the Xp22 region. In two female patients, from two families, with MLS and a normal karyotype, we identified heterozygous de novo point mutations—a missense mutation (p.R217C) and a nonsense mutation (p.R197X)—in the HCCS gene. HCCS encodes the mitochondrial holocytochrome c–type synthase that functions as heme lyase by covalently adding the prosthetic heme group to both apocytochrome c and c1. We investigated a third family, displaying phenotypic variability, in which the mother and two of her daughters carry an 8.6-kb submicroscopic deletion encompassing part of the HCCS gene. Functional analysis demonstrates that both mutant proteins (R217C and Δ197–268) were unable to complement a Saccharomyces cerevisiae mutant deficient for the HCCS orthologue Cyc3p, in contrast to wild-type HCCS. Moreover, ectopically expressed HCCS wild-type and the R217C mutant protein are targeted to mitochondria in CHO-K1 cells, whereas the C-terminal–truncated Δ197–268 mutant failed to be sorted to mitochondria. Cytochrome c, the final product of holocytochrome c–type synthase activity, is implicated in both oxidative phosphorylation (OXPHOS) and apoptosis. We hypothesize that the inability of HCCS-deficient cells to undergo cytochrome c–mediated apoptosis may push cell death toward necrosis that gives rise to severe deterioration of the affected tissues. In summary, we suggest that disturbance of both OXPHOS and the balance between apoptosis and necrosis, as well as the X-inactivation pattern, may contribute to the variable phenotype observed in patients with MLS. PMID:17033964

Genetics Home Reference: Wiskott-Aldrich syndrome

MedlinePlus

... other disorders: X-linked thrombocytopenia and severe congenital neutropenia . These conditions have overlapping signs and symptoms and ... Aldrich syndrome , X-linked thrombocytopenia , and severe congenital neutropenia are sometimes collectively referred to as WAS-related ...

The metabolic syndrome X and peripheral cortisol synthesis.

PubMed

Bähr, V; Pfeiffer, A F; Diederich, S

2002-10-01

The metabolic syndrome X and Cushing's syndrome show similar symptoms but one major difference: Plasma cortisol is not elevated in the metabolic syndrome. Evidence is presented, that by the action of 11 beta-hydroxysteroid dehydrogenase 1 (11 beta HSD1) higher intracellular cortisol concentration may be created that may be relevant to induce insulin resistance and metabolic disturbances. Regulation of 11 beta HSD1 expression by hormones, growth factors, cytokines and transcription factors enables tissue specific adjustments of glucocorticoid receptor activation by cortisol. Specific inhibition of 11 beta HSD1 would help to understand aspects of the pathogenesis of syndrome X and to develop new therapeutic perspectives.

Genetic studies in a patient with X-linked retinoschisis coexisting with developmental delay and sensorineural hearing loss.

PubMed

Sudha, Dhandayuthapani; Patric, Irene Rosita Pia; Ganapathy, Aparna; Agarwal, Smitha; Krishna, Shuba; Neriyanuri, Srividya; Sripriya, Sarangapani; Sen, Parveen; Chidambaram, Subbulakshmi; Arunachalam, Jayamuruga Pandian

2017-01-01

In this study, we present a juvenile retinoschisis patient with developmental delay, sensorineural hearing loss, and reduced axial tone. X-linked juvenile retinoschisis (XLRS) is a retinal dystrophy, most often not associated with systemic anomalies and also not showing any locus heterogeneity. Therefore it was of interest to understand the genetic basis of the condition in this patient. RS1 gene screening for XLRS was performed by Sanger sequencing. Whole genome SNP 6.0 array analysis was carried out to investigate gross chromosomal aberrations that could result in systemic phenotype. In addition, targeted next generation sequencing (NGS) was employed to determine any possible involvement of X-linked syndromic and non-syndromic mental retardation genes. This NGS panel consisted of 550 genes implicated in several other rare inherited diseases. RS1 gene screening revealed a pathogenic hemizygous splice site mutation (c.78+1G>T), inherited from the mother. SNP 6.0 array analysis did not indicate any significant chromosomal aberrations that could be disease-associated. Targeted resequencing did not identify any mutations in the X-linked mental retardation genes. However, variations in three other genes (NSD1, LARGE, and POLG) were detected, which were all inherited from the patient's unaffected father. Taken together, RS1 mutation was found to segregate with retinoschisis phenotype while none of the other identified variations were co-segregating with the systemic defects. Hereby, we infer that the multisystemic defects harbored by the patient are a rare coexistence of XLRS, developmental delay, sensorineural hearing loss, and reduced axial tone reported for the first time in the literature.

Memory Skills of Boys with Fragile X Syndrome

ERIC Educational Resources Information Center

Ornstein, Peter A.; Schaaf, Jennifer M.; Hooper, Stephen R.; Hatton, Deborah D.; Mirrett, Penny; Bailey, Donald B., Jr.

2008-01-01

Multiple aspects of memory were examined in 42 boys with fragile X syndrome and a comparison group of 42 typically developing boys matched on MA. Working memory, incidental memory, and deliberate memory were assessed with a battery that included both free-recall and recognition tasks. Findings indicated that boys with fragile X syndrome performed…

Effects of Sampling Context on Spontaneous Expressive Language in Males with Fragile X Syndrome or Down Syndrome

PubMed Central

Kover, Sara T.; McDuffie, Andrea; Abbeduto, Leonard; Brown, W. Ted

2012-01-01

Purpose This study examined the impact of sampling context on multiple aspects of expressive language in males with fragile X syndrome in comparison to males with Down syndrome or typical development. Method Participants with fragile X syndrome (n = 27), ages 10 to 17 years, were matched groupwise on nonverbal mental age to adolescents with Down syndrome (n = 15) and typically developing 3- to 6-year-olds (n = 15). Language sampling contexts were an interview-style conversation and narration of a wordless book, with scripted examiner behavior. Language was assessed in terms of amount of talk, MLU of communication unit (MLCU), lexical diversity, fluency, and intelligibility. Results Participants with fragile X syndrome had lower MLCU and lexical diversity than participants with typical development. Participants with Down syndrome produced yet lower MLCU. A differential effect of context among those with fragile X syndrome, Down syndrome, and typical development emerged for the number of attempts per minute, MLCU, and fluency. For participants with fragile X syndrome, autism symptom severity related to the number of utterances produced in conversation. Aspects of examiner behavior related to participant performance. Conclusions Sampling context characteristics should be considered when assessing expressive language in individuals with neurodevelopmental disabilities. PMID:22232386

Isolated and syndromic forms of congenital anosmia.

PubMed

Karstensen, H G; Tommerup, N

2012-03-01

Loss of smell (anosmia) is common in the general population and the frequency increases with age. A much smaller group have no memory of ever being able to smell and are classified as having isolated congenital anosmia (ICA). Families are rare, and tend to present in a dominant inheritance pattern. Despite a strong degree of heritability, no human disease-causing mutations have been identified. Anosmia is part of the clinical spectrum in various diseases, as seen in Kallmann syndrome, various ciliopathies and congenital insensitivity to pain. This review will focus on ICA through already published families and cases as well as syndromes where anosmia is part of the clinical disease spectrum. Furthermore, olfactory signal transduction pathway genes and animal models may shed light on potential candidate genes and pathways involved in ICA. © 2011 John Wiley & Sons A/S.

An Extra X or Y Chromosome: Contrasting the Cognitive and Motor Phenotypes in Childhood in Boys with 47,XYY Syndrome or 47,XXY Klinefelter Syndrome

ERIC Educational Resources Information Center

Ross, Judith L.; Zeger, Martha P. D.; Kushner, Harvey; Zinn, Andrew R.; Roeltgen, David P.

2009-01-01

Objective: The goal of this study was to contrast the cognitive phenotypes in boys with 47,XYY (XYY) karyotype and boys with 47,XXY karyotype [Klinefelter syndrome, (KS)], who share an extra copy of the X-Y pseudoautosomal region but differ in their dosage of strictly sex-linked genes. Methods: Neuropsychological evaluation of general cognitive…

Studies of EBV-lymphoid cell interactions in two patients with the X-linked lymphoproliferative syndrome: normal EBV-specific HLA-restricted cytotoxicity.

PubMed

Rousset, F; Souillet, G; Roncarolo, M G; Lamelin, J P

1986-02-01

Two X-linked lymphoproliferative syndrome (XLP) patients with the hypogammaglobulinemia phenotype were investigated at a time remote from their primary infection with the Epstein-Barr virus (EBV). The lymphoblastoid cell lines derived from these patients expressed the phenotypic markers characteristic of normal mature B lymphocytes and produced normal levels of immunoglobulins (Ig). These observations imply that at least some of their B cells are phenotypically normal. The natural killer (NK) activity of the two patients was low. In one patient, activated lymphocyte killer (ALK) activity was inefficient. These two XLP patients expressed a normal EBV-specific, HLA-restricted cytotoxic activity. It thus appears, from the present findings and those in cases published previously (6/11 patients expressing normal EBV-specific cytotoxic activity), that the notion of poor specific T cell memory for EBV may not be as pivotal ass suggested or, alternatively, that this defect may not be common in hypogammaglobulinemic survivors.

FARVATX: Family-Based Rare Variant Association Test for X-Linked Genes.

PubMed

Choi, Sungkyoung; Lee, Sungyoung; Qiao, Dandi; Hardin, Megan; Cho, Michael H; Silverman, Edwin K; Park, Taesung; Won, Sungho

2016-09-01

Although the X chromosome has many genes that are functionally related to human diseases, the complicated biological properties of the X chromosome have prevented efficient genetic association analyses, and only a few significantly associated X-linked variants have been reported for complex traits. For instance, dosage compensation of X-linked genes is often achieved via the inactivation of one allele in each X-linked variant in females; however, some X-linked variants can escape this X chromosome inactivation. Efficient genetic analyses cannot be conducted without prior knowledge about the gene expression process of X-linked variants, and misspecified information can lead to power loss. In this report, we propose new statistical methods for rare X-linked variant genetic association analysis of dichotomous phenotypes with family-based samples. The proposed methods are computationally efficient and can complete X-linked analyses within a few hours. Simulation studies demonstrate the statistical efficiency of the proposed methods, which were then applied to rare-variant association analysis of the X chromosome in chronic obstructive pulmonary disease. Some promising significant X-linked genes were identified, illustrating the practical importance of the proposed methods. © 2016 WILEY PERIODICALS, INC.

FARVATX: FAmily-based Rare Variant Association Test for X-linked genes

PubMed Central

Choi, Sungkyoung; Lee, Sungyoung; Qiao, Dandi; Hardin, Megan; Cho, Michael H.; Silverman, Edwin K; Park, Taesung; Won, Sungho

2016-01-01

Although the X chromosome has many genes that are functionally related to human diseases, the complicated biological properties of the X chromosome have prevented efficient genetic association analyses, and only a few significantly associated X-linked variants have been reported for complex traits. For instance, dosage compensation of X-linked genes is often achieved via the inactivation of one allele in each X-linked variant in females; however, some X-linked variants can escape this X chromosome inactivation. Efficient genetic analyses cannot be conducted without prior knowledge about the gene expression process of X-linked variants, and misspecified information can lead to power loss. In this report, we propose new statistical methods for rare X-linked variant genetic association analysis of dichotomous phenotypes with family-based samples. The proposed methods are computationally efficient and can complete X-linked analyses within a few hours. Simulation studies demonstrate the statistical efficiency of the proposed methods, which were then applied to rare-variant association analysis of the X chromosome in chronic obstructive pulmonary disease (COPD). Some promising significant X-linked genes were identified, illustrating the practical importance of the proposed methods. PMID:27325607

Neuronal profilins in health and disease: Relevance for spine plasticity and Fragile X syndrome

PubMed Central

Michaelsen-Preusse, Kristin; Zessin, Sabine; Grigoryan, Gayane; Scharkowski, Franziska; Feuge, Jonas; Remus, Anita; Korte, Martin

2016-01-01

Learning and memory, to a large extent, depend on functional changes at synapses. Actin dynamics orchestrate the formation of synapses, as well as their stabilization, and the ability to undergo plastic changes. Hence, profilins are of key interest as they bind to G-actin and enhance actin polymerization. However, profilins also compete with actin nucleators, thereby restricting filament formation. Here, we provide evidence that the two brain isoforms, profilin1 (PFN1) and PFN2a, regulate spine actin dynamics in an opposing fashion, and that whereas both profilins are needed during synaptogenesis, only PFN2a is crucial for adult spine plasticity. This finding suggests that PFN1 is the juvenile isoform important during development, whereas PFN2a is mandatory for spine stability and plasticity in mature neurons. In line with this finding, only PFN1 levels are altered in the mouse model of the developmental neurological disorder Fragile X syndrome. This finding is of high relevance because Fragile X syndrome is the most common monogenetic cause for autism spectrum disorder. Indeed, the expression of recombinant profilins rescued the impairment in spinogenesis, a hallmark in Fragile X syndrome, thereby linking the regulation of actin dynamics to synapse development and possible dysfunction. PMID:26951674

X-linked congenital panhypopituitarism.

PubMed

Schimke, R N; Spaulding, J J; Hollowell, J G

1971-05-01

Two half brothers with panhypopituitary dwarfism are reported who have the same mother and different, unrelated fathers. The subject of hereditary panhypopituitarism is reviewed briefly. It is concluded that there are at least two forms of hereditary panhypopituitary dwarfism, one of which may be X-linked.

Learning about Fragile X Syndrome

MedlinePlus

... Physical problems that have been seen include eye, orthopedic, heart and skin problems. Girls who have the ... to their sons. Top of page NHGRI Clinical Research on Fragile X Syndrome Currently, NHGRI is not ...

Vascular and connective tissue anomalies associated with X-linked periventricular heterotopia due to mutations in Filamin A

PubMed Central

Reinstein, Eyal; Frentz, Sophia; Morgan, Tim; García-Miñaúr, Sixto; Leventer, Richard J; McGillivray, George; Pariani, Mitchel; van der Steen, Anthony; Pope, Michael; Holder-Espinasse, Muriel; Scott, Richard; Thompson, Elizabeth M; Robertson, Terry; Coppin, Brian; Siegel, Robert; Bret Zurita, Montserrat; Rodríguez, Jose I; Morales, Carmen; Rodrigues, Yuri; Arcas, Joaquín; Saggar, Anand; Horton, Margaret; Zackai, Elaine; Graham, John M; Rimoin, David L; Robertson, Stephen P

2013-01-01

Mutations conferring loss of function at the FLNA (encoding filamin A) locus lead to X-linked periventricular nodular heterotopia (XL-PH), with seizures constituting the most common clinical manifestation of this disorder in female heterozygotes. Vascular dilatation (mainly the aorta), joint hypermobility and variable skin findings are also associated anomalies, with some reports suggesting that this might represents a separate syndrome allelic to XL-PH, termed as Ehlers-Danlos syndrome-periventricular heterotopia variant (EDS-PH). Here, we report a cohort of 11 males and females with both hypomorphic and null mutations in FLNA that manifest a wide spectrum of connective tissue and vascular anomalies. The spectrum of cutaneous defects was broader than previously described and is inconsistent with a specific type of EDS. We also extend the range of vascular anomalies associated with XL-PH to included peripheral arterial dilatation and atresia. Based on these observations, we suggest that there is little molecular or clinical justification for considering EDS-PH as a separate entity from XL-PH, but instead propose that there is a spectrum of vascular and connective tissues anomalies associated with this condition for which all individuals with loss-of-function mutations in FLNA should be evaluated. In addition, since some patients with XL-PH can present primarily with a joint hypermobility syndrome, we propose that screening for cardiovascular manifestations should be offered to those patients when there are associated seizures or an X-linked pattern of inheritance. PMID:23032111

Discriminating Down Syndrome and Fragile X Syndrome Based on Language Ability

ERIC Educational Resources Information Center

Finestack, Lizbeth H.; Sterling, Audra M.; Abbeduto, Leonard

2013-01-01

This study compared the receptive and expressive language profiles of verbally expressive children and adolescents with Down Syndrome (DS) and those with Fragile X syndrome (FXS) and examined the extent to which these profiles reliably differentiate the diagnostic groups. A total of twenty-four verbal participants with DS (mean age: 12 years),…

Usher syndrome: molecular links of pathogenesis, proteins and pathways.

PubMed

Kremer, Hannie; van Wijk, Erwin; Märker, Tina; Wolfrum, Uwe; Roepman, Ronald

2006-10-15

Usher syndrome is the most common form of deaf-blindness. The syndrome is both clinically and genetically heterogeneous, and to date, eight causative genes have been identified. The proteins encoded by these genes are part of a dynamic protein complex that is present in hair cells of the inner ear and in photoreceptor cells of the retina. The localization of the Usher proteins and the phenotype in animal models indicate that the Usher protein complex is essential in the morphogenesis of the stereocilia bundle in hair cells and in the calycal processes of photoreceptor cells. In addition, the Usher proteins are important in the synaptic processes of both cell types. The association of other proteins with the complex indicates functional links to a number of basic cell-biological processes. Prominently present is the connection to the dynamics of the actin cytoskeleton, involved in cellular morphology, cell polarity and cell-cell interactions. The Usher protein complex can also be linked to the cadherins/catenins in the adherens junction-associated protein complexes, suggesting a role in cell polarity and tissue organization. A third link can be established to the integrin transmembrane signaling network. The Usher interactome, as outlined in this review, participates in pathways common in inner ear and retina that are disrupted in the Usher syndrome.

Phenotype-genotype correlations in X linked retinitis pigmentosa.

PubMed Central

Kaplan, J; Pelet, A; Martin, C; Delrieu, O; Aymé, S; Bonneau, D; Briard, M L; Hanauer, A; Larget-Piet, L; Lefrançois, P

1992-01-01

Retinitis pigmentosa (RP) represents a group of clinically heterogeneous retinal degenerations in which all modes of inheritance have been described. We have previously found two different clinical profiles in X linked RP as a function of age and mode of onset. The first clinical form has very early onset with severe myopia. The second form starts later with night blindness with mild myopia or none. At least two genes have been identified in X linked forms, namely RP2 (linked to DXS7, DXS255, and DXS14) and RP3 (linked to DXS84 and OTC) on the short arm of the X chromosome. In order to contribute to phenotype-genotype correlations in X linked RP, we tested the hypothesis that the two clinical profiles could be accounted for by the two different gene loci. The present study provides evidence for linkage of the clinical form with early myopia as the onset symptom with the RP2 gene (pairwise linkage to DXS255: Z = 3.13 at theta = 0), while the clinical form with later night blindness as the onset symptom is linked to the RP3 gene (pairwise linkage to OTC: Z = 4.16 at theta = 0). Images PMID:1357178

Sex-specific silencing of X-linked genes by Xist RNA

PubMed Central

Gayen, Srimonta; Maclary, Emily; Hinten, Michael; Kalantry, Sundeep

2016-01-01

X-inactive specific transcript (Xist) long noncoding RNA (lncRNA) is thought to catalyze silencing of X-linked genes in cis during X-chromosome inactivation, which equalizes X-linked gene dosage between male and female mammals. To test the impact of Xist RNA on X-linked gene silencing, we ectopically induced endogenous Xist by ablating the antisense repressor Tsix in mice. We find that ectopic Xist RNA induction and subsequent X-linked gene silencing is sex specific in embryos and in differentiating embryonic stem cells (ESCs) and epiblast stem cells (EpiSCs). A higher frequency of XΔTsixY male cells displayed ectopic Xist RNA coating compared with XΔTsixX female cells. This increase reflected the inability of XΔTsixY cells to efficiently silence X-linked genes compared with XΔTsixX cells, despite equivalent Xist RNA induction and coating. Silencing of genes on both Xs resulted in significantly reduced proliferation and increased cell death in XΔTsixX female cells relative to XΔTsixY male cells. Thus, whereas Xist RNA can inactivate the X chromosome in females it may not do so in males. We further found comparable silencing in differentiating XΔTsixY and 39,XΔTsix (XΔTsixO) ESCs, excluding the Y chromosome and instead implicating the X-chromosome dose as the source of the sex-specific differences. Because XΔTsixX female embryonic epiblast cells and EpiSCs harbor an inactivated X chromosome prior to ectopic inactivation of the active XΔTsix X chromosome, we propose that the increased expression of one or more X-inactivation escapees activates Xist and, separately, helps trigger X-linked gene silencing. PMID:26739568

Behaviour Problems, Maternal Internalising Symptoms and Family Relations in Families of Adolescents and Adults with Fragile X Syndrome

ERIC Educational Resources Information Center

Baker, J. K.; Seltzer, M. M.; Greenberg, J. S.

2012-01-01

Background: Studies have linked the behaviour problems of children with fragile X syndrome (FXS) to maternal well-being, but less is known about how behaviour problems relate to important family factors such as marital satisfaction and family cohesion. Methods: Married mothers of 115 adolescents and adults with FXS completed questionnaires and…

Review Recent progress in identification and characterization of loci associated with sex-linked congenital cataract.

PubMed

Zhang, D D; Du, J Z; Topolewski, J; Wang, X M

2016-07-29

Congenital cataract is a common cause of blindness in children; however, its pathogenesis remains unclear. Genetic factors have been shown to play an important role in the pathogenesis of congenital cataract. The current genetic models of congenital cataract include autosomal dominant, autosomal recessive, and sex-linked inheritance. Sex-linked congenital cataract could be inherited through the X or Y chromosome. Congenital cataract is a symptom associated with several X-linked disorders, including Nance-Horan syndrome, Lowe syndrome, Conradi-Hünermann-Happle syndrome, oculo-facio-cardio-dental syndrome, and Alport syndrome. On the other hand, the mechanism and characteristics of Y-linked congenital cataract remains to be identified. Despite its rarity, sex-linked congenital cataract has been known to seriously affect the quality of life of patients. In this review, we present our current understanding of the genes and loci associated with sex-linked congenital cataract. This could help identify novel approaches for the prevention, early diagnosis, and comprehensive disease treatment.

Effects of Sampling Context on Spontaneous Expressive Language in Males with Fragile X Syndrome or Down Syndrome

ERIC Educational Resources Information Center

Kover, Sara T.; McDuffie, Andrea; Abbeduto, Leonard; Brown, W. Ted

2012-01-01

Purpose: In this study, the authors examined the impact of sampling context on multiple aspects of expressive language in male participants with fragile X syndrome in comparison to male participants with Down syndrome or typical development. Method: Participants with fragile X syndrome (n = 27), ages 10-17 years, were matched groupwise on…

Insulin-like peptide 3 (INSL3) in men with congenital hypogonadotropic hypogonadism/Kallmann syndrome and effects of different modalities of hormonal treatment: a single-center study of 281 patients.

PubMed

Trabado, Séverine; Maione, Luigi; Bry-Gauillard, Hélène; Affres, Hélène; Salenave, Sylvie; Sarfati, Julie; Bouvattier, Claire; Delemer, Brigitte; Chanson, Philippe; Le Bouc, Yves; Brailly-Tabard, Sylvie; Young, Jacques

2014-02-01

Insulin-like factor 3 (INSL3) is a testicular hormone secreted during fetal life, the neonatal period, and after puberty. To measure INSL3 levels in a large series of men with congenital hypogonadotropic hypogonadism (CHH)/ Kallmann syndrome (KS), in order to assess its diagnostic value and to investigate its regulation. We studied 281 CHH/KS patients (91 untreated, 96 receiving T, and 94 receiving combined gonadotropin therapy [human chorionic gonadotropin, hCG, and FSH]) and 72 age-matched healthy men. Serum INSL3 was immunoassayed with a validated RIA. Mean (±SD) INSL3 levels (pg/mL) were 659 ± 279 in controls and lower (60 ± 43; P < .001) in untreated CHH/KS patients, with no overlap between the two groups, when the threshold of 250 pg/mL was used. Basal INSL3 levels were lower in both untreated CHH/KS men with cryptorchidism than in those with intrascrotal testes and in patients with testicular volumes below 4 mL. Significant positive correlations between INSL3 and both serum total T and LH levels were observed in untreated CHH/KS. Mean INSL3 levels remained low in T-treated CHH/KS patients and were significantly higher in men receiving combined hCG-FSH therapy (P < .001), but the increase was lower cryptorchid patients. FSH-hCG combination therapy or hCG monotherapy, contrary to T and FSH monotherapies, significantly increased INSL3 levels in CHH/KS. INSL3 is as sensitive a marker as T for the evaluation of altered Leydig cell function in CHH/KS patients. INSL3 levels correlate with LH levels in CHH/KS men showing, together with the rise in INSL3 levels during hCG therapy, that INSL3 secretion seems not constitutively secreted during adulthood but is dependence on pituitary LH.

Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease

PubMed Central

Bustamante, Jacinta; Arias, Andres A; Vogt, Guillaume; Picard, Capucine; Galicia, Lizbeth Blancas; Prando, Carolina; Grant, Audrey V; Marchal, Christophe C; Hubeau, Marjorie; Chapgier, Ariane; de Beaucoudrey, Ludovic; Puel, Anne; Feinberg, Jacqueline; Valinetz, Ethan; Jannière, Lucile; Besse, Céline; Boland, Anne; Brisseau, Jean-Marie; Blanche, Stéphane; Lortholary, Olivier; Fieschi, Claire; Emile, Jean-François; Boisson-Dupuis, Stéphanie; Al-Muhsen, Saleh; Woda, Bruce; Newburger, Peter E; Condino-Neto, Antonio; Dinauer, Mary C; Abel, Laurent; Casanova, Jean-Laurent

2011-01-01

Germline mutations in CYBB, the human gene encoding the gp91phox subunit of the phagocyte NADPH oxidase, impair the respiratory burst of all types of phagocytes and result in X-linked chronic granulomatous disease (CGD). We report here two kindreds in which otherwise healthy male adults developed X-linked recessive Mendelian susceptibility to mycobacterial disease (MSMD) syndromes. These patients had previously unknown mutations in CYBB that resulted in an impaired respiratory burst in monocyte-derived macrophages but not in monocytes or granulocytes. The macrophage-specific functional consequences of the germline mutation resulted from cell-specific impairment in the assembly of the NADPH oxidase. This ‘experiment of nature’ indicates that CYBB is associated with MSMD and demonstrates that the respiratory burst in human macrophages is a crucial mechanism for protective immunity to tuberculous mycobacteria. PMID:21278736

A Comparison of Selective Pressures in Plant X-Linked and Autosomal Genes

PubMed Central

Krasovec, Marc; Filatov, Dmitry A.

2018-01-01

Selection is expected to work differently in autosomal and X-linked genes because of their ploidy difference and the exposure of recessive X-linked mutations to haploid selection in males. However, it is not clear whether these expectations apply to recently evolved sex chromosomes, where many genes retain functional X- and Y-linked gametologs. We took advantage of the recently evolved sex chromosomes in the plant Silene latifolia and its closely related species to compare the selective pressures between hemizygous and non-hemizygous X-linked genes as well as between X-linked genes and autosomal genes. Our analysis, based on over 1000 genes, demonstrated that, similar to animals, X-linked genes in Silene evolve significantly faster than autosomal genes—the so-called faster-X effect. Contrary to expectations, faster-X divergence was detectable only for non-hemizygous X-linked genes. Our phylogeny-based analyses of selection revealed no evidence for faster adaptation in X-linked genes compared to autosomal genes. On the other hand, partial relaxation of purifying selection was apparent on the X-chromosome compared to the autosomes, consistent with a smaller genetic diversity in S. latifolia X-linked genes (πx = 0.016; πaut = 0.023). Thus, the faster-X divergence in S. latifolia appears to be a consequence of the smaller effective population size rather than of a faster adaptive evolution on the X-chromosome. We argue that this may be a general feature of “young” sex chromosomes, where the majority of X-linked genes are not hemizygous, preventing haploid selection in heterogametic sex. PMID:29751495

A Comparison of Selective Pressures in Plant X-Linked and Autosomal Genes.

PubMed

Krasovec, Marc; Nevado, Bruno; Filatov, Dmitry A

2018-05-03

Selection is expected to work differently in autosomal and X-linked genes because of their ploidy difference and the exposure of recessive X-linked mutations to haploid selection in males. However, it is not clear whether these expectations apply to recently evolved sex chromosomes, where many genes retain functional X- and Y-linked gametologs. We took advantage of the recently evolved sex chromosomes in the plant Silene latifolia and its closely related species to compare the selective pressures between hemizygous and non-hemizygous X-linked genes as well as between X-linked genes and autosomal genes. Our analysis, based on over 1000 genes, demonstrated that, similar to animals, X-linked genes in Silene evolve significantly faster than autosomal genes—the so-called faster-X effect. Contrary to expectations, faster-X divergence was detectable only for non-hemizygous X-linked genes. Our phylogeny-based analyses of selection revealed no evidence for faster adaptation in X-linked genes compared to autosomal genes. On the other hand, partial relaxation of purifying selection was apparent on the X-chromosome compared to the autosomes, consistent with a smaller genetic diversity in S. latifolia X-linked genes (π x = 0.016; π aut = 0.023). Thus, the faster-X divergence in S. latifolia appears to be a consequence of the smaller effective population size rather than of a faster adaptive evolution on the X-chromosome. We argue that this may be a general feature of “young” sex chromosomes, where the majority of X-linked genes are not hemizygous, preventing haploid selection in heterogametic sex.

Disruption of RAB40AL function leads to Martin--Probst syndrome, a rare X-linked multisystem neurodevelopmental human disorder.

PubMed

Bedoyan, Jirair Krikor; Schaibley, Valerie M; Peng, Weiping; Bai, Yongsheng; Mondal, Kajari; Shetty, Amol C; Durham, Mark; Micucci, Joseph A; Dhiraaj, Arti; Skidmore, Jennifer M; Kaplan, Julie B; Skinner, Cindy; Schwartz, Charles E; Antonellis, Anthony; Zwick, Michael E; Cavalcoli, James D; Li, Jun Z; Martin, Donna M

2012-05-01

Martin--Probst syndrome (MPS) is a rare X-linked disorder characterised by deafness, cognitive impairment, short stature and distinct craniofacial dysmorphisms, among other features. The authors sought to identify the causative mutation for MPS. Massively parallel sequencing in two affected, related male subjects with MPS identified a RAB40AL (also called RLGP) missense mutation (chrX:102,079,078-102,079,079AC→GA p.D59G; hg18). RAB40AL encodes a small Ras-like GTPase protein with one suppressor of cytokine signalling box. The p.D59G variant is located in a highly conserved region of the GTPase domain between β-2 and β-3 strands. Using RT-PCR, the authors show that RAB40AL is expressed in human fetal and adult brain and kidney, and adult lung, heart, liver and skeletal muscle. RAB40AL appears to be a primate innovation, with no orthologues found in mouse, Xenopus or zebrafish. Western analysis and fluorescence microscopy of GFP-tagged RAB40AL constructs from transiently transfected COS7 cells show that the D59G missense change renders RAB40AL unstable and disrupts its cytoplasmic localisation. This is the first study to show that mutation of RAB40AL is associated with a human disorder. Identification of RAB40AL as the gene mutated in MPS allows for further investigations into the molecular mechanism(s) of RAB40AL and its roles in diverse processes such as cognition, hearing and skeletal development.

Disruption of RAB40AL function leads to Martin–Probst syndrome, a rare X-linked multisystem neurodevelopmental human disorder

PubMed Central

Bedoyan, Jirair Krikor; Schaibley, Valerie M; Peng, Weiping; Bai, Yongsheng; Mondal, Kajari; Shetty, Amol C; Durham, Mark; Micucci, Joseph A; Dhiraaj, Arti; Skidmore, Jennifer M; Kaplan, Julie B; Skinner, Cindy; Schwartz, Charles E; Antonellis, Anthony; Zwick, Michael E; Cavalcoli, James D; Li, Jun Z

2012-01-01

Background and aim Martin–Probst syndrome (MPS) is a rare X-linked disorder characterised by deafness, cognitive impairment, short stature and distinct craniofacial dysmorphisms, among other features. The authors sought to identify the causative mutation for MPS. Methods and results Massively parallel sequencing in two affected, related male subjects with MPS identified a RAB40AL (also called RLGP) missense mutation (chrX:102,079,078-102,079,079AC→GA p.D59G; hg18). RAB40AL encodes a small Ras-like GTPase protein with one suppressor of cytokine signalling box. The p.D59G variant is located in a highly conserved region of the GTPase domain between β-2 and β-3 strands. Using RT-PCR, the authors show that RAB40AL is expressed in human fetal and adult brain and kidney, and adult lung, heart, liver and skeletal muscle. RAB40AL appears to be a primate innovation, with no orthologues found in mouse, Xenopus or zebrafish. Western analysis and fluorescence microscopy of GFP-tagged RAB40AL constructs from transiently transfected COS7 cells show that the D59G missense change renders RAB40AL unstable and disrupts its cytoplasmic localisation. Conclusions This is the first study to show that mutation of RAB40AL is associated with a human disorder. Identification of RAB40AL as the gene mutated in MPS allows for further investigations into the molecular mechanism(s) of RAB40AL and its roles in diverse processes such as cognition, hearing and skeletal development. PMID:22581972

Microdeletion syndromes, balanced translocations, and gene mapping.

PubMed Central

Schinzel, A

1988-01-01

High resolution prometaphase chromosome banding has allowed the detection of discrete chromosome aberrations which escaped earlier metaphase examinations. Consistent tiny deletions have been detected in some well established malformation syndromes: an interstitial deletion in 15q11/12 in the majority of patients with the Prader-Willi syndrome and in a minority of patients with the Angelman (happy puppet) syndrome; a terminal deletion of 17p13.3 in most patients examined with the Miller-Dieker syndrome; an interstitial deletion of 8q23.3/24.1 in a large majority of patients with the Giedion-Langer syndrome; an interstitial deletion of 11p13 in virtually all patients with the WAGR (Wilms' tumour-aniridia-gonadoblastoma-retardation) syndrome; and an interstitial deletion in 22q11 in about one third of patients with the DiGeorge sequence. In addition, a combination of chromosome prometaphase banding and DNA marker studies has allowed the localisation of the genes for retinoblastoma and for Wilms' tumour and the clarification of both the autosomal recessive nature of the mutation and the possible somatic mutations by which the normal allele can be lost in retina and kidney cells. After a number of X linked genes had been mapped, discrete deletions in the X chromosome were detected by prometaphase banding with specific attention paid to the sites of the gene(s) in males who had from one to up to four different X linked disorders plus mental retardation. Furthermore, the detection of balanced translocations in probands with disorders caused by autosomal dominant or X linked genes has allowed a better insight into the localisation of these genes. In some females with X linked disorders, balanced X; autosomal translocations have allowed the localisation of X linked genes at the breakpoint on the X chromosome. Balanced autosome; autosome translocations segregating with autosomal dominant conditions have provided some clues to the gene location of these conditions. In two

CHILD syndrome in a boy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Happle, R.; Effendy, I., Megahed, M.; Orlow, S.J.

CHILD syndrome (congential hemidysplasia with ichthyosiform nevus and limb defects) occurs, as a rule, exclusively in girls because of the underlying X-linked gene exerts a lethal effect on male embryos. In this report the characteristic manifestations of CHILD syndrome are described in a 2-year-old boy with a normal chromosome constitution 46,XY. This exceptional case is best explained by the assumption of an early somatic mutation and thus compatible with the concept of X-linked dominant male-lethal inheritance of this trait. 18 refs., 6 figs.

Assessing the Fragile X Syndrome Newborn Screening Landscape.

PubMed

Riley, Catharine; Wheeler, Anne

2017-06-01

Fragile X syndrome (FXS) is the most common known inherited form of intellectual disability. Early identification is an important step in linking FXS individuals with appropriate and timely medical and social services. Newborn screening (NBS) is 1 approach that has been used for other conditions to facilitate early identification. A literature review was conducted to identify issues, barriers, challenges, and approaches to addressing challenges related to NBS for FXS. Search terms included: fragile X syndrome, FMR1, newborn screening, screening, and genetic testing. To supplement the literature review, 9 key informant interviews were conducted. Information gathered through these interviews supplemented what was identified in the literature. Information from both the literature review and supplemental interviews was reviewed by 3 researchers who discussed and came to consensus on thematic areas and categorization of issues. The barriers and challenges related to NBS for FXS identified in the literature and by experts and stakeholders are categorized into 5 thematic areas: public health burden, treatment, timing, screening/testing methodologies, and translating results. Summaries of these issues and barriers are provided, along with potential approaches to addressing them. The issues and barriers described in this article highlight limited areas of knowledge that need be addressed to improve our understanding of FXS and the potential benefit of NBS. The landscape of NBS for FXS could be influenced by a series of research findings over time or a larger breakthrough that demonstrates an effective targeted treatment that has to be implemented early in life. Copyright © 2017 by the American Academy of Pediatrics.

Craniofacial morphometric analysis of individuals with X-linked hypohidrotic ectodermal dysplasia.

PubMed

Goodwin, Alice F; Larson, Jacinda R; Jones, Kyle B; Liberton, Denise K; Landan, Maya; Wang, Zhifeng; Boekelheide, Anne; Langham, Margaret; Mushegyan, Vagan; Oberoi, Snehlata; Brao, Rosalie; Wen, Timothy; Johnson, Ramsey; Huttner, Kenneth; Grange, Dorothy K; Spritz, Richard A; Hallgrímsson, Benedikt; Jheon, Andrew H; Klein, Ophir D

2014-09-01

Hypohidrotic ectodermal dysplasia (HED) is the most prevalent type of ectodermal dysplasia (ED). ED is an umbrella term for a group of syndromes characterized by missing or malformed ectodermal structures, including skin, hair, sweat glands, and teeth. The X-linked recessive (XL), autosomal recessive (AR), and autosomal dominant (AD) types of HED are caused by mutations in the genes encoding ectodysplasin (EDA1), EDA receptor (EDAR), or EDAR-associated death domain (EDARADD). Patients with HED have a distinctive facial appearance, yet a quantitative analysis of the HED craniofacial phenotype using advanced three-dimensional (3D) technologies has not been reported. In this study, we characterized craniofacial morphology in subjects with X-linked hypohidrotic ectodermal dysplasia (XLHED) by use of 3D imaging and geometric morphometrics (GM), a technique that uses defined landmarks to quantify size and shape in complex craniofacial morphologies. We found that the XLHED craniofacial phenotype differed significantly from controls. Patients had a smaller and shorter face with a proportionally longer chin and midface, prominent midfacial hypoplasia, a more protrusive chin and mandible, a narrower and more pointed nose, shorter philtrum, a narrower mouth, and a fuller and more rounded lower lip. Our findings refine the phenotype of XLHED and may be useful both for clinical diagnosis of XLHED and to extend understanding of the role of EDA in craniofacial development.

Heart Activity and Autistic Behavior in Infants and Toddlers with Fragile X Syndrome

PubMed Central

Roberts, Jane E.; Tonnsen, Bridgette; Robinson, Ashley; Shinkareva, Svetlana V.

2014-01-01

The present study contrasted physiological arousal in infants and toddlers with fragile X syndrome to typically developing control participants and examined physiological predictors early in development to autism severity later in development in fragile X syndrome. Thirty-one males with fragile X syndrome (ages 8–40 months) and 25 age-matched control participants were included. The group with fragile X syndrome showed shorter interbeat intervals (IBIs), lower vagal tone (VT), and less modulation of IBI. Data suggested a nonlinear effect with IBI and autistic behavior; however, a linear effect with VT and autistic behavior emerged. These findings suggest that atypical physiological arousal emerges within the first year and predicts severity of autistic behavior in fragile X syndrome. These relationships are complex and dynamic, likely reflecting endogenous factors assumed to reflect atypical brain function secondary to reduced fragile X mental retardation protein. This research has important implications for the early identification and treatment of autistic behaviors in young children with fragile X syndrome. PMID:22515825

Obesity, Food Selectivity, and Physical Activity in Individuals with Fragile X Syndrome

ERIC Educational Resources Information Center

Raspa, Melissa; Bailey, Donald B., Jr.; Bishop, Ellen; Holiday, David; Olmsted, Murrey

2010-01-01

National survey data from 884 families were used to examine the overall health of children and adults with fragile X syndrome. Results indicate the rate of obesity in adults with fragile X syndrome is similar to the general population (30%). Male children with fragile X syndrome, however, had higher rates of obesity (31%) when compared with…

Tenascin-X, Collagen, Elastin and the Ehlers-Danlos Syndrome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bristow, James; Carey, William; Schalkwijk, Joost

2005-08-31

Tenascin-X is an extracellular matrix protein initially identified because of its overlap with the human CYP21B gene. Because studies of gene and protein function of other tenascins had been poorly predictive of essential functions in vivo, we used a genetic approach that critically relied on an understanding of the genomic locus to uncover an association between inactivating tenascin-X mutations and novel recessive and dominant forms of Ehlers-Danlos syndrome. Tenascin-X provides the first example of a gene outside of the fibrillar collagens and their processing enzymes that causes Ehlers-Danlos syndrome. Tenascin-X null mice recapitulate the skin findings of the human disease,more » confirming a causative role for this gene in Ehlers-Danlos syndrome. Further evaluation of these mice showed that tenascin-X is an important regulator of collagen deposition in vivo, suggesting a novel mechanism of disease in this form of Ehlers-Danlos syndrome. Further studies suggest that tenascin-X may do this through both direct and indirect interactions with the collagen fibril. Recent studies show that TNX effects on matrix extend beyond the collagen to the elastogenic pathway and matrix remodeling enzymes. Tenascin-X serves as a compelling example of how human experiments of nature can guide us to an understanding of genes whose function may not be evident from their sequence or in vitro studies of their encoded proteins.« less

Clinical aspects of the fragile X syndrome.

PubMed

Brown, W Ted

2012-01-01

Fragile X syndrome patients express a wide array of cognitive and other gender-specific phenotypic features. These manifestations result not only from molecular mechanisms that are altered as a result of the expansion of a CGG-repeat region in the FMR1 promoter, but also genetic factors such as founder effects and mosaicism. In this chapter, I will summarize the many and varied features of fragile X syndrome as they present themselves in a clinical setting and describe the procedures that are used to diagnose patients. Finally, I will briefly touch on recent developments that will affect patient screening in the future.

X-linked dominant retinitis pigmentosa in an American family

DOE Office of Scientific and Technical Information (OSTI.GOV)

McGuire, R.E.; Daiger, S.P.; Blanton, S.H.

1994-09-01

Retinitis pigmentosa is a genetically heterogeneous disease with autosomal dominant (adRP), autosomal recessive and X-linked forms. At least 3 forms of X-linked retinitis pigmentosa have been reported: RP2 which maps to Xp11.4-p 11.23, RP3 which maps to Xp21.1 and RP6, which maps to Xp21.3-p21.1. The X-linked forms of retinitis pigmentosa are generally considered to be recessive as female carriers are not affected or are much less affected than males. Here we report a five generation American family with X-linked retinitis pigmentosa in which both males and females are significantly affected. The disease locus in this family appears to be distinctmore » from RP2 and RP3. The American family (UTAD054) presents with early-onset retinitis pigmentosa. The family appeared to fit an autosomal dominant pattern; however, linkage testing excluded all known adRP loci. Absence of male-to-male transmission in the pedigree suggested the possibility of X-linked dominant inheritance. Thus we tested six microsatellite markers that map to Xp (DXS987, DXS989, DXS993, DXS999, DXS1003 and DXS1110). Of these, DXS989 showed tight linkage with one allele (199) showing a 100% concordance with disease status. The odds favoring an X-linked dominant mode of inheritance in this family, versus autosomal dominant, are 10{sup 5}:1. In addition, recombinations for DXS999, and dXS1110, the two markers flanking DXS989, were observed in affected individuals. These data map the disease locus in this family to a 9 mb region on the X chromosome between Xp22.11 and Xp21.41. In addition, the recombinant individuals exclude close linkage to RP2 and RP3. The observance of high penetrance in females indicates that this family has X-linked dominant retinitis pigmentosa. We suggest that this mode of inheritance should be considered in other families with dominant retinitis pigmentosa but an absence of male-to-male transmission.« less

Screening for fragile X syndrome.

PubMed

Murray, J; Cuckle, H; Taylor, G; Hewison, J

1997-01-01

BACKGROUND AND AIM OF REVIEW. In 1991, the gene responsible for fragile X syndrome, a common cause of learning disability, was discovered. As a result, diagnosis of the disorder has improved and its molecular genetics are now understood. This report seems to provide the information needed to decide whether to use DNA testing to screen for the disorder. HOW THE RESEARCH WAS CONDUCTED. A literature search of electronic reference databases of published and 'grey' literature was undertaken together with hand searching of the most recent publications. RESEARCH FINDINGS. NATURAL HISTORY. Physical characteristics of fragile X syndrome include facial atypia, joint laxity and, in boys, macro-orchidism. Most affected males have moderate-to-severe learning disabilities with IQs under 50 whereas most females have borderline IQs of 70-85. Behavioural problems are similar to those seen with autism and attention-deficit disorders. Although fragile X syndrome is not curable there are a number of medical, educational, psychological and social interventions that can improve the symptoms. About 6% of those with learning disabilities tested in institutions have fragile X syndrome. Population prevalence figures are 1 in 4000 in males and 1 in 8000 in females. GENETICS. The disorder is caused by a mutation in a gene on the X chromosome which includes a trinucleotide repeat sequence. The mutation is characterized by hyper-expansion of the repeat sequence leading to down-regulation of the gene. In males an allele with repeat size in excess of 200, termed a full mutation (FM), is always associated with the affected phenotype, whereas in females only half are affected. Individuals with alleles having repeat size in the range 55-199 are unaffected but in females the sequence is heritably unstable so that it is at high risk of expansion to an FM in her offspring. This allele is known as a pre-mutation (PM) to contrast it with the FM found in the affected individual. No spontaneous expansions

Role of prostaglandins in the pathogenesis of X-linked hypophosphatemia.

PubMed

Baum, Michel; Syal, Ashu; Quigley, Raymond; Seikaly, Mouin

2006-08-01

X-linked hypophosphatemia is an X-linked dominant disorder resulting from a mutation in the PHEX gene. PHEX stands for phosphate-regulating gene with endopeptidase activity, which is located on the X chromosome. Patients with X-linked hypophosphatemia have hypophosphatemia due to renal phosphate wasting and low or inappropriately normal levels of 1,25-dihydroxyvitamin D. The renal phosphate wasting is not intrinsic to the kidney but likely due to an increase in serum levels of fibroblast growth factor-23 (FGF-23), and perhaps other phosphate-wasting peptides previously known as phosphatonins. Patients with X-linked hypophosphatemia have short stature, rickets, bone pain and dental abscesses. Current therapy is oral phosphate and vitamin D which effectively treats the rickets and bone pain but does not adequately improve short stature. In this review, we describe recent observations using Hyp mice; mice with the same mutation as patients with X-linked hypophosphatemia. We have recently found that Hyp mice have abnormal renal prostaglandin production, which may be an important factor in the pathogenesis of this disorder. Administration of FGF-23 in vivo results in phosphaturia and an increase in prostaglandin excretion, and FGF-23 increases proximal tubule prostaglandin production in vitro. In Hyp mice, indomethacin improves the phosphate transport defect in vitro and in vivo. Whether indomethacin has the same effect in patients with X-linked hypophosphatemia is unknown.

Refinement of the X-linked cataract locus (CXN) and gene analysis for CXN and Nance-Horan syndrome (NHS).

PubMed

Brooks, Simon; Ebenezer, Neil; Poopalasundaram, Subathra; Maher, Eamonn; Francis, Peter; Moore, Anthony; Hardcastle, Alison

2004-06-01

The X-linked congenital cataract (CXN) locus has been mapped to a 3-cM (approximately 3.5 Mb) interval on chromosome Xp22.13, which is syntenic to the mouse cataract disease locus Xcat and encompasses the recently refined Nance-Horan syndrome (NHS) locus. A positional cloning strategy has been adopted to identify the causative gene. In an attempt to refine the CXN locus, seven microsatellites were analysed within 21 individuals of a CXN family. Haplotypes were reconstructed confirming disease segregation with markers on Xp22.13. In addition, a proximal cross-over was observed between markers S3 and S4, thereby refining the CXN disease interval by approximately 400 Kb to 3.2 Mb, flanked by markers DXS9902 and S4. Two known genes (RAI2 and RBBP7) and a novel gene (TL1) were screened for mutations within an affected male from the CXN family and an NHS family by direct sequencing of coding exons and intron- exon splice sites. No mutations or polymorphisms were identified, therefore excluding them as disease-causative in CXN and NHS. In conclusion, the CXN locus has been successfully refined and excludes PPEF1 as a candidate gene. A further three candidates were excluded based on sequence analysis. Future positional cloning efforts will focus on the region of overlap between CXN, Xcat, and NHS.

Fragile X Syndrome: Keys to the Molecular Genetics of Synaptic Plasticity

ERIC Educational Resources Information Center

Lombroso, Paul J.; Ogren, Marilee P.

2008-01-01

Fragile X syndrome, the most common form of inherited mental retardation is discussed. The relationship between specific impairments in synaptic plasticity and Fragile X syndrome is investigated as it strengthens synaptic contacts between neurons.

The Chemical Chaperone, PBA, Reduces ER Stress and Autophagy and Increases Collagen IV α5 Expression in Cultured Fibroblasts From Men With X-Linked Alport Syndrome and Missense Mutations.

PubMed

Wang, Dongmao; Mohammad, Mardhiah; Wang, Yanyan; Tan, Rachel; Murray, Lydia S; Ricardo, Sharon; Dagher, Hayat; van Agtmael, Tom; Savige, Judy

2017-07-01

X-linked Alport syndrome (OMIM 301050) is caused by COL4A5 missense variants in 40% of families. This study examined the effects of chemical chaperone treatment (sodium 4-phenylbutyrate) on fibroblast cell lines derived from men with missense mutations. Dermal fibroblast cultures were established from 2 affected men and 3 normals. Proliferation rates were examined, the collagen IV α5 chain localized with immunostaining, and levels of the intra- and extracellular chains quantitated with an in-house enzyme-linked immunosorbent assay. COL4A5 mRNA was measured using quantitative reverse transcriptase polymerase chain reaction. Endoplasmic reticulum (ER) size was measured on electron micrographs and after HSP47 immunostaining. Markers of ER stress (ATF6, HSPA5, DDIT3), autophagy (ATG5, BECN1, ATG7), and apoptosis (CASP3, BAD, BCL 2 ) were also quantitated by quantitative reverse transcriptase polymerase chain reaction. Measurements were repeated after 48 hours of incubation with 10 mM sodium 4-phenylbutyrate acid. Both COL4A5 missense variants were associated with reduced proliferation rates on day 6 ( P  = 0.01 and P  = 0.03), ER enlargement, and increased mRNA for ER stress and autophagy (all P values < 0.05) when compared with normal. Sodium 4-phenylbutyrate treatment increased COL4A5 transcript levels ( P  < 0.01), and reduced ER size ( P  < 0.01 by EM and P  < 0.001 by immunostaining), ER stress (p HSPA5 and DDIT3, all P values < 0.01) and autophagy (ATG7, P  < 0.01). Extracellular collagen IV α5 chain was increased in the M1 line only ( P  = 0.06). Sodium 4-phenylbutyrate increases collagen IV α5 mRNA levels, reduces ER stress and autophagy, and possibly facilitates collagen IV α5 extracellular transport. Whether these actions delay end-stage renal failure in men with X-linked Alport syndrome and missense mutations will only be determined with clinical trials.

Nance-Horan syndrome in females due to a balanced X;1 translocation that disrupts the NHS gene: Familial case report and review of the literature.

PubMed

Gómez-Laguna, Laura; Martínez-Herrera, Alejandro; Reyes-de la Rosa, Alejandra Del Pilar; García-Delgado, Constanza; Nieto-Martínez, Karem; Fernández-Ramírez, Fernando; Valderrama-Atayupanqui, Tania Yanet; Morales-Jiménez, Ariadna Berenice; Villa-Morales, Judith; Kofman, Susana; Cervantes, Alicia; Morán-Barroso, Verónica Fabiola

2018-01-01

The Nance-Horan syndrome is an X-linked disorder characterized by congenital cataract, facial features, microcornea, microphthalmia, and dental anomalies; most of the cases are due to NHS gene mutations on Xp22.13. Heterozygous carrier females generally present less severe features, and up to 30% of the affected males have intellectual disability. We describe two patients, mother and daughter, manifesting Nance-Horan syndrome. The cytogenetic and molecular analyses demonstrated a 46,X,t(X;1)(p22.13;q22) karyotype in each of them. No copy-number genomic imbalances were detected by high-density microarray analysis. The mother had a preferential inactivation of the normal X chromosome; expression analysis did not detect any mRNA isoform of NHS. This is the first report of Nance-Horan syndrome due to a skewed X chromosome inactivation resulting from a balanced translocation t(X;1) that disrupts the NHS gene expression, with important implications for clinical presentation and genetic counseling.

Using Perceptual Signatures to Define and Dissociate Condition-Specific Neural Etiology: Autism and Fragile X Syndrome as Model Conditions

ERIC Educational Resources Information Center

Bertone, Armando; Hanck, Julie; Kogan, Cary; Chaudhuri, Avi; Cornish, Kim

2010-01-01

The functional link between genetic alteration and behavioral end-state is rarely straightforward and never linear. Cases where neurodevlopmental conditions defined by a distinct genetic etiology share behavioral phenotypes are exemplary, as is the case for autism and Fragile X Syndrome (FXS). In this paper and its companion paper, we propose a…

Mathematics Learning Disability in Girls with Turner Syndrome or Fragile X Syndrome

ERIC Educational Resources Information Center

Murphy, Melissa M.; Mazzocco, Michele M. M.; Gerner, Gwendolyn; Henry, Anne E.

2006-01-01

Two studies were carried out to examine the persistence (Study 1) and characteristics (Study 2) of mathematics learning disability (MLD) in girls with Turner syndrome or fragile X during the primary school years (ages 5-9 years). In Study 1, the rate of MLD for each syndrome group exceeded the rate observed in a grade-matched comparison group,…

Degraded speech sound processing in a rat model of fragile X syndrome

PubMed Central

Engineer, Crystal T.; Centanni, Tracy M.; Im, Kwok W.; Rahebi, Kimiya C.; Buell, Elizabeth P.; Kilgard, Michael P.

2014-01-01

Fragile X syndrome is the most common inherited form of intellectual disability and the leading genetic cause of autism. Impaired phonological processing in fragile X syndrome interferes with the development of language skills. Although auditory cortex responses are known to be abnormal in fragile X syndrome, it is not clear how these differences impact speech sound processing. This study provides the first evidence that the cortical representation of speech sounds is impaired in Fmr1 knockout rats, despite normal speech discrimination behavior. Evoked potentials and spiking activity in response to speech sounds, noise burst trains, and tones were significantly degraded in primary auditory cortex, anterior auditory field and the ventral auditory field. Neurometric analysis of speech evoked activity using a pattern classifier confirmed that activity in these fields contains significantly less information about speech sound identity in Fmr1 knockout rats compared to control rats. Responses were normal in the posterior auditory field, which is associated with sound localization. The greatest impairment was observed in the ventral auditory field, which is related to emotional regulation. Dysfunction in the ventral auditory field may contribute to poor emotional regulation in fragile X syndrome and may help explain the observation that later auditory evoked responses are more disturbed in fragile X syndrome compared to earlier responses. Rodent models of fragile X syndrome are likely to prove useful for understanding the biological basis of fragile X syndrome and for testing candidate therapies. PMID:24713347

Molecular mechanisms of fragile X syndrome: a twenty-year perspective.

PubMed

Santoro, Michael R; Bray, Steven M; Warren, Stephen T

2012-01-01

Fragile X syndrome (FXS) is a common form of inherited intellectual disability and is one of the leading known causes of autism. The mutation responsible for FXS is a large expansion of the trinucleotide CGG repeat in the 5' untranslated region of the X-linked gene FMR1. This expansion leads to DNA methylation of FMR1 and to transcriptional silencing, which results in the absence of the gene product, FMRP, a selective messenger RNA (mRNA)-binding protein that regulates the translation of a subset of dendritic mRNAs. FMRP is critical for mGluR (metabotropic glutamate receptor)-dependent long-term depression, as well as for other forms of synaptic plasticity; its absence causes excessive and persistent protein synthesis in postsynaptic dendrites and dysregulated synaptic function. Studies continue to refine our understanding of FMRP's role in synaptic plasticity and to uncover new functions of this protein, which have illuminated therapeutic approaches for FXS.

Heart Activity and Autistic Behavior in Infants and Toddlers with Fragile X Syndrome

ERIC Educational Resources Information Center

Roberts, Jane E.; Tonnsen, Bridgette; Robinson, Ashley; Shinkareva, Svetlana V.

2012-01-01

The present study contrasted physiological arousal in infants and toddlers with fragile X syndrome to typically developing control participants and examined physiological predictors early in development to autism severity later in development in fragile X syndrome. Thirty-one males with fragile X syndrome (ages 8-40 months) and 25 age-matched…

Fragile X Syndrome--From Genes to Cognition

ERIC Educational Resources Information Center

Schneider, A.; Hagerman, R. J.; Hessl, D.

2009-01-01

Fragile X syndrome (FXS), a single gene disorder with an expanded CGG allele on the X chromosome, is the most common form of inherited cognitive impairment. The cognitive deficit ranges from mild learning disabilities to severe intellectual disability. The phenotype includes hyperactivity, short attention span, emotional problems including…

Contemporary Medical and Surgical Management of X-linked Hypophosphatemic Rickets.

PubMed

Sharkey, Melinda S; Grunseich, Karl; Carpenter, Thomas O

2015-07-01

X-linked hypophosphatemia is an inheritable disorder of renal phosphate wasting that clinically manifests with rachitic bone pathology. X-linked hypophosphatemia is frequently misdiagnosed and mismanaged. Optimized medical therapy is the cornerstone of treatment. Even with ideal medical management, progressive bony deformity may develop in some children and adults. Medical treatment is paramount to the success of orthopaedic surgical procedures in both children and adults with X-linked hypophosphatemia. Successful correction of complex, multiapical bone deformities found in patients with X-linked hypophosphatemia is possible with careful surgical planning and exacting surgical technique. Multiple methods of deformity correction are used, including acute and gradual correction. Treatment of some pediatric bony deformity with guided growth techniques may be possible. Copyright 2015 by the American Academy of Orthopaedic Surgeons.

Viewing Social Scenes: A Visual Scan-Path Study Comparing Fragile X Syndrome and Williams Syndrome

ERIC Educational Resources Information Center

Williams, Tracey A.; Porter, Melanie A.; Langdon, Robyn

2013-01-01

Fragile X syndrome (FXS) and Williams syndrome (WS) are both genetic disorders which present with similar cognitive-behavioral problems, but distinct social phenotypes. Despite these social differences both syndromes display poor social relations which may result from abnormal social processing. This study aimed to manipulate the location of…

Fragile X Syndrome in Males: Diagnostic, Behavioral, and Educational Implications.

ERIC Educational Resources Information Center

Bellinger, Diane; And Others

This paper reviews the research on fragile X syndrome, the second most common cause of mental retardation related to chromosomal anomaly. It notes that far more males than females are affected by the fragile X syndrome, which typically results in craniofacial changes, delays in growth and development, speech/language difficulties, and cognitive…

Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)

ERIC Educational Resources Information Center

Hagerman, Paul J.; Hagerman, Randi J.

2004-01-01

Carriers of fragile X mental retardation 1 ("FMR1") premutation alleles (55 to 200 CGG repeats) are generally spared the more serious neurodevelopmental problems associated with the full-mutation carriers (greater than 200 repeats) of fragile X syndrome. However, some adult male premutation carriers (55-200 repeats) develop a neurological syndrome…

A novel germline PIGA mutation in Ferro-Cerebro-Cutaneous syndrome: a neurodegenerative X-linked epileptic encephalopathy with systemic iron-overload.

PubMed

Swoboda, Kathryn J; Margraf, Rebecca L; Carey, John C; Zhou, Holly; Newcomb, Tara M; Coonrod, Emily; Durtschi, Jacob; Mallempati, Kalyan; Kumanovics, Attila; Katz, Ben E; Voelkerding, Karl V; Opitz, John M

2014-01-01

Three related males presented with a newly recognized x-linked syndrome associated with neurodegeneration, cutaneous abnormalities, and systemic iron overload. Linkage studies demonstrated that they shared a haplotype on Xp21.3-Xp22.2 and exome sequencing was used to identify candidate variants. Of the segregating variants, only a PIGA mutation segregated with disease in the family. The c.328_330delCCT PIGA variant predicts, p.Leu110del (or c.1030_1032delCTT, p.Leu344del depending on the reference sequence). The unaffected great-grandfather shared his X allele with the proband but he did not have the PIGA mutation, indicating that the mutation arose de novo in his daughter. A single family with a germline PIGA mutation has been reported; affected males had a phenotype characterized by multiple congenital anomalies and severe neurologic impairment resulting in infantile lethality. In contrast, affected boys in the family described here were born without anomalies and were neurologically normal prior to onset of seizures after 6 months of age, with two surviving to the second decade. PIGA encodes an enzyme in the GPI anchor biosynthesis pathway. An affected individual in the family studied here was deficient in GPI anchor proteins on granulocytes but not erythrocytes. In conclusion, the PIGA mutation in this family likely causes a reduction in GPI anchor protein cell surface expression in various cell types, resulting in the observed pleiotropic phenotype involving central nervous system, skin, and iron metabolism. © 2013 Wiley Periodicals, Inc.

Down Syndrome and Fragile X Syndrome in a Colombian Woman: Case Report

ERIC Educational Resources Information Center

Saldarriaga, Wilmar; Ruiz, Fabian Andres; Tassone, Flora; Hagerman, Randi

2017-01-01

Background: Down syndrome (DS) and Fragile X syndrome (FXS) are the major genetic causes of intellectual disabilities. Here, we present a case of a 32-year-old woman with the diagnosis of both FXS and DS. She is the daughter of a 47-year-old pre-mutation woman who also has three sons with FXS. Methods: Cytogenetic testing detected the presence of…

Triple X Syndrome: Symptoms and Causes

MedlinePlus

... be more pronounced — possibly including developmental delays and learning disabilities. Treatment for triple X syndrome depends on which ... motor skills, such as sitting up and walking Learning disabilities, such as difficulty with reading (dyslexia), understanding or ...

Triple X syndrome: a review of the literature.

PubMed

Otter, Maarten; Schrander-Stumpel, Constance T R M; Curfs, Leopold M G

2010-03-01

The developmental and clinical aspects in the literature on triple X syndrome are reviewed. Prenatal diagnosis depends on karyotyping. The incidence is 1 of 1000 females. At birth, 47,XXX girls have a lower mean birth weight and a smaller head circumference. Triple X diagnosis was not suspected at birth. The maternal age seems to be increased. Toddlers with triple X syndrome show delayed language development. The youngest girls show accelerated growth until puberty. EEG abnormalities seem to be rather common. Many girls show motor-coordination problems and auditory-processing disorders are not rare. Scoliosis is probably more common in adolescent cases. The IQ levels are 20 points below that of controls, and verbal IQ is lowest. The girls struggle with low self-esteem and they need psychological, behavioural and educational support. They perform best in stable families. After leaving school they seem to feel better. In adults, premature ovarian failure seems to be more prevalent than in controls. MRIs of the brain seem to show decreased brain volumes. The 47,XXX women most often find jobs that reflect their performance abilities. Psychotic illness seems to be more prevalent in triple X adult women than in controls. Psychotic disorders respond well to psychotropic drugs. Triple X adults suffer more frequently from cyclothymic and labile personality traits. Research on triple X syndrome may yield more insight into brain and behaviour relations, developmental psychopathology, auditory-processing disorders, EEG disorders, personality and psychotic disorders, etc.

Molecular genetics in neurology.

PubMed

Martin, J B

1993-12-01

There has been remarkable progress in the identification of mutations in genes that cause inherited neurological disorders. Abnormalities in the genes for Huntington disease, neurofibromatosis types 1 and 2, one form of familial amyotrophic lateral sclerosis, fragile X syndrome, myotonic dystrophy, Kennedy syndrome, Menkes disease, and several forms of retinitis pigmentosa have been elucidated. Rare disorders of neuronal migration such as Kallmann syndrome, Miller-Dieker syndrome, and Norrie disease have been shown to be due to specific gene defects. Several muscle disorders characterized by abnormal membrane excitability have been defined as mutations of the muscle sodium or chloride channels. These advances provide opportunity for accurate molecular diagnosis of at-risk individuals and are the harbinger of new approaches to therapy of these diseases.

Do individuals with fragile X syndrome show developmental stuttering or not? Comment on "Speech fluency in fragile X syndrome" by van Borsel, Dor and Rondal.

PubMed

Howell, Peter

2008-02-01

Van Borsel, Dor, and Rondal (2007) examined the speech of seven boys and two young male adults with fragile X syndrome and considered whether their speech was comparable to that reported in the developmental stuttering literature. They listed five criteria which led them to conclude that the speech patterns of speakers with fragile X syndrome differed from those observed in developmental stuttering. The differences noted were: 1) distribution of type of dysfluency; 2) the class of word on which dysfluency occurred; 3) whether word length affected dysfluency; 4) number of times words and phrases were repeated; and 5) whether there were influences of material type on fluency (spontaneous speech, repeated material etc.). They concluded that the speech of speakers with fragile X syndrome differed from developmental stuttering. The comparisons that van Borsel et al. (2007) made between participant groups were not for speakers of comparable ages. Comparisons with groups of corresponding ages support the opposite conclusion, namely the young speakers with fragile X syndrome show patterns similar to developmental stuttering.

X-linked hypophosphatemia attributable to pseudoexons of the PHEX gene.

PubMed

Christie, P T; Harding, B; Nesbit, M A; Whyte, M P; Thakker, R V

2001-08-01

X-linked hypophosphatemia is commonly caused by mutations of the coding region of PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome). However, such PHEX mutations are not detected in approximately one third of X-linked hypophosphatemia patients who may harbor defects in the noncoding or intronic regions. We have therefore investigated 11 unrelated X-linked hypophosphatemia patients in whom coding region mutations had been excluded, for intronic mutations that may lead to mRNA splicing abnormalities, by the use of lymphoblastoid RNA and RT-PCRs. One X-linked hypophosphatemia patient was found to have 3 abnormally large transcripts, resulting from 51-bp, 100-bp, and 170-bp insertions, all of which would lead to missense peptides and premature termination codons. The origin of these transcripts was a mutation (g to t) at position +1268 of intron 7, which resulted in the occurrence of a high quality novel donor splice site (ggaagg to gtaagg). Splicing between this novel donor splice site and 3 preexisting, but normally silent, acceptor splice sites within intron 7 resulted in the occurrences of the 3 pseudoexons. This represents the first report of PHEX pseudoexons and reveals further the diversity of genetic abnormalities causing X-linked hypophosphatemia.

Unraveling unusual X-chromosome patterns during fragile-X syndrome genetic testing.

PubMed

Esposito, Gabriella; Tremolaterra, Maria Roberta; Savarese, Maria; Spiniello, Michele; Patrizio, Maria Pia; Lombardo, Barbara; Pastore, Lucio; Salvatore, Francesco; Carsana, Antonella

2018-01-01

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability (ID). Together with fragile X-associated tremor and ataxia (FXTAS) and fragile X-associated premature ovarian failure (POF)/primary ovarian insufficiency (POI), FXS depends on dysfunctional expression of the FMR1 gene on Xq27.3. In most cases, FXS is caused by a >200 CGG repeats in FMR1 5'-untranslated region (UTR) and by promoter hypermethylation that results in gene silencing. Males and females with unmethylated premutated alleles (repeats between 55 and 200) are at risk for FXTAS and POF/POI. FXS molecular testing relied on PCR and methylation-specific Southern blot analysis of the FMR1 5'UTR. Atypical Southern blot patterns were studied by X-chromosome microsatellite analysis, copy number dosage at DMD locus, amelogenin gender-marker analysis and array-comparative genomic hybridization (array-CGH). Six men affected by ID and three women affected by ID and POF/POI underwent FXS molecular testing. They had normal FMR1 CGG repeats, but atypical X chromosome patterns. Further investigations revealed that the six males had Klinefelter syndrome (XXY), one female was a Turner mosaic (X0/XX) and two women had novel rearrangements involving X chromosome. Diagnostic investigation of atypical patterns at FMR1 locus can address patients and/or their relatives to further verify the condition by performing karyotyping and/or array-CGH. Copyright © 2017. Published by Elsevier B.V.

Impaired plasticity of macrophages in X-linked adrenoleukodystrophy.

PubMed

Weinhofer, Isabelle; Zierfuss, Bettina; Hametner, Simon; Wagner, Magdalena; Popitsch, Niko; Machacek, Christian; Bartolini, Barbara; Zlabinger, Gerhard; Ohradanova-Repic, Anna; Stockinger, Hannes; Köhler, Wolfgang; Höftberger, Romana; Regelsberger, Günther; Forss-Petter, Sonja; Lassmann, Hans; Berger, Johannes

2018-05-30

X-linked adrenoleukodystrophy is caused by ATP-binding cassette transporter D1 (ABCD1) mutations and manifests by default as slowly progressive spinal cord axonopathy with associated demyelination (adrenomyloneuropathy). In 60% of male cases, however, X-linked adrenoleukodystrophy converts to devastating cerebral inflammation and demyelination (cerebral adrenoleukodystrophy) with infiltrating blood-derived monocytes and macrophages and cytotoxic T cells that can only be stopped by allogeneic haematopoietic stem cell transplantation or gene therapy at an early stage of the disease. Recently, we identified monocytes/macrophages but not T cells to be severely affected metabolically by ABCD1 deficiency. Here we found by whole transcriptome analysis that, although monocytes of patients with X-linked adrenoleukodystrophy have normal capacity for macrophage differentiation and phagocytosis, they are pro-inflammatory skewed also in patients with adrenomyloneuropathy in the absence of cerebral inflammation. Following lipopolysaccharide activation, the ingestion of myelin debris, normally triggering anti-inflammatory polarization, did not fully reverse the pro-inflammatory status of X-linked adrenoleukodystrophy macrophages. Immunohistochemistry on post-mortem cerebral adrenoleukodystrophy lesions reflected the activation pattern by prominent presence of enlarged lipid-laden macrophages strongly positive for the pro-inflammatory marker co-stimulatory molecule CD86. Comparative analyses of lesions with matching macrophage density in cases of cerebral adrenoleukodystrophy and acute multiple sclerosis showed a similar extent of pro-inflammatory activation but a striking reduction of anti-inflammatory mannose receptor (CD206) and haemoglobin-haptoglobin receptor (CD163) expression on cerebral adrenoleukodystrophy macrophages. Accordingly, ABCD1-deficiency leads to an impaired plasticity of macrophages that is reflected in incomplete establishment of anti-inflammatory responses

Infant Development in Fragile X Syndrome: Cross-Syndrome Comparisons

ERIC Educational Resources Information Center

Roberts, Jane E.; McCary, Lindsay M.; Shinkareva, Svetlana V.; Bailey, Donald B., Jr.

2016-01-01

This study examined the developmental profile of male infants with fragile X syndrome (FXS) and its divergence from typical development and development of infants at high risk for autism associated with familial recurrence (ASIBs). Participants included 174 boys ranging in age from 5 to 28 months. Cross-sectional profiles on the Mullen Scales of…

[Metabolic syndrome and bipolar disorder: Is sleep the missing link?

PubMed

Brochard, H; Boudebesse, C; Henry, C; Godin, O; Leboyer, M; Étain, B

2016-12-01

To examine the pathophysiologic mechanisms that may link circadian disorder and metabolic syndrome in bipolar disorder (BP). A systematic review of the literature was conducted from January 2013 to January 2015, using the Medline and Cochrane databases, using the keywords "metabolic syndrome", "obesity", "leptin" and "circadian disorders", "sleeping disorders" and cross-referencing them with "bipolar disorder". The following types of publications were candidates for review: (i) clinical trials; (ii) studies involving patients diagnosed with bipolar disorder; (iii) studies involving patients with sleeping disorder; or (iv) data about metabolic syndrome. Forty articles were selected. The prevalence of metabolic syndrome in BP was significantly higher compared to the general population (from 36 to 49% in the USA [Vancampfort, 2013]), and could be explained by several factors including reduced exercise and poor diet, genetic vulnerability, frequent depressive episodes, psychiatric comorbidity and psychotropic treatment. This high frequency of metabolic syndrome worsens the prognosis of these patients, increasing morbidity and mortality. Secondly, patients with BP experienced circadian and sleep disturbance, including modification in melatonin secretion. These perturbations are known to persist in periods of mood stabilization and are found in patients' relatives. Circadian disturbances are factors of relapse in bipolar patients, and they may also have a role in the metabolic comorbidities of these patients. Recent studies show that in populations of patients with bipolar disorder, a correlation between circadian disturbance and metabolic parameters are found. To identify the pathophysiological pathway connecting both could lead to a better comprehension of the disease and new therapeutics. In the overall population, mechanisms have been identified linking circadian and metabolic disorder involving hormones like leptin and ghrelin. These hormones are keys to

Academic Skills of Boys With Fragile X Syndrome: Profiles and Predictors

ERIC Educational Resources Information Center

Roberts, Jane E.; Schaaf, Jennifer M.; Skinner, Martie; Wheeler, Anne; Hooper, Stephen; Hatton, Deborah D.; Bailey, Donald B., Jr.

2005-01-01

The academic achievement of boys with fragile X syndrome and the relation between several predictive factors and academic performance are reported. Boys with fragile X syndrome displayed significant deficits in all academic skill areas. Relative strengths were observed in general knowledge, reflecting the ability to integrate experiential…

Genetics Home Reference: X-linked spondyloepiphyseal dysplasia tarda

MedlinePlus

... Educational Resources (6 links) Cincinnati Children's Hospital: Coxa Vera Disease InfoSearch: Spondyloepiphyseal dysplasia tarda X-linked Johns ... Free article on PubMed Central Savarirayan R, Thompson E, Gécz J. Spondyloepiphyseal dysplasia tarda (SEDL, MIM #313400). ...

High functioning male with fragile X syndrome and fragile X-associated tremor/ataxia syndrome.

PubMed

Basuta, Kirin; Schneider, Andrea; Gane, Louise; Polussa, Jonathan; Woodruff, Bryan; Pretto, Dalyir; Hagerman, Randi; Tassone, Flora

2015-09-01

Fragile X syndrome (FXS) affects individuals with more than 200 CGG repeats (full mutation) in the fragile X mental retardation 1 (FMR1) gene. Those born with FXS experience cognitive and social impairments, developmental delays, and some features of autism spectrum disorders. Carriers of a premutation (55-200 CGG repeats) are generally not severely affected early in life; however, are at high risk of developing the late onset neurodegenerative disorder, Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), or Fragile X-associated Primary Ovarian Insufficiency (FXPOI), and may have other medical conditions such as developmental delay, autism spectrum disorders, hypertension, anxiety, and immune-mediated disorders. Here we present a case of a 58-year-old man with a borderline IQ, average memory skills, and executive function deficits. He met criteria for multiple psychiatric diagnoses and presented with tremor and ataxia, meeting criteria for FXTAS. Molecular testing unveiled a completely unmethylated FMR1 full mutation in peripheral blood mononucleated cells with elevated FMR1 mRNA and premutation alleles of different sizes in two other tissues (primary fibroblasts and sperm), indicating the presence of allele instability based on both inter- and intra-tissue mosaicism. The observation of FXTAS in this case of a full mutation mosaic man suggests that the pathogenic mechanism underlying this disorder is not observed exclusively in premutation carriers as it was originally thought. The concomitant presence of features of FXS and late onset neurological deterioration with probable FXTAS likely result from a combined molecular pathology of elevated FMR1 mRNA levels, a molecular hallmark of FXTAS and low FMRP expression that leads to FXS. © 2015 Wiley Periodicals, Inc.

Targeted pharmacological treatment of autism spectrum disorders: fragile X and Rett syndromes

PubMed Central

Wang, Hansen; Pati, Sandipan; Pozzo-Miller, Lucas; Doering, Laurie C.

2015-01-01

Autism spectrum disorders (ASDs) are genetically and clinically heterogeneous and lack effective medications to treat their core symptoms. Studies of syndromic ASDs caused by single gene mutations have provided insights into the pathophysiology of autism. Fragile X and Rett syndromes belong to the syndromic ASDs in which preclinical studies have identified rational targets for drug therapies focused on correcting underlying neural dysfunction. These preclinical discoveries are increasingly translating into exciting human clinical trials. Since there are significant molecular and neurobiological overlaps among ASDs, targeted treatments developed for fragile X and Rett syndromes may be helpful for autism of different etiologies. Here, we review the targeted pharmacological treatment of fragile X and Rett syndromes and discuss related issues in both preclinical studies and clinical trials of potential therapies for the diseases. PMID:25767435

Cognitive, Environmental, and Linguistic Predictors of Syntax in Fragile X Syndrome and Down Syndrome

ERIC Educational Resources Information Center

Estigarribia, Bruno; Martin, Gary E.; Roberts, Joanne E.

2012-01-01

Purpose: To examine which cognitive, environmental, and speech-language variables predict expressive syntax in boys with fragile X syndrome (FXS), boys with Down syndrome (DS), and typically developing (TD) boys, and whether predictive relationships differed by group. Method: We obtained Index of Productive Syntax ( Scarborough, 1990) scores for…

Autism Profiles of Males With Fragile X Syndrome

ERIC Educational Resources Information Center

Harris, Susan W.; Hessl, David; Goodlin-Jones, Beth; Ferranti, Jessica; Bacalman, Susan; Barbato, Ingrid; Tassone, Flora; Hagerman, Paul J.; Herman, Kristin; Hagerman, Randi J.

2008-01-01

Autism, which is common in individuals with fragile X syndrome, is often difficult to diagnose. We compared the diagnostic classifications of two measures for autism diagnosis, the ADOS and the ADI-R, in addition to the DSM-IV-TR in 63 males with this syndrome. Overall, 30% of the subjects met criteria for autistic disorder and 30% met criteria…

siRNAs from an X-linked satellite repeat promote X-chromosome recognition in Drosophila melanogaster.

PubMed

Menon, Debashish U; Coarfa, Cristian; Xiao, Weimin; Gunaratne, Preethi H; Meller, Victoria H

2014-11-18

Highly differentiated sex chromosomes create a lethal imbalance in gene expression in one sex. To accommodate hemizygosity of the X chromosome in male fruit flies, expression of X-linked genes increases twofold. This is achieved by the male- specific lethal (MSL) complex, which modifies chromatin to increase expression. Mutations that disrupt the X localization of this complex decrease the expression of X-linked genes and reduce male survival. The mechanism that restricts the MSL complex to X chromatin is not understood. We recently reported that the siRNA pathway contributes to localization of the MSL complex, raising questions about the source of the siRNAs involved. The X-linked 1.688 g/cm(3) satellite related repeats (1.688(X) repeats) are restricted to the X chromosome and produce small RNA, making them an attractive candidate. We tested RNA from these repeats for a role in dosage compensation and found that ectopic expression of single-stranded RNAs from 1.688(X) repeats enhanced the male lethality of mutants with defective X recognition. In contrast, expression of double-stranded hairpin RNA from a 1.688(X) repeat generated abundant siRNA and dramatically increased male survival. Consistent with improved survival, X localization of the MSL complex was largely restored in these males. The striking distribution of 1.688(X) repeats, which are nearly exclusive to the X chromosome, suggests that these are cis-acting elements contributing to identification of X chromatin.

An Investigation of Narrative Ability in Boys with Autism and Fragile X Syndrome

ERIC Educational Resources Information Center

Hogan-Brown, Abigail L.; Losh, Molly; Martin, Gary E.; Mueffelmann, Deborah J.

2013-01-01

Whereas pragmatic language difficulties are characteristic of both autism and Fragile X syndrome, it is unclear whether such deficits are qualitatively similar or whether certain skills are differentially affected. This study compared narrative competence in boys with autism, Fragile X syndrome, Down syndrome, and typical development. Results…

Resolution of spatial and temporal visual attention in infants with fragile X syndrome.

PubMed

Farzin, Faraz; Rivera, Susan M; Whitney, David

2011-11-01

Fragile X syndrome is the most common cause of inherited intellectual impairment and the most common single-gene cause of autism. Individuals with fragile X syndrome present with a neurobehavioural phenotype that includes selective deficits in spatiotemporal visual perception associated with neural processing in frontal-parietal networks of the brain. The goal of the current study was to examine whether reduced resolution of spatial and/or temporal visual attention may underlie perceptual deficits related to fragile X syndrome. Eye tracking was used to psychophysically measure the limits of spatial and temporal attention in infants with fragile X syndrome and age-matched neurotypically developing infants. Results from these experiments revealed that infants with fragile X syndrome experience drastically reduced resolution of temporal attention in a genetic dose-sensitive manner, but have a spatial resolution of attention that is not impaired. Coarse temporal attention could have significant knock-on effects for the development of perceptual, cognitive and motor abilities in individuals with the disorder.

Resolution of spatial and temporal visual attention in infants with fragile X syndrome

PubMed Central

Rivera, Susan M.; Whitney, David

2011-01-01

Fragile X syndrome is the most common cause of inherited intellectual impairment and the most common single-gene cause of autism. Individuals with fragile X syndrome present with a neurobehavioural phenotype that includes selective deficits in spatiotemporal visual perception associated with neural processing in frontal–parietal networks of the brain. The goal of the current study was to examine whether reduced resolution of spatial and/or temporal visual attention may underlie perceptual deficits related to fragile X syndrome. Eye tracking was used to psychophysically measure the limits of spatial and temporal attention in infants with fragile X syndrome and age-matched neurotypically developing infants. Results from these experiments revealed that infants with fragile X syndrome experience drastically reduced resolution of temporal attention in a genetic dose-sensitive manner, but have a spatial resolution of attention that is not impaired. Coarse temporal attention could have significant knock-on effects for the development of perceptual, cognitive and motor abilities in individuals with the disorder. PMID:22075522

Math Learning Disability and Math LD Subtypes: Evidence from Studies of Turner Syndrome, Fragile X Syndrome, and Neurofibromatosis Type 1.

ERIC Educational Resources Information Center

Mazzocco, Michele M. M.

2001-01-01

This study examined whether indicators of math learning disability were observed in 35 5- and 6-year-olds with either neurofibromatosis, Turner Syndrome, or fragile X syndrome and compared to controls. Findings indicate that girls with fragile X or Turner syndrome but not neurofibromatosis are significantly more likely to have specific math…

Genetics Home Reference: X-linked agammaglobulinemia

MedlinePlus

... Sep;104(3):221-30. Citation on PubMed Smith CIE, Berglöf A. X-Linked Agammaglobulinemia. 2001 Apr ... Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews® [Internet]. Seattle (WA): ...

Family Environment and Behavior Problems in Children, Adolescents, and Adults with Fragile X Syndrome

ERIC Educational Resources Information Center

Greenberg, Jan S.; Seltzer, Marsha Mailick; Baker, Jason K.; Smith, Leann E.; Warren, Steven F.; Brady, Nancy; Hong, Jinkuk

2012-01-01

We examine how the family environment is associated with aspects of the Fragile X syndrome phenotype during childhood, adolescence, and adulthood. Mothers of children (n = 48), adolescents (n = 85), and adults (n = 34) with Fragile X syndrome participated in a multisite study. For children and adults with Fragile X syndrome, the presence of warmth…

Examining the Function of Problem Behavior in Fragile X Syndrome: Preliminary Experimental Analysis

ERIC Educational Resources Information Center

Langthorne, Paul; McGill, Peter; O'Reilly, Mark F.; Lang, Russell; Machalicek, Wendy; Chan, Jeffrey Michael; Rispoli, Mandy

2011-01-01

Fragile X syndrome is the most common inherited cause of intellectual and developmental disability. The influence of environmental variables on behaviors associated with the syndrome has received only scant attention. The current study explored the function served by problem behavior in fragile X syndrome by using experimental functional analysis…

Collaboration in Referential Communication: Comparison of Youth with Down Syndrome or Fragile X Syndrome

ERIC Educational Resources Information Center

Abbeduto, Leonard; Murphy, Melissa M.; Richmond, Erica K.; Amman, Adrienne; Beth, Patti; Weissman, Michelle D.; Kim, Jee-Seon; Cawthon, Stephanie W.; Karadottir, Selma

2006-01-01

Referential communication was examined in youth with Down syndrome or fragile X syndrome in comparison to each other and to MA-matched typically developing children. A non-face-to-face task was used in which the participant repeatedly described novel shapes to listeners. Several dimensions of referential communication were especially challenging…

Expert guidelines for the management of Alport syndrome and thin basement membrane nephropathy.

PubMed

Savige, Judy; Gregory, Martin; Gross, Oliver; Kashtan, Clifford; Ding, Jie; Flinter, Frances

2013-02-01

Few prospective, randomized controlled clinical trials address the diagnosis and management of patients with Alport syndrome or thin basement membrane nephropathy. Adult and pediatric nephrologists and geneticists from four continents whose clinical practice focuses on these conditions have developed the following guidelines. The 18 recommendations are based on Level D (Expert opinion without explicit critical appraisal, or based on physiology, bench research, or first principles-National Health Service category) or Level III (Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees-U.S. Preventive Services Task Force) evidence. The recommendations include the use of genetic testing as the gold standard for the diagnosis of Alport syndrome and the demonstration of its mode of inheritance; the need to identify and follow all affected members of a family with X-linked Alport syndrome, including most mothers of affected males; the treatment of males with X-linked Alport syndrome and individuals with autosomal recessive disease with renin-angiotensin system blockade, possibly even before the onset of proteinuria; discouraging the affected mothers of males with X-linked Alport syndrome from renal donation because of their own risk of kidney failure; and consideration of genetic testing to exclude X-linked Alport syndrome in some individuals with thin basement membrane nephropathy. The authors recognize that as evidence emerges, including data from patient registries, these guidelines will evolve further.

Behavioral Intervention for Problem Behavior in Children with Fragile X Syndrome

ERIC Educational Resources Information Center

Moskowitz, Lauren J.; Carr, Edward G.; Durand, V. Mark

2011-01-01

Parents and professionals typically report problem behavior as a significant concern for children with fragile X syndrome. In the present study, the authors explored whether behaviorally based interventions would result in a reduction in problem behavior and an improvement in quality of life for 3 children with fragile X syndrome and their…

Expressive Language during Conversational Speech in Boys with Fragile X Syndrome

ERIC Educational Resources Information Center

Roberts, Joanne E.; Hennon, Elizabeth A.; Price, Johanna R.; Dear, Elizabeth; Anderson, Kathleen; Vandergrift, Nathan A.

2007-01-01

We compared the expressive syntax and vocabulary skills of 35 boys with fragile X syndrome and 27 younger typically developing boys who were at similar nonverbal mental levels. During a conversational speech sample, the boys with fragile X syndrome used shorter, less complex utterances and produced fewer different words than did the typically…

Severe manifestations in carrier females in X linked retinitis pigmentosa.

PubMed Central

Souied, E; Segues, B; Ghazi, I; Rozet, J M; Chatelin, S; Gerber, S; Perrault, I; Michel-Awad, A; Briard, M L; Plessis, G; Dufier, J L; Munnich, A; Kaplan, J

1997-01-01

Retinitis pigmentosa (RP) is a group of progressive hereditary disorders of the retina in which various modes of inheritance have been described. Here, we report on X linked RP in nine families with constant and severe expression in carrier females. In our series, however, the phenotype was milder and delayed in carrier females compared to hemizygous males. This form of X linked RP could be regarded therefore as partially dominant. The disease gene maps to chromosome Xp2.1 in the genetic interval encompassing the RP3 locus (Zmax=13.71 at the DXS1100 locus). Single strand conformation polymorphism and direct sequence analysis of the retinitis pigmentosa GTPase regulator (RPGR) gene, which accounts for RP3, failed to detect any mutation in our families. Future advances in the identification of X linked RP genes will hopefully help to elucidate the molecular basis of this X linked dominant RP. Images PMID:9350809

Mucoadhesive polymers in the treatment of dry X syndrome.

PubMed

Partenhauser, Alexandra; Bernkop-Schnürch, Andreas

2016-07-01

Mucoadhesive polymers are an essential tool in the treatment of diseases where dry mucosal surfaces are involved. In this review, we focus on the application of mucoadhesive polymers in the context of dry eye, dry mouth, and dry vagina syndrome, collectively named 'dry X syndrome'. With a prolonged residence time on mucosal membranes, mucoadhesive materials are as targeted treatment option, with the mucosa as an intended site of action. Thus, mucoadhesive polymers are able to ease local irritation or itching, alleviate chewing difficulties, improve tear-film break-up time, and help to restore physiological conditions. Here, we discuss the different classes of mucoadhesive material and their performance in the treatment of dry X syndrome. Copyright © 2016 Elsevier Ltd. All rights reserved.

Coffin-Lowry syndrome: a multicenter study.

PubMed

Gilgenkrantz, S; Mujica, P; Gruet, P; Tridon, P; Schweitzer, F; Nivelon-Chevallier, A; Nivelon, J L; Couillault, G; David, A; Verloes, A

1988-10-01

The Coffin-Lowry syndrome is an inherited syndrome of mental retardation, characteristic facies and skeletal anomalies. The occurrence of severe manifestations in males, with no instance of male-to-male transmission, suggests an X-linked inheritance. The paper describes seven families from five European Centers.

X-Linked and Autosomal Recessive Alport Syndrome: Pathogenic Variant Features and Further Genotype-Phenotype Correlations

PubMed Central

Savige, Judith; Storey, Helen; Il Cheong, Hae; Gyung Kang, Hee; Park, Eujin; Hilbert, Pascale; Persikov, Anton; Torres-Fernandez, Carmen; Ars, Elisabet; Torra, Roser; Hertz, Jens Michael; Thomassen, Mads; Shagam, Lev; Wang, Dongmao; Wang, Yanyan; Flinter, Frances; Nagel, Mato

2016-01-01

Alport syndrome results from mutations in the COL4A5 (X-linked) or COL4A3/COL4A4 (recessive) genes. This study examined 754 previously- unpublished variants in these genes from individuals referred for genetic testing in 12 accredited diagnostic laboratories worldwide, in addition to all published COL4A5, COL4A3 and COL4A4 variants in the LOVD databases. It also determined genotype-phenotype correlations for variants where clinical data were available. Individuals were referred for genetic testing where Alport syndrome was suspected clinically or on biopsy (renal failure, hearing loss, retinopathy, lamellated glomerular basement membrane), variant pathogenicity was assessed using currently-accepted criteria, and variants were examined for gene location, and age at renal failure onset. Results were compared using Fisher’s exact test (DNA Stata). Altogether 754 new DNA variants were identified, an increase of 25%, predominantly in people of European background. Of the 1168 COL4A5 variants, 504 (43%) were missense mutations, 273 (23%) splicing variants, 73 (6%) nonsense mutations, 169 (14%) short deletions and 76 (7%) complex or large deletions. Only 135 of the 432 Gly residues in the collagenous sequence were substituted (31%), which means that fewer than 10% of all possible variants have been identified. Both missense and nonsense mutations in COL4A5 were not randomly distributed but more common at the 70 CpG sequences (p<10−41 and p<0.001 respectively). Gly>Ala substitutions were underrepresented in all three genes (p< 0.0001) probably because of an association with a milder phenotype. The average age at end-stage renal failure was the same for all mutations in COL4A5 (24.4 ±7.8 years), COL4A3 (23.3 ± 9.3) and COL4A4 (25.4 ± 10.3) (COL4A5 and COL4A3, p = 0.45; COL4A5 and COL4A4, p = 0.55; COL4A3 and COL4A4, p = 0.41). For COL4A5, renal failure occurred sooner with non-missense than missense variants (p<0.01). For the COL4A3 and COL4A4 genes, age at renal

X-Linked and Autosomal Recessive Alport Syndrome: Pathogenic Variant Features and Further Genotype-Phenotype Correlations.

PubMed

Savige, Judith; Storey, Helen; Il Cheong, Hae; Gyung Kang, Hee; Park, Eujin; Hilbert, Pascale; Persikov, Anton; Torres-Fernandez, Carmen; Ars, Elisabet; Torra, Roser; Hertz, Jens Michael; Thomassen, Mads; Shagam, Lev; Wang, Dongmao; Wang, Yanyan; Flinter, Frances; Nagel, Mato

2016-01-01

Alport syndrome results from mutations in the COL4A5 (X-linked) or COL4A3/COL4A4 (recessive) genes. This study examined 754 previously- unpublished variants in these genes from individuals referred for genetic testing in 12 accredited diagnostic laboratories worldwide, in addition to all published COL4A5, COL4A3 and COL4A4 variants in the LOVD databases. It also determined genotype-phenotype correlations for variants where clinical data were available. Individuals were referred for genetic testing where Alport syndrome was suspected clinically or on biopsy (renal failure, hearing loss, retinopathy, lamellated glomerular basement membrane), variant pathogenicity was assessed using currently-accepted criteria, and variants were examined for gene location, and age at renal failure onset. Results were compared using Fisher's exact test (DNA Stata). Altogether 754 new DNA variants were identified, an increase of 25%, predominantly in people of European background. Of the 1168 COL4A5 variants, 504 (43%) were missense mutations, 273 (23%) splicing variants, 73 (6%) nonsense mutations, 169 (14%) short deletions and 76 (7%) complex or large deletions. Only 135 of the 432 Gly residues in the collagenous sequence were substituted (31%), which means that fewer than 10% of all possible variants have been identified. Both missense and nonsense mutations in COL4A5 were not randomly distributed but more common at the 70 CpG sequences (p<10-41 and p<0.001 respectively). Gly>Ala substitutions were underrepresented in all three genes (p< 0.0001) probably because of an association with a milder phenotype. The average age at end-stage renal failure was the same for all mutations in COL4A5 (24.4 ±7.8 years), COL4A3 (23.3 ± 9.3) and COL4A4 (25.4 ± 10.3) (COL4A5 and COL4A3, p = 0.45; COL4A5 and COL4A4, p = 0.55; COL4A3 and COL4A4, p = 0.41). For COL4A5, renal failure occurred sooner with non-missense than missense variants (p<0.01). For the COL4A3 and COL4A4 genes, age at renal failure

Fragile X syndrome: from molecular genetics to therapy.

PubMed

D'Hulst, C; Kooy, R F

2009-09-01

Fragile X syndrome, the main cause of inherited mental retardation, is caused by transcriptional silencing of the fragile X mental retardation gene, FMR1. Absence of the associated protein FMRP leads to the dysregulation of many genes creating a phenotype of ADHD, anxiety, epilepsy and autism. The core aim of this review is to summarise two decades of molecular research leading to the characterisation of cellular and molecular pathways involved in the pathology of this disease and as a consequence to the identification of two new promising targets for rational therapy of fragile X syndrome, namely the group 1 metabotrope glutamate receptors (Gp1 mGluRs) and the gamma-amino butyric acid A receptors (GABA(A)Rs). As no current clinical treatments are directed specifically at the underlying neuronal defect due to absence of FMRP, this might open new powerful therapeutic strategies.

Fragile X syndrome in incestuous families

DOE Office of Scientific and Technical Information (OSTI.GOV)

Seemanova, E.

1996-11-11

Reed suggested the investigation of children 219 from incestuous unions as a method for calculation of the detrimental heterozygosity of man. Some studies of latent genetics load in man have been based on the comparison of health status of incestuous children with their half-sibs born to the same mothers in matings with nonconsanguineous partners. These studies were limited to the detection of autosomal-recessive genes leading to abnormal phenotypes or mental deficiency in homozygotes. The highest coefficient of inbreeding in human beings is 1/4 in offspring of incestuous matings: hence, the high proportion of affected homozygotes and low incidence of affectedmore » individuals among their maternal half-sibs. Mental deficiency in incestuous children represents not only cases of simple recessive inheritance. Recently, we observed three incestuous families in which fragile X syndrome was detected. The fra(X) children were born to carriers from incestuous unions as well as to unrelated partners. Therefore, we recommend use of incestuous children and their maternal half-sibs as a control group for studies estimating latent genetic load after investigation for fra(X). The incidence of fra(X) syndrome is high, and mental retardation in heterozygotes is uncommon. Both of these factors can play a role in the occurrence of incest, and in pregnancy at young age, as well as in multiple partnerships. Families of heterozygotes for fragile X should be excluded from the material for the calculation of human latent detrimental (autosomal-recessive) genetic load. 3 refs., 3 figs.« less

The Neuroanatomy and Neuroendocrinology of Fragile X Syndrome

ERIC Educational Resources Information Center

Hessl, David; Rivera, Susan M.; Reiss, Allan L.

2004-01-01

Fragile X syndrome (FXS), caused by a single gene mutation on the X chromosome, offers a unique opportunity for investigation of gene-brain-behavior relationships. Recent advances in molecular genetics, human brain imaging, and behavioral studies have started to unravel the complex pathways leading to the cognitive, psychiatric, and physical…

A Simulation of X-Linked Inheritance.

ERIC Educational Resources Information Center

Harrell, Pamela Esprivalo

1997-01-01

Describes how to lead students through a classroom-based simulation to teach a variety of concepts such as X-linked traits, sex determination, and sex anomalies. The simulation utilizes inexpensive materials such as plastic eggs that twist apart to represent human eggs and sperm. (AIM)

Fragile X Mental Retardation Syndrome: Structure of the KH1-KH2 Domains of Fragile X Mental Retardation Protein

DOE Office of Scientific and Technical Information (OSTI.GOV)

Valverde,R.; Poznyakova, I.; Kajander, T.

Fragile X syndrome is the most common form of inherited mental retardation in humans, with an estimated prevalence of about 1 in 4000 males. Although several observations indicate that the absence of functional Fragile X Mental Retardation Protein (FMRP) is the underlying basis of Fragile X syndrome, the structure and function of FMRP are currently unknown. Here, we present an X-ray crystal structure of the tandem KH domains of human FMRP, which reveals the relative orientation of the KH1 and KH2 domains and the location of residue Ile304, whose mutation to Asn is associated with a particularly severe incidence ofmore » Fragile X syndrome. We show that the Ile304Asn mutation both perturbs the structure and destabilizes the protein.« less

Simultaneous Occurence of an Autosomal Dominant Inherited MSX1 Mutation and an X-linked Recessive Inherited EDA Mutation in One Chinese Family with Non-syndromic Oligodontia.

PubMed

Zhang, Xiao Xia; Wong, Sing Wai; Han, Dong; Feng, Hai Lan

2015-01-01

To describe the simultaneous occurence of an autosomal dominant inherited MSX1 mutation and an X-linked recessive inherited EDA mutation in one Chinese family with nonsyndromic oligodontia. Clinical data of characteristics of tooth agenesis were collected. MSX1 and EDA gene mutations were detected in a Chinese family of non-syndromic oligodontia. Mild hypodontia in the parents and severe oligodontia in the son was recorded. A novel missense heterozygous mutation c.517C>A (p.Arg173Ser) was detected in the MSX1 gene in the boy and the father. A homozygous missense mutation c.1001G>A (p.Arg334His) was detected in the EDA gene in the boy and the same mutant occurred heterozygously in the mother. Simultaneous occurence of two different gene mutations with different inheritence patterns, which both caused oligodontia, which occurred in one subject and in one family, was reported.

Escape of X-linked miRNA genes from meiotic sex chromosome inactivation

PubMed Central

Sosa, Enrique; Flores, Luis; Yan, Wei; McCarrey, John R.

2015-01-01

Past studies have indicated that transcription of all X-linked genes is repressed by meiotic sex chromosome inactivation (MSCI) during the meiotic phase of spermatogenesis in mammals. However, more recent studies have shown an increase in steady-state levels of certain X-linked miRNAs in pachytene spermatocytes, suggesting that either synthesis of these miRNAs increases or that degradation of these miRNAs decreases dramatically in these cells. To distinguish between these possibilities, we performed RNA-FISH to detect nascent transcripts from multiple miRNA genes in various spermatogenic cell types. Our results show definitively that Type I X-linked miRNA genes are subject to MSCI, as are all or most X-linked mRNA genes, whereas Type II and III X-linked miRNA genes escape MSCI by continuing ongoing, active transcription in primary spermatocytes. We corroborated these results by co-localization of RNA-FISH signals with both a corresponding DNA-FISH signal and an immunofluorescence signal for RNA polymerase II. We also found that X-linked miRNA genes that escape MSCI locate non-randomly to the periphery of the XY body, whereas genes that are subject to MSCI remain located within the XY body in pachytene spermatocytes, suggesting that the mechanism of escape of X-linked miRNA genes from MSCI involves their relocation to a position outside of the repressive chromatin domain associated with the XY body. The fact that Type II and III X-linked miRNA genes escape MSCI suggests an immediacy of function of the encoded miRNAs specifically required during the meiotic stages of spermatogenesis. PMID:26395485

Aberrant Neural Function during Emotion Attribution in Female Subjects with Fragile X Syndrome

ERIC Educational Resources Information Center

Hagan, Cindy C.; Hoeft, Fumiko; Mackey, Allyson; Mobbs, Dean; Reiss, Allan L.

2008-01-01

The neurobiological systems which underlie emotion attribution among female patients with Fragile X (FraX) syndrome are examined. Results show that the emotion circuit which regulates responses to facial stimuli is potentially disrupted among female subjects with FraX syndrome. Anterior cingulate cortex activity in female subjects with FraX…

Finiteness Marking in Boys with Fragile X Syndrome

ERIC Educational Resources Information Center

Sterling, Audra M.; Rice, Mabel L.; Warren, Steven F.

2012-01-01

Purpose: The current study investigated finiteness marking (e.g., he walk "s", he walk "ed") in boys with fragile X syndrome (FXS); the boys were grouped based on receptive vocabulary (i.e., borderline, impaired). Method: Twenty-one boys with the full mutation of fragile X, between the ages of 8 and 16 years participated. The…

Expressive Language Profiles of Verbally Expressive Adolescents and Young Adults with Down Syndrome or Fragile X Syndrome

ERIC Educational Resources Information Center

Finestack, Lizbeth H.; Abbeduto, Leonard

2010-01-01

Purpose: In this study, the authors examined the expressive language abilities of a subset of highly verbally expressive adolescents and young adults with Down syndrome (DS) and those with fragile X syndrome (FXS) for evidence of syndrome-related differences. FXS gender differences were also examined in an exploratory fashion. Method: The authors…

Sjögren's syndrome X-chromosome dose effect: An epigenetic perspective.

PubMed

Mougeot, J-Lc; Noll, B D; Bahrani Mougeot, F K

2018-01-09

Sjögren's syndrome (SS) is a chronic autoimmune disease affecting exocrine glands leading to mouth and eyes dryness. The extent to which epigenetic DNA methylation changes are responsible for an X-chromosome dose effect has yet to be determined. Our objectives were to (i) describe how epigenetic DNA methylation changes could explain an X-chromosome dose effect in SS for women with normal 46,XX genotype and (ii) determine the relevant relationships to this dose effect, between X-linked genes, genes controlling X-chromosome inactivation (XCI) and genes encoding associated transcription factors, all of which are differentially expressed and/or differentially methylated in the salivary glands of patients with SS. We identified 58 upregulated X-chromosome genes, including 22 genes previously shown to escape XCI, based on the analysis of SS patient salivary gland GEO2R gene expression datasets. Moreover, we found XIST and its cis regulators RLIM, FTX, and CHIC1, and polycomb repressor genes of the PRC1/2 complexes to be upregulated. Many of the X-chromosome genes implicated in SS pathogenesis can be regulated by transcription factors which we found to be overexpressed and/or differentially methylated in patients with SS. Determination of the mechanisms underlying methylation-dependent gene expression and impaired XCI is needed to further elucidate the etiopathogenesis of SS. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. All rights reserved.

Molecular analyses of neurogenic defects in a human pluripotent stem cell model of fragile X syndrome.

PubMed

Boland, Michael J; Nazor, Kristopher L; Tran, Ha T; Szücs, Attila; Lynch, Candace L; Paredes, Ryder; Tassone, Flora; Sanna, Pietro Paolo; Hagerman, Randi J; Loring, Jeanne F

2017-03-01

New research suggests that common pathways are altered in many neurodevelopmental disorders including autism spectrum disorder; however, little is known about early molecular events that contribute to the pathology of these diseases. The study of monogenic, neurodevelopmental disorders with a high incidence of autistic behaviours, such as fragile X syndrome, has the potential to identify genes and pathways that are dysregulated in autism spectrum disorder as well as fragile X syndrome. In vitro generation of human disease-relevant cell types provides the ability to investigate aspects of disease that are impossible to study in patients or animal models. Differentiation of human pluripotent stem cells recapitulates development of the neocortex, an area affected in both fragile X syndrome and autism spectrum disorder. We have generated induced human pluripotent stem cells from several individuals clinically diagnosed with fragile X syndrome and autism spectrum disorder. When differentiated to dorsal forebrain cell fates, our fragile X syndrome human pluripotent stem cell lines exhibited reproducible aberrant neurogenic phenotypes. Using global gene expression and DNA methylation profiling, we have analysed the early stages of neurogenesis in fragile X syndrome human pluripotent stem cells. We discovered aberrant DNA methylation patterns at specific genomic regions in fragile X syndrome cells, and identified dysregulated gene- and network-level correlates of fragile X syndrome that are associated with developmental signalling, cell migration, and neuronal maturation. Integration of our gene expression and epigenetic analysis identified altered epigenetic-mediated transcriptional regulation of a distinct set of genes in fragile X syndrome. These fragile X syndrome-aberrant networks are significantly enriched for genes associated with autism spectrum disorder, giving support to the idea that underlying similarities exist among these neurodevelopmental diseases. © The

Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function.

PubMed

Bassell, Gary J; Warren, Stephen T

2008-10-23

Fragile X syndrome is the most common inherited form of cognitive deficiency in humans and perhaps the best-understood single cause of autism. A trinucleotide repeat expansion, inactivating the X-linked FMR1 gene, leads to the absence of the fragile X mental retardation protein. FMRP is a selective RNA-binding protein that regulates the local translation of a subset of mRNAs at synapses in response to activation of Gp1 metabotropic glutamate receptors (mGluRs) and possibly other receptors. In the absence of FMRP, excess and dysregulated mRNA translation leads to altered synaptic function and loss of protein synthesis-dependent plasticity. Recent evidence indicates the role of FMRP in regulated mRNA transport in dendrites. New studies also suggest a possible local function of FMRP in axons that may be important for guidance, synaptic development, and formation of neural circuits. The understanding of FMRP function at synapses has led to rationale therapeutic approaches.

Genetics Home Reference: Kallmann syndrome

MedlinePlus

... a part of the brain called the hypothalamus. Males born with hypogonadotropic hypogonadism often have an unusually ... facial hair and deepening of the voice in males, the start of monthly periods (menstruation) and breast ...

X-exome sequencing in Finnish families with Intellectual Disability - four novel mutations and two novel syndromic phenotypes

PubMed Central

2014-01-01

Background X-linked intellectual disability (XLID) is a group of genetically heterogeneous disorders characterized by substantial impairment in cognitive abilities, social and behavioral adaptive skills. Next generation sequencing technologies have become a powerful approach for identifying molecular gene mutations relevant for diagnosis. Methods & objectives Enrichment of X-chromosome specific exons and massively parallel sequencing was performed for identifying the causative mutations in 14 Finnish families, each of them having several males affected with intellectual disability of unknown cause. Results We found four novel mutations in known XLID genes. Two mutations; one previously reported missense mutation (c.1111C > T), and one novel frameshift mutation (c. 990_991insGCTGC) were identified in SLC16A2, a gene that has been linked to Allan-Herndon-Dudley syndrome (AHDS). One novel missense mutation (c.1888G > C) was found in GRIA3 and two novel splice donor site mutations (c.357 + 1G > C and c.985 + 1G > C) were identified in the DLG3 gene. One missense mutation (c.1321C > T) was identified in the candidate gene ZMYM3 in three affected males with a previously unrecognized syndrome characterized by unique facial features, aortic stenosis and hypospadia was detected. All of the identified mutations segregated in the corresponding families and were absent in > 100 Finnish controls and in the publicly available databases. In addition, a previously reported benign variant (c.877G > A) in SYP was identified in a large family with nine affected males in three generations, who have a syndromic phenotype. Conclusions All of the mutations found in this study are being reported for the first time in Finnish families with several affected male patients whose etiological diagnoses have remained unknown to us, in some families, for more than 30 years. This study illustrates the impact of X-exome sequencing to identify rare gene mutations

Screening for X-linked adrenoleukodystrophy among adult men with Addison's disease.

PubMed

Horn, Morten A; Erichsen, Martina M; Wolff, Anette S B; Månsson, Jan-Eric; Husebye, Eystein S; Tallaksen, Chantal M E; Skjeldal, Ola H

2013-09-01

X-linked adrenoleukodystrophy is an important cause of Addison's disease in boys, but less is known about its contribution to Addison's disease in adult men. After surveying all known cases of X-linked adrenoleukodystrophy in Norway in a separate study, we aimed to look for any missed cases among the population of adult men with nonautoimmune Addison's disease. Among 153 adult men identified in a National Registry for Addison's Disease (75% of identified male cases of Addison's disease in Norway), those with negative indices for 21-hydroxylase autoantibodies were selected. Additionally, cases with low autoantibody indices (48-200) were selected. Sera from subjects included were analysed for levels of very long-chain fatty acids, which are diagnostic for X-linked adrenoleukodystrophy in men. Eighteen subjects had negative indices and 17 had low indices for 21-hydroxylase autoantibodies. None of those with low indices and only one of those with negative indices were found to have X-linked adrenoleukodystrophy; this subject had already been diagnosed because of the neurological symptoms. Cases of Addison's disease proved to be caused by X-linked adrenoleukodystrophy constitute 1·5% of all adult male cases in Norway; the proportion among nonautoimmune cases was 15%. We found X-linked adrenoleukodystrophy to be an uncommon cause of Addison's disease in adult men. However, this aetiological diagnosis has far-reaching consequences both for the patient and for his extended family. We therefore recommend that all adult men with nonautoimmune Addison's disease be analysed for levels of very long-chain fatty acids. © 2013 John Wiley & Sons Ltd.

Behavioral intervention for problem behavior in children with fragile X syndrome.

PubMed

Moskowitz, Lauren J; Carr, Edward G; Durand, V Mark

2011-11-01

Parents and professionals typically report problem behavior as a significant concern for children with fragile X syndrome. In the present study, the authors explored whether behaviorally based interventions would result in a reduction in problem behavior and an improvement in quality of life for 3 children with fragile X syndrome and their families. A multiple baseline design was used to demonstrate intervention effects for specific high-priority contexts (i.e., bedtime, running errands, and toileting). A multicomponent intervention plan was developed to teach the parents and child to effectively cope with the particular context. After intervention, there were substantial improvements in problem behavior and family quality of life within the given contexts. Results of this study demonstrated the effectiveness of behavioral intervention for children with fragile X syndrome.

MULTIMODAL IMAGING OF MOSAIC RETINOPATHY IN CARRIERS OF HEREDITARY X-LINKED RECESSIVE DISEASES.

PubMed

Wu, An-Lun; Wang, Jung-Pan; Tseng, Yun-Ju; Liu, Laura; Kang, Yu-Chuan; Chen, Kuan-Jen; Chao, An-Ning; Yeh, Lung-Kun; Chen, Tun-Lu; Hwang, Yih-Shiou; Wu, Wei-Chi; Lai, Chi-Chun; Wang, Nan-Kai

2018-05-01

To investigate the clinical features in carriers of X-linked retinitis pigmentosa, X-linked ocular albinism, and choroideremia (CHM) using multimodal imaging and to assess their diagnostic value in these three mosaic retinopathies. We prospectively examined 14 carriers of 3 X-linked recessive disorders (X-linked retinitis pigmentosa, X-linked ocular albinism, and CHM). Details of abnormalities of retinal morphology were evaluated using fundus photography, fundus autofluorescence (FAF) imaging, and spectral domain optical coherence tomography. In six X-linked retinitis pigmentosa carriers, fundus appearance varied from unremarkable to the presence of tapetal-like reflex and pigmentary changes. On FAF imaging, all carriers exhibited a bright radial reflex against a dark background. By spectral domain optical coherence tomography, loss of the ellipsoid zone in the macula was observed in 3 carriers (50%). Regarding the retinal laminar architecture, 4 carriers (66.7%) showed thinning of the outer nuclear layer and a dentate appearance of the outer plexiform layer. All five X-linked ocular albinism carriers showed a characteristic mud-splatter patterned fundus, dark radial streaks against a bright background on FAF imaging, and a normal-appearing retinal structure by spectral domain optical coherence tomography imaging. Two of the 3 CHM carriers (66.7%) showed a diffuse moth-eaten appearance of the fundus, and all 3 showed irregular hyper-FAF and hypo-FAF spots throughout the affected area. In the CHM carriers, the structural changes observed by spectral domain optical coherence tomography imaging were variable. Our findings in an Asian cohort suggest that FAF imaging is a practical diagnostic test for differentiating X-linked retinitis pigmentosa, X-linked ocular albinism, and CHM carriers. Wide-field FAF is an easy and helpful adjunct to testing for the correct diagnosis and identification of lyonization in carriers of these three mosaic retinopathies.

Fragile X Syndrome: Genetic Predisposition to Psychopathology.

ERIC Educational Resources Information Center

Bregman, Joel D.; And Others

1988-01-01

Psychiatric evaluation of 14 males (ages 3-27 years) with the fragile X syndrome found pervasive hyperactivity, impulsivity, and attentional deficits, and a significant degree of anxiety. However, diagnostic criteria for persistent pervasive developmental disorder and autism were not met. (Author/DB)

Expression of selected genes escaping from X inactivation in the 41, XX(Y)* mouse model for Klinefelter's syndrome.

PubMed

Werler, Steffi; Poplinski, Andreas; Gromoll, Jörg; Wistuba, Joachim

2011-06-01

We hypothesized that patients with Klinefelter's syndrome (KS) not only undergo X inactivation, but also that genes escape from inactivation. Their transcripts would constitute a significant difference, as male metabolism is not adapted to a 'female-like' gene dosage. We evaluated the expression of selected X-linked genes in our 41, XX(Y)* male mice to determine whether these genes escape inactivation and whether tissue-specific differences occur. Correct X inactivation was identified by Xist expression. Relative expression of X-linked genes was examined in liver, kidney and brain tissue by real-time PCR in adult XX(Y)* and XY* males and XX females. Expression of genes known to escape X inactivation was analysed. Relative mRNA levels of Pgk1 (control, X inactivated), and the genes Eif2s3x, Kdm5c, Ddx3x and Kdm6a escaping from X inactivation were quantified from liver, kidney and brain. Pgk1 mRNA expression showed no difference, confirming correct X inactivation. In kidney and liver, XX(Y)* males resembled the female expression pattern in all four candidate genes and were distinguishable from XY* males. Contrastingly, in brain tissue XX(Y)* males expressed all four genes higher than male and female controls. Altered expression of genes escaping X inactivation probably contributes directly to the XX(Y)* phenotype. © 2011 The Author(s)/Acta Paediatrica © 2011 Foundation Acta Paediatrica.

Exome Sequencing Identified a Splice Site Mutation in FHL1 that Causes Uruguay Syndrome, an X-Linked Disorder With Skeletal Muscle Hypertrophy and Premature Cardiac Death.

PubMed

Xue, Yuan; Schoser, Benedikt; Rao, Aliz R; Quadrelli, Roberto; Vaglio, Alicia; Rupp, Verena; Beichler, Christine; Nelson, Stanley F; Schapacher-Tilp, Gudrun; Windpassinger, Christian; Wilcox, William R

2016-04-01

Previously, we reported a rare X-linked disorder, Uruguay syndrome in a single family. The main features are pugilistic facies, skeletal deformities, and muscular hypertrophy despite a lack of exercise and cardiac ventricular hypertrophy leading to premature death. An ≈19 Mb critical region on X chromosome was identified through identity-by-descent analysis of 3 affected males. Exome sequencing was conducted on one affected male to identify the disease-causing gene and variant. A splice site variant (c.502-2A>G) in the FHL1 gene was highly suspicious among other candidate genes and variants. FHL1A is the predominant isoform of FHL1 in cardiac and skeletal muscle. Sequencing cDNA showed the splice site variant led to skipping of exons 6 of the FHL1A isoform, equivalent to the FHL1C isoform. Targeted analysis showed that this splice site variant cosegregated with disease in the family. Western blot and immunohistochemical analysis of muscle from the proband showed a significant decrease in protein expression of FHL1A. Real-time polymerase chain reaction analysis of different isoforms of FHL1 demonstrated that the FHL1C is markedly increased. Mutations in the FHL1 gene have been reported in disorders with skeletal and cardiac myopathy but none has the skeletal or facial phenotype seen in patients with Uruguay syndrome. Our data suggest that a novel FHL1 splice site variant results in the absence of FHL1A and the abundance of FHL1C, which may contribute to the complex and severe phenotype. Mutation screening of the FHL1 gene should be considered for patients with uncharacterized myopathies and cardiomyopathies. © 2016 American Heart Association, Inc.

Family Environment and Behavior Problems in Children, Adolescents, and Adults with Fragile X Syndrome

PubMed Central

Greenberg, Jan S.; Seltzer, Marsha Mailick; Baker, Jason K.; Smith, Leann E.; Warren, Steven F.; Brady, Nancy; Hong, Jinkuk

2012-01-01

We examine how the family environment is associated with aspects of the Fragile X syndrome phenotype during childhood, adolescence, and adulthood. Mothers of children (n = 48), adolescents (n = 85), and adults (n = 34) with Fragile X syndrome participated in a multisite study. For children and adults with Fragile X syndrome, the presence of warmth and positivity and the absence of criticism were associated with fewer behavior problems. Although a higher level of criticism was significantly associated with greater behavior problems, there were only trend-level associations between levels of warmth and positivity and behavior problems during the adolescent years. The provision of family psychoeducation programs, which can reduce parental criticism, would likely benefit both the individual with Fragile X syndrome and the family. PMID:22809078

Perseveration in the Connected Speech of Boys with Fragile X Syndrome with and Without Autism Spectrum Disorder

PubMed Central

Martin, Gary E.; Roberts, Joanne E.; Helm-Estabrooks, Nancy; Sideris, John; Vanderbilt, Jacqueline; Moskowitz, Lauren

2012-01-01

Verbal perseveration is a frequently reported language characteristic of males with Fragile X syndrome and may be a defining feature or hallmark of the syndrome. We compared the verbal perseveration of boys with Fragile X syndrome with (n = 29) and without (n = 30) autism spectrum disorder, boys with Down syndrome (n = 27), and typically developing boys (n = 25) at similar nonverbal mental ages. During a social interaction, boys with both Fragile X syndrome and autism spectrum disorder produced significantly more topic perseveration than all other groups. In social interaction as compared to narration, boys with Fragile X syndrome (regardless of autism status) produced significantly more topic perseveration. These findings suggest that autism status, as well as language sampling context, affect perseveration in boys with Fragile X syndrome. PMID:22998486

Familial idiopathic gonadotropin deficiency not linked to gene for gonadotropin-releasing hormone (GnRH) in Brazilian kindred

DOE Office of Scientific and Technical Information (OSTI.GOV)

Faraco, J.; Francke, U.; Toledo, S.

Familial idiopathic gonadotropin deficiency (FIGD) is an autosomal recessive disorder which results in failure to develop secondary sexual characteristics. The origin is a hypothalamic defect resulting in insufficient secretion of gonadotropin-releasing hormone GnRH (also called LHRH, luteinizing hormone releasing hormone) and follicle-stimuating hormone (FSH). FIGD has been determined to be a separate entity from Kallmann syndrome which presents with hypogonadism as well as anosmia. The FIGD phenotype appears to be analogous to the phenotype of the hpg (hypogonadal) mouse. Because the hpg phenotype is the result of a structurally abnormal GnRH gene, we have studied the GnRH gene in individualsmore » from a previously reported Brazilian FIGD family. An informative dimorphic marker in the signal peptide sequence of the GnRH gene allowed assessment of linkage between the disease gene and the GnRH locus in this pedigree. We have concluded that the GnRH locus is not linked to the disease-causing mutation in these hypogonadal individuals. Recent evidence suggests that neuropeptide Y (NPY) may play a role in the initiation of puberty. We hypothesize that mutations in NPY may result in failure to secrete GnRH. We have characterized three diallelic frequent-cutter restriction fragment length polymorphisms within the human NPY locus, and are currently using these markers to determine if the NPY gene is linked to, and possibly the site of the disease mutation in this kindred.« less

The Caenorhabditis elegans Ephrin EFN-4 Functions Non-cell Autonomously with Heparan Sulfate Proteoglycans to Promote Axon Outgrowth and Branching

PubMed Central

Schwieterman, Alicia A.; Steves, Alyse N.; Yee, Vivian; Donelson, Cory J.; Bentley, Melissa R.; Santorella, Elise M.; Mehlenbacher, Taylor V.; Pital, Aaron; Howard, Austin M.; Wilson, Melissa R.; Ereddia, Danielle E.; Effrein, Kelsie S.; McMurry, Jonathan L.; Ackley, Brian D.; Chisholm, Andrew D.; Hudson, Martin L.

2016-01-01

The Eph receptors and their cognate ephrin ligands play key roles in many aspects of nervous system development. These interactions typically occur within an individual tissue type, serving either to guide axons to their terminal targets or to define boundaries between the rhombomeres of the hindbrain. We have identified a novel role for the Caenorhabditis elegans ephrin EFN-4 in promoting primary neurite outgrowth in AIY interneurons and D-class motor neurons. Rescue experiments reveal that EFN-4 functions non-cell autonomously in the epidermis to promote primary neurite outgrowth. We also find that EFN-4 plays a role in promoting ectopic axon branching in a C. elegans model of X-linked Kallmann syndrome. In this context, EFN-4 functions non-cell autonomously in the body-wall muscle and in parallel with HS modification genes and HSPG core proteins. This is the first report of an epidermal ephrin providing a developmental cue to the nervous system. PMID:26645816

X-linked microtubule-associated protein, Mid1, regulates axon development

PubMed Central

Lu, Tingjia; Chen, Renchao; Cox, Timothy C.; Moldrich, Randal X.; Kurniawan, Nyoman; Tan, Guohe; Perry, Jo K.; Ashworth, Alan; Bartlett, Perry F.; Xu, Li; Zhang, Jing; Lu, Bin; Wu, Mingyue; Shen, Qi; Liu, Yuanyuan; Richards, Linda J.; Xiong, Zhiqi

2013-01-01

Opitz syndrome (OS) is a genetic neurological disorder. The gene responsible for the X-linked form of OS, Midline-1 (MID1), encodes an E3 ubiquitin ligase that regulates the degradation of the catalytic subunit of protein phosphatase 2A (PP2Ac). However, how Mid1 functions during neural development is largely unknown. In this study, we provide data from in vitro and in vivo experiments suggesting that silencing Mid1 in developing neurons promotes axon growth and branch formation, resulting in a disruption of callosal axon projections in the contralateral cortex. In addition, a similar phenotype of axonal development was observed in the Mid1 knockout mouse. This defect was largely due to the accumulation of PP2Ac in Mid1-depleted cells as further down-regulation of PP2Ac rescued the axonal phenotype. Together, these data demonstrate that Mid1-dependent PP2Ac turnover is important for normal axonal development and that dysregulation of this process may contribute to the underlying cause of OS. PMID:24194544

X-linked microtubule-associated protein, Mid1, regulates axon development.

PubMed

Lu, Tingjia; Chen, Renchao; Cox, Timothy C; Moldrich, Randal X; Kurniawan, Nyoman; Tan, Guohe; Perry, Jo K; Ashworth, Alan; Bartlett, Perry F; Xu, Li; Zhang, Jing; Lu, Bin; Wu, Mingyue; Shen, Qi; Liu, Yuanyuan; Richards, Linda J; Xiong, Zhiqi

2013-11-19

Opitz syndrome (OS) is a genetic neurological disorder. The gene responsible for the X-linked form of OS, Midline-1 (MID1), encodes an E3 ubiquitin ligase that regulates the degradation of the catalytic subunit of protein phosphatase 2A (PP2Ac). However, how Mid1 functions during neural development is largely unknown. In this study, we provide data from in vitro and in vivo experiments suggesting that silencing Mid1 in developing neurons promotes axon growth and branch formation, resulting in a disruption of callosal axon projections in the contralateral cortex. In addition, a similar phenotype of axonal development was observed in the Mid1 knockout mouse. This defect was largely due to the accumulation of PP2Ac in Mid1-depleted cells as further down-regulation of PP2Ac rescued the axonal phenotype. Together, these data demonstrate that Mid1-dependent PP2Ac turnover is important for normal axonal development and that dysregulation of this process may contribute to the underlying cause of OS.

Mathematics learning disabilities in girls with fragile X or Turner syndrome during late elementary school.

PubMed

Murphy, Melissa M; Mazzocco, Michèle M M

2008-01-01

The present study focuses on math and related skills among 32 girls with fragile X (n = 14) or Turner (n = 18) syndrome during late elementary school. Performance in each syndrome group was assessed relative to Full Scale IQ-matched comparison groups of girls from the general population (n = 32 and n = 89 for fragile X syndrome and Turner syndrome, respectively). Differences between girls with fragile X and their comparison group emerged on untimed arithmetic calculations, mastery of counting skills, and arithmetic problem verification accuracy. Relative to girls in the comparison group, girls with Turner syndrome did not differ on untimed arithmetic calculations or problem verification accuracy, but they had limited mastery of counting skills and longer response times to complete the problem verification task. Girls with fragile X or Turner syndrome also differed from their respective comparison groups on math-related abilities, including visual-spatial, working memory, and reading skills, and the associations between math and those related skills. Together, these findings support the notion that difficulty with math and related skills among girls with fragile X or Turner syndrome continues into late elementary school and that the profile of math and related skill difficulty distinguishes the two syndrome groups from each other.

An Investigation of Narrative Ability in Boys with Autism and Fragile X Syndrome

PubMed Central

Hogan-Brown, Abigail L.; Losh, Molly; Martin, Gary E.; Mueffelmann, Deborah J.

2012-01-01

Whereas pragmatic language difficulties are characteristic of both autism and Fragile X syndrome, it is unclear whether such deficits are qualitatively similar or whether certain skills are differentially affected. This study compared narrative competence in boys with autism, Fragile X syndrome, Down syndrome, and typical development. Results revealed that an interaction between diagnosis and nonverbal mental age predicted narrative microstructure (e.g., complex syntax) but not macrostructure (e.g., thematic maintenance). Correlations with FMR1-related variation were investigated in children with Fragile X syndrome. While CGG repeat length was associated with many language characteristics, nonverbal IQ appeared to mediate these relationships. These findings are an important step toward understanding narrative abilities in boys with and without the FMR1 mutation. PMID:23464607

X-derived marker chromosome in patient with mosaic Turner syndrome and Dandy-Walker syndrome: a case report.

PubMed

Telepova, Alena S; Romanenko, Svetlana A; Lemskaya, Natalya A; Maksimova, Yulia V; Shorina, Asia R; Yudkin, Dmitry V

2017-01-01

Small supernumerary marker chromosomes can be derived from autosomes and sex chromosomes and can accompany chromosome pathologies, such as Turner syndrome. Here, we present a case report of a patient with mosaic Turner syndrome and Dandy-Walker syndrome carrying a marker chromosome. We showed the presence of the marker chromosome in 33.8% of blood cells. FISH of the probe derived from the marker chromosome by microdissection revealed that it originated from the centromeric region of chromosome X. Additionally, we showed no telomeric sequences and no XIST sequence in the marker chromosome. This is the first report of these two syndromes accompanied by the presence of a marker chromosome. Marker chromosome was X-derived and originated from centromeric region. Patient has mild symptoms but there is no XIST gene in marker chromosome. CPG137. Registered 03 March 2017.

Multiple Behavior Phenotypes of the Fragile-X Syndrome Mouse Model Respond to Chronic Inhibition of Phosphodiesterase-4D (PDE4D).

PubMed

Gurney, Mark E; Cogram, Patricia; Deacon, Robert M; Rex, Christopher; Tranfaglia, Michael

2017-11-07

Fragile-X syndrome (FXS) patients display intellectual disability and autism spectrum disorder due to silencing of the X-linked, fragile-X mental retardation-1 (FMR1) gene. Dysregulation of cAMP metabolism is a consistent finding in patients and in the mouse and fly FXS models. We therefore explored if BPN14770, a prototypic phosphodiesterase-4D negative allosteric modulator (PDE4D-NAM) in early human clinical trials, might provide therapeutic benefit in the mouse FXS model. Daily treatment of adult male fmr1 C57Bl6 knock-out mice with BPN14770 for 14 days reduced hyperarousal, improved social interaction, and improved natural behaviors such as nesting and marble burying as well as dendritic spine morphology. There was no decrement in behavioral scores in control C57Bl6 treated with BPN14770. The behavioral benefit of BPN14770 persisted two weeks after washout of the drug. Thus, BPN14770 may be useful for the treatment of fragile-X syndrome and other disorders with decreased cAMP signaling.

The X linked recessive form of XY gonadal dysgenesis with a high incidence of gonadal germ cell tumours: clinical and genetic studies.

PubMed

Mann, J R; Corkery, J J; Fisher, H J; Cameron, A H; Mayerová, A; Wolf, U; Kennaugh, A A; Woolley, V

1983-08-01

Five phenotypic females in one family had the genotype 46,XY and all had gonadal germ cell tumours. Studies of the family pedigree suggest that this form of XY gonadal dysgenesis is inherited in an X linked recessive manner. G banding of elongated metaphase chromosomes from two subjects with XY gonadal dysgenesis and a female carrier showed no aberrations of the X chromosome. The titres of H-Y antigen in three girls with XY gonadal dysgenesis were in the male control range. Thus it appears that, in the X linked form, XY gonadal dysgenesis may be caused by a point deletion or mutation of a gene on the X chromosome, which controls the gonad specific receptor for the H-Y antigen. Studies of Xg blood groups were uninformative about linkage of Xg with the X borne gene causing the XY gonadal dysgenesis. Dermatoglyphic studies in the girls with XY gonadal dysgenesis and female carriers revealed high a-b palmar ridge counts and a tendency for the A mainline to terminate in the thenar area. Both of these features have been described in patients with Turner's syndrome.

Structural Pituitary Abnormalities Associated With CHARGE Syndrome

PubMed Central

Gregory, Louise C.; Gevers, Evelien F.; Baker, Joanne; Kasia, Tessa; Chong, Kling; Josifova, Dragana J.; Caimari, Maria; Bilan, Frederic; McCabe, Mark J.

2013-01-01

Introduction: CHARGE syndrome is a multisystem disorder that, in addition to Kallmann syndrome/isolated hypogonadotrophic hypogonadism, has been associated with anterior pituitary hypoplasia (APH). However, structural abnormalities such as an ectopic posterior pituitary (EPP) have not yet been described in such patients. Objective: The aims of the study were: 1) to describe the association between CHARGE syndrome and a structurally abnormal pituitary gland; and 2) to investigate whether CHD7 variants, which are identified in 65% of CHARGE patients, are common in septo-optic dysplasia /hypopituitarism. Methods: We describe 2 patients with features of CHARGE and EPP. CHD7 was sequenced in these and other patients with septo-optic dysplasia/hypopituitarism. Results: EPP, APH, and GH, TSH, and probable LH/FSH deficiency were present in 1 patient, and EPP and APH with GH, TSH, LH/FSH, and ACTH deficiency were present in another patient, both of whom had features of CHARGE syndrome. Both had variations in CHD7 that were novel and undetected in control cohorts or in the international database of CHARGE patients, but were also present in their unaffected mothers. No CHD7 variants were detected in the patients with septo-optic dysplasia/hypopituitarism without additional CHARGE features. Conclusion: We report a novel association between CHARGE syndrome and structural abnormalities of the pituitary gland in 2 patients with variations in CHD7 that are of unknown significance. However, CHD7 mutations are an uncommon cause of septo-optic dysplasia or hypopituitarism. Our data suggest the need for evaluation of pituitary function/anatomy in patients with CHARGE syndrome. PMID:23526466

Analysis of the parental origin of de novo MECP2 mutations and X chromosome inactivation in 24 sporadic patients with Rett syndrome in China.

PubMed

Zhu, Xingwang; Li, Meirong; Pan, Hong; Bao, Xinhua; Zhang, Jingjing; Wu, Xiru

2010-07-01

Rett syndrome is an X-linked neurodevelopmental disorder that predominantly affects females. It is caused by mutations in methyl-CpG-binding protein 2 gene. Due to the sex-limited expression, it has been suggested that de novo X-linked mutations may exclusively occur in male germ cells and thus only females are affected. In this study, the authors have analyzed the parental origin of mutations and the X-chromosome inactivation status in 24 sporadic patients with identified methyl-CpG-binding protein 2 gene mutations. The results showed that 22 of 24 patients have a paternal origin. Only 2 patients have a maternal origin. Except for 2 cases which were homozygotic at the androgen receptor gene locus, of the remaining 22 cases, 16 cases have a random X-chromosome inactivation pattern; the other 6 cases have a skewed X-chromosome inactivation and they favor expression of the wild allele. The relationship between X-chromosome inactivation and phenotype may need more cases to explore.

Fragile X mutation and FG syndrome-like phenotype

DOE Office of Scientific and Technical Information (OSTI.GOV)

Piussan, C.; Mathieu, M.; Berquin, P.

1996-08-09

We present data on 4 mentally retarded brothers, 2 of whom were dizygotic twins with congenital hypotonia, constipation, head size disproportionately large for length or height, and a combination of minor anomalies suggestive of FG syndrome. These brothers have a mentally retarded full sister with similar minor anomalies and an older half-brother with the Martin-Bell syndrome. The mother is mentally retarded; 4 of 7 individuals are positive for fragile X, but all have a CGG expansion ranging from 0.2-2 to 4 kb. Although the phenotype is not completely typical of the FG syndrome and the coincidence of the FMR1 mutationmore » and segregation of the MCA/MR phenotype are highly unlikely, the FMR1 mutation may affect morphogenesis more extensively and differently than the Martin-Bell syndrome does to effect an FG syndrome-like phenotype in certain families. This phenotype does not appear to be a contiguous gene syndrome, but an effect of the FMR1 mutation on an adjacent gene must be considered. 18 refs., 4 figs.« less

Family environment and behavior problems in children, adolescents, and adults with fragile X syndrome.

PubMed

Greenberg, Jan; Seltzer, Marsha; Baker, Jason; Smith, Leann; Warren, Steven F; Brady, Nancy; Hong, Jinkuk

2012-07-01

We examine how the family environment is associated with aspects of the Fragile X syndrome phenotype during childhood, adolescence, and adulthood. Mothers of children (n  =  48), adolescents (n  =  85), and adults (n  =  34) with Fragile X syndrome participated in a multisite study. For children and adults with Fragile X syndrome, the presence of warmth and positivity and the absence of criticism were associated with fewer behavior problems. Although a higher level of criticism was significantly associated with greater behavior problems, there were only trend-level associations between levels of warmth and positivity and behavior problems during the adolescent years. The provision of family psychoeducation programs, which can reduce parental criticism, would likely benefit both the individual with Fragile X syndrome and the family.

CUL4B ubiquitin ligase in mouse development: a model for human X-linked mental retardation syndrome?

PubMed

Zhao, Yongchao; Sun, Yi

2012-08-01

CUL4B, a member of the cullin-RING ubiquitin ligase family, is frequently mutated in X-linked mental retardation (XLMR) patients. The study by Liu et al. showed that Cul4b plays an essential developmental role in the extra-embryonic tissues, while it is dispensable in the embryo proper during mouse embryogenesis. Viable Cul4b-null mice provide the first animal model to study neuronal and behavioral deficiencies seen in human CUL4B XLMR patients.

Mutations in CUL4B, which encodes a ubiquitin E3 ligase subunit, cause an X-linked mental retardation syndrome associated with aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus, and tremor.

PubMed

Tarpey, Patrick S; Raymond, F Lucy; O'Meara, Sarah; Edkins, Sarah; Teague, Jon; Butler, Adam; Dicks, Ed; Stevens, Claire; Tofts, Calli; Avis, Tim; Barthorpe, Syd; Buck, Gemma; Cole, Jennifer; Gray, Kristian; Halliday, Kelly; Harrison, Rachel; Hills, Katy; Jenkinson, Andrew; Jones, David; Menzies, Andrew; Mironenko, Tatiana; Perry, Janet; Raine, Keiran; Richardson, David; Shepherd, Rebecca; Small, Alexandra; Varian, Jennifer; West, Sofie; Widaa, Sara; Mallya, Uma; Moon, Jenny; Luo, Ying; Holder, Susan; Smithson, Sarah F; Hurst, Jane A; Clayton-Smith, Jill; Kerr, Bronwyn; Boyle, Jackie; Shaw, Marie; Vandeleur, Lucianne; Rodriguez, Jayson; Slaugh, Rachel; Easton, Douglas F; Wooster, Richard; Bobrow, Martin; Srivastava, Anand K; Stevenson, Roger E; Schwartz, Charles E; Turner, Gillian; Gecz, Jozef; Futreal, P Andrew; Stratton, Michael R; Partington, Michael

2007-02-01

We have identified three truncating, two splice-site, and three missense variants at conserved amino acids in the CUL4B gene on Xq24 in 8 of 250 families with X-linked mental retardation (XLMR). During affected subjects' adolescence, a syndrome emerged with delayed puberty, hypogonadism, relative macrocephaly, moderate short stature, central obesity, unprovoked aggressive outbursts, fine intention tremor, pes cavus, and abnormalities of the toes. This syndrome was first described by Cazebas et al., in a family that was included in our study and that carried a CUL4B missense variant. CUL4B is a ubiquitin E3 ligase subunit implicated in the regulation of several biological processes, and CUL4B is the first XLMR gene that encodes an E3 ubiquitin ligase. The relatively high frequency of CUL4B mutations in this series indicates that it is one of the most commonly mutated genes underlying XLMR and suggests that its introduction into clinical diagnostics should be a high priority.

Genetics Home Reference: FG syndrome

MedlinePlus

... inheritance is that fathers cannot pass X-linked traits to their sons. Related Information What does it ... Opitz JO. Behavior phenotype of FG syndrome: cognition, personality, and behavior in eleven affected boys. Am J ...

Anthropometric and craniofacial patterns in mentally retarded males with emphasis on the fragile X syndrome.

PubMed

Butler, M G; Pratesi, R; Watson, M S; Breg, W R; Singh, D N

1993-09-01

Anthropometric and craniofacial profile patterns indicating the percent difference from the overall mean were developed on 34 physical parameters with 31 white, mentally retarded males (23 adults and 8 children) with the fra(X) syndrome matched for age with 31 white, mentally retarded males without a known cause of their retardation. The fra(X) syndrome males consistently showed larger dimensions for all anthropometric variables, with significant differences for height, sitting height, arm span, hand length, middle finger length, hand breadth, foot length, foot breadth, and testicular volume. A craniofacial pattern did emerge between the two groups of mentally retarded males, but with overlap of several variables. Significant differences were noted for head circumference, head breadth, lower face height, bizygomatic diameter, inner canthal distance, ear length and ear width, with the fra(X) syndrome males having larger head dimensions (head circumference, head breadth, head length, face height and lower face height), but smaller measurements for minimal frontal diameter, bizygomatic diameter, bigonial diameter, and inner canthal distance. Several significant correlations were found with the variables for both mentally retarded males with and without the fra(X) syndrome. In a combined anthropometric and craniofacial profile of 19 variables comparing 26 white fra(X) syndrome males (13 with high expression (> 30%) and 13 with low expression (< 30%), but matched for age), a relatively flat profile was observed with no significant differences for any of the variables. Generally, fra(X) syndrome males with increased fragile X chromosome expression have larger amplifications of the CGG trinucleotide repeat of the FMR-1 gene. No physical differences were detectable in our study between fra(X) males with high expression and apparently larger amplifications of the CGG trinucleotide repeats compared with those patients with low expression. Our research illustrates the use of

Anthropometric and craniofacial patterns in mentally retarded males with emphasis on the fragile X syndrome

PubMed Central

Butler, Merlin G.; Pratesi, Riccardo; Watson, Michael S.; Breg, W. Roy; Singh, Dharmdeo N.

2017-01-01

Anthropometric and craniofacial profile patterns indicating the percent difference from the overall mean were developed on 34 physical parameters with 31 white, mentally retarded males (23 adults and 8 children) with the fra(X) syndrome matched for age with 31 white, mentally retarded males without a known cause of their retardation. The fra(X) syndrome males consistently showed larger dimensions for all anthropometric variables, with significant differences for height, sitting height, arm span, hand length, middle finger length, hand breadth, foot length, foot breadth, and testicular volume. A craniofacial pattern did emerge between the two groups of mentally retarded males, but with overlap of several variables. Significant differences were noted for head circumference, head breadth, lower face height, bizygomatic diameter, inner canthal distance, ear length and ear width, with the fra(X) syndrome males having larger head dimensions (head circumference, head breadth, head length, face height and lower face height), but smaller measurements for minimal frontal diameter, bizygomatic diameter, bigonial diameter, and inner canthal distance. Several significant correlations were found with the variables for both mentally retarded males with and without the fra(X) syndrome. In a combined anthropometric and craniofacial profile of 19 variables comparing 26 white fra(X) syndrome males (13 with high expression (>30%) and 13 with low expression (< 30%), but matched for age), a relatively flat profile was observed with no significant differences for any of the variables. Generally, fra(X) syndrome males with increased fragile X chromosome expression have larger amplifications of the CGG trinucleotide repeat of the FMR-1 gene. No physical differences were detectable in our study between fra(X) males with high expression and apparently larger amplifications of the CGG trinucleotide repeats compared with those patients with low expression. Our research illustrates the use of

The psychiatric phenotype in triple X syndrome: New hypotheses illustrated in two cases

PubMed Central

Otter, Maarten; Schrander-Stumpel, Constance T. R. M.; Didden, Robert; Curfs, Leopold M. G.

2012-01-01

Background: Triple X syndrome (47,XXX or trisomy X) is a relatively frequent cytogenetic condition with a large variety of physical and behavioural phenotypes. Method: Two adult patients with a triple X karyotype are described. Results: Their karyotype was unknown until some years ago. What these patients have in common is that they were diagnosed with a broader autism phenotype, they were sexually abused, they suffer from psychotic illness and they show challenging behaviour, suicidality and a decline in occupational capacity. Discussion: These gene-environment interactions are discussed. Gene-environment interactions may explain the variety of behavioural and psychiatric phenotypes in triple X syndrome. Ongoing atypical development in adults is hypothesized. Conclusions: Gene-environment interactions and ongoing atypical development in adults should be taken into account in research concerning the psychiatric phenotype of developmental disorders, especially those involving triple X syndrome. PMID:22582855

Exome sequencing identifies a novel mutation of the GDI1 gene in a Chinese non-syndromic X-linked intellectual disability family

PubMed Central

Duan, Yongheng; Lin, Sheng; Xie, Lichun; Zheng, Kaifeng; Chen, Shiguo; Song, Hui; Zeng, Xuchun; Gu, Xueying; Wang, Heyun; Zhang, Linghua; Shao, Hao; Hong, Wenxu; Zhang, Lijie; Duan, Shan

2017-01-01

Abstract X-linked intellectual disability (XLID) has been associated with various genes. Diagnosis of XLID, especially for non-syndromic ones (NS-XLID), is often hampered by the heterogeneity of this disease. Here we report the case of a Chinese family in which three males suffer from intellectual disability (ID). The three patients shared the same phenotype: no typical clinical manifestation other than IQ score ≤ 70. For a genetic diagnosis for this family we carried out whole exome sequencing on the proband, and validated 16 variants of interest in the genomic DNA of all the family members. A missense mutation (c.710G > T), which mapped to exon 6 of the Rab GDP-Dissociation Inhibitor 1 (GDI1) gene, was found segregating with the ID phenotype, and this mutation changes the 237th position in the guanosine diphosphate dissociation inhibitor (GDI) protein from glycine to valine (p. Gly237Val). Through molecular dynamics simulations we found that this substitution results in a conformational change of GDI, possibly affecting the Rab-binding capacity of this protein. In conclusion, our study identified a novel GDI1 mutation that is possibly NS-XLID causative, and showed that whole exome sequencing provides advantages for detecting novel ID-associated variants and can greatly facilitate the genetic diagnosis of the disease. PMID:28863211

Resolution of Spatial and Temporal Visual Attention in Infants with Fragile X Syndrome

ERIC Educational Resources Information Center

Farzin, Faraz; Rivera, Susan M.; Whitney, David

2011-01-01

Fragile X syndrome is the most common cause of inherited intellectual impairment and the most common single-gene cause of autism. Individuals with fragile X syndrome present with a neurobehavioural phenotype that includes selective deficits in spatiotemporal visual perception associated with neural processing in frontal-parietal networks of the…

Functional consequences of mutations in CDKL5, an X-linked gene involved in infantile spasms and mental retardation.

PubMed

Bertani, Ilaria; Rusconi, Laura; Bolognese, Fabrizio; Forlani, Greta; Conca, Barbara; De Monte, Lucia; Badaracco, Gianfranco; Landsberger, Nicoletta; Kilstrup-Nielsen, Charlotte

2006-10-20

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in patients with Rett syndrome, West syndrome, and X-linked infantile spasms sharing the common features of generally intractable early seizures and mental retardation. Disease-causing mutations are distributed in both the catalytic domain and in the large COOH terminus. In this report, we examine the functional consequences of some Rett mutations of CDKL5 together with some synthetically designed derivatives useful to underline the functional domains of the protein. The mutated CDKL5 derivatives have been subjected to in vitro kinase assays and analyzed for phosphorylation of the TEY (Thr-Glu-Tyr) motif within the activation loop, their subcellular localization, and the capacity of CDKL5 to interact with itself. Whereas wild-type CDKL5 autophosphorylates and mediates the phosphorylation of the methyl-CpG-binding protein 2 (MeCP2) in vitro, Rett-mutated proteins show both impaired and increased catalytic activity suggesting that a tight regulation of CDKL5 is required for correct brain functions. Furthermore, we show that CDKL5 can self-associate and mediate the phosphorylation of its own TEY (Thr-Glu-Tyr) motif. Eventually, we show that the COOH terminus regulates CDKL5 properties; in particular, it negatively influences the catalytic activity and is required for its proper sub-nuclear localization. We propose a model in which CDKL5 phosphorylation is required for its entrance into the nucleus whereas a portion of the COOH-terminal domain is responsible for a stable residency in this cellular compartment probably through protein-protein interactions.

Emotion Potentiated Startle in Fragile X Syndrome

ERIC Educational Resources Information Center

Ballinger, Elizabeth C.; Cordeiro, Lisa; Chavez, Alyssa D.; Hagerman, Randi J.; Hessl, David

2014-01-01

Social avoidance and anxiety are prevalent in fragile X syndrome (FXS) and are potentially mediated by the amygdala, a brain region critical for social behavior. Unfortunately, functional brain resonance imaging investigation of the amygdala in FXS is limited by the difficulties experienced by intellectually impaired and anxious participants. We…

Iron accumulation and dysregulation in the putamen in fragile X-associated tremor/ataxia syndrome.

PubMed

Ariza, Jeanelle; Rogers, Hailee; Hartvigsen, Anna; Snell, Melissa; Dill, Michael; Judd, Derek; Hagerman, Paul; Martínez-Cerdeño, Verónica

2017-04-01

Fragile X-associated tremor/ataxia syndrome is an adult-onset disorder associated with premutation alleles of the FMR1 gene. This disorder is characterized by progressive action tremor, gait ataxia, and cognitive decline. Fragile X-associated tremor/ataxia syndrome pathology includes dystrophic white matter and intranuclear inclusions in neurons and astrocytes. We previously demonstrated that the transport of iron into the brain is altered in fragile X-associated tremor/ataxia syndrome; therefore, we also expect an alteration of iron metabolism in brain areas related to motor control. Iron is essential for cell metabolism, but uncomplexed iron leads to oxidative stress and contributes to the development of neurodegenerative diseases. We investigated a potential iron modification in the putamen - a structure that participates in motor learning and performance - in fragile X-associated tremor/ataxia syndrome. We used samples of putamen obtained from 9 fragile X-associated tremor/ataxia syndrome and 9 control cases to study iron localization using Perl's method, and iron-binding proteins using immunostaining. We found increased iron deposition in neuronal and glial cells in the putamen in fragile X-associated tremor/ataxia syndrome. We also found a generalized decrease in the amount of the iron-binding proteins transferrin and ceruloplasmin, and decreased number of neurons and glial cells that contained ceruloplasmin. However, we found increased levels of iron, transferrin, and ceruloplasmin in microglial cells, indicating an attempt by the immune system to remove the excess iron. Overall, found a deficit in proteins that eliminate extra iron from the cells with a concomitant increase in the deposit of cellular iron in the putamen in Fragile X-associated tremor/ataxia syndrome. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.

Fragile X syndrome and an isodicentric X chromosome in a woman with multiple anomalies, developmental delay, and normal pubertal development.

PubMed

Freedenberg, D L; Gane, L W; Richards, C S; Lampe, M; Hills, J; O'Connor, R; Manchester, D; Taylor, A; Tassone, F; Hulseberg, D; Hagerman, R J; Patil, S R

1999-07-30

We report on an individual with developmental delays, short stature, skeletal abnormalities, normal pubertal development, expansion of the fragile X triplet repeat, as well as an isodicentric X chromosome. S is a 19-year-old woman who presented for evaluation of developmental delay. Pregnancy was complicated by a threatened miscarriage. She was a healthy child with intellectual impairment noted in infancy. Although she had global delays, speech was noted to be disproportionately delayed with few words until age 3.5 years. Facial appearance was consistent with fragile X syndrome. Age of onset of menses was 11 years with normal breast development. A maternal male second cousin had been identified with fragile X syndrome based on DNA studies. The mother of this child (S's maternal first cousin) and the grandfather (S's maternal uncle) were both intellectually normal but were identified as carrying triplet expansions in the premutation range. S's mother had some school difficulties but was not identified as having global delays. Molecular analysis of S's fragile X alleles noted an expansion of more than 400 CGG repeats in one allele. Routine cytogenetic studies of peripheral blood noted the presence of an isodicentric X in 81of 86 cells scored. Five of 86 cells were noted to be 45,X. Cytogenetic fra(X) studies from peripheral blood showed that the structurally normal chromosome had the fragile site in approximately 16% of the cells. Analysis of maternal fragile X alleles identified an allele with an expansion to approximately 110 repeats. FMRP studies detected the expression of the protein in 24% of cells studied. To our knowledge, this is the first patient reported with an isodicentric X and fragile X syndrome. Whereas her clinical phenotype is suggestive of fragile X syndrome, her skeletal abnormalities may represent the presence of the isodicentric X. Treatment of S with 20 mg/day of Prozac improved her behavior. In the climate of cost con trol, this individual

Fragile X-associated tremor/ataxia syndrome: another phenotype of the fragile X gene.

PubMed

Hessl, David; Grigsby, Jim

2016-08-01

Neuropsychologists have an important role in evaluating patients with fragile X-associated disorders, but most practitioners are unaware of the recently identified neurodegenerative movement disorder known as fragile X-associated tremor ataxia syndrome (FXTAS). The objective of this editorial is to orient the reader to FXTAS and highlight the importance of clinical neuropsychology in describing the fragile X premutation phenotype and the role practitioners may have in assessing and monitoring patients with or at risk for neurodegeneration. We issued a call for papers for the special issue, highlighting the primary objective of familiarizing clinical neuropsychologists with FXTAS, and with the neuropsychological phenotype of both male and female asymptomatic carriers. Eight papers are included, including an overview of the fragile X-associated disorders (Grigsby), a review of the neuroradiological and neurological aspects of FXTAS and how the disorder compares to other movement disorders (O'Keefe et al.), a perspective on the prominence of white matter disease and dementia in FXTAS (Filley), and a review of mouse models of FXTAS (Foote). There are four research papers, including one on self-reported memory problems in FXTAS (Birch et al.), and three papers focused on the neuropsychiatric aspects of the fragile X premutation, a review (Bourgeois), an examination of autism-related traits (Schneider), and a research paper on executive functioning and psychopathology (Grigsby). The issue highlights the importance of awareness of fragile X-associated disorders for neuropsychologists, an awareness that must reach beyond neurodevelopmental aspects related to fragile X syndrome into the realm of neurodegenerative disease and aging.

The Efficacy of Melatonin for Sleep Problems in Children with Autism, Fragile X Syndrome, or Autism and Fragile X Syndrome

PubMed Central

Wirojanan, Juthamas; Jacquemont, Sebastien; Diaz, Rafael; Bacalman, Susan; Anders, Thomas F.; Hagerman, Randi J.; Goodlin-Jones, Beth L.

2009-01-01

Study Objective: To determine the efficacy of melatonin on sleep problems in children with autistic spectrum disorder (ASD) and fragile X syndrome (FXS). Methods: A 4-week, randomized, double blind, placebo-controlled, crossover design was conducted following a 1-week baseline period. Either melatonin, 3 mg, or placebo was given to participants for 2 weeks and then alternated for another 2 weeks. Sleep variables, including sleep duration, sleep-onset time, sleep-onset latency time, and the number of night awakenings, were recorded using an Actiwatch and from sleep diaries completed by parents. All participants had been thoroughly assessed for ASD and also had DNA testing for the diagnosis of FXS. Results: Data were successfully obtained from the 12 of 18 subjects who completed the study (11 males, age range 2 to 15.25 years, mean 5.47, SD 3.6). Five participants met diagnostic criteria for ASD, 3 for FXS alone, 3 for FXS and ASD, and 1 for fragile X premutation. Eight out of 12 had melatonin first. The conclusions from a nonparametric repeated-measures technique indicate that mean night sleep duration was longer on melatonin than placebo by 21 minutes (p = .02), mean sleep-onset latency was shorter by 28 minutes (p = .0001), and mean sleep-onset time was earlier by 42 minutes (p = .02). Conclusion: The results of this study support the efficacy and tolerability of melatonin treatment for sleep problems in children with ASD and FXS. Citation: Wirojanan J; Jacquemont S; Diaz R; Bacalman S; Anders TF; Hagerman RJ; Goodlin-Jones BL. The Efficacy of Melatonin for Sleep Problems in Children with Autism, Fragile X Syndrome, or Autism and Fragile X Syndrome. J Clin Sleep Med 2009;5(2):145-150. PMID:19968048

Differential Impact of the "FMR1" Gene on Visual Processing in Fragile X Syndrome

ERIC Educational Resources Information Center

Kogan, Cary S.; Boutet, Isabelle; Cornish, Kim; Zangenehpour, Shahin; Mullen, Kathy T.; Holden, Jeanette J. A.; Kaloustian, Vazken M. Der; Andermann, Eva; Chaudhuri, Avi

2004-01-01

Fragile X syndrome (FXS) is the most common form of heritable mental retardation, affecting (~ around) 1 in 4000 males. The syndrome arises from expansion of a trinucleotide repeat in the 5'-untranslated region of the fragile X mental retardation 1 ("FMR1") gene, leading to methylation of the promoter sequence and lack of the fragile X mental…

Arousal Modulation in Females with Fragile X or Turner Syndrome

ERIC Educational Resources Information Center

Roberts, Jane; Mazzocco, Michele M. M.; Murphy, Melissa M.; Hoehn-Saric, Rudolf

2008-01-01

The present study was carried out to examine physiological arousal modulation (heart activity and skin conductance), across baseline and cognitive tasks, in females with fragile X or Turner syndrome and a comparison group of females with neither syndrome. Relative to the comparison group, for whom a greater increase in skin conductance was…

X-chromosomal inactivation directly influences the phenotypic manifestation of X-linked protoporphyria

PubMed Central

Brancaleoni, V.; Balwani, M.; Granata, F.; Graziadei, G.; Missineo, P.; Fiorentino, V.; Fustinoni, S.; Cappellini, M.D.; Naik, H.; Desnick, R.J.; Di Pierro, E.

2015-01-01

X-linked protoporphyria (XLP), a rare erythropoietic porphyria, results from terminal exon gain-of-function mutations in the ALAS2 gene causing increased ALAS2 activity and markedly increased erythrocyte protoporphyrin levels. Patients present with severe cutaneous photosensitivity and may develop liver dysfunction. XLP was originally reported as X-linked dominant with 100% penetrance in males and females. We characterized 11 heterozygous females from six unrelated XLP families and show markedly varying phenotypic and biochemical heterogeneity, reflecting the degree of X-chromsomal inactivation of the mutant gene. ALAS2 sequencing identified the specific mutation and confirmed heterozygosity among the females. Clinical history, plasma and erythrocyte protoporphyrin levels were determined. Methylation assays of the androgen receptor and zinc-finger MYM type 3 short tandem repeat polymorphisms estimated each heterozygotes X-chromosomal inactivation pattern. Heterozygotes with equal or increased skewing, favoring expression of the wild-type allele had no clinical symptoms and only slightly increased erythrocyte protoporphyrin concentrations and/or frequency of protoporphyrin-containing peripheral blood fluorocytes. When the wild-type allele was preferentially inactivated, heterozygous females manifested the disease phenotype and had both higher erythrocyte protoporphyrin levels and circulating fluorocytes. These findings confirm that the previous dominant classification of XLP is inappropriate and genetically misleading, as the disorder is more appropriately designated XLP. PMID:25615817

Linkage localization of X-linked Charcot-Marie-Tooth disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bergoffen, J.; Trofatter, J.; Haines, J.L.

1993-02-01

Charcot-Marie-Tooth disease (CMT), also known as hereditary motor and sensory neuropathy, is a heterogeneous group of slowly progressive, degenerative disorders of peripheral nerve. X-linked CMT (CMTX) (McKusick 302800), a subdivision of type I, or demyelinating, CMT is an X-linked dominant condition with variable penetrance. Previous linkage analysis using RFLPs demonstrated linkage to markers on the proximal long and short arms of the X chromosome, with the more likely localization on the proximal long arm of the X chromosome. Available variable simple-sequence repeats (VSSRs) broaden the possibilities for linkage analysis. This paper presents new linkage data and recombination analysis derived frommore » work with four VSSR markers - AR, PGKP1, DXS453, and DXYS1X - in addition to analysis using RFLP markers described elsewhere. These studies localize the CMTX gene to the proximal Xq segment between PGKP1 (Xq11.2-12) and DXS72 (Xq21.1), with a combined maximum multipoint lod score of 15.3 at DXS453 ([theta] = 0). 32 refs., 3 figs., 2 tabs.« less

Parenting of children with Down syndrome compared to fragile X syndrome.

PubMed

Sterling, Audra; Warren, Steven F

2018-01-01

Children with Down syndrome (DS) and fragile X syndrome (FXS) struggle with language development. Parenting variables, such as responsiveness to children's communication attempts (Maternal Responsivity), and techniques used to support and teach appropriate behavior (Behavior Management) are known to have a significant impact on early child development. We examined these two aspects of parenting style via coded, videotaped parent-child interactions in two groups of participants matched on child age (2-5 years) and child expressive language level: mothers of children with DS and mothers of children with FXS. The mothers differed in their use of gestures and redirecting the child's attention. Overall, mothers in both groups of children appeared to adapt appropriately to their children's developmental needs.

Articulation and Noncomprehension Signaling in Adolescent and Adult Males with Down Syndrome and Fragile X Syndrome

ERIC Educational Resources Information Center

Fedak, Larissa Ann

2012-01-01

The purpose of this study was to determine whether or not decreased articulation of speech played a role in the ability of an individual with Down syndrome or Fragile X syndrome to signal noncomprehension and whether the two groups differed in their levels of articulation of speech and noncomprehension signaling ability. The research was conducted…

Hypogonadotropic hypogonadism revisited.

PubMed

Fraietta, Renato; Zylberstejn, Daniel Suslik; Esteves, Sandro C

2013-01-01

Impaired testicular function, i.e., hypogonadism, can result from a primary testicular disorder (hypergonadotropic) or occur secondary to hypothalamic-pituitary dysfunction (hypogonadotropic). Hypogonadotropic hypogonadism can be congenital or acquired. Congenital hypogonadotropic hypogonadism is divided into anosmic hypogonadotropic hypogonadism (Kallmann syndrome) and congenital normosmic isolated hypogonadotropic hypogonadism (idiopathic hypogonadotropic hypogonadism). The incidence of congenital hypogonadotropic hypogonadism is approximately 1-10:100,000 live births, and approximately 2/3 and 1/3 of cases are caused by Kallmann syndrome (KS) and idiopathic hypogonadotropic hypogonadism, respectively. Acquired hypogonadotropic hypogonadism can be caused by drugs, infiltrative or infectious pituitary lesions, hyperprolactinemia, encephalic trauma, pituitary/brain radiation, exhausting exercise, abusive alcohol or illicit drug intake, and systemic diseases such as hemochromatosis, sarcoidosis and histiocytosis X. The clinical characteristics of hypogonadotropic hypogonadism are androgen deficiency and a lack/delay/stop of pubertal sexual maturation. Low blood testosterone levels and low pituitary hormone levels confirm the hypogonadotropic hypogonadism diagnosis. A prolonged stimulated intravenous GnRH test can be useful. In Kallmann syndrome, cerebral MRI can show an anomalous morphology or even absence of the olfactory bulb. Therapy for hypogonadotropic hypogonadism depends on the patient's desire for future fertility. Hormone replacement with testosterone is the classic treatment for hypogonadism. Androgen replacement is indicated for men who already have children or have no desire to induce pregnancy, and testosterone therapy is used to reverse the symptoms and signs of hypogonadism. Conversely, GnRH or gonadotropin therapies are the best options for men wishing to have children. Hypogonadotropic hypogonadism is one of the rare conditions in which specific

Hypogonadotropic Hypogonadism Revisited

PubMed Central

Fraietta, Renato; Zylberstejn, Daniel Suslik; Esteves, Sandro C

2013-01-01

Impaired testicular function, i.e., hypogonadism, can result from a primary testicular disorder (hypergonadotropic) or occur secondary to hypothalamic-pituitary dysfunction (hypogonadotropic). Hypogonadotropic hypogonadism can be congenital or acquired. Congenital hypogonadotropic hypogonadism is divided into anosmic hypogonadotropic hypogonadism (Kallmann syndrome) and congenital normosmic isolated hypogonadotropic hypogonadism (idiopathic hypogonadotropic hypogonadism). The incidence of congenital hypogonadotropic hypogonadism is approximately 1-10:100,000 live births, and approximately 2/3 and 1/3 of cases are caused by Kallmann syndrome (KS) and idiopathic hypogonadotropic hypogonadism, respectively. Acquired hypogonadotropic hypogonadism can be caused by drugs, infiltrative or infectious pituitary lesions, hyperprolactinemia, encephalic trauma, pituitary/brain radiation, exhausting exercise, abusive alcohol or illicit drug intake, and systemic diseases such as hemochromatosis, sarcoidosis and histiocytosis X. The clinical characteristics of hypogonadotropic hypogonadism are androgen deficiency and a lack/delay/stop of pubertal sexual maturation. Low blood testosterone levels and low pituitary hormone levels confirm the hypogonadotropic hypogonadism diagnosis. A prolonged stimulated intravenous GnRH test can be useful. In Kallmann syndrome, cerebral MRI can show an anomalous morphology or even absence of the olfactory bulb. Therapy for hypogonadotropic hypogonadism depends on the patient's desire for future fertility. Hormone replacement with testosterone is the classic treatment for hypogonadism. Androgen replacement is indicated for men who already have children or have no desire to induce pregnancy, and testosterone therapy is used to reverse the symptoms and signs of hypogonadism. Conversely, GnRH or gonadotropin therapies are the best options for men wishing to have children. Hypogonadotropic hypogonadism is one of the rare conditions in which specific

Early White-Matter Abnormalities of the Ventral Frontostriatal Pathway in Fragile X Syndrome

ERIC Educational Resources Information Center

Haas, Brian W.; Barnea-Goraly, Naama; Lightbody, Amy A.; Patnaik, Swetapadma S.; Hoeft, Fumiko; Hazlett, Heather; Piven, Joseph; Reiss, Allan L.

2009-01-01

Aim: Fragile X syndrome is associated with cognitive deficits in inhibitory control and with abnormal neuronal morphology and development. Method: In this study, we used a diffusion tensor imaging (DTI) tractography approach to reconstruct white-matter fibers in the ventral frontostriatal pathway in young males with fragile X syndrome (n = 17;…

Predictors of Stress in Mothers and Fathers of Children with Fragile X Syndrome

ERIC Educational Resources Information Center

McCarthy, Annette; Cuskelly, Monica; van Kraayenoord, Christina E.; Cohen, Jonathan

2006-01-01

This study examined parental and family stress and functioning where there is a child with fragile X syndrome. Mothers and fathers in 40 families were asked about their child with fragile X syndrome, family supports, their psychological stress, the marital relationship, and their family stress. Results indicate parents were well adjusted in terms…

X-inactivation patterns in female Leber`s hereditary optic neuropathy patients do not support a strong X-linked determinant

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pegoraro, E.; Hoffman, E.P.; Carelli, V.

1996-02-02

Leber`s hereditary optic neuropathy (LHON) accounts for about 3% of the cases of blindness in young adult males. The underlying mitochondrial pathogenesis of LHON has been well studied, with specific mitochondrial DNA (mtDNA) mutations of structural genes described and well characterized. However, enigmatic aspects of the disease are not explained by mutation data, such as the higher proportion of affected males, the later onset of the disease in females, and the presence of unaffected individuals with a high proportion of mutant mtDNA. A hypothesis which has been put forward to explain the unusual disease expression is a dual model ofmore » mtDNA and X-linked nuclear gene inheritance. If a nuclear X-linked modifier gene influences the expression of the mitochondrial-linked mutant gene then the affected females should be either homozygous for the nuclear determinant, or if heterozygous, lyonization should favor the mutant X. In order to determine if an X-linked gene predisposes to LHON phenotype we studied X-inactivation patterns in 35 females with known mtDNA mutations from 10 LHON pedigrees. Our results do not support a strong X-linked determinant in LHON cause: 2 of the 10 (20%) manifesting carriers showed skewing of X-inactivation, as did 3 of the 25 (12%) nonmanifesting carriers. 39 refs., 2 figs., 1 tab.« less

[Norrie syndrome (author's transl)].

PubMed

Schmitz-Valckenberg, P; Scholz, W

1977-10-01

The Norrie syndrome, an x-chromosomal linked, recessive genetic disease, is described using ophthalmologic and genetic examinations of a family in three generations. The main symptom of this syndrome is retinal detachment with hemorrhages, which generally leads to blindness in early childhood. In addition to this, in 25--35% of the cases mental retardation and hearing problems are found. Special significance is to be attached to the differential diagnosis of this syndrome because the vascular proliferation on the retina is a non-specific, secondary reaction in children, which also occurs symptomatically in several other diseases.

Genome-wide misexpression of X-linked versus autosomal genes associated with hybrid male sterility.

PubMed

Lu, Xuemei; Shapiro, Joshua A; Ting, Chau-Ti; Li, Yan; Li, Chunyan; Xu, Jin; Huang, Huanwei; Cheng, Ya-Jen; Greenberg, Anthony J; Li, Shou-Hsien; Wu, Mao-Lien; Shen, Yang; Wu, Chung-I

2010-08-01

Postmating reproductive isolation is often manifested as hybrid male sterility, for which X-linked genes are overrepresented (the so-called large X effect). In contrast, X-linked genes are significantly under-represented among testis-expressing genes. This seeming contradiction may be germane to the X:autosome imbalance hypothesis on hybrid sterility, in which the X-linked effect is mediated mainly through the misexpression of autosomal genes. In this study, we compared gene expression in fertile and sterile males in the hybrids between two Drosophila species. These hybrid males differ only in a small region of the X chromosome containing the Ods-site homeobox (OdsH) (also known as Odysseus) locus of hybrid sterility. Of genes expressed in the testis, autosomal genes were, indeed, more likely to be misexpressed than X-linked genes under the sterilizing action of OdsH. Since this mechanism of X:autosome interaction is only associated with spermatogenesis, a connection between X:autosome imbalance and the high rate of hybrid male sterility seems plausible.

Behavioral Assessment of Social Anxiety in Females with Turner or Fragile X Syndrome.

ERIC Educational Resources Information Center

Lesniak-Karpiak, Katarzyna; Mazzocco, Michele M. M.; Ross, Judith L.

2003-01-01

This study compared 29 females with Turner syndrome and 21 females with fragile X syndrome (ages 6-22) on a videotaped role-play interaction with 34 females in a comparison group. Three of eight behavioral measures of social skills differentiated the participant groups. Fragile-X subjects required more time to initiate interactions and Turner…

Unusual Turner syndrome mosaic with a triple x cell line (47,X/49,XXX) in a western lowland gorilla (Gorilla gorilla gorilla).

PubMed

Bradford, Carol M; Tupa, Lynn; Wiese, Debbie; Hurley, Timothy J; Zimmerman, Ralph

2013-12-01

A 29-yr-old female western lowland gorilla (Gorilla gorilla gorilla) was evaluated for low fertility and a midterm abortion. Laboratory testing included karyotyping, which revealed an unusual mosaicism for Turner syndrome with Triple X (47,X/49,XXX). This appears to be the first report of Turner syndrome in a great ape. In humans, Turner syndrome occurs in approximately 1 in 3,000 females, with half of those monosomic for the X chromosome. A small proportion is mosaic for a triple X cell line (3-4%). In humans, Turner syndrome is associated with characteristic phenotype including short stature, obesity, a broad chest with widely spaced nipples, webbing of the neck, and anteverted ears. This individual gorilla is significantly shorter in stature than conspecifics and is obese despite normal caloric intake. Individuals with Turner syndrome should also be screened for common health issues, including congenital heart defects, obesity, kidney abnormalities, hypertension, hypothyroidism, and diabetes mellitus. Animals with decreased fertility, multiple miscarriages, fetal losses, unusual phenotypes, or a combination of these symptoms should be evaluated for genetic abnormalities.

Open-Label Memantine in Fragile X Syndrome

ERIC Educational Resources Information Center

Erickson, Craig A.; Mullett, Jennifer E.; McDougle, Christopher J.

2009-01-01

Glutamatergic dysfunction is implicated in the pathophysiology of fragile X syndrome (FXS). The purpose of this pilot study was to examine the effectiveness and tolerability of memantine for a number of target symptoms associated with FXS. Medical records describing open-label treatment with memantine in 6 patients with FXS and a comorbid…

[No X-chromosome linked juvenile foveal retinoschisis].

PubMed

Pérez Alvarez, M J; Clement Fernández, F

2002-08-01

To describe the clinical characteristics of two cases of juvenile foveal retinoschisis in women with an atypical hereditary pattern, no X-chromosome linked. An autosomal recessive inheritance is proposed. Two generations of a family (5 members) in which only two sisters were evaluated. The complete examination of these two cases includes retinography, fluorescein angiography, automated perimetry, color vision testing, electroretinogram, electrooculogram and visually evoked potentials. Comparing our cases with the classic form of X-linked juvenile retinoschisis, they are less severely affected. The best visual acuity and the less disturbed or even normal electroretinogram confirm this fact. We emphasise the existence of isolated plaques of retinal pigment epithelium atrophy with perivascular pigment clumps without foveal schisis in one patient, which could represent an evolved form of this entity. The hereditary foveal juvenile retinoschisis in women suggests an autosomal inheritance (autosomal recessive in our cases) and presents less severe involvement (Arch Soc Esp Oftalmol 2002; 77: 443-448).

Theory of Mind Deficits in Children with Fragile X Syndrome

ERIC Educational Resources Information Center

Cornish, K.; Burack, J. A.; Rahman, A.; Munir, F.; Russo, N.; Grant, C.

2005-01-01

Given the consistent findings of theory of mind deficits in children with autism, it would be extremely beneficial to examine the profile of theory of mind abilities in other clinical groups such as fragile X syndrome (FXS) and Down syndrome (DS). The aim of the present study was to assess whether boys with FXS are impaired in simple social…

Mathematics Learning Disabilities in Girls with Fragile X or Turner Syndrome during Late Elementary School

ERIC Educational Resources Information Center

Murphy, Melissa M.; Mazzocco, Michele M. M.

2008-01-01

The present study focuses on math and related skills among 32 girls with fragile X (n = 14) or Turner (n = 18) syndrome during late elementary school. Performance in each syndrome group was assessed relative to Full Scale IQ-matched comparison groups of girls from the general population (n = 32 and n = 89 for fragile X syndrome and Turner…

Differential splicing of human androgen receptor pre-mRNA in X-linked reifenstein syndrome, because of a deletion involving a putative branch site

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ris-Stalpers, C.; Verleun-Mooijman, M.C.T.; Blaeij, T.J.P. de

1994-04-01

The analysis of the androgen receptor (AR) gene, mRNA, and protein in a subject with X-linked Reifenstein syndrome (partial androgen insensitivity) is reported. The presence of two mature AR transcripts in genital skin fibroblasts of the patient is established, and, by reverse transcriptase-PCR and RNase transcription analysis, the wild-type transcript and a transcript in which exon 3 sequences are absent without disruption of the translational reading frame are identified. Sequencing and hybridization analysis show a deletion of >6 kb in intron 2 of the human AR gene, starting 18 bp upstream of exon 3. The deletion includes the putative branch-pointmore » sequence (BPS) but not the acceptor splice site on the intron 2/exon 3 boundary. The deletion of the putative intron 2 BPS results in 90% inhibition of wild-type splicing. The mutant transcript encodes an AR protein lacking the second zinc finger of the DNA-binding domain. Western/immunoblotting analysis is used to show that the mutant AR protein is expressed in genital skin fibroblasts of the patient. The residual 10% wild-type transcript can be the result of the use of a cryptic BPS located 63 bp upstream of the intron 2/exon 3 boundary of the mutant AR gene. The mutated AR protein has no transcription-activating potential and does not influence the transactivating properties of the wild-type AR, as tested in cotransfection studies. It is concluded that the partial androgen-insensitivity syndrome of this patient is the consequence of the limited amount of wild-type AR protein expressed in androgen target cells, resulting from the deletion of the intron 2 putative BPS. 42 refs., 6 figs., 1 tab.« less

The Coffin-Lowry syndrome: an inherited faciodigital mental retardation syndrome.

PubMed

Temtamy, S A; Miller, J D; Hussels-Maumenee, I

1975-05-01

Eight patients in three families had mental retardation, characteristic facies and hands, and skeletal changes; the clinical features suggested to us that they had a syndrome previously thought to represent two entities described by Lowry and associates and by Coffin and associates, respectively. New findings include skeletal, orodental, and dermatoglyphic abnormalities and histopathologic changes suggesting that the syndrome is a heritable disorder of connective tissue. Severe expression in males and transmission through mildly affected females suggest X-linked or sex-influenced autosomal dominant inheritance.

Modeling Family Adaptation to Fragile X Syndrome

ERIC Educational Resources Information Center

Raspa, Melissa; Bailey, Donald, Jr.; Bann, Carla; Bishop, Ellen

2014-01-01

Using data from a survey of 1,099 families who have a child with Fragile X syndrome, we examined adaptation across 7 dimensions of family life: parenting knowledge, social support, social life, financial impact, well-being, quality of life, and overall impact. Results illustrate that although families report a high quality of life, they struggle…

Learning potential and cognitive abilities in preschool boys with fragile X and Down syndrome.

PubMed

Valencia-Naranjo, Nieves; Robles-Bello, Mª Auxiliadora

2017-01-01

Enhancing cognitive abilities is relevant when devising treatment plans. This study examined the performance of preschool boys with Down syndrome and fragile X syndrome in cognitive tasks (e.g., nonverbal reasoning and short-term memory), as well as in improving cognitive functions by means of a learning potential methodology. The basic scales corresponding to the Skills and Learning Potential Preschool Scale were administered to children with Down syndrome and others with fragile X syndrome, matched for chronological age and nonverbal cognitive development level. The fragile X syndrome group showed stronger performance on short-term memory tasks than the Down syndrome group prior to intervention, with no differences recorded in nonverbal reasoning tasks. In addition, both groups' cognitive performance improved significantly between pre- and post-intervention. However, learning potential relative to auditory memory was limited in both groups, and for rule-based categorization in Down syndrome children. The scale offered the opportunity to assess young children's abilities and identify the degree of cognitive modifiability. Furthermore, factors that may potentially affect the children's performance before and during learning potential assessment are discussed. Copyright © 2016 Elsevier Ltd. All rights reserved.

BCOR analysis in patients with OFCD and Lenz microphthalmia syndromes, mental retardation with ocular anomalies, and cardiac laterality defects

PubMed Central

Hilton, Emma; Johnston, Jennifer; Whalen, Sandra; Okamoto, Nobuhiko; Hatsukawa, Yoshikazu; Nishio, Juntaro; Kohara, Hiroshi; Hirano, Yoshiko; Mizuno, Seiji; Torii, Chiharu; Kosaki, Kenjiro; Manouvrier, Sylvie; Boute, Odile; Perveen, Rahat; Law, Caroline; Moore, Anthony; Fitzpatrick, David; Lemke, Johannes; Fellmann, Florence; Debray, François-Guillaume; Dastot-Le-Moal, Florence; Gerard, Marion; Martin, Josiane; Bitoun, Pierre; Goossens, Michel; Verloes, Alain; Schinzel, Albert; Bartholdi, Deborah; Bardakjian, Tanya; Hay, Beverly; Jenny, Kim; Johnston, Kathreen; Lyons, Michael; Belmont, John W; Biesecker, Leslie G; Giurgea, Irina; Black, Graeme

2009-01-01

Oculofaciocardiodental (OFCD) and Lenz microphthalmia syndromes form part of a spectrum of X-linked microphthalmia disorders characterized by ocular, dental, cardiac and skeletal anomalies and mental retardation. The two syndromes are allelic, caused by mutations in the BCL-6 corepressor gene (BCOR). To extend the series of phenotypes associated with pathogenic mutations in BCOR, we sequenced the BCOR gene in patients with (1) OFCD syndrome, (2) putative X-linked (‘Lenz') microphthalmia syndrome, (3) isolated ocular defects and (4) laterality phenotypes. We present a new cohort of females with OFCD syndrome and null mutations in BCOR, supporting the hypothesis that BCOR is the sole molecular cause of this syndrome. We identify for the first time mosaic BCOR mutations in two females with OFCD syndrome and one apparently asymptomatic female. We present a female diagnosed with isolated ocular defects and identify minor features of OFCD syndrome, suggesting that OFCD syndrome may be mild and underdiagnosed. We have sequenced a cohort of males diagnosed with putative X-linked microphthalmia and found a mutation, p.P85L, in a single case, suggesting that BCOR mutations are not a major cause of X-linked microphthalmia in males. The absence of BCOR mutations in a panel of patients with non-specific laterality defects suggests that mutations in BCOR are not a major cause of isolated heart and laterality defects. Phenotypic analysis of OFCD and Lenz microphthalmia syndromes shows that in addition to the standard diagnostic criteria of congenital cataract, microphthalmia and radiculomegaly, patients should be examined for skeletal defects, particularly radioulnar synostosis, and cardiac/laterality defects. PMID:19367324

Cardiac Autonomic Regulation in Autism and Fragile X Syndrome: A Review

PubMed Central

Klusek, Jessica; Roberts, Jane E.; Losh, Molly

2014-01-01

Despite the significance of efforts to understand the biological basis of autism, progress in this area has been hindered, in part, by the considerable heterogeneity in the disorder. Fragile X syndrome (FXS), a monogenic condition associated with high risk for autism, may pave the way for the dissection of biological heterogeneity within idiopathic autism. This paper adopts a cross-syndrome biomarker approach to evaluate potentially overlapping profiles of cardiac arousal dysregulation (and broader autonomic dysfunction) in autism and FXS. Approaches such as this, aimed at delineating shared mechanisms across genetic syndromes, hold great potential for improving diagnostic precision, promoting earlier identification, and uncovering key systems that can be targeted in pharmaceutical/behavioral interventions. Biomarker approaches may be vital to deconstructing complex psychiatric disorders, and are currently promoted as such by major research initiatives such as the NIMH Research Domain Criteria (RDoC). Evidence reviewed here supports physiological dysregulation in a subset of individuals with autism, as evidenced by patterns of hyperarousal and dampened parasympathetic vagal tone, which overlap with the well-documented physiological profile of FXS. Moreover, there is growing support for a link between aberrant cardiac activity and core deficits associated with autism, such as communication and social impairment. The delineation of physiological mechanisms common to autism and FXS could lend insight into relationships between genetic etiology and behavioral endstates, highlighting FMR1 as a potential candidate gene. Research gaps and potential pitfalls are discussed to inform timely, well-controlled biomarker research that will ultimately promote better diagnosis and treatment of autism and associated conditions. PMID:25420222

Genome-wide misexpression of X-linked versus autosomal genes associated with hybrid male sterility

PubMed Central

Lu, Xuemei; Shapiro, Joshua A.; Ting, Chau-Ti; Li, Yan; Li, Chunyan; Xu, Jin; Huang, Huanwei; Cheng, Ya-Jen; Greenberg, Anthony J.; Li, Shou-Hsien; Wu, Mao-Lien; Shen, Yang; Wu, Chung-I

2010-01-01

Postmating reproductive isolation is often manifested as hybrid male sterility, for which X-linked genes are overrepresented (the so-called large X effect). In contrast, X-linked genes are significantly under-represented among testis-expressing genes. This seeming contradiction may be germane to the X:autosome imbalance hypothesis on hybrid sterility, in which the X-linked effect is mediated mainly through the misexpression of autosomal genes. In this study, we compared gene expression in fertile and sterile males in the hybrids between two Drosophila species. These hybrid males differ only in a small region of the X chromosome containing the Ods-site homeobox (OdsH) (also known as Odysseus) locus of hybrid sterility. Of genes expressed in the testis, autosomal genes were, indeed, more likely to be misexpressed than X-linked genes under the sterilizing action of OdsH. Since this mechanism of X:autosome interaction is only associated with spermatogenesis, a connection between X:autosome imbalance and the high rate of hybrid male sterility seems plausible. PMID:20511493

Modulation of the GABAergic pathway for the treatment of fragile X syndrome.

PubMed

Lozano, Reymundo; Hare, Emma B; Hagerman, Randi J

2014-01-01

Fragile X syndrome (FXS) is the most common genetic cause of intellectual disability and the most common single-gene cause of autism. It is caused by mutations on the fragile X mental retardation gene (FMR1) and lack of fragile X mental retardation protein, which in turn, leads to decreased inhibition of translation of many synaptic proteins. The metabotropic glutamate receptor (mGluR) hypothesis states that the neurological deficits in individuals with FXS are due mainly to downstream consequences of overstimulation of the mGluR pathway. The main efforts have focused on mGluR5 targeted treatments; however, investigation on the gamma-aminobutyric acid (GABA) system and its potential as a targeted treatment is less emphasized. The fragile X mouse models (Fmr1-knock out) show decreased GABA subunit receptors, decreased synthesis of GABA, increased catabolism of GABA, and overall decreased GABAergic input in many regions of the brain. Consequences of the reduced GABAergic input in FXS include oversensitivity to sensory stimuli, seizures, and anxiety. Deficits in the GABA receptors in different regions of the brain are associated with behavioral and attentional processing deficits linked to anxiety and autistic behaviors. The understanding of the neurobiology of FXS has led to the development of targeted treatments for the core behavioral features of FXS, which include social deficits, inattention, and anxiety. These symptoms are also observed in individuals with autism and other neurodevelopmental disorders, therefore the targeted treatments for FXS are leading the way in the treatment of other neurodevelopmental syndromes and autism. The GABAergic system in FXS represents a target for new treatments. Herein, we discuss the animal and human trials of GABAergic treatment in FXS. Arbaclofen and ganaxolone have been used in individuals with FXS. Other potential GABAergic treatments, such as riluzole, gaboxadol, tiagabine, and vigabatrin, will be also discussed. Further

Brief Report: Acamprosate in Fragile X Syndrome

ERIC Educational Resources Information Center

Erickson, Craig A.; Mullett, Jennifer E.; McDougle, Christopher J.

2010-01-01

Glutamatergic dysfunction is implicated in the pathophysiology of fragile X syndrome (FXS). We report on the first trial of acamprosate, a drug with putative mGluR5 antagonism, in three adults with FXS and autism. Medical records describing open-label treatment with acamprosate in 3 patients with FXS and a comorbid diagnosis of autistic disorder…

Genetics Home Reference: X-linked cardiac valvular dysplasia

MedlinePlus

... inflammation of the inner lining of the heart (endocarditis), abnormal blood clots, or sudden death. X-linked ... Johns Hopkins Medicine: Mitral Valve Prolapse MedlinePlus Encyclopedia: Endocarditis MedlinePlus Encyclopedia: Mitral Valve Prolapse General Information from ...

Novel syndrome of cataracts, retinitis pigmentosa, late onset deafness and sperm abnormalities: a new Usher syndrome subtype with X-linked inheritance?

PubMed

Malekpour, Mahdi; Shahidi, Arash; Khorsandi Ashtiani, Mohammad Taghi; Motasaddi Zarandy, Masoud

2007-07-15

Tissues of the auditory, ocular and reproductive systems have some similarities in their protein families and structures. Consequently, syndromes comprising these systems are described. Hearing loss alone is a component of more than 400 known syndromes and is a common nonsyndromic congenital disorder. Here we describe a syndrome in five brothers with the distinctive presentation of late-onset progressive hearing loss, cataracts, retinitis pigmentosa, sperm motility and shape problems in a family from the Kurdish population in Iran. The clinical findings of these patients are presented in detail and compared to the classical Usher syndromes. (c) 2007 Wiley-Liss, Inc

Perseveration in the Connected Speech of Boys with Fragile X Syndrome with and without Autism Spectrum Disorder

ERIC Educational Resources Information Center

Martin, Gary E.; Roberts, Joanne E.; Helm-Estabrooks, Nancy; Sideris, John; Vanderbilt, Jacqueline; Moskowitz, Lauren

2012-01-01

Verbal perseveration is a frequently reported language characteristic of males with Fragile X syndrome and may be a defining feature or hallmark of the syndrome. We compared the verbal perseveration of boys with Fragile X syndrome with (n = 29) and without (n = 30) autism spectrum disorder, boys with Down syndrome (n = 27), and typically…

Hippocampal dysfunction and cognitive impairment in Fragile-X Syndrome.

PubMed

Bostrom, Crystal; Yau, Suk-Yu; Majaess, Namat; Vetrici, Mariana; Gil-Mohapel, Joana; Christie, Brian R

2016-09-01

Fragile-X Syndrome (FXS) is the most common form of inherited intellectual disability and the leading genetic cause of autism spectrum disorder. FXS is caused by transcriptional silencing of the Fragile X Mental Retardation 1 (Fmr1) gene due to a CGG repeat expansion, resulting in the loss of Fragile X Mental Retardation Protein (FMRP). FMRP is involved in transcriptional regulation and trafficking of mRNA from the nucleus to the cytoplasm and distal sites both in pre- and post-synaptic terminals. Consequently, FXS is a multifaceted disorder associated with impaired synaptic plasticity. One region of the brain that is significantly impacted by the loss of FMRP is the hippocampus, a structure that plays a critical role in the regulation of mood and cognition. This review provides an overview of the neuropathology of Fragile-X Syndrome, highlighting how structural and synaptic deficits in hippocampal subregions, including the CA1 exhibiting exaggerated metabotropic glutamate receptor dependent long-term depression and the dentate gyrus displaying hypofunction of N-methyl-d-aspartate receptors, contribute to cognitive impairments associated with this neurodevelopmental disorder. Copyright © 2016 Elsevier Ltd. All rights reserved.

Xp11.22 deletions encompassing CENPVL1, CENPVL2, MAGED1 and GSPT2 as a cause of syndromic X-linked intellectual disability.

PubMed

Grau, Christina; Starkovich, Molly; Azamian, Mahshid S; Xia, Fan; Cheung, Sau Wai; Evans, Patricia; Henderson, Alex; Lalani, Seema R; Scott, Daryl A

2017-01-01

By searching a clinical database of over 60,000 individuals referred for array-based CNV analyses and online resources, we identified four males from three families with intellectual disability, developmental delay, hypotonia, joint hypermobility and relative macrocephaly who carried small, overlapping deletions of Xp11.22. The maximum region of overlap between their deletions spanned ~430 kb and included two pseudogenes, CENPVL1 and CENPVL2, whose functions are not known, and two protein coding genes-the G1 to S phase transition 2 gene (GSPT2) and the MAGE family member D1 gene (MAGED1). Deletions of this ~430 kb region have not been previously implicated in human disease. Duplications of GSPT2 have been documented in individuals with intellectual disability, but the phenotypic consequences of a loss of GSPT2 function have not been elucidated in humans or mouse models. Changes in MAGED1 have not been associated with intellectual disability in humans, but loss of MAGED1 function is associated with neurocognitive and neurobehavioral phenotypes in mice. In all cases, the Xp11.22 deletion was inherited from an unaffected mother. Studies performed on DNA from one of these mothers did not show evidence of skewed X-inactivation. These results suggest that deletions of an ~430 kb region on chromosome Xp11.22 that encompass CENPVL1, CENPVL2, GSPT2 and MAGED1 cause a distinct X-linked syndrome characterized by intellectual disability, developmental delay, hypotonia, joint hypermobility and relative macrocephaly. Loss of GSPT2 and/or MAGED1 function may contribute to the intellectual disability and developmental delay seen in males with these deletions.

X-linked mental retardation associated with macro-orchidism.

PubMed Central

Turner, G; Eastman, C; Casey, J; McLeay, A; Procopis, P; Turner, B

1975-01-01

Two families are described with an X-linked form of mental retardation in whom the affected males were found to have bilateral enlargement of the testes. No conclusive evidence of any endocrinological disturbance was found. Images PMID:1240971

Narrative Development in Adolescents and Young Adults with Fragile X Syndrome

ERIC Educational Resources Information Center

Keller-Bell, Yolanda D.; Abbeduto, Leonard D.

2007-01-01

The narratives of 18 adolescents and young adults with fragile X syndrome were compared to those of 23 adolescents with Down syndrome and 21 typically developing children matched for nonverbal MA. Narratives were elicited using a wordless picture book and analyzed for use of narrative evaluation, linguistic productivity, and complexity. Results…

The Role of Prokineticins in the Pathogenesis of Hypogonadotropic Hypogonadism

PubMed Central

Abreu, Ana Paula; Kaiser, Ursula B.; Latronico, Ana Claudia

2010-01-01

The prokineticin system comprises two multifunctional secreted proteins, prokineticin-1 (PROK1) and prokineticin-2 (PROK2), and their cognate G protein-coupled receptors. The prokineticins were originally identified as endogenous regulators of gastrointestinal motility. Currently, these bioactive peptides are involved in a wide spectrum of biological functions, including angiogenesis, neurogenesis, circadian rhythms, nociception, hematopoiesis and immune response. Mice homozygous for null mutations in Prokr2 or Prok2 recapitulate the human phenotype of Kallmann syndrome, exhibiting severe atrophy of the reproductive system and hypoplastic olfactory bulbs. Indeed, the evidence from several naturally inactivating mutations in the PROK2 and PROKR2 genes in patients with Kallmann syndrome and normosmic hypogonadotropic hypogonadism also indicate the essential role of PROK2 in olfactory bulb morphogenesis and GnRH secretion in humans. PMID:20502053

Genetics Home Reference: L1 syndrome

MedlinePlus

... X-linked hydrocephalus: evidence for closely related clinical entities of unknown molecular bases. Acta Neuropathol. 2013 Sep; ... F. Three cases with L1 syndrome and two novel mutations in the L1CAM gene. Eur J Pediatr. ...

Delineating the Profile of Autism Spectrum Disorder Characteristics in Cornelia de Lange and Fragile X Syndromes

ERIC Educational Resources Information Center

Moss, Joanna; Oliver, Chris; Nelson, Lisa; Richards, Caroline; Hall, Scott

2013-01-01

An atypical presentation of autism spectrum disorder is noted in Cornelia de Lange and Fragile X syndromes, but there are few detailed empirical descriptions. Participants in this study were individuals with Cornelia de Lange syndrome (n = 130, M age = 17.19), Fragile X syndrome (n = 182, M age = 16.94), and autism spectrum disorder (n = 142, M…

An Indirect Examination of the Function of Problem Behavior Associated with Fragile X Syndrome and Smith-Magenis Syndrome

ERIC Educational Resources Information Center

Langthorne, Paul; McGill, Peter

2012-01-01

Fragile X syndrome (FXS) and Smith-Magenis syndrome (SMS) are associated with a number of specific topographies of problem behavior. Very few studies have examined the function served by problem behavior in these groups. Using the Questions About Behavioral Function scale Matson and Vollmer (User's guide: questions about behavioral function…

Prenatal diagnosis and prognosis of triple X syndrome: 47, XXX.

PubMed

Ben Hamouda, H; Mkacher, N; Elghezal, H; Bannour, H; Kamoun, M; Soua, H; Saad, A; Souissi, M M; Sfar, M T

2009-11-01

Triple X syndrome is a relatively common sex chromosomal abnormality occurring in 0,1% of live-born female infants. Most of these infants have a normal phenotype and only a few cases with 47, XXX karyotype have congenital malformations. We report three cases of triple X syndrome that were diagnosed prenatally by genetic amniocentesis for advanced maternal age and have been observed from birth to age of 3 to 12 years. A description of their growth and development is presented. The birth weight was normal in all patients and one of them had facial dysmorphism with right microphtalmia and auricular septal defect. During the first 2 years of life, the neuromotor development of these infants was not distinguishable from chromosomally normal children. By 3 years of age, two patients have a moderate developmental delay in speech and language. One girl 12-year-old had normal schooling. The diagnosis of the triple X syndrome can be never made because clinical demonstrations are not rather important to arouse the demand of a karyotype. Prenatal diagnosis is often made in front of the advanced maternal age. Expectant parents must be counseled as to the significance of this 47, XXX karyotype and prognostic information must be given.

The multifocal electroretinogram in X-linked juvenile retinoschisis.

PubMed

Huang, Shizhou; Wu, Dezheng; Jiang, Futian; Luo, Guangwei; Liang, Jiongji; Wen, Feng; Yu, Minzhong; Long, Shixian; Wu, Lezheng

2003-05-01

To measure and compare the multifocal electroretinography in normal control and X-linked juvenile retinoschisis, 13 cases (13 right eyes) of normal control and nine cases (17 eyes) of X-linked juvenile retinoschisis were measured with VERIS Science 4.0. Four cases (eight eyes) out of the nine retinoschisis cases were tested with Ganzfeld ERG at the same day. The results showed statistically significant difference of average response densities and latencies in six ring retinal regions between the normal control and retinoschisis. The trace array and 3-D topography of multifocal ERG showed multi-area amplitude decrease with absence or reduction of central peak amplitude in patients with retinoschisis. The P1/N1 ratio of multifocal ERG average response densities in six ring retinal regions was different from the b/a ratio of Ganzfeld ERG. The multifocal ERG and Ganzfeld ERG each had its advantage in the diagnosis of retinoschisis.

Kabuki syndrome in a girl with mosaic 45,X/47,XXX and aortic coarctation.

PubMed

Chen, Chih-Ping; Lin, Shuan-Pei; Tsai, Fuu-Jen; Chern, Schu-Rern; Wang, Wayseen

2008-06-01

To describe the clinical findings of a patient with mosaic 45,X/47,XXX and aortic coarctation. Descriptive case study. Tertiary medical center. A 6-year-old girl with stigmata of Turner syndrome, aortic coarctation, patent ductus arteriosus, and a peculiar facial appearance. None. Cytogenetic analysis. The patient manifested a characteristic Kabuki syndrome facial appearance with long palpebral fissures, everted lateral third of lower eyelids, arched eyebrows, a depressed nasal tip, large dysplastic ears and epicanthic folds. She had undergone cardiac surgery for treatment of aortic coarctation and patent ductus arteriosus. Cytogenetic analysis of the blood lymphocytes revealed a karyotype of mos 45,X,9ph [35 cells]/47,XXX,9ph [5 cells]. This is the first report of mosaic 45,X/47,XXX associated with Kabuki syndrome. We emphasize that Kabuki syndrome, a peculiar facial appearance and aortic coarctation, should be considered in girls with sex chromosome abnormalities.

Do Individuals with Fragile X Syndrome Show Developmental Stuttering or Not? Comment on "Speech Fluency in Fragile X Syndrome" by Van Borsel, Dor and Rondal

ERIC Educational Resources Information Center

Howell, Peter

2008-01-01

Van Borsel, Dor, and Rondal (2007) examined the speech of seven boys and two young male adults with fragile X syndrome and considered whether their speech was comparable to that reported in the developmental stuttering literature. They listed five criteria which led them to conclude that the speech patterns of speakers with fragile X syndrome…

Psychological Well-Being in Fathers of Adolescents and Young Adults with Down Syndrome, Fragile X Syndrome, and Autism

ERIC Educational Resources Information Center

Hartley, Sigan L.; Seltzer, Marsha Mailick; Head, Lara; Abbeduto, Leonard

2012-01-01

The psychological well-being of fathers of children with developmental disabilities remains poorly understood. The present study examined depressive symptoms, pessimism, and coping in fathers of adolescents and young adults with Down syndrome (DS;n = 59), autism spectrum disorders (ASDs;n = 135), and Fragile X syndrome (n = 46). Fathers of sons or…

Imitation in Fragile X Syndrome: Implications for Autism

ERIC Educational Resources Information Center

Macedoni-Luksic, Marta; Greiss-Hess, Laura; Rogers, Sally J.; Gosar, David; Lemons-Chitwood, Kerrie; Hagerman, Randi

2009-01-01

To address the specific impairment of imitation in autism, the imitation abilities of 22 children with fragile X syndrome (FXS) with and without autism were compared. Based on previous research, we predicted that children with FXS and autism would have significantly more difficulty with non-meaningful imitation tasks. After controlling for…

Psychopharmacology in Fragile X Syndrome--Present and Future

ERIC Educational Resources Information Center

Berry-Kravis, Elizabeth; Potanos, Kristina

2004-01-01

In addition to cognitive disability, fragile X syndrome (FXS) is associated with behavioral problems that are often functionally limiting. There are few controlled trials to guide treatment; however, available information does suggest that medications can be quite helpful for a number of categories of behavioral disturbance in FXS. Specifically,…

Temporal retinal thinning and the diagnosis of Alport syndrome and Thin basement membrane nephropathy.

PubMed

Chen, Yan; Colville, Deb; Ierino, Francesco; Symons, Andrew; Savige, Judy

2018-04-01

Alport syndrome is an inherited disease characterized by renal failure, hearing loss, and ocular abnormalities, including temporal retinal thinning. This study compared retinal thinning in Alport syndrome and other renal diseases. Alport syndrome was diagnosed on renal biopsy and genetic testing. Subjects underwent optical coherence tomography (OCT) (Spectralis OCT, Heidelberg Instruments). Retinal thinning was determined from horizontal macular OCT scans through the foveal center using the formula: Temporal thickness index (TTI) = (nasal - temporal thickness) ÷ nasal thickness × 100%, and compared with the normal range for each age group. Statistical analysis was performed using Student's t test, Mann-Whitney U test, and ROC analysis (SPPS, IBM). The mean temporal retinal thickness index was 12.4 ± 5.2% in men (n = 19) and 7.4 ± 1.4% in women (n = 28) with X-linked Alport syndrome; 13.1 ± 4.5% (n = 4) in recessive disease; 6.4 ± 2.2% (n = 5) in Thin basement membrane nephropathy; and 6.3 ± 3.3% (n = 14) in other renal diseases. Thinning was worse in men than women with X-linked disease (p < 0.01), and worse in men who developed early onset renal failure (R 2  = 0.75). Temporal retinal thinning was 84% sensitive for men with X-linked Alport syndrome and 67% specific (AUC = 0.83) compared with other renal diseases. Retinal temporal thinning is diagnostic for X-linked Alport syndrome in men and distinguishes them this condition from Thin basement membrane nephropathy, but only in men (p = 0.002). Temporal retinal thinning may also identify men and women with the rarer autosomal recessive disease.

X-Linked Retinoschisis: Phenotypic Variability in a Chinese Family

PubMed Central

Xiao, Yangyan; Liu, Xiao; Tang, Luosheng; Wang, Xia; Coursy, Terry; Guo, Xiaojian; Li, Zhuo

2016-01-01

X-linked juvenile retinoschisis (XLRS), a leading cause of juvenile macular degeneration, is characterized by a spoke-wheel pattern in the macular region of the retina and splitting of the neurosensory retina. Our study is to describe the clinical characteristics of a four generations of this family (a total of 18 members)with X-linked retinoschisis (XLRS) and detected a novel mutations of c.3G > A (p.M1?) in the initiation codon of the RS1 gene. by direct sequencing.Identification of this mutation in this family provides evidence about potential genetic or environmental factors on its phenotypic variance, as patients presented with different phenotypes regardless of having the same mutation. Importantly, OCT has proven vital for XLRS diagnosis in children. PMID:26823236

X-Linked Retinoschisis: Phenotypic Variability in a Chinese Family.

PubMed

Xiao, Yangyan; Liu, Xiao; Tang, Luosheng; Wang, Xia; Coursey, Terry G; Coursy, Terry; Guo, Xiaojian; Li, Zhuo

2016-01-29

X-linked juvenile retinoschisis (XLRS), a leading cause of juvenile macular degeneration, is characterized by a spoke-wheel pattern in the macular region of the retina and splitting of the neurosensory retina. Our study is to describe the clinical characteristics of a four generations of this family (a total of 18 members)with X-linked retinoschisis (XLRS) and detected a novel mutations of c.3G > A (p.M1?) in the initiation codon of the RS1 gene. by direct sequencing.Identification of this mutation in this family provides evidence about potential genetic or environmental factors on its phenotypic variance, as patients presented with different phenotypes regardless of having the same mutation. Importantly, OCT has proven vital for XLRS diagnosis in children.

X-linked adrenoleukodystrophy in heterozygous female patients: women are not just carriers.

PubMed

Lourenço, Charles Marques; Simão, Gustavo Novelino; Santos, Antonio Carlos; Marques, Wilson

2012-07-01

X-linked adrenoleukodystrophy (X-ALD) is a recessive X-linked disorder associated with marked phenotypic variability. Female carriers are commonly thought to be normal or only mildly affected, but their disease still needs to be better described and systematized. To review and systematize the clinical features of heterozygous women followed in a Neurogenetics Clinic. We reviewed the clinical, biochemical, and neuroradiological data of all women known to have X-ADL. The nine women identified were classified into three groups: with severe and aggressive diseases; with slowly progressive, spastic paraplegia; and with mildly decreased vibratory sensation, brisk reflexes, and no complaints. Many of these women did not have a known family history of X-ALD. Heterozygous women with X-ADL have a wide spectrum of clinical manifestations, ranging from mild to severe phenotypes.

Triple X Egyptian woman and a Down's syndrome offspring

PubMed Central

El-Dahtory, Faeza Abdel Mogib

2013-01-01

The 47, XXX karyotype (triple X) has a frequency of 1 in 1000 female newborns. However, this karyotype is not usually suspected at birth or childhood. Female patients with a sex chromosome abnormality may be fertile. In patients with a 47, XXX cell line there appears to be an increased risk of a cytogenetically abnormal child but the extent of this risk cannot yet be determined; it is probably lower in the non-mosaic 47, XXX patient than the mosaic 46, XX/47, XXX one. We describe a new rare case of triple X woman and a Down's syndrome offspring. The patient is 26 years of age. She is a housewife, her height is 160 cm and weight is 68 kg and her physical features and mentality are normal. She has had one pregnancy at the age of 25 years resulted in a girl with Down's syndrome. The child had 47 chromosomes with trisomy 21 (47, XX, +21) Figure 1. The patient also has 47 chromosomes with a triple X karyotype (47, XX, +X) Figure 2. The patient's husband (27 years old) is physically and mentally normal. He has 46 chromosomes with a normal XY karyotype (46, XY). There are neither Consanguinity between her parent's nor she and her husband. PMID:23901206

Side Effects of Minocycline Treatment in Patients with Fragile X Syndrome and Exploration of Outcome Measures

ERIC Educational Resources Information Center

Utari, Agustini; Chonchaiya, Weerasak; Rivera, Susan M.; Schneider, Andrea; Hagerman, Randi J.; Faradz, Sultana M. H.; Ethell, Iryna M.; Nguyen, Danh V.

2010-01-01

Minocycline can rescue the dendritic spine and synaptic structural abnormalities in the fragile X knock-out mouse. This is a review and preliminary survey to document side effects and potential outcome measures for minocycline use in the treatment of individuals with fragile X syndrome. We surveyed 50 patients with fragile X syndrome who received…

Craniofacial and dental manifestations of triple X syndrome associated with congenital hypothyroidism: a case report.

PubMed

Ferrazzo, Kívia Linhares; Payeras, Marcia Rodrigues; Ferrazzo, Vilmar Antonio; Mezomo, Maurício Barbieri

2014-01-01

Triple X syndrome (47,XXX) is a numerical chromosomal alteration that affects 1/1,000 women, in which the woman is born with an extra X chromosome. Some oral changes have been reported in the literature, as hypodontia, influence on deposition of crown enamel and discrepancies in cephalometric measurements. Other systemic complications may lead to oral abnormalities similar to those seen in triple X patients, such as congenital hypothyroidism (CH). This paper reports a triple X syndrome case associated with CH later treated. Besides delay in cognitive and intellectual development, the patient had changes in teeth development and in cephalometric measurements with deficiencies in the maxilla and mandible. This is the first report of a triple X syndrome associated with CH. Both conditions may result in changes in dentofacial development. © 2013 Special Care Dentistry Association and Wiley Periodicals, Inc.

Language and Learning in Boys with Fragile X Syndrome: Syntactic Processing and the Role of Phonological Memory

ERIC Educational Resources Information Center

Kover, Sara T.

2012-01-01

Fragile X syndrome is the leading inherited cause of intellectual disability. Most boys with fragile X syndrome have impaired cognition and language deficits, with significant within-syndrome variability. Syntax may be especially delayed relative to nonverbal cognition; however, little is known about the specificity of delay, the sources of that…

Longitudinal Profiles of Expressive Vocabulary, Syntax and Pragmatic Language in Boys with Fragile X Syndrome or Down Syndrome

ERIC Educational Resources Information Center

Martin, Gary E.; Losh, Molly; Estigarribia, Bruno; Sideris, John; Roberts, Joanne

2013-01-01

Background: Fragile X syndrome (FXS) and Down syndrome (DS) are the two leading genetic causes of intellectual disability, and FXS is the most common known genetic condition associated with autism. Both FXS and DS are associated with significant language impairment, but little is known about expressive language across domains over time or the role…

Boys with fragile X syndrome: investigating temperament in early childhood.

PubMed

Low Kapalu, C M; Gartstein, M A

2016-09-01

Fragile X syndrome (FXS) is an x-linked genetic disorder that represents the most common hereditary cause of Intellectual Disability (ID). Very specific behavioural features (e.g. attention deficit hyperactivity disorder and stereotyped behaviour) are associated with FXS in adolescents and adults, yet research on temperament and behavioural characteristics in young children with FXS has been more limited and less conclusive. This study investigated temperament differences in young boys (3-7 years old) with FXS (N = 26) recruited from a national FXS centre and controls (N = 26) matched on age, gender and race. Compared with controls, boys with FXS exhibited less overall surgency/extraversion and effortful control. Boys with FXS also displayed significantly greater activity and shyness and less attentional focusing, inhibitory control, soothability and high intensity pleasure (tendency to enjoy intense/complex activities), relative to comparison children. A significant interaction between age and diagnosis (FXS or control) was observed for negative affectivity only. Attention difficulties commonly found in adolescents and adults with FXS appear to also be characteristic of young boys with FXS, as reflected by lower effortful control. Age-related findings concerning negative affectivity may be particularly significant, leading to improved intervention/preventative efforts. © 2016 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.

Alport syndrome and thin glomerular basement membrane nephropathy: a practical approach to diagnosis.

PubMed

Haas, Mark

2009-02-01

Alport syndrome and thin glomerular basement membrane nephropathy (TBMN) are genetically heterogeneous conditions characterized by structural abnormalities in the glomerular basement membrane and an initial presentation that usually involves hematuria. Approximately 40% of patients with TBMN are heterozygous carriers for autosomal recessive Alport syndrome, with mutations at the genetic locus encoding type IV collagen alpha(3) [alpha(3)(IV)] and alpha(4) chains. However, although the clinical course of TBMN is usually benign, Alport syndrome, particularly the X-linked form with mutations in the locus encoding the alpha(5) chain of type IV collagen [alpha(5)(IV)], typically results in end-stage renal disease. Electron microscopy is essential to diagnosis of TBMN and Alport syndrome on renal biopsy, although electron microscopy alone is of limited value in distinguishing between TBMN, the heterozygous carrier state of X-linked Alport syndrome, autosomal recessive Alport syndrome, and even early stages of X-linked Alport syndrome. To review diagnostic pathologic features of each of the above conditions, emphasizing the need for immunohistology for alpha(3)(IV) and alpha(5)(IV) in addition to electron microscopy to resolve this differential diagnosis on a renal biopsy. The diagnostic value of immunofluorescence studies for alpha(5)(IV) on a skin biopsy in family members of patients with Alport syndrome also is reviewed. Original and comprehensive review articles on the diagnosis of Alport syndrome and TBMN from the past 35 years, primarily the past 2 decades, and experience in our own renal pathology laboratory. Although Alport syndrome variants and TBMN do not show characteristic light microscopic findings and can be difficult to differentiate from each other even by electron microscopy, using a combination of electron microscopy and immunohistology for alpha(3)(IV) and alpha(5)(IV) enables pathologists to definitively diagnose these disorders on renal biopsy in most

Characterization of X-OCRL, a Xenopus laevis homologue of OCRL-1, the Lowe oculocerebrorenal syndrome candidate gene

DOE Office of Scientific and Technical Information (OSTI.GOV)

Reilly, D.S.; Nussbaum, R.L.

1994-09-01

The Lowe oculocerebrorenal syndrome (OCRL) is an X-linked disease characterized by congenital cataract, mental retardation, and renal tubular dysfunction. A candidate cDNA, OCRL-1, was identified by positional cloning and mutations in OCRL-1 have been detected in patients with Lowe syndrome. The OCRL-1 nucleotide sequence encodes a predicted protein of 968 amino acids and shares 51% amino acid identity with a human inositol polyphosphate-5-phosphatase. This suggests that the underlying defect in OCRL may be due to a defect in inositol phosphate metabolism. The isolation of OCRL-1 provides the opportunity to investigate its function through the use of animal model systems. Wemore » have isolated a partial cDNA clone encoding an OCRL-1 homologue, X-OCRL, from the South African clawed frog, Xenopus laevis. We used a portion of the human cDNA to screen a Xenopus laevis embryo cDNA library and isolated four positive clones. One clone, 42-5A, is a 650 bp insert with over 75% amino acid identity to the corresponding region of the human OCRL-1 sequence. 42-5A detects messenger RNA in adult Xenopus brain, stomach, small intestine, skin, muscle, lung, blood, and oviduct. X-OCRL messenger RNA is first detected during late gastrula and continues to be expressed throughout Xenopus development. In situ hybridization studies are underway to identify the cellular localization of X-OCRL expression in Xenopus embryos and adult tissues. We are especially interested in characterizing X-OCRL expression during formation of the amphibian lens since congenital cataracts are a constant feature of the human disease.« less

Ocular Motor Indicators of Executive Dysfunction in Fragile X and Turner Syndromes

ERIC Educational Resources Information Center

Lasker, Adrian G.; Mazzocco, Michele M. M.; Zee, David S.

2007-01-01

Fragile X and Turner syndromes are two X-chromosome-related disorders associated with executive function and visual spatial deficits. In the present study, we used ocular motor paradigms to examine evidence that disruption to different neurological pathways underlies these deficits. We tested 17 females with fragile X, 19 females with Turner…

Adaptive Skills, Behavior Problems, and Parenting Stress in Mothers of Boys with Fragile X Syndrome

ERIC Educational Resources Information Center

Sarimski, Klaus

2010-01-01

The relationship of temperament, atypical behaviors, and adaptive behavior of young boys with Fragile X syndrome on mothers' parenting stress was analyzed. Twenty-six boys with Fragile X syndrome (30-88 months of age) participated. The overall development of the participants was significantly delayed with a specific profile of adaptive behaviors…

Cotinine administration improves impaired cognition in the mouse model of Fragile X syndrome.

PubMed

Pardo, Marta; Beurel, Eleonore; Jope, Richard S

2017-02-01

Cotinine is the major metabolite of nicotine and has displayed some capacity for improving cognition in mouse models following chronic administration. We tested if acute cotinine treatment is capable of improving cognition in the mouse model of Fragile X syndrome, Fmr1 -/- knockout mice, and if this is related to inhibition by cotinine treatment of glycogen synthase kinase-3β (GSK3β), which is abnormally active in Fmr1 -/- mice. Acute cotinine treatment increased the inhibitory serine-phosphorylation of GSK3β and the activating phosphorylation of AKT, which can mediate serine-phosphorylation of GSK3β, in both wild-type and Fmr1 -/- mouse hippocampus. Acute cotinine treatment improved cognitive functions of Fmr1 -/- mice in coordinate and categorical spatial processing, novel object recognition, and temporal ordering. However, cotinine failed to restore impaired cognition in GSK3β knockin mice, in which a serine9-to-alanine9 mutation blocks the inhibitory serine phosphorylation of GSK3β, causing GSK3β to be hyperactive. These results indicate that acute cotinine treatment effectively repairs impairments of these four cognitive tasks in Fmr1 -/- mice, and suggest that this cognition-enhancing effect of cotinine is linked to its induction of inhibitory serine-phosphorylation of GSK3. Taken together, these results show that nicotinic receptor agonists can act as cognitive enhancers in a mouse model of Fragile X syndrome and highlight the potential role of inhibiting GSK3β in mediating the beneficial effects of cotinine on memory. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Paternal inheritance of classic X-linked bilateral periventricular nodular heterotopia.

PubMed

Kasper, Burkhard S; Kurzbuch, Katrin; Chang, Bernard S; Pauli, Elisabeth; Hamer, Hajo M; Winkler, Jürgen; Hehr, Ute

2013-06-01

Periventricular nodular heterotopia (PNH) is a developmental disorder of the central nervous system, characterized by heterotopic nodules of gray matter resulting from disturbed neuronal migration. The most common form of bilateral PNH is X-linked dominant inherited, caused by mutations in the Filamin A gene (FLNA) and associated with a wide variety of other clinical findings including congenital heart disease. The typical patient with FLNA-associated PNH is female and presents with difficult to treat seizures. In contrast, hemizygous FLNA loss of function mutations in males are reported to be perinatally lethal. In X-linked dominant traits like FLNA-associated PNH the causal mutation is commonly inherited from the mother. Here, we present an exceptional family with paternal transmission of classic bilateral FLNA-associated PNH from a mildly affected father with somatic and germline mosaicism for a c.5686G>A FLNA splice mutation to both daughters with strikingly variable clinical manifestation and PNH extent in cerebral MR imaging. Our observations emphasize the importance to consider in genetic counseling and risk assessment the rare genetic constellation of paternal transmission for families with X-linked dominant inherited FLNA-associated PNH. Copyright © 2013 Wiley Periodicals, Inc.

Plasma kisspeptin levels in male cases with hypogonadism.

PubMed

Kotani, Masato; Katagiri, Fumihiko; Hirai, Tsuyoshi; Kagawa, Jiro

2014-01-01

The hypothalamic hormone kisspeptin (metastin) regulates human reproduction by modulating gonadotropin-releasing hormone (GnRH) secretion. Kisspeptin is detected in peripheral blood, although GnRH is not. In this study, we measured plasma kisspeptin levels in four male cases with hypogonadism and seven normal male controls using enzyme immunoassay (EIA) to elucidate the clinical implications of kisspeptin levels in male hypogonadism. The results showed a variety of plasma kisspeptin levels: 6.0 fmol/mL in a male with isolated hypogonadotropic hypogonadism (IHH), 43.2 fmol/mL in a male with Kallmann's syndrome, 40.7 fmol/mL in a male with azoospermia, 323.2 fmol/mL in a male with hypergonadotropic hypogonadism, and 12.3 ± 2.5 fmol/mL (mean ± SD) in seven normal controls. Except for the case with IHH, the plasma kisspetin levels were elevated in the three cases with Kallmann's syndrome, azoospermia, and hypergonadotropic hypogonadism. The reason why the three cases had high values was their lesions were downstream of the kisspeptin neuron in the hypothalamic-pituitary-gonadal axis, suggesting that elevated kisspeptin levels were implicated in hypothalamic kisspeptin secretion under decreased negative feedback of gonadal steroids. The result that the plasma kisspeptin levels were decreased by gonadotropin therapy in the case with Kallmann's syndrome supported this hypothesis. In conclusion, to measure plasma kisspeptin levels could be useful for better understanding of male hypogonadism.

Impaired inhibitory control of cortical synchronization in fragile X syndrome.

PubMed

Paluszkiewicz, Scott M; Olmos-Serrano, Jose Luis; Corbin, Joshua G; Huntsman, Molly M

2011-11-01

Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by severe cognitive impairments, sensory hypersensitivity, and comorbidities with autism and epilepsy. Fmr1 knockout (KO) mouse models of FXS exhibit alterations in excitatory and inhibitory neurotransmission, but it is largely unknown how aberrant function of specific neuronal subtypes contributes to these deficits. In this study we show specific inhibitory circuit dysfunction in layer II/III of somatosensory cortex of Fmr1 KO mice. We demonstrate reduced activation of somatostatin-expressing low-threshold-spiking (LTS) interneurons in response to the group I metabotropic glutamate receptor (mGluR) agonist 3,5-dihydroxyphenylglycine (DHPG) in Fmr1 KO mice, resulting in impaired synaptic inhibition. Paired recordings from pyramidal neurons revealed reductions in synchronized synaptic inhibition and coordinated spike synchrony in response to DHPG, indicating a weakened LTS interneuron network in Fmr1 KO mice. Together, these findings reveal a functional defect in a single subtype of cortical interneuron in Fmr1 KO mice. This defect is linked to altered activity of the cortical network in line with the FXS phenotype.

Social Approach and Emotion Recognition in Fragile X Syndrome

ERIC Educational Resources Information Center

Williams, Tracey A.; Porter, Melanie A.; Langdon, Robyn

2014-01-01

Evidence is emerging that individuals with Fragile X syndrome (FXS) display emotion recognition deficits, which may contribute to their significant social difficulties. The current study investigated the emotion recognition abilities, and social approachability judgments, of FXS individuals when processing emotional stimuli. Relative to…

No evidence for involvement of genetic variants in the X-linked neuroligin genes NLGN3 and NLGN4X in probands with autism spectrum disorder on high functioning level.

PubMed

Wermter, Anne-Kathrin; Kamp-Becker, Inge; Strauch, Konstantin; Schulte-Körne, Gerd; Remschmidt, Helmut

2008-06-05

Several lines of evidence indicate a role of mutations in the two X-linked genes neuroligin 3 (NLGN3) and neuroligin 4 (NLGN4X) in the etiology of autistic spectrum disorders. To analyze whether genetic variants in the NLGN3 and NLGN4X genes occurs in patients with autistic disorders on high functioning level, we performed a mutation screen of both genes using SSCP in 107 probands with Asperger syndrome, high-functioning autism and atypical autism. We identified four polymorphisms (rs2290488, rs7049300, rs3747333, rs3747334) and one novel synonymous variant (A558) in the NLGN4X. The polymorphisms rs7049300, rs3747333, and rs3747334 did not cause any amino acid substitutions in the total of the eight detected carriers. A family-based association study for rs2290488 in 101 trios did not reveal association of this polymorphism with autistic disorders on high functioning level. We conclude that there is no evidence for an involvement of NLGN3 and NLGN4X genetic variants with autism spectrum disorder on high functioning level in our study group. (c) 2008 Wiley-Liss, Inc.

Neovascular glaucoma in a patient with X-linked juvenile retinoschisis.

PubMed

Zuo, Chengguo; Chen, Changzheng; Xing, Yiqiao; Du, Lei

2005-09-01

To report the rubeosis iridis and neovascular glaucoma findings in one patient of X-linked juvenile retinoschisis(XLRS). Color fundus photography, fluorescein angiography (FFA), OCT and B-scan were performed in a patient with X-linked juvenile retinoschisis complicated with neovascular glaucoma. Color fundus photography, fluorescein angiography (FFA), OCT and B-scan unveiled a rare condition of XLRS complicated with neovascular glaucoma. XLRS may complicate with neovascular glaucoma. It is necessary to test OCT, FFA, ERG and carefully examine the fundus of the follow eye when it comes to uncertain neovascular glaucoma of youth and child. And only in this way, can we exclude XLRS.

Autism in Fragile X Syndrome: A Category Mistake?

ERIC Educational Resources Information Center

Hall, Scott S.; Lightbody, Amy A.; Hirt, Melissa; Rezvani, Ava; Reiss, Allan L.

2010-01-01

Objective: Many investigators now routinely classify children with fragile X syndrome (FXS) according to whether or not they also meet diagnostic criteria for autism. To determine whether this classification is appropriate, we examined the profiles of autistic behaviors shown by boys and girls with FXS. Method: Individuals with FXS, aged 5 to 25…

A small and active ring X chromosome in a female with features of Kabuki syndrome.

PubMed

Rodríguez, L; Diego-Alvarez, D; Lorda-Sanchez, I; Gallardo, F L; Martínez-Fernández, M L; Arroyo-Muñoz, M E; Martínez-Frías, M L

2008-11-01

A ring X chromosome is found in about 6% of patients with Turner syndrome (TS), often with mosaicism for a 45,X cell line. Patients with this karyotype are reported to have a higher incidence of a more severe phenotype including mental retardation. In fact, some studies have shown a correlation between this severity and the presence or absence of an intact and functional X inactivation center (XIST). However, the phenotype of the individuals with r(X) cannot be entirely defined in terms of their X-inactivation patterns. Nevertheless, a small group of these patients have been described to manifest clinical features reminiscent of the Kabuki syndrome. Here we present a female patient with clinical features resembling Kabuki syndrome and a mos 45,X/46,X,r(X) karyotype. Methylation analyses of polymorphic alleles of the androgen receptor gene showed that both alleles were unmethylated suggesting an active ring chromosome. A specific X chromosome array CGH was performed estimating the size of the ring to be 17 Mb, lacking the XIST gene, and including some genes with possible implications in the phenotype of the patient. Copyright 2008 Wiley-Liss, Inc.

Neuropsychiatry of fragile X-premutation carriers with and without fragile X-associated tremor-ataxia syndrome: implications for neuropsychology.

PubMed

Bourgeois, James A

2016-08-01

Clinical neuropsychologists benefit from clinical currency in recently ascertained neuropsychiatric illness, such as fragile X premutation (FXPM) disorders. The author reviewed the clinical literature through 2016 for neuropsychiatric phenotypes in FXPM disorders, including patients with fragile X-associated tremor/ataxia syndrome (FXTAS). A PubMed search using the search terms 'Fragile X,' 'Premutation,' 'Carriers,' 'Psychiatric,' 'Dementia,' 'Mood,' and 'Anxiety' for citations in the clinical literature through 2016 was reviewed for studies specifically examining the neuropsychiatric phenotype in FXPM patients. The relevant articles were classified according to specific neuropsychiatric syndromes, including child onset, adult onset with and without FXTAS, as well as common systemic comorbidities in FXPM patients. Eighty-six articles were reviewed for the neuropsychiatric and other phenotypes in FXPM patients. The neuropsychiatric phenotype in FXPM patients is distinct from that of full mutation (Fragile X Syndrome) patients. FXTAS is associated with a specific cortical-subcortical major or mild neurocognitive disorder (NCD). FXPM patients are at risk for neuropsychiatric illness. In addition, FXPM patients are at risk for other systemic conditions that should raise suspicion for FXPM-associated illnesses. Clinicians should consider a diagnosis of FXPM-associated neuropsychiatric illness when patients with specific clinical scenarios are encountered; especially in patient pedigrees consistent with a typical (often multigenerational) presentation of fragile X-associated conditions, confirmatory genetic testing should be considered. Clinical management should take into account the psychological challenges of a multigenerational genetic neuropsychiatric illness with a variable CNS and systemic clinical phenotype.

Co-incidence of Turner syndrome and Duchenne muscular dystrophy - an important problem for the clinician.

PubMed

Kaczorowska, Ewa; Zimowski, Janusz; Cichoń-Kotek, Monika; Mrozińska, Agnieszka; Purzycka, Joanna; Wierzba, Jolanta; Limon, Janusz; Lipska-Ziętkiewicz, Beata S

Turner syndrome is a relatively common chromosomal disorder which affects about one in 2000 live born females. Duchenne muscular dystrophy is an X-linked recessive disorder affecting 1:3600 live born males. Considering the above, the coexistence of these two diseases may occur only anecdotally. Here, we report a 4 ½ year-old female with classical 45,X Turner syndrome who also had Duchenne muscular dystrophy caused by a point mutation in the dystrophin gene (c.9055delG). The patient showed the typical phenotype of Turner syndrome including distinctive dysmorphic features (short neck, low posterior hairline, wide position of nipples), aortic coarctation and feet lymphedema. Besides, she presented with an unusually early beginning of muscular dystrophy symptoms with infantile-onset motor developmental delay, intellectual disability and early calf muscular hypertrophy. The coexistence of an X-linked recessive disorder should be considered in women affected by Turner syndrome presenting with additional atypical clinical features.

Genotypic analysis of X-linked retinoschisis in Western Australia.

PubMed

Lamey, Tina; Laurin, Sarina; Chelva, Enid; De Roach, John

2010-01-01

X-linked Retinoschisis is a leading cause of juvenile macular degeneration. Four Western Australian families affected by X-Linked Retinoschisis were analysed using DNA and clinical information from the Australian Inherited Retinal Disease (IRD) Register and DNA Bank. By direct sequencing of the RS1 gene, three genetic variants were identified; 52+1G > T, 289T > G and 416delA. 289T > G has not been previously reported and is likely to cause a substitution of a membrane binding residue (W92G) in the functional discoidin domain. All clinically diagnosed individuals showed typical electronegative ERGs. The 52+1G > T obligate carrier also recorded a bilaterally abnormal rod ERG and mildly abnormal photopic responses. mfERG trace arrays showed reduced response densities in the paramacular region extending futher temporally for each eye.

The Trajectory of Mathematics Skills and Working Memory Thresholds in Girls with Fragile X Syndrome

ERIC Educational Resources Information Center

Murphy, Melissa M.; Mazzocco, Michele M. M.

2009-01-01

Fragile X syndrome is a common genetic disorder associated with executive function deficits and poor mathematics achievement. In the present study, we examined changes in math performance during the elementary and middle school years in girls with fragile X syndrome, changes in the working memory loads under which children could complete a…

Viewing social scenes: a visual scan-path study comparing fragile X syndrome and Williams syndrome.

PubMed

Williams, Tracey A; Porter, Melanie A; Langdon, Robyn

2013-08-01

Fragile X syndrome (FXS) and Williams syndrome (WS) are both genetic disorders which present with similar cognitive-behavioral problems, but distinct social phenotypes. Despite these social differences both syndromes display poor social relations which may result from abnormal social processing. This study aimed to manipulate the location of socially salient information within scenes to investigate the visual attentional mechanisms of: capture, disengagement, and/or general engagement. Findings revealed that individuals with FXS avoid social information presented centrally, at least initially. The WS findings, on the other hand, provided some evidence that difficulties with attentional disengagement, rather than attentional capture, may play a role in the WS social phenotype. These findings are discussed in relation to the distinct social phenotypes of these two disorders.

Pyoderma Gangrenosum–Like Ulcer in a Patient With X-Linked Agammaglobulinemia

PubMed Central

Murray, Patrick R.; Jain, Ashish; Uzel, Gulbu; Ranken, Raymond; Ivy, Cristina; Blyn, Lawrence B.; Ecker, David J.; Sampath, Rangarajan; Lee, Chyi-Chia Richard; Turner, Maria L.

2011-01-01

Background Pyoderma gangrenosum–like ulcers and cellulitis of the lower extremities associated with recurrent fevers in patients with X-linked (Bruton) agammaglobulinemia have been reported to be caused by Helicobacter bilis (formerly classified as Flexispira rappini and then Helicobacter strain flexispira taxon 8). Consistent themes in these reports are the difficulty in recovering this organism in blood and wound cultures and in maintaining isolates in vitro. We confirmed the presence of this organism in a patient’s culture by using a novel application of gene amplification polymerase chain reaction and electrospray ionization time-of-flight mass spectrometry. Observation An adolescent boy with X-linked agammaglobulinemia presented with indurated plaques and a chronic leg ulcer whose origin was strongly suspected to be an H bilis organism. Histologic analysis demonstrated positive Warthin-Starry staining of curvilinear rods, which grew in culture but failed to grow when sub-cultured. They could not be identified by conventional techniques. A combination of gene amplification by polymerase chain reaction and electrospray ionization time-of-flight mass spectrometry confirmed the identity of this organism. Conclusions This novel technology was useful in the identification of a difficult-to-grow Helicobacter organism, the cause of pyoderma gangrenosum–like leg ulcers in patients with X-linked agammaglobulinemia. Correct identification of this organism as the cause of pyoderma gangrenosum–like ulcers in patients with X-linked agammaglobulinemia is of great importance for the early initiation of appropriate and curative antibiotic therapy. PMID:20479300

Social Behavior and Cortisol Reactivity in Children with Fragile X Syndrome

ERIC Educational Resources Information Center

Hessl, David; Glaser, Bronwyn; Dyer-Friedman, Jennifer; Reiss, Allan L.

2006-01-01

Objective: To examine the association between limbic-hypothalamic-pituitary-adrenal (L-HPA) axis reactivity and social behavior in children with fragile X syndrome (FXS). Method: Salivary cortisol changes and concurrent anxiety-related behaviors consistent with the behavioral phenotype of FXS were measured in 90 children with the fragile X full…

Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia.

PubMed

Jonsson, Kenneth B; Zahradnik, Richard; Larsson, Tobias; White, Kenneth E; Sugimoto, Toshitsugu; Imanishi, Yasuo; Yamamoto, Takehisa; Hampson, Geeta; Koshiyama, Hiroyuki; Ljunggren, Osten; Oba, Koichi; Yang, In Myung; Miyauchi, Akimitsu; Econs, Michael J; Lavigne, Jeffrey; Jüppner, Harald

2003-04-24

Mutations in fibroblast growth factor 23 (FGF-23) cause autosomal dominant hypophosphatemic rickets. Clinical and laboratory findings in this disorder are similar to those in oncogenic osteomalacia, in which tumors abundantly express FGF-23 messenger RNA, and to those in X-linked hypophosphatemia, which is caused by inactivating mutations in a phosphate-regulating endopeptidase called PHEX. Recombinant FGF-23 induces phosphaturia and hypophosphatemia in vivo, suggesting that it has a role in phosphate regulation. To determine whether FGF-23 circulates in healthy persons and whether it is elevated in those with oncogenic osteomalacia or X-linked hypophosphatemia, an immunometric assay was developed to measure it. Using affinity-purified, polyclonal antibodies against [Tyr223]FGF-23(206-222)amide and [Tyr224]FGF-23(225-244)amide, we developed a two-site enzyme-linked immunosorbent assay that detects equivalently recombinant human FGF-23, the mutant form in which glutamine is substituted for arginine at position 179 (R179Q), and synthetic human FGF-23(207-244)amide. Plasma or serum samples from 147 healthy adults (mean [+/-SD] age, 48.4+/-19.6 years) and 26 healthy children (mean age, 10.9+/-5.5 years) and from 17 patients with oncogenic osteomalacia (mean age, 43.0+/-13.3 years) and 21 patients with X-linked hypophosphatemia (mean age, 34.9+/-17.2 years) were studied. Mean FGF-23 concentrations in the healthy adults and children were 55+/-50 and 69+/-36 reference units (RU) per milliliter, respectively. Four patients with oncogenic osteomalacia had concentrations ranging from 426 to 7970 RU per milliliter, which normalized after tumor resection. FGF-23 concentrations were 481+/-528 RU per milliliter in those with suspected oncogenic osteomalacia and 353+/-510 RU per milliliter (range, 31 to 2335) in those with X-linked hypophosphatemia. FGF-23 is readily detectable in the plasma or serum of healthy persons and can be markedly elevated in those with oncogenic

Unusual phenotypic expression of an XLRS1 mutation in X-linked juvenile retinoschisis.

PubMed

Dodds, Jodi A; Srivastava, Anand K; Holden, Kenton R

2006-04-01

X-linked juvenile retinoschisis is a rare progressive vitreoretinal degenerative process that appears in early childhood, results in decreased visual acuity and blindness (if severe), and is caused by various mutations within the XLRS1 gene at Xp22.2. We report an affected family of Western European ancestry with X-linked juvenile retinoschisis. The family was found to carry a 304C-->T substitution in exon 4 of the XLRS1 gene, resulting in an Arg102Trp amino acid substitution. Two of the four available clinical cases in this family were found to carry the mutation. All available mothers of affected males were found to be unaffected carriers of the mutation, a typical feature of X-linked diseases. Two new female carriers, sisters of affected males, were identified and counseled accordingly. Questionnaires on visual functioning were given to the affected family members to examine the psychologic and sociologic impact of X-linked juvenile retinoschisis, which documented an associated stigma even when affected with a "mild" phenotype.

Advanced glycation end products: A link between metabolic and endothelial dysfunction in polycystic ovary syndrome?

PubMed

Pertynska-Marczewska, Magdalena; Diamanti-Kandarakis, Evanthia; Zhang, John; Merhi, Zaher

2015-11-01

Polycystic ovary syndrome (PCOS), a heterogeneous syndrome of reproductive and metabolic alterations, is associated with increased long-term risk of cardiovascular complications. This phenomenon has been linked to an increase in oxidative stress and inflammatory markers. Advanced glycation end products (AGEs) are pro-inflammatory molecules that trigger a state of intracellular oxidative stress and inflammation after binding to their cell membrane receptors RAGE. The activation of the AGE-RAGE axis has been well known to play a role in atherosclerosis in both men and women. Women with PCOS have systemic chronic inflammatory condition even at the ovarian level as represented by elevated levels of serum/ovarian AGEs and increased expression of the pro-inflammatory RAGE in ovarian tissue. Data also showed the presence of sRAGE in the follicular fluid and its potential protective role against the harmful effect of AGEs on ovarian function. Thus, whether AGE-RAGE axis constitutes a link between metabolic and endothelial dysfunction in women with PCOS is addressed in this review. Additionally, we discuss the role of hormonal changes observed in PCOS and how they are linked with the AGE-RAGE axis in order to better understand the nature of this complex syndrome whose consequences extend well beyond reproduction. Copyright © 2015 Elsevier Inc. All rights reserved.

Expression pattern of X-linked genes in sex chromosome aneuploid bovine cells.

PubMed

Basrur, Parvathi K; Farazmand, Ali; Stranzinger, Gerald; Graphodatskaya, Daria; Reyes, Ed R; King, W Allan

2004-01-01

Expression of the X-inactive specific transcript (XIST) gene is a prerequisite step for dosage compensation in mammals, accomplished by silencing one of the two X chromosomes in normal female diploid cells or all X chromosomes in excess of one in sex chromosome aneuploids. Our previous studies showing that XIST expression does not eventuate the inactivation of X-linked genes in fetal bovine testis had suggested that XIST expression may not be an indicator of X inactivation in this species. In this study, we used a semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) approach on cultures of bovine cells with varying sex chromosome constitution (XY, XX, XXY and XXX) to test whether the levels of XIST expressed conform to the number of late replicating (inactive) X chromosomes displayed by proliferating cells in these cultures. Expression patterns of four X-linked genes, including hypoxanthine phosphorybosyl transferase (HPRT), glucose-6-phosphate dehydrogenase (G6PD), zinc finger protein locus on the X (ZFX). and 'selected mouse cDNA on the X' (SMCX), in all these cells were also tested. Results showed that XIST expression was significantly higher (p < 0.05) in XXX cells compared to XX and XXY cells and that G6PD. HPRT, and SMCX loci are subject to X inactivation. The significantly higher levels of ZFX expressed in XXX cells compared to XX and XXY cells (p < 0.05) confirmed that this bovine locus, as human ZFX, escapes X inactivation. However, the levels of XIST and ZFX expressed were not proportional to the X chromosome load in these cells suggesting that X-linked loci escaping inactivation may be regulated at transcription (or post-transcription) level by mechanisms that prevent gene-specific product accumulation beyond certain levels in sex chromosome aneuploids.

Lack of significant association between spina bifida and the fragile X syndrome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schiano, C.M.; Demb, H.B.; Brown, W.T.

1995-12-04

Folic acid is involved in two common disorders associated with developmental disabilities. Spina bifida is a malformation that may be associated with mental retardation, learning disabilities, and epilepsy. Its incidence can be reduced by the ingestion of folic acid before, and at the time of, conception. The fragile X syndrome is a genetic disorder which is the most common form of inherited mental retardation. This disorder can be diagnosed by the induction of fragile sites on the X chromosome which is cultured in a medium deficient in folic acid. In several studies, folic acid was reported to alleviate some ofmore » the developmental and behavioral manifestations associated in the fragile X syndrome, while in others, it has no effect. 9 refs.« less

Fragile X Syndrome. Early Developments. Volume 8, Number 2, Summer 2004

ERIC Educational Resources Information Center

Manuel, John

2004-01-01

Eleven years ago, FPG Child Development Institute (FPG) launched a longitudinal study of a little known form of mental retardation known as fragile X syndrome (FXS). The Carolina Fragile X Project has since grown into a multidisciplinary team studying diverse aspects of the condition, ranging from early identification to school performance. The…

Targeted Upregulation of FMRP Expression as an Approach to the Treatment of Fragile X Syndrome

DTIC Science & Technology

2015-08-01

form of autism, and a relatively common cause of epilepsy . The syndrome is caused by partial or complete silencing of the fragile X (FMR1) gene when...potential to correct ALL of the clinical domains of fragile X syndrome, including epilepsy -like activity observed for both those with FXS and carriers of...the FMR1 gene. 15. SUBJECT TERMS Fragile X, autism, FMR1, FXTAS, CGG repeat, epilepsy , seizures, FMRP, PTSD, premutation, iPSC, progenitor, calcium

JS-X syndrome: A multiple congenital malformation with vocal cord paralysis, ear deformity, hearing loss, shoulder musculature underdevelopment, and X-linked recessive inheritance.

PubMed

Hoeve, Hans L J; Brooks, Alice S; Smit, Liesbeth S

2015-07-01

We report on a family with a not earlier described multiple congenital malformation. Several male family members suffer from laryngeal obstruction caused by bilateral vocal cord paralysis, outer and middle ear deformity with conductive and sensorineural hearing loss, facial dysmorphisms, and underdeveloped shoulder musculature. The affected female members only have middle ear deformity and hearing loss. The pedigree is suggestive of an X-linked recessive inheritance pattern. SNP-array revealed a deletion and duplication on Xq28 in the affected family members. A possible aetiology is a neurocristopathy with most symptoms expressed in structures derived from branchial arches. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

X-Linked Intellectual Disability: Unique Vulnerability of the Male Genome

ERIC Educational Resources Information Center

Stevenson, Roger E.; Schwartz, Charles E.

2009-01-01

X-linked intellectual disability (XLID) accounts for approximately 16% of males with intellectual disability (ID). This is, in part, related to the fact that males have a single X chromosome. Progress in the clinical and molecular characterization of XLID has outpaced progress in the delineation of ID due to genes on the other 22 chromosomes.…

Silencing of X-Linked MicroRNAs by Meiotic Sex Chromosome Inactivation

PubMed Central

Royo, Hélène; Seitz, Hervé; ElInati, Elias; Peters, Antoine H. F. M.; Stadler, Michael B.; Turner, James M. A.

2015-01-01

During the pachytene stage of meiosis in male mammals, the X and Y chromosomes are transcriptionally silenced by Meiotic Sex Chromosome Inactivation (MSCI). MSCI is conserved in therian mammals and is essential for normal male fertility. Transcriptomics approaches have demonstrated that in mice, most or all protein-coding genes on the X chromosome are subject to MSCI. However, it is unclear whether X-linked non-coding RNAs behave in a similar manner. The X chromosome is enriched in microRNA (miRNA) genes, with many exhibiting testis-biased expression. Importantly, high expression levels of X-linked miRNAs (X-miRNAs) have been reported in pachytene spermatocytes, indicating that these genes may escape MSCI, and perhaps play a role in the XY-silencing process. Here we use RNA FISH to examine X-miRNA expression in the male germ line. We find that, like protein-coding X-genes, X-miRNAs are expressed prior to prophase I and are thereafter silenced during pachynema. X-miRNA silencing does not occur in mouse models with defective MSCI. Furthermore, X-miRNAs are expressed at pachynema when present as autosomally integrated transgenes. Thus, we conclude that silencing of X-miRNAs during pachynema in wild type males is MSCI-dependent. Importantly, misexpression of X-miRNAs during pachynema causes spermatogenic defects. We propose that MSCI represents a chromosomal mechanism by which X-miRNAs, and other potential X-encoded repressors, can be silenced, thereby regulating genes with critical late spermatogenic functions. PMID:26509798

Social Cognition in Adolescent Girls with Fragile X Syndrome

ERIC Educational Resources Information Center

Turkstra, Lyn S.; Abbeduto, Leonard; Meulenbroek, Peter

2014-01-01

This study aimed to characterize social cognition, executive functions (EFs), and everyday social functioning in adolescent girls with fragile X syndrome, and identify relationships among these variables. Participants were 20 girls with FXS and 20 age-matched typically developing peers. Results showed significant between-groups differences in…

Ocular Features in Alport Syndrome: Pathogenesis and Clinical Significance

PubMed Central

Sheth, Shivanand; Leys, Anita; Nicholson, Anjali; Mack, Heather G.; Colville, Deb

2015-01-01

Alport syndrome is an inherited disease characterized by progressive renal failure, hearing loss, and ocular abnormalities. Mutations in the COL4A5 (X-linked), or COL4A3 and COL4A4 (autosomal recessive) genes result in absence of the collagen IV α3α4α5 network from the basement membranes of the cornea, lens capsule, and retina and are associated with corneal opacities, anterior lenticonus, fleck retinopathy, and temporal retinal thinning. Typically, these features do not affect vision or, in the case of lenticonus, are correctable. In contrast, the rarer ophthalmic complications of posterior polymorphous corneal dystrophy, giant macular hole, and maculopathy all produce visual loss. Many of the ocular features of Alport syndrome are common, easily recognizable, and thus, helpful diagnostically, and in identifying the likelihood of early-onset renal failure. Lenticonus and central fleck retinopathy strongly suggest the diagnosis of Alport syndrome and are associated with renal failure before the age of 30 years, in males with X-linked disease. Sometimes, ophthalmic features suggest the mode of inheritance. A peripheral retinopathy in the mother of a male with hematuria suggests X-linked inheritance, and central retinopathy or lenticonus in a female means that recessive disease is likely. Ocular examination, retinal photography, and optical coherence tomography are widely available, safe, fast, inexpensive, and acceptable to patients. Ocular examination is particularly helpful in the diagnosis of Alport syndrome when genetic testing is not readily available or the results are inconclusive. It also detects complications, such as macular hole, for which new treatments are emerging. PMID:25649157

Mutational studies in X-linked Charcot-Marie-Tooth disease (CMTX)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cherryson, A.K.; Yeung, L.; Kennerson, M.L.

1994-09-01

Charcot-Marie-Tooth disease, also known as hereditary motor and sensory neuropathy (HMSN), is a heterogeneous group of slowly progressive disorders of the peripheral nerve. X-linked CMT (CMTX) is characterized by slow motor nerve conduction velocities in affected males and the presence of mildly affected or normal carrier females with intermediate or normal nerve conduction velocities. CMTX, which has an incidence of 3.1 per 100,000 and accounts for approximately 10% of CMT cases, has been mapped to Xq13. One of the genes lying in this region, connexin 32, has been found to contain alterations in individuals affected with X-linked CMT. We havemore » identified our X-linked families from dominant type 1 CMT families using the clinical criteria given above. These families were screened for point mutations in connexin 32. We have identified three missense mutations, a G{r_arrow}A transition at amino acid 35 (valine to methionine), a C{r_arrow}G transition at amino acid 158 (proline to alanine) and a T{r_arrow}A transition at amino acid 182 (serine to threonine). Another family showed a 18 bp deletion, which removed the amino acid 111 to 116 inclusive (histidine, glycine, aspartic acid, proline, leucine, histidine).« less

Surgical treatment for medically refractory focal epilepsy in a patient with fragile X syndrome.

PubMed

Kenmuir, Cynthia; Richardson, Mark; Ghearing, Gena

2015-10-01

Medication resistant temporal lobe epilepsy occurs in a small population of patients with fragile X syndrome. We present the case of a 24-year-old man with medically refractory temporal lobe epilepsy and fragile X syndrome who underwent left anterior temporal lobectomy resulting in cessation of seizures. Our patient was diagnosed with fragile X syndrome with a fully mutated, fully methylated FMR1 gene resulting in 572 CGG repeats. He developed seizures initially controlled with Depakote monotherapy, but progressed to become medically refractive to combination treatment with Depakote, lamotrigine and zonisamide. Prolonged video EEG monitoring revealed interictal left temporal sharp waves and slowing as well as subclinical and clinical seizures, each with left temporal onset. 3T MRI was consistent with left mesial temporal sclerosis. After discussing the case in our multidisciplinary surgical epilepsy conference, he was referred for presurgical evaluation including neuropsychological testing and Wada testing. He underwent an asleep left anterior temporal lobectomy, sparing the superior temporal gyrus. Pathology showed neuronal loss and gliosis in the hippocampus and amygdala. Twelve months after surgery, the patient has not experienced a seizure. He is described by his parents as less perseverative and less restless. We have presented the case of a 24 year-old-man with fragile X syndrome who underwent successful left anterior temporal lobectomy for the treatment of medically refractory epilepsy who is now seizure free without further functional impairment. This case report demonstrates the feasibility of surgical treatment for a patient with comorbid fragile X syndrome and mesial temporal sclerosis. Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Genetics Home Reference: X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia

MedlinePlus

... Share: Email Facebook Twitter Home Health Conditions XMEN X-linked immunodeficiency with magnesium defect, Epstein-Barr virus ... Javascript to view the expand/collapse boxes. Description X-linked immunodeficiency with magnesium defect, Epstein-Barr virus ...

Central Sensitivity Syndromes: Mounting Pathophysiologic Evidence to Link Fibromyalgia with other Common Chronic Pain Disorders

PubMed Central

Kindler, Lindsay L.; Bennett, Robert M.; Jones, Kim D.

2009-01-01

Objective To review emerging data from the fields of nursing, rheumatology, dentistry, gastroenterology, gynecology, neurology, and orthopedics that supports or disputes pathophysiologic similarities in pain syndromes studied by each specialty. Methods A literature search was performed through PubMed and Ovid using the terms fibromyalgia, temporomandibular joint disorder, irritable bowel syndrome, irritable bladder/interstitial cystitis, headache, chronic low back pain, chronic neck pain, functional syndromes and somatization. Each term was linked with pathophysiology and/or central sensitization. This paper presents a review of relevant articles with a specific goal of identifying pathophysiological findings related to nociceptive processing. Results The extant literature presents considerable overlap in the pathophysiology of these diagnoses. Given the psychosomatic lens through which many of these disorders are viewed, demonstration of evidence based links supporting shared pathophysiology between these disorders could provide direction to clinicians and researchers working to treat these diagnoses. Conclusions Central sensitivity syndromes denotes an emerging nomenclature that could be embraced by researchers investigating each of these disorders. Moreover, a shared paradigm would be useful in promoting cross-fertilization between researchers. Scientists and clinicians could most effectively forward the understanding and treatment of fibromyalgia and other common chronic pain disorders through an appreciation of their shared pathophysiology. PMID:21349445

Receptive Vocabulary, Expressive Vocabulary, and Speech Production of Boys with Fragile X Syndrome in Comparison to Boys with Down Syndrome

ERIC Educational Resources Information Center

Roberts, Joanne; Price, Johanna; Barnes, Elizabeth; Nelson, Lauren; Burchinal, Margaret; Hennon, Elizabeth A.; Moskowitz, Lauren; Edwards, Anne; Malkin, Cheryl; Anderson, Kathleen; Misenheimer, Jan; Hooper, Stephen R.

2007-01-01

Boys with fragile X syndrome with (n = 49) and without (n = 33) characteristics of autism spectrum disorder, boys with Down syndrome (39), and typically developing boys (n = 41) were compared on standardized measures of receptive vocabulary, expressive vocabulary, and speech administered annually over 4 years. Three major findings emerged. Boys…

Differential expression of CK20, β-catenin, and MUC2/5AC/6 in Lynch syndrome and familial colorectal cancer type X.

PubMed

Haraldsson, Stefan; Klarskov, Louise; Nilbert, Mef; Bernstein, Inge; Bonde, Jesper; Holck, Susanne

2017-01-01

Hereditary non-polyposis colorectal cancer comprises Lynch syndrome and familial colorectal cancer type X (FCCTX). Differences in genetics, demographics and histopathology have been extensively studied. The purpose of this study is to characterize their immunoprofile of markers other than MMR proteins. We compared the expression patterns of cytokeratins (CK7 and CK20), mucins (MUC2/5 AC/6), CDX2 and β-catenin in Lynch syndrome and FCCTX. Differences were identified for CK20 and nuclear β-catenin, which were significantly more often expressed in FCCTX than in Lynch syndrome ( p  < 0.001), whereas MUC2, MUC5AC and MUC6 were overexpressed in Lynch syndrome tumors compared with FCCTX tumors ( p  = 0.001, < 0.01, and < 0.001, respectively). We observed no differences in the expression patterns of CK7 and CDX2. In summary, we identified significant differences in the immunoprofiles of colorectal cancers linked to FCCTX and Lynch syndrome with a more sporadic-like profile in the former group and a more distinct profile with frequent MUC6 positivity in the latter group.

Molecular genetic analysis of patients with sporadic and X-linked infantile nystagmus

PubMed Central

Zhao, Hui; Huang, Xiu-Feng; Zheng, Zhi-Li; Deng, Wen-Li; Lei, Xin-Lan; Xing, Dong-Jun; Ye, Liang; Xu, Su-Zhong; Chen, Jie; Zhang, Fang; Yu, Xin-Ping; Jin, Zi-Bing

2016-01-01

Objectives Infantile nystagmus (IN) is a genetically heterogeneous condition characterised by involuntary rhythmic oscillations of the eyes accompanied by different degrees of vision impairment. Two genes have been identified as mainly causing IN: FRMD7 and GPR143. The aim of our study was to identify the genetic basis of both sporadic IN and X-linked IN. Design Prospective analysis. Patients Twenty Chinese patients, including 15 sporadic IN cases and 5 from X-linked IN families, were recruited and underwent molecular genetic analysis. We first performed PCR-based DNA sequencing of the entire coding region and the splice junctions of the FRMD7 and GPR143 genes in participants. Mutational analysis and co-segregation confirmation were then performed. Setting All clinical examinations and genetic experiments were performed in the Eye Hospital of Wenzhou Medical University. Results Two mutations in the FRMD7 gene, including one novel nonsense mutation (c.1090C>T, p.Q364X) and one reported missense mutation (c.781C>G, p.R261G), were identified in two of the five (40%) X-linked IN families. However, none of putative mutations were identified in FRMD7 or GPR143 in any of the sporadic cases. Conclusions The results suggest that mutations in FRMD7 appeared to be the major genetic cause of X-linked IN, but not of sporadic IN. Our findings provide further insights into FRMD7 mutations, which could be helpful for future genetic diagnosis and genetic counselling of Chinese patients with nystagmus. PMID:27036142

X-linked intellectual disability update 2017.

PubMed

Neri, Giovanni; Schwartz, Charles E; Lubs, Herbert A; Stevenson, Roger E

2018-04-25

The X-chromosome comprises only about 5% of the human genome but accounts for about 15% of the genes currently known to be associated with intellectual disability. The early progress in identifying the X-linked intellectual disability (XLID)-associated genes through linkage analysis and candidate gene sequencing has been accelerated with the use of high-throughput technologies. In the 10 years since the last update, the number of genes associated with XLID has increased by 96% from 72 to 141 and duplications of all 141 XLID genes have been described, primarily through the application of high-resolution microarrays and next generation sequencing. The progress in identifying genetic and genomic alterations associated with XLID has not been matched with insights that improve the clinician's ability to form differential diagnoses, that bring into view the possibility of curative therapies for patients, or that inform scientists of the impact of the genetic alterations on cell organization and function. © 2018 Wiley Periodicals, Inc.

A family study of congenital X linked sideroblastic anaemia.

PubMed Central

Holmes, J; May, A; Geddes, D; Jacobs, A

1990-01-01

We report on the cytogenetic findings in a family study of pyridoxine responsive, X linked sideroblastic anaemia. An increase in the number of X chromosomes was observed in a small proportion of metaphases prepared from five female members, but these findings did not strictly correlate with the carrier status of the condition. No consistent cytogenetic abnormality could be identified or associated with this rare familial condition. The diagnosis and counselling of carriers of this condition is discussed. Images PMID:2308152

Use of topical dorzolamide for patients with X-linked juvenile retinoschisis: case report.

PubMed

Bastos, André Luís Carvalho de Moura; Freitas, Bruno de Paula; Villas Boas, Oscar; Ramiro, Alexandre Campelo

2008-01-01

X-linked juvenile retinoschisis (XLRS) is a recessively inherited vitreoretinal degeneration characterized by macular pathology and splitting of the neuroretinal layers that is associated with alterations in the XLRS1 gene. There have been no therapeutic interventions known to be effective for patients with X-linked juvenile retinoschisis, but some studies are trying to determine the importance of dorzolamide for the treatment of foveal lesions in this disease. The authors, using optical coherence tomography, describe findings in a patient with X-linked juvenile retinoschisis, before and after a topical use of dorzolamide. Besides the improvement in his visual acuity, further studies are required to elucidate the real prevalence of nonresponse to dorzolamide and the frequency with which there may be a recurrence of foveal cystic changes during continued treatment.

Modelling fragile X syndrome in the laboratory setting: A behavioral perspective.

PubMed

Melancia, Francesca; Trezza, Viviana

2018-04-25

Fragile X syndrome is the most common form of inherited mental retardation and the most frequent monogenic cause of syndromic autism spectrum disorders. The syndrome is caused by the loss of the Fragile X Mental Retardation Protein (FMRP), a key RNA-binding protein involved in synaptic plasticity and neuronal morphology. Patients show intellectual disability, social deficits, repetitive behaviors and impairments in social communication. The aim of this review is to outline the importance of behavioral phenotyping of animal models of FXS from a developmental perspective, by showing how the behavioral characteristics of FXS at the clinical level can be translated into effective, developmentally-specific and clinically meaningful behavioral readouts in the laboratory setting. After introducing the behavioral features, diagnostic criteria and off-label pharmacotherapy of FXS, we outline how FXS-relevant behavioral features can be modelled in laboratory animals in the course of development: we review the progress to date, discuss how behavioral phenotyping in animal models of FXS is essential to identify potential treatments, and discuss caveats and future directions in this research field. Copyright © 2018. Published by Elsevier B.V.

Lamellar macular hole in X linked retinoschisis

PubMed Central

Kumar, Vinod; Goel, Neha

2016-01-01

X linked retinoschisis (XLRS) is the most common juvenile onset retinal degeneration. The disorder leads to poor vision in old age. Complications, however, can lead to earlier loss of vision in this condition. This report describes two patients of XLRS, who had presented with poor vision because of having had a lamellar macular hole at a young age. Lamellar macular holes are rare and have never been reported to cause early onset poor vision in XLRS. PMID:27170611

Optical coherence tomography in the diagnosis of juvenile X-linked retinoschisis.

PubMed

Eriksson, Urban; Larsson, Eva; Holmström, Gerd

2004-04-01

To describe the value of optical coherence tomography (OCT) as a diagnostic tool in the diagnosis of X-linked retinoschisis. We report three boys aged between 8 and 17 years, diagnosed with X-linked retinoschisis. During investigations they were examined with OCT (Zeiss Humphrey OCT 1, upgraded version). Single scans of the central posterior pole and the region around the vascular arcades were obtained. Two of the boys underwent full-field ERG according to ISCEV standards. Genetic analysis was performed in all three boys, with sequencing of the XLRS gene. The OCT results revealed a pattern with a cleavage of the retina in two distinct planes, one deep (outer retina) and one superficial. This was very obvious in one patient and a similar but not as pronounced pattern was seen in the other two cases. The two layers were superficially connected with thin-walled, vertical palisades, separated by low reflective, cystoid spaces, confluent and most prominent in the foveal region. Full-field ERG and/or DNA analysis are well known methods used for diagnosis of X-linked juvenile retinoschisis. In this paper, we suggest that OCT can also be a helpful diagnostic tool.