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Sample records for galactosemias

  1. Galactosemia (image)

    MedlinePlus

    ... galactosemia is unable to use (metabolize) the simple sugar galactose, which reaches high levels in the body, causing damage to the liver, central nervous system and various other body systems. An infant with ...

  2. Genetics Home Reference: galactosemia

    MedlinePlus

    ... mutations in a particular gene and affect different enzymes involved in breaking down galactose. Classic galactosemia , also ... cause galactosemia . These genes provide instructions for making enzymes that are essential for processing galactose obtained from ...

  3. Verbal dyspraxia and galactosemia.

    PubMed

    Webb, Amy Leigh; Singh, Rani H; Kennedy, Mary Jane; Elsas, Louis J

    2003-03-01

    Classical galactosemia is an autosomal recessive disorder resulting from deficient galactose-1-phosphateuridyl transferase (GALT) activity. Verbal dyspraxia is an unusual outcome in galactosemia. Here we validated a simplified breath test of total body galactose oxidation against genotype and evaluated five potential biochemical risk indicators for verbal dyspraxia in galactosemia: cumulative percentage dose (CUMPCD) of (13)CO(2) in breath, mean erythrocyte galactose-1-phosphate, highest erythrocyte galactose-1-phosphate, mean urinary galactitol, and erythrocyte GALT activity. Thirteen controls and 42 patients with galactosemia took a (13)C-galactose bolus, and the (CUMPCD) of (13)CO(2) in expired air was determined. Patients with <5% CUMPCD had mutant alleles that severely impaired human GALT enzyme catalysis. Patients with > or =5% CUMPCD had milder mutant human GALT alleles. Twenty-four patients consented to formal speech evaluation; 15 (63%) had verbal dyspraxia. Dyspraxic patients had significantly lower CUMPCD values (2.84 +/- 5.76% versus 11.51 +/- 7.67%; p < 0.008) and significantly higher mean erythrocyte galactose-1-phosphate (3.38 +/- 0.922 mg/dL versus 1.92 +/- 1.28 mg/dL; p = 0.019) and mean urinary galactitol concentrations (192.4 +/- 75.8 mmol/mol creatinine versus 122.0 +/- 56.4; p = 0.048) than patients with normal speech. CUMPCD values <5%, mean erythrocyte galactose-1-phosphate levels >2.7 mg/dL, and mean urinary galactitol levels >135 mmol/mol creatinine were associated with dyspraxic outcome with odds ratios of 21, 13, and 5, respectively. We conclude that total body oxidation of galactose to CO(2) in expired air reflects genotype and that this breath test is a sensitive predictor of verbal dyspraxia in patients with galactosemia. PMID:12595586

  4. Dietary management of galactosemia.

    PubMed

    Thompson, Susan M; Arrowsmith, Fiona E; Allen, Jane R

    2003-01-01

    Galactosemia is detected by newborn screening in New South Wales and managed by the metabolic team at the Children's Hospital at Westmead. Infants with the Duarte variant are not treated. Management is based on the Handbook for Galactosemia prepared in 1998. This handbook provides information for the family on the dietary management, inheritance and ovarian function. The major dietary sources of galactose are milk and milk products. Breastfeeding must be ceased and replaced with a soy formula. Once solid foods are commenced certain foods should be avoided. Other foods, which may contain some free galactose are recommended in limited quantities only. There is no restriction on other fruits and vegetables. An ongoing issue with dietary management is adequate nutrient intake, particularly of calcium. Intake of milk substitutes and calcium supplements is often inadequate. PMID:15906738

  5. Galactosemia and phantom absence seizures.

    PubMed

    Aydin-Özemir, Zeynep; Tektürk, Pınar; Uyguner, Zehra Oya; Baykan, Betül

    2014-01-01

    Generalized and focal seizures can rarely be seen in galactosemia patients, but absence seizures were not reported previously. An 18-year-old male was diagnosed as galactosemia at the age of 8 months. No family history of epilepsy was present. His absence seizures realized at the age of 9 years. Generalized 3-4 Hz spike-wave discharges were identified in his electroencephalography. Homozygous mutation at exon 6 c. 563A > G was identified. The electroencephalogram of his sibling was unremarkable. Our aim was to present the long-term follow-up of a patient diagnosed with galactosemia, who had phantom absence seizures and typical 3-4 Hz spike-wave discharges in his electroencephalogram to draw attention to this rare association. PMID:25624930

  6. Fertility preservation in female classic galactosemia patients.

    PubMed

    van Erven, Britt; Gubbels, Cynthia S; van Golde, Ron J; Dunselman, Gerard A; Derhaag, Josien G; de Wert, Guido; Geraedts, Joep P; Bosch, Annet M; Treacy, Eileen P; Welt, Corrine K; Berry, Gerard T; Rubio-Gozalbo, M Estela

    2013-01-01

    Almost every female classic galactosemia patient develops primary ovarian insufficiency (POI) as a diet-independent complication of the disease. This is a major concern for patients and their parents, and physicians are often asked about possible options to preserve fertility. Unfortunately, there are no recommendations on fertility preservation in this group. The unique pathophysiology of classic galactosemia with a severely reduced follicle pool at an early age requires an adjusted approach. In this article recommendations for physicians based on current knowledge concerning galactosemia and fertility preservation are made. Fertility preservation is only likely to be successful in very young prepubertal patients. In this group, cryopreservation of ovarian tissue is currently the only available technique. However, this technique is not ready for clinical application, it is considered experimental and reduces the ovarian reserve. Fertility preservation at an early age also raises ethical questions that should be taken into account. In addition, spontaneous conception despite POI is well described in classic galactosemia. The uncertainty surrounding fertility preservation and the significant chance of spontaneous pregnancy warrant counseling towards conservative application of these techniques. We propose that fertility preservation should only be offered with appropriate institutional research ethics approval to classic galactosemia girls at a young prepubertal age. PMID:23866841

  7. Fertility preservation in female classic galactosemia patients

    PubMed Central

    2013-01-01

    Almost every female classic galactosemia patient develops primary ovarian insufficiency (POI) as a diet-independent complication of the disease. This is a major concern for patients and their parents, and physicians are often asked about possible options to preserve fertility. Unfortunately, there are no recommendations on fertility preservation in this group. The unique pathophysiology of classic galactosemia with a severely reduced follicle pool at an early age requires an adjusted approach. In this article recommendations for physicians based on current knowledge concerning galactosemia and fertility preservation are made. Fertility preservation is only likely to be successful in very young prepubertal patients. In this group, cryopreservation of ovarian tissue is currently the only available technique. However, this technique is not ready for clinical application, it is considered experimental and reduces the ovarian reserve. Fertility preservation at an early age also raises ethical questions that should be taken into account. In addition, spontaneous conception despite POI is well described in classic galactosemia. The uncertainty surrounding fertility preservation and the significant chance of spontaneous pregnancy warrant counseling towards conservative application of these techniques. We propose that fertility preservation should only be offered with appropriate institutional research ethics approval to classic galactosemia girls at a young prepubertal age. PMID:23866841

  8. Galactosemia

    MedlinePlus

    ... Blood culture for bacterial infection ( E coli sepsis ) Enzyme activity in the red blood cells Ketones in the urine Prenatal diagnosis by directly measuring the enzyme galactose-1-phosphate uridyl transferase "Reducing substances" in ...

  9. Galactosemia

    MedlinePlus

    ... You Can Use April May Calendar Liver Lowdown Mar 2014 Calendar of Events In The News Academic ... 2016 Calendar Jan Feb 2016 recipe Liver Lowdown Mar/Apr 2016 Liver Lowdown August 2016 Know Your ...

  10. Galactosemia

    MedlinePlus

    ... other foods that contain galactose, for life. Read product labels to make sure you or your child with the condition are not eating foods that contain galactose. Infants can ... hydrolysate formula) Calcium supplements are recommended.

  11. The molecular basis of galactosemia - Past, present and future.

    PubMed

    Timson, David J

    2016-09-10

    Galactosemia, an inborn error of galactose metabolism, was first described in the 1900s by von Ruess. The subsequent 100years has seen considerable progress in understanding the underlying genetics and biochemistry of this condition. Initial studies concentrated on increasing the understanding of the clinical manifestations of the disease. However, Leloir's discovery of the pathway of galactose catabolism in the 1940s and 1950s enabled other scientists, notably Kalckar, to link the disease to a specific enzymatic step in the pathway. Kalckar's work established that defects in galactose 1-phosphate uridylyltransferase (GALT) were responsible for the majority of cases of galactosemia. However, over the next three decades it became clear that there were two other forms of galactosemia: type II resulting from deficiencies in galactokinase (GALK1) and type III where the affected enzyme is UDP-galactose 4'-epimerase (GALE). From the 1970s, molecular biology approaches were applied to galactosemia. The chromosomal locations and DNA sequences of the three genes were determined. These studies enabled modern biochemical studies. Structures of the proteins have been determined and biochemical studies have shown that enzymatic impairment often results from misfolding and consequent protein instability. Cellular and model organism studies have demonstrated that reduced GALT or GALE activity results in increased oxidative stress. Thus, after a century of progress, it is possible to conceive of improved therapies including drugs to manipulate the pathway to reduce potentially toxic intermediates, antioxidants to reduce the oxidative stress of cells or use of "pharmacological chaperones" to stabilise the affected proteins. PMID:26143117

  12. AB154. Molecular characterization of Filipino patients with variant galactosemia

    PubMed Central

    Estrada, Sylvia; Silao, Catherine Lynn; Canson, Daffodil

    2015-01-01

    Background Classical galactosemia is a disorder of carbohydrate metabolism caused by low to absent activity of the GALT (galactose-1-phosphate uridyltransferase) enzyme. The clinical manifestations occur early and are severe if untreated. In contrast, patients with variant galactosemia (VG) are apparently healthy and do not manifest elevated galactose levels in spite of low GALT activity. The question of whether to restrict dietary galactose in variant VG remains unanswered. The Philippine newborn screening program does not impose any dietary restriction on patients with VG but monitors their total blood galactose for 5 years. The objective of the study was to determine the molecular basis of VG in 13 clinically diagnosed patients. Methods The coding sequence of the GALT gene of 13 Filipino patients clinically diagnosed to have VG was examined. GALT exons were PCR-amplified using genomic DNA as template and subsequently sequenced in both forward and reverse directions. Results None of the patients had the D/G galactosemia variant genotype. Five patients were heterozygous for classic galactosemia allele/potential G allele (G/- genotype), while three patients were heterozygous for the Duarte allele, p.N314D in cis configuration with c.-119_-116delGTCA, (D/- genotype). Five patients did not have detectable mutations in the coding region of the GALT gene. Two mutations, p.R80Q and p.Y89C, are novel, but cursory in silico analysis predicts that these are deleterious mutations. Three of the five patients without detectable mutations by sequence analysis were each assessed to have one of the following: learning disability, attention deficit disorder and global delay. Another two patients were assessed to have an error of refraction. Conclusions Mutations not evident by direct sequence analysis may be present in the GALT gene of the five patients without detectable mutations. Therefore, additional molecular testing aside from direct sequence analysis (e.g., whole gene

  13. Newborn screening for galactosemia in the United States: looking back, looking around, and looking ahead.

    PubMed

    Pyhtila, Brook M; Shaw, Kelly A; Neumann, Samantha E; Fridovich-Keil, Judith L

    2015-01-01

    It has been 50 years since the first newborn screening (NBS) test for galactosemia was conducted in Oregon, and almost 10 years since the last US state added galactosemia to their NBS panel. During that time an estimated >2,500 babies with classic galactosemia have been identified by NBS. Most of these infants were spared the trauma of acute disease by early diagnosis and intervention, and many are alive today because of NBS. Newborn screening for galactosemia is a success story, but not yet a story with a completely happy ending. NBS, follow-up testing, and intervention for galactosemia continue to present challenges that highlight gaps in our knowledge. Here we compare galactosemia screening and follow-up data from 39 NBS programs gathered from the states directly or from public sources. On some matters the programs agreed: for example, those providing relevant data all identify classic galactosemia in close to 1/50,000 newborns and recommend immediate and lifelong dietary restriction of galactose for those infants. On other matters the programs disagree. For example, Duarte galactosemia (DG) detection rates vary dramatically among states, largely reflecting differences in screening approach. For infants diagnosed with DG, >80% of the programs surveyed recommend complete or partial dietary galactose restriction for the first year of life, or give mixed recommendations; <20% recommend no intervention. This disparity presents an ongoing dilemma for families and healthcare providers that could and should be resolved. PMID:24718839

  14. Affected functional networks associated with sentence production in classic galactosemia.

    PubMed

    Timmers, Inge; van den Hurk, Job; Hofman, Paul Am; Zimmermann, Luc Ji; Uludağ, Kâmil; Jansma, Bernadette M; Rubio-Gozalbo, M Estela

    2015-08-01

    Patients with the inherited metabolic disorder classic galactosemia have language production impairments in several planning stages. Here, we assessed potential deviations in recruitment and connectivity across brain areas responsible for language production that may explain these deficits. We used functional magnetic resonance imaging (fMRI) to study neural activity and connectivity while participants carried out a language production task. This study included 13 adolescent patients and 13 age- and gender-matched healthy controls. Participants passively watched or actively described an animated visual scene using two conditions, varying in syntactic complexity (single words versus a sentence). Results showed that patients recruited additional and more extensive brain regions during sentence production. Both groups showed modulations with syntactic complexity in left inferior frontal gyrus (IFG), a region associated with syntactic planning, and in right insula. In addition, patients showed a modulation with syntax in left superior temporal gyrus (STG), whereas the controls did not. Further, patients showed increased activity in right STG and right supplementary motor area (SMA). The functional connectivity data showed similar patterns, with more extensive connectivity with frontal and motor regions, and restricted and weaker connectivity with superior temporal regions. Patients also showed higher baseline cerebral blood flow (CBF) in right IFG and trends towards higher CBF in bilateral STG, SMA and the insula. Taken together, the data demonstrate that language abnormalities in classic galactosemia are associated with specific changes within the language network. These changes point towards impairments related to both syntactic planning and speech motor planning in these patients. PMID:25979518

  15. Innovative Therapy for Classic Galactosemia - Tale of Two HTS

    PubMed Central

    Tang, M; Odejinmi, SI; Vankayalapati, H; Wierenga, K; Lai, K

    2011-01-01

    Classic Galactosemia is an autosomal recessive disorder caused by the deficiency of galactose-1-phosphate uridylyltransferase (GALT), one of the key enzymes in the Leloir pathway of galactose metabolism. While the neonatal morbidity and mortality of the disease are now mostly prevented by newborn screening and galactose restriction, long-term outcome for older children and adults with this disorder remains unsatisfactory. The pathophysiology of Classic Galactosemia is complex, but there is convincing evidence that galactose-1-phosphate (gal-1P) accumulation is a major, if not the sole pathogenic factor. Galactokinase (GALK) inhibition will eliminate the accumulation of gal-1P from both dietary sources and endogenous production, and efforts towards identification of therapeutic small molecule GALK inhibitors are reviewed in detail. Experimental and computational high-throughput screenings of compound libraries to identify GALK inhibitors have been conducted, and subsequent studies aimed to characterize, prioritize, as well as to optimize the identified positives have been implemented to improve the potency of promising compounds. Although none of the identified GALK inhibitors inhibit glucokinase and hexokinase, some of them cross-inhibit other related enzymes in the GHMP small molecule kinase superfamily. While this finding may render the on-going hit-to-lead process more challenging, there is growing evidence that such cross-inhibition could also lead to advances in antimicrobial and anti-cancer therapies. PMID:22018723

  16. Speech and Language Deficits in Early-Treated Children with Galactosemia.

    ERIC Educational Resources Information Center

    Waisbren, Susan E.; And Others

    1983-01-01

    Intelligence and speech-language development of eight children (3.6 to 11.6 years old) with classic galactosemia were assessed by standardized tests. Each of the children had delays of early speech difficulties, and all but one had language disorders in at least one area. Available from: Journal of Pediatrics, C.V. Mosby Co., 11830 Westline…

  17. Prevalence and Phenotype of Childhood Apraxia of Speech in Youth with Galactosemia

    ERIC Educational Resources Information Center

    Shriberg, Lawrence D.; Potter, Nancy L.; Strand, Edythe A.

    2011-01-01

    Purpose: In this article, the authors address the hypothesis that the severe and persistent speech disorder reported in persons with galactosemia meets contemporary diagnostic criteria for Childhood Apraxia of Speech (CAS). A positive finding for CAS in this rare metabolic disorder has the potential to impact treatment of persons with galactosemia…

  18. Epimerase-Deficiency Galactosemia Is Not a Binary Condition

    PubMed Central

    Openo, Kimberly K.; Schulz, Jenny M.; Vargas, Claudia A.; Orton, Corey S.; Epstein, Michael P.; Schnur, Rhonda E.; Scaglia, Fernando; Berry, Gerard T.; Gottesman, Gary S.; Ficicioglu, Can; Slonim, Alfred E.; Schroer, Richard J.; Yu, Chunli; Rangel, Vanessa E.; Keenan, Jennifer; Lamance, Kerri; Fridovich-Keil, Judith L.

    2006-01-01

    Epimerase-deficiency galactosemia results from the impairment of UDP-galactose 4′-epimerase (GALE), the third enzyme in the Leloir pathway of galactose metabolism. Originally identified as a clinically benign “peripheral” condition with enzyme impairment restricted to circulating blood cells, GALE deficiency was later demonstrated also to exist in a rare but clinically severe “generalized” form, with enzyme impairment affecting a range of tissues. Isolated cases of clinically and/or biochemically intermediate cases of epimerase deficiency have also been reported. We report here studies of 10 patients who, in the neonatal period, received the diagnosis of hemolysate epimerase deficiency. We have characterized these patients with regard to three parameters: (1) GALE activity in transformed lymphoblasts, representing a “nonperipheral” tissue, (2) metabolic sensitivity of those lymphoblasts to galactose challenge in culture, and (3) evidence of normal versus abnormal galactose metabolism in the patients themselves. Our results demonstrate two important points. First, whereas some of the patients studied exhibited near-normal levels of GALE activity in lymphoblasts, consistent with a diagnosis of peripheral epimerase deficiency, many did not. We detected a spectrum of GALE activity levels ranging from 15%–64% of control levels, demonstrating that epimerase deficiency is not a binary condition; it is a continuum disorder. Second, lymphoblasts demonstrating the most severe reduction in GALE activity also demonstrated abnormal metabolite levels in the presence of external galactose and, in some cases, also in the absence of galactose. These abnormalities included elevated galactose-1P, elevated UDP-galactose, and deficient UDP-glucose. Moreover, some of the patients themselves also demonstrated metabolic abnormalities, both on and off galactose-restricted diet. Long-term follow-up studies of these and other patients will be required to elucidate the

  19. Diversity of approaches to classic galactosemia around the world: a comparison of diagnosis, intervention, and outcomes

    PubMed Central

    Jumbo-Lucioni, Patricia P.; Garber, Kathryn; Kiel, John; Baric, Ivo; Berry, Gerard T.; Bosch, Annet; Burlina, Alberto; Chiesa, Ana; Pico, Maria Luz Couce; Estrada, Sylvia C.; Henderson, Howard; Leslie, Nancy; Longo, Nicola; Morris, Andrew A. M.; Ramirez-Farias, Carlett; Schweitzer-Krantz, Susanne; Silao, Catherine Lynn T.; Vela-Amieva, Marcela; Waisbren, Susan; Fridovich-Keil, Judith L.

    2013-01-01

    Without intervention, classic galactosemia is a potentially fatal disorder in infancy. With the benefit of early diagnosis and dietary restriction of galactose, the acute sequelae of classic galactosemia can be prevented or reversed. However, despite early and lifelong dietary treatment, many galactosemic patients go on to experience serious long-term complications including cognitive disability, speech problems, neurological and/or movement disorders and, in girls and women, ovarian dysfunction. Further, there remains uncertainty surrounding what constitutes a ‘best practice’ for treating this disorder. To explore the extent and implications of this uncertainty, we conducted a small but global survey of healthcare providers who follow patients with classic galactosemia, seeking to compare established protocols for diagnosis, intervention, and follow-up, as well as the outcomes and outcome frequencies seen in the patient populations cared for by these providers. We received 13 survey responses representing five continents and 11 countries. Respondents underscored disparities in approaches to diagnosis, management and follow-up care. Notably, we saw no clear relationship between differing approaches to care and long-term outcomes in the populations studied. Negative outcomes occurred in the majority of cases regardless of when treatment was initiated, how tightly galactose intake was restricted, or how closely patients were monitored. We document here what is, to our knowledge, the first global comparison of healthcare approaches to classic galactosemia. These data reinforce the idea that there is currently no one best practice for treating patients with classic galactosemia, and underscore the need for more extensive and statistically powerful comparative studies to reveal potential positive or negative impacts of differing approaches. PMID:22450714

  20. A De Novo Variant in Galactose-1-P Uridylyltransferase (GALT) Leading to Classic Galactosemia.

    PubMed

    Tran, Thanh-Thanh Claire V; Liu, Ying; Zwick, Michael E; Ramachandran, Dhanya; Cutler, David J; Huang, Xiaoping; Berry, Gerard T; Fridovich-Keil, Judith L

    2015-01-01

    Classic galactosemia (CG) is a potentially lethal genetic disease that results from profound impairment of galactose-1-P uridylyltransferase (GALT), the middle enzyme in the Leloir pathway of galactose metabolism. Patients with CG carry pathogenic loss-of-function mutations in both of their GALT alleles; the parents of patients are considered obligate carriers. We report here a first exception to that rule - a de novo GALT variant in a patient with classic galactosemia. The new variant, c.563A>C (p.Q188P), which introduces a missense substitution near the active site of the GALT enzyme, was found in the compound heterozygous state in a child with classic galactosemia, but not in either of her parents. Extensive genomic studies of DNA from the child and both parents confirmed the expected degrees of relationship in the trio as well as inheritance of a common c.563A>G (p.Q188R) GALT mutation from the mother. This result demonstrates that not all pathogenic GALT mutations are inherited and raises concern that GALT may have a higher new mutation rate than previously believed. PMID:25681079

  1. Functional and structural impact of the most prevalent missense mutations in classic galactosemia.

    PubMed

    Coelho, Ana I; Trabuco, Matilde; Ramos, Ruben; Silva, Maria João; Tavares de Almeida, Isabel; Leandro, Paula; Rivera, Isabel; Vicente, João B

    2014-11-01

    Galactose-1-phosphate uridylyltransferase (GALT) is a key enzyme in galactose metabolism, particularly important in the neonatal period due to ingestion of galactose-containing milk. GALT deficiency results in the genetic disorder classic galactosemia, whose pathophysiology is still not fully elucidated. Whereas classic galactosemia has been hypothesized to result from GALT misfolding, a thorough functional-structural characterization of GALT most prevalent variants was still lacking, hampering the development of alternative therapeutic approaches. The aim of this study was to investigate the structural-functional effects of nine GALT mutations, four of which account for the vast majority of the mutations identified in galactosemic patients. Several methodologies were employed to evaluate the mutations' impact on GALT function, on the protein secondary and tertiary structures, and on the aggregation propensity. The major structural effect concerns disturbed propensity for aggregation, particularly striking for the p.Q188R variant, resulting from the most frequent (∼60%) allele at a worldwide scale. The absence of major effects at the secondary and tertiary structure levels suggests that the disturbed aggregation results from subtle perturbations causing a higher and/or longer exposure of hydrophobic residues in the variants as compared to WT GALT. The results herein described indicate a possible benefit from introducing proteostasis regulators and/or chemical/pharmacological chaperones to prevent the accumulation of protein aggregates, in new avenues of therapeutic research for classic galactosemia. PMID:25614870

  2. A re-evaluation of life-long severe galactose restriction for the nutrition management of classic galactosemia.

    PubMed

    Van Calcar, Sandra C; Bernstein, Laurie E; Rohr, Frances J; Scaman, Christine H; Yannicelli, Steven; Berry, Gerard T

    2014-07-01

    The galactose-restricted diet is life-saving for infants with classic galactosemia. However, the benefit and extent of dietary galactose restriction required after infancy remain unclear and variation exists in practice. There is a need for evidence-based recommendations to better standardize treatment for this disorder. This paper reviews the association between diet treatment and outcomes in classic galactosemia and evaluates the contribution of food sources of free galactose in the diet. Recommendations include allowing all fruits, vegetables, legumes, soy products that are not fermented, various aged cheeses and foods containing caseinates. Further research directions are discussed. PMID:24857409

  3. N- and O-linked glycosylation of total plasma glycoproteins in galactosemia

    PubMed Central

    Liu, Ying; Xia, Baoyun; Gleason, Tyler J.; Castañeda, Uriel; He, Miao; Berry, Gerard T.; Fridovich-Keil, Judith L.

    2012-01-01

    Classic galactosemia is a potentially lethal metabolic disorder that results from profound impairment of the enzyme galactose-1-phosphate uridylyltransferase (GALT); despite decades of research, the underlying mechanism of pathophysiology remains unclear. Previous studies of plasma and tissue samples from patients with classic galactosemia have revealed defects of protein and lipid glycosylation, however, the underlying bases for these defects and their clinical significance, if any, has remained unclear. As a step toward addressing these questions we characterized both the N- and O-linked glycomes of plasma proteins from neonates, infants, children, and adults with galactosemia using mass spectrometry and asked (1) whether similar or disparate defects exist for N-linked and O-linked modifications, (2) what factors correlate with the severity of these defects in different patients, and perhaps most important, (3) whether there is any apparent relationship between chronic glycosylation defects and long-term outcome in patients. We found that some but not all of the galactosemic neonates tested exhibited abnormal N- and O-linked glycosylation of plasma proteins. The types of abnormalities seen were similar between N- and O-linked moieties, but the extent of the defects varied between patients. Age, gender, GALT genotype, and predicted residual GALT activity all failed to explain the extent of the glycosylation defect in the samples studied. Dietary galactose restriction markedly normalized both the N- and O-linked glycosylation patterns for all infants tested; however, any remaining glycosylation defects evident in the plasma of older children or adults on galactose-restricted diets showed no correlation with clinical outcome. These data cannot rule out the possibility that subtle or localized glycosylation defects, not detectable by our methods or not reflected in plasma, may contribute to acute or long-term outcome severity. PMID:22743281

  4. Developmental Outcomes of School-Age Children with Duarte Galactosemia: A Pilot Study.

    PubMed

    Lynch, Mary Ellen; Potter, Nancy L; Coles, Claire D; Fridovich-Keil, Judith L

    2015-01-01

    Duarte galactosemia (DG) is a mild allelic variant of classic galactosemia that results from partial impairment of galactose-1P uridylyltransferase (GALT). Although infants with DG are detected by newborn screening in some US states at close to 1/4,000 live births, most are discharged from follow-up very early in life and there is no consensus on whether these children are at increased risk for any of the long-term developmental delays seen in classic galactosemia. There is also no consensus on whether infants with DG benefit from dietary restriction of galactose. Reflecting the current uncertainty, some states choose to identify infants with DG by newborn screening and others do not. As a first step toward characterizing the developmental outcomes of school-age children with DG, we conducted a pilot study, testing 10 children with DG and 5 unaffected siblings from the same group of families. All children tested were between 6 and 11 years old. We used standardized direct assessments and parent-response surveys to collect information regarding cognition, communication, socio-emotional, adaptive behavior, and physical development for each child. Despite the small sample size, our data demonstrated some notable differences between cases and controls in socio-emotional development, in delayed recall, and in auditory processing speed. These results confirm that direct assessment of school-age children with DG can detect subtle but potentially problematic developmental deficits, and underscore the need for a larger study which has sufficient power to evaluate these outcomes while controlling for potentially confounding factors. PMID:25681083

  5. Developmental Defects in a Caenorhabditis elegans Model for Type III Galactosemia

    PubMed Central

    Brokate-Llanos, Ana M.; Monje, José M.; Murdoch, Piedad del Socorro; Muñoz, Manuel J.

    2014-01-01

    Type III galactosemia is a metabolic disorder caused by reduced activity of UDP-galactose-4-epimerase, which participates in galactose metabolism and the generation of various UDP-sugar species. We characterized gale-1 in Caenorhabditis elegans and found that a complete loss-of-function mutation is lethal, as has been hypothesized for humans, whereas a nonlethal partial loss-of-function allele causes a variety of developmental abnormalities, likely resulting from the impairment of the glycosylation process. We also observed that gale-1 mutants are hypersensitive to galactose as well as to infections. Interestingly, we found interactions between gale-1 and the unfolded protein response. PMID:25298520

  6. Capillary bedside blood glucose measurement in neonates: missing a diagnosis of galactosemia.

    PubMed

    Özbek, Mehmet Nuri; Öcal, Murat; Tanrıverdi, Sibel; Baysal, Birsen; Deniz, Ahmet; Öncel, Kahraman; Demirbilek, Hüseyin

    2015-03-01

    A number of factors may lead to inaccuracy in measurement of capillary blood glucose with a glucometer. Measurement of other carbohydrate molecules such as galactose and fructose along with glucose can potentially be a cause of error. We report a newborn patient who was referred to our hospital with conjugated bilirubinemia, hepatomegaly and high capillary blood glucose levels measured with a glucometer. Simultaneous biochemical measurements revealed normal blood glucose levels. Further investigation led to a diagnosis of classical galactosemia. Capillary blood glucose level measured with glucometer also dropped to normal values following cessation of breastfeeding and initiation of feeding with a lactose-free formula. PMID:25800483

  7. Developmental defects in a Caenorhabditis elegans model for type III galactosemia.

    PubMed

    Brokate-Llanos, Ana M; Monje, José M; Murdoch, Piedad Del Socorro; Muñoz, Manuel J

    2014-12-01

    Type III galactosemia is a metabolic disorder caused by reduced activity of UDP-galactose-4-epimerase, which participates in galactose metabolism and the generation of various UDP-sugar species. We characterized gale-1 in Caenorhabditis elegans and found that a complete loss-of-function mutation is lethal, as has been hypothesized for humans, whereas a nonlethal partial loss-of-function allele causes a variety of developmental abnormalities, likely resulting from the impairment of the glycosylation process. We also observed that gale-1 mutants are hypersensitive to galactose as well as to infections. Interestingly, we found interactions between gale-1 and the unfolded protein response. PMID:25298520

  8. Galactose content of legumes, caseinates, and some hard cheeses: implications for diet treatment of classic galactosemia.

    PubMed

    Van Calcar, Sandra C; Bernstein, Laurie E; Rohr, Frances J; Yannicelli, Steven; Berry, Gerard T; Scaman, Christine H

    2014-02-12

    There are inconsistent reports on the lactose and/or galactose content of some foods traditionally restricted from the diet for classic galactosemia. Therefore, samples of cheeses, caseinates, and canned black, pinto, kidney, and garbanzo beans were analyzed for free galactose content using HPLC with refractive index or pulsed amperometric detection. Galactose concentrations in several hard and aged cheeses and three mild/medium Cheddars, produced by smaller local dairies, was <10 mg/100 g sample compared to 55.4 mg/100 g sample in four sharp Cheddars produced by a multinational producer. Galactose in sodium and calcium caseinate ranged from undetectable to 95.5 mg/100 g sample. Free galactose level in garbanzo beans was lower than previously reported at 24.6 mg/100 g sample; black beans contained 5.3 mg/100 g, and free galactose was not detected in red kidney or pinto beans. These data provide a basis for recommending inclusion of legumes, caseinate-containing foods, and some aged hard cheeses that had been previously restricted in the diet for individuals with galactosemia. PMID:24456566

  9. [Biological assay for galactose-1 phosphate measurement application in subjects with galactosemia].

    PubMed

    Braham, Imene; Charfeddine, Bassem; Ben Othmene, Leila; Neffati, Souhir; Mtar, Aida; Ben Abdallah, Jihene; Ali Smach, Med; Dridi, Hedi; Limem, Khalifa

    2012-01-01

    Congenital galactosemia is a hereditary, autosomal recessive and metabolic disease. It is linked to an enzyme deficiency, more commonly known by the deficiency of galactose-1- phosphate uridyltransferase (GALT), which is responsible for an accumulation of galactose-1- phosphate in the blood. Clinical symptoms appear early in infancy from the second week of life. They generally manifested by some disorders within liver, kidney, eye, gastrointestinal, neurological and also with cataracts. Currently, the clinical diagnosis remains difficult hence the importance of further investigations based on effective biological assessments to highlight the disease. The diagnosis of galactosemia is made by the laboratory test. The latter includes the determination of Gal-1-P which is done by a fluorometric method spot test. This study was conducted in order to assess the repeatability, reproducibility, accuracy, and effectiveness of the techniques used. We have found the CV for a repeatability (CV = 5 %), reproducibility (CV = 4 %) which confirms the accuracy of the method proceeded in this study. This method allows us to have a degree of inaccuracy less than 1%. According to the study of the effectiveness of "spot test", we found that our technique is specific (Sp = 93 %) and sensitive (Se = 83 %). PMID:22294140

  10. White matter microstructure pathology in classic galactosemia revealed by neurite orientation dispersion and density imaging.

    PubMed

    Timmers, Inge; Zhang, Hui; Bastiani, Matteo; Jansma, Bernadette M; Roebroeck, Alard; Rubio-Gozalbo, M Estela

    2015-03-01

    White matter abnormalities have been observed in patients with classic galactosemia, an inborn error of galactose metabolism. However, magnetic resonance imaging (MRI) data collected in the past were generally qualitative in nature. Our objective was to investigate white matter microstructure pathology and examine correlations with outcome and behaviour in this disease, by using multi-shell diffusion weighted imaging. In addition to standard diffusion tensor imaging (DTI), neurite orientation dispersion and density imaging (NODDI) was used to estimate density and orientation dispersion of neurites in a group of eight patients (aged 16-21 years) and eight healthy controls (aged 15-20 years). Extensive white matter abnormalities were found: neurite density index (NDI) was lower in the patient group in bilateral anterior areas, and orientation dispersion index (ODI) was increased mainly in the left hemisphere. These specific regional profiles are in agreement with the cognitive profile observed in galactosemia, showing higher order cognitive impairments, and language and motor impairments, respectively. Less favourable white matter properties correlated positively with age and age at onset of diet, and negatively with behavioural outcome (e.g. visual working memory). To conclude, this study provides evidence of white matter pathology regarding density and dispersion of neurites in these patients. The results are discussed in light of suggested pathophysiological mechanisms. PMID:25344151

  11. Cryptic residual GALT activity is a potential modifier of scholastic outcome in school age children with classic galactosemia

    PubMed Central

    Ryan, Emily L.; Lynch, Mary Ellen; Taddeo, Elles; Gleason, Tyler J.; Epstein, Michael P.; Fridovich-Keil, Judith L.

    2013-01-01

    Summary Classic galactosemia is a potentially lethal disorder that results from profound deficiency of galactose-1-phosphate uridylyltransferase (GALT), the second enzyme in the Leloir pathway of galactose metabolism. Although early diagnosis and rigorous dietary restriction of galactose prevent or resolve the potentially lethal acute symptoms, patients are at markedly increased risk of long term complications including significant cognitive, speech, and behavioral difficulties, among other problems. The mechanisms that underlie these long-term complications remain unclear, as do the factors that modify their severity. Here we explored the scholastic and behavioral outcomes experienced by a cohort of 54 school age children with classic galactosemia. Data collected included survey responses from parents and teachers, school records including standardized test scores, and GALT genotype data used to estimate predicted residual GALT activity based on a yeast expression system. As expected, many but not all of the children in our study demonstrated speech, scholastic, and behavioral difficulties. Perhaps most striking, we found that predicted cryptic residual GALT activity, often below the threshold of detection of clinical assays, appeared to modify scholastic outcome. These data raise the intriguing possibility that cryptic GALT activity might also influence the severity of other long-term complications in classic galactosemia. PMID:23319291

  12. Cryptic residual GALT activity is a potential modifier of scholastic outcome in school age children with classic galactosemia.

    PubMed

    Ryan, Emily L; Lynch, Mary Ellen; Taddeo, Elles; Gleason, Tyler J; Epstein, Michael P; Fridovich-Keil, Judith L

    2013-11-01

    Classic galactosemia is a potentially lethal disorder that results from profound deficiency of galactose-1-phosphate uridylyltransferase (GALT), the second enzyme in the Leloir pathway of galactose metabolism. Although early diagnosis and rigorous dietary restriction of galactose prevent or resolve the potentially lethal acute symptoms, patients are at markedly increased risk of long-term complications including significant cognitive, speech, and behavioral difficulties, among other problems. The mechanisms that underlie these long-term complications remain unclear, as do the factors that modify their severity. Here we explored the scholastic and behavioral outcomes experienced by a cohort of 54 school age children with classic galactosemia. Data collected included survey responses from parents and teachers, school records including standardized test scores, and GALT genotype data used to estimate predicted residual GALT activity based on a yeast expression system. As expected, many but not all of the children in our study demonstrated speech, scholastic, and behavioral difficulties. Perhaps most striking, we found that predicted cryptic residual GALT activity, often below the threshold of detection of clinical assays, appeared to modify scholastic outcome. These data raise the intriguing possibility that cryptic GALT activity might also influence the severity of other long-term complications in classic galactosemia. PMID:23319291

  13. Neurologic sequela in a patient with galactosemia potentially mediated by interleukin-11 dysfunction.

    PubMed

    Winter, Gidon N; Ben-Pazi, Hilla

    2015-06-01

    A 16-year-old galactosemic patient, homozygous for the 5.5-kb gene deletion, suffered severe neurologic regression following streptococcal infection. Since the gene deletion includes the promoter of interleukin-11a receptor involved in neuronal apoptosis, we questioned whether this patient had no interleukin-11a receptor activity-resulting in neuronal toxicity during septicemia. We hypothesized that interleukin-11 levels would be elevated because of a loss of feedback induced by the absent interleukin-11Ra receptor complex. To assess this, we compared interleukin-11 levels in the proband and 2 of his siblings with the same genetic deletion, to age-matched controls. No differences were found in interleukin-11 levels between groups. Our study was not carried out during acute infective states, when the disrupted immunoregulation triggered by sepsis is relevant, and is thus limited. In conclusion, although interleukin-11 was not chronically elevated in individuals with galactosemia and 5.5-kb gene deletion, data do not rule out potential interleukin-11 dysfunction during acute infection. PMID:25008910

  14. Differential phonological awareness skills in children with classic galactosemia: a descriptive study of four cases.

    PubMed

    Lewis, Fiona M; Coman, David J; Syrmis, Maryann; Kilcoyne, Sarah; Murdoch, Bruce E

    2013-01-01

    Educational achievement, which for individuals with the metabolic disorder classic galactosemia (GAL) is significantly lower than in the wider population, correlates with self-reported quality of life. Phonological awareness skills underpin the development of literacy, and although literacy is a key contributor to successful academic outcomes, no study to date has investigated phonological awareness skills in children with GAL. This study investigated phonological awareness (PA) in four school-aged children with the disorder, two of whom were siblings. Age range for the children was 7 years 7 months to 9 years 2 months. Each child was assessed with the Phonological Awareness criterion-referenced subtest from the Clinical Evaluation of Language Fundamentals-Fourth Edition. Included in the data for analysis was each child's performance measures obtained from their most recent assessment of cognitive and lexical development. A number of descriptive analyses were undertaken on the data. One child, who met her age criterion for PA, had cognitive and lexical development skills in the average range. The remaining three children failed to meet their age criteria. Although these three children presented with clinically similar cognitive and lexical development skills, disparate PA skills were identified. The PA skills of one of the sibling pair were notably more advanced than his older sibling. The limitations of relying on behavioural test results in children with GAL to predict those most at risk of reduced skill development are discussed in terms future research directions. PMID:23430800

  15. Overelaborated synaptic architecture and reduced synaptomatrix glycosylation in a Drosophila classic galactosemia disease model

    PubMed Central

    Jumbo-Lucioni, Patricia; Parkinson, William; Broadie, Kendal

    2014-01-01

    Classic galactosemia (CG) is an autosomal recessive disorder resulting from loss of galactose-1-phosphate uridyltransferase (GALT), which catalyzes conversion of galactose-1-phosphate and uridine diphosphate (UDP)-glucose to glucose-1-phosphate and UDP-galactose, immediately upstream of UDP–N-acetylgalactosamine and UDP–N-acetylglucosamine synthesis. These four UDP-sugars are essential donors for driving the synthesis of glycoproteins and glycolipids, which heavily decorate cell surfaces and extracellular spaces. In addition to acute, potentially lethal neonatal symptoms, maturing individuals with CG develop striking neurodevelopmental, motor and cognitive impairments. Previous studies suggest that neurological symptoms are associated with glycosylation defects, with CG recently being described as a congenital disorder of glycosylation (CDG), showing defects in both N- and O-linked glycans. Here, we characterize behavioral traits, synaptic development and glycosylated synaptomatrix formation in a GALT-deficient Drosophila disease model. Loss of Drosophila GALT (dGALT) greatly impairs coordinated movement and results in structural overelaboration and architectural abnormalities at the neuromuscular junction (NMJ). Dietary galactose and mutation of galactokinase (dGALK) or UDP-glucose dehydrogenase (sugarless) genes are identified, respectively, as critical environmental and genetic modifiers of behavioral and cellular defects. Assaying the NMJ extracellular synaptomatrix with a broad panel of lectin probes reveals profound alterations in dGALT mutants, including depletion of galactosyl, N-acetylgalactosamine and fucosylated horseradish peroxidase (HRP) moieties, which are differentially corrected by dGALK co-removal and sugarless overexpression. Synaptogenesis relies on trans-synaptic signals modulated by this synaptomatrix carbohydrate environment, and dGALT-null NMJs display striking changes in heparan sulfate proteoglycan (HSPG) co-receptor and Wnt ligand

  16. Overelaborated synaptic architecture and reduced synaptomatrix glycosylation in a Drosophila classic galactosemia disease model.

    PubMed

    Jumbo-Lucioni, Patricia; Parkinson, William; Broadie, Kendal

    2014-12-01

    Classic galactosemia (CG) is an autosomal recessive disorder resulting from loss of galactose-1-phosphate uridyltransferase (GALT), which catalyzes conversion of galactose-1-phosphate and uridine diphosphate (UDP)-glucose to glucose-1-phosphate and UDP-galactose, immediately upstream of UDP-N-acetylgalactosamine and UDP-N-acetylglucosamine synthesis. These four UDP-sugars are essential donors for driving the synthesis of glycoproteins and glycolipids, which heavily decorate cell surfaces and extracellular spaces. In addition to acute, potentially lethal neonatal symptoms, maturing individuals with CG develop striking neurodevelopmental, motor and cognitive impairments. Previous studies suggest that neurological symptoms are associated with glycosylation defects, with CG recently being described as a congenital disorder of glycosylation (CDG), showing defects in both N- and O-linked glycans. Here, we characterize behavioral traits, synaptic development and glycosylated synaptomatrix formation in a GALT-deficient Drosophila disease model. Loss of Drosophila GALT (dGALT) greatly impairs coordinated movement and results in structural overelaboration and architectural abnormalities at the neuromuscular junction (NMJ). Dietary galactose and mutation of galactokinase (dGALK) or UDP-glucose dehydrogenase (sugarless) genes are identified, respectively, as critical environmental and genetic modifiers of behavioral and cellular defects. Assaying the NMJ extracellular synaptomatrix with a broad panel of lectin probes reveals profound alterations in dGALT mutants, including depletion of galactosyl, N-acetylgalactosamine and fucosylated horseradish peroxidase (HRP) moieties, which are differentially corrected by dGALK co-removal and sugarless overexpression. Synaptogenesis relies on trans-synaptic signals modulated by this synaptomatrix carbohydrate environment, and dGALT-null NMJs display striking changes in heparan sulfate proteoglycan (HSPG) co-receptor and Wnt ligand levels

  17. Rapid screening of classic galactosemia patients: a proof-of-concept study using high-throughput FTIR analysis of plasma.

    PubMed

    Lacombe, Caroline; Untereiner, Valérie; Gobinet, Cyril; Zater, Mokhtar; Sockalingum, Ganesh D; Garnotel, Roselyne

    2015-04-01

    Classic galactosemia is an autosomal recessive metabolic disease involving the galactose pathway, caused by the deficiency of galactose-1-phosphate uridyltransferase. Galactose accumulation induces in newborns many symptoms, such as liver disease, cataracts, and sepsis leading to death if untreated. Neonatal screening is developed and applied in many countries using several methods to detect galactose or its derived product accumulation in blood or urine. High-throughput FTIR spectroscopy was investigated as a potential tool in the current screening methods. IR spectra were obtained from blood plasma of healthy, diabetic, and galactosemic patients. The major spectral differences were in the carbohydrate region, which was first analysed in an exploratory manner using principal component analysis (PCA). PCA score plots showed a clear discrimination between diabetic and galactosemic patients and this was more marked as a function of the glucose and galactose increased concentration in these patients' plasma respectively. Then, a support vector machine leave-one-out cross-validation (SVM-LOOCV) classifier was built with the PCA scores as the input and the model was tested on median, mean and all spectra from the three population groups. This classifier was able to discriminate healthy/diabetic, healthy/galactosemic, and diabetic/galactosemic patients with sensitivity and specificity rates ranging from 80% to 94%. The total accuracy rate ranged from 87% to 96%. High-throughput FTIR spectroscopy combined with the SVM-LOOCV classification procedure appears to be a promising tool in the screening of galactosemia patients, with good sensitivity and specificity. Furthermore, this approach presents the advantages of being cost-effective, fast, and straightforward in the screening of galactosemic patients. PMID:25622686

  18. Biochemical and computational analyses of two phenotypically related GALT mutations (S222N and S135L) that lead to atypical galactosemia.

    PubMed

    Cocanougher, Benjamin; Aypar, Umut; McDonald, Amber; Hasadsri, Linda; Bennett, Michael J; Edward Highsmith, W; D׳Aco, Kristin

    2015-06-01

    Galactosemia is a metabolic disorder caused by mutations in the GALT gene [1,2]. We encountered a patient heterozygous for a known pathogenic H132Q mutation and a novel S222N variant of unknown significance [3]. Reminiscent of patients with the S135L mutation, our patient had loss of GALT enzyme activity in erythrocytes but a very mild clinical phenotype [3-8]. We performed splicing experiments and computational structural analyses to investigate the role of the novel S222N variant. Alamut software data predicted loss of splicing enhancers for the S222N and S135L mutations [9,10]. A cDNA library was generated from our patient׳s RNA to investigate for splicing errors, but no change in transcript length was seen [3]. In silico structural analysis was performed to investigate enzyme stability and attempt to understand the mechanism of the atypical galactosemia phenotype. Stability results are publicly available in the GALT Protein Database 2.0 [11-14]. Animations were created to give the reader a dynamic view of the enzyme structure and mutation locations. Protein database files and python scripts are included for further investigation. PMID:26217714

  19. Using a Personal Glucose Meter and Alkaline Phosphatase for Point-of-Care Quantification of Galactose-1-Phosphate Uridyltransferase in Clinical Galactosemia Diagnosis.

    PubMed

    Zhang, Jingjing; Xiang, Yu; Novak, Donna E; Hoganson, George E; Zhu, Junjie; Lu, Yi

    2015-10-01

    The personal glucose meter (PGM) was recently shown to be a general meter to detect many targets. Most studies, however, focus on transforming either target binding or enzymatic activity that cleaves an artificial substrate into the production of glucose. More importantly, almost all reports exhibit their methods by using artificial samples, such as buffers or serum samples spiked with the targets. To expand the technology to even broader targets and to validate its potential in authentic, more complex clinical samples, we herein report expansion of the PGM method by using alkaline phosphatase (ALP) that links the enzymatic activity of galactose-1-phosphate uridyltransferase to the production of glucose, which allows point-of-care galactosemia diagnosis in authentic human clinical samples. Given the presence of ALP in numerous enzymatic assays for clinical diagnostics, the methods demonstrated herein advance the field closer to point-of-care detection of a wide range of targets in real clinical samples. PMID:26350570

  20. Manganese-Based Superoxide Dismutase Mimics Modify Both Acute and Long-Term Outcome Severity in a Drosophila melanogaster Model of Classic Galactosemia

    PubMed Central

    Jumbo-Lucioni, Patricia P.; Ryan, Emily L.; Hopson, Marquise L.; Bishop, Heather M.; Weitner, Tin; Tovmasyan, Artak; Spasojevic, Ivan; Batinic-Haberle, Ines; Liang, Yongliang; Jones, Dean P.

    2014-01-01

    Abstract Aims: The goal of this study was to use two manganese (Mn)-based superoxide dismutase (SOD) mimics to test the hypothesis that reactive oxygen species contribute to both acute and long-term outcomes in a galactose-1P uridylyltransferase (GALT)-null Drosophila melanogaster model of classic galactosemia. Results: We tested the impact of each of two Mn porphyrin SOD mimics, MnTnBuOE-2-PyP5+, and MnTE-2-PyP5+, (i) on survival of GALT-null Drosophila larvae reared in the presence versus absence of dietary galactose and (ii) on the severity of a long-term movement defect in GALT-null adult flies. Both SOD mimics conferred a significant survival benefit to GALT-null larvae exposed to galactose but not to controls or to GALT-null larvae reared in the absence of galactose. One mimic, MnTE-2-PyP5+, also largely rescued a galactose-independent long-term movement defect otherwise seen in adult GALT-null flies. The survival benefit of both SOD mimics occurred despite continued accumulation of elevated galactose-1P in the treated animals, and studies of thiolated proteins demonstrated that in both the presence and absence of dietary galactose MnTE-2-PyP5+ largely prevented the elevated protein oxidative damage otherwise seen in GALT-null animals relative to controls. Innovation and Conclusions: Our results confirm oxidative stress as a mediator of acute galactose sensitivity in GALT-null Drosophila larvae and demonstrate for the first time that oxidative stress may also contribute to galactose-independent adult outcomes in GALT deficiency. Finally, our results demonstrate for the first time that both MnTnBuOE-2-PyP5+ and MnTE-2-PyP5+ are bioavailable and effective when administered through an oral route in a D. melanogaster model of classic galactosemia. Antioxid. Redox Signal. 20, 2361–2371. PMID:23758052

  1. The metastability of human UDP-galactose 4'-epimerase (GALE) is increased by variants associated with type III galactosemia but decreased by substrate and cofactor binding.

    PubMed

    Pey, Angel L; Padín-Gonzalez, Esperanza; Mesa-Torres, Noel; Timson, David J

    2014-11-15

    Type III galactosemia is an inherited disease caused by mutations which affect the activity of UDP-galactose 4'-epimerase (GALE). We evaluated the impact of four disease-associated variants (p.N34S, p.G90E, p.V94M and p.K161N) on the conformational stability and dynamics of GALE. Thermal denaturation studies showed that wild-type GALE denatures at temperatures close to physiological, and disease-associated mutations often reduce GALE's thermal stability. This denaturation is under kinetic control and results partly from dimer dissociation. The natural ligands, NAD(+) and UDP-glucose, stabilize GALE. Proteolysis studies showed that the natural ligands and disease-associated variations affect local dynamics in the N-terminal region of GALE. Proteolysis kinetics followed a two-step irreversible model in which the intact protein is cleaved at Ala38 forming a long-lived intermediate in the first step. NAD(+) reduces the rate of the first step, increasing the amount of undigested protein whereas UDP-glucose reduces the rate of the second step, increasing accumulation of the intermediate. Disease-associated variants affect these rates and the amounts of protein in each state. Our results also suggest communication between domains in GALE. We hypothesize that, in vivo, concentrations of natural ligands modulate GALE stability and that it should be possible to discover compounds which mimic the stabilising effects of the natural ligands overcoming mutation-induced destabilization. PMID:25150110

  2. Identification and characterization of a mutation, in the human UDP-galactose-4-epimerase gene, associated with generalized epimerase-deficiency galactosemia.

    PubMed

    Wohlers, T M; Christacos, N C; Harreman, M T; Fridovich-Keil, J L

    1999-02-01

    Epimerase-deficiency galactosemia results from impairment of the human enzyme UDP-galactose-4-epimerase (hGALE). We and others have identified substitution mutations in the hGALE alleles of patients with the clinically mild, peripheral form of epimerase deficiency. We report here the first identification of an hGALE mutation in a patient with the clinically severe, generalized form of epimerase deficiency. The mutation, V94M, was found on both GALE alleles of this patient. This same mutation also was found in the homozygous state in two additional patients with generalized epimerase deficiency. The specific activity of the V94M-hGALE protein expressed in yeast was severely reduced with regard to UDP-galactose and partially reduced with regard to UDP-N-acetylgalactosamine. In contrast, two GALE-variant proteins associated with peripheral epimerase deficiency, L313M-hGALE and D103G-hGALE, demonstrated near-normal levels of activity with regard to both substrates, but a third allele, G90E-hGALE, demonstrated little, if any, detectable activity, despite near-normal abundance. G90E originally was identified in a heterozygous patient whose other allele remains uncharacterized. Thermal lability and protease-sensitivity studies demonstrated compromised stability in all of the partially active mutant enzymes. PMID:9973283

  3. Identification and characterization of a mutation, in the human UDP-galactose-4-epimerase gene, associated with generalized epimerase-deficiency galactosemia.

    PubMed Central

    Wohlers, T M; Christacos, N C; Harreman, M T; Fridovich-Keil, J L

    1999-01-01

    Epimerase-deficiency galactosemia results from impairment of the human enzyme UDP-galactose-4-epimerase (hGALE). We and others have identified substitution mutations in the hGALE alleles of patients with the clinically mild, peripheral form of epimerase deficiency. We report here the first identification of an hGALE mutation in a patient with the clinically severe, generalized form of epimerase deficiency. The mutation, V94M, was found on both GALE alleles of this patient. This same mutation also was found in the homozygous state in two additional patients with generalized epimerase deficiency. The specific activity of the V94M-hGALE protein expressed in yeast was severely reduced with regard to UDP-galactose and partially reduced with regard to UDP-N-acetylgalactosamine. In contrast, two GALE-variant proteins associated with peripheral epimerase deficiency, L313M-hGALE and D103G-hGALE, demonstrated near-normal levels of activity with regard to both substrates, but a third allele, G90E-hGALE, demonstrated little, if any, detectable activity, despite near-normal abundance. G90E originally was identified in a heterozygous patient whose other allele remains uncharacterized. Thermal lability and protease-sensitivity studies demonstrated compromised stability in all of the partially active mutant enzymes. PMID:9973283

  4. Identification and functional analysis of three distinct mutations in the human galactose-1-phosphate uridyltransferase gene associated with galactosemia in a single family

    SciTech Connect

    Fridovich-Keil, J.L.; Langley, S.D.; Mazur, L.A.; Lennon, J.C.; Dembure, P.O.; Elsas, L.J. II

    1995-03-01

    We have identified three mutations associated with transferase-deficiency galactosemia in a three-generation family including affected members in two generations and have modeled all three mutations in a yeast-expression system. A sequence of pedigree, biochemical, and molecular analyses of the galactose-1-phosphate uridyltransferase (GALT) enzyme and genetic locus in both affected and carrier individuals revealed three distinct base substitutions in this family, two (Q188R and S135L) that had been reported previously and one (V151A) that was novel. Biochemical analyses of red-blood-cell lysates from the relevant family members suggested that each of these mutations was associated with dramatic impairment of GALT activity in these cells. While this observation was consistent with our previous findings concerning the Q188R mutation expressed both in humans and in a yeast-model system, it was at odds with a report by Reichardt and colleagues, indicating that in their COS cell-expression system the S135L substitution behaved as a neutral polymorphism. To address this apparent paradox, as well as to investigate the functional significance of the newly identified V151A substitution, all three mutations were recreated by site-directed mutagenesis of the otherwise wild-type human GALT sequence and were expressed both individually and in the appropriate allelic combinations in a GALT-deficient strain of the yeast Saccharomyces cerevisiae. The results of these yeast-modeling studies were fully consistent with the patient data, leading us to conclude that, at least within the context of the cell types studied, in the homozygous state Q188R is a mutation that eliminates GALT activity, and S135L and V151A are both mutations that impair GALT activity to <6% of wild-type values. 22 refs., 5 figs.

  5. Newborn Screening: National Library of Medicine Literature Search, January 1980 through March 1987. No. 87-2.

    ERIC Educational Resources Information Center

    Patrias, Karen

    This bibliography, prepared by the National Library of Medicine through a literature search of its online databases, covers all aspects of newborn screening. It includes references to screening for: inborn errors of metabolism, such as phenylketonuria and galactosemia; hemoglobinopathies, particularly sickle cell disease; congenital hypothyroidism…

  6. Nutritional Considerations for Severely Handicapped Children.

    ERIC Educational Resources Information Center

    Sobsey, Dick

    Children and adults with severe disabilities may have nutritional problems due to the effects of the primary disability (including such syndromes as phenylketonuria, galactosemia, and Hurler's Disease), effects related to medications (including anticonvulsants, tranquilizers, and laxatives), effects of food preferences (restrictive food…

  7. 21 CFR 862.1315 - Galactose-1-phosphate uridyl transferase test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Galactose-1-phosphate uridyl transferase test system. 862.1315 Section 862.1315 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND... hereditary disease galactosemia (disorder of galactose metabolism) in infants. (b) Classification. Class II....

  8. 21 CFR 862.1315 - Galactose-1-phosphate uridyl transferase test system.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Galactose-1-phosphate uridyl transferase test system. 862.1315 Section 862.1315 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND... hereditary disease galactosemia (disorder of galactose metabolism) in infants. (b) Classification. Class II....

  9. 21 CFR 862.1310 - Galactose test system.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Galactose test system. 862.1310 Section 862.1310 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... hereditary disease galactosemia (a disorder of galactose metabolism) in infants. (b) Classification. Class I....

  10. Newborn Screening To Prevent Mental Retardation. The Arc Q & A.

    ERIC Educational Resources Information Center

    Arc, Arlington, TX.

    This information fact sheet on screening newborns to prevent mental retardation defines newborn screening and outlines how screening is performed. It discusses the six most common disorders resulting in mental retardation for which states most commonly screen. These include phenylketonuria, congenital hypothyroidism, galactosemia, maple syrup…

  11. Electrokinetic probes for single-step screening of polyol stereoisomers: the virtues of ternary boronate ester complex formation.

    PubMed

    Kaiser, Claire; Segui-Lines, Giselle; D'Amaral, Jason C; Ptolemy, Adam S; Britz-McKibbin, Philip

    2008-01-21

    Electrokinetic probes based on the differential migration of ternary boronate ester complexes permit the selective analysis of micromolar levels of UV-transparent polyol stereoisomers in urine samples via dynamic complexation-capillary electrophoresis that is applicable to single-step screening of in-born errors of sugar metabolism, such as galactosemia. PMID:18399200

  12. Galactose-1-phosphate uridyltransferase blood test

    MedlinePlus

    Galactosemia screen; GALT; Gal-1-PUT ... which is found in milk and dairy products. 1 out of 65,000 newborns lack a substance ( ... Veins and arteries vary in size from one infant to another and from ... other. Obtaining a blood sample from some infants may be more ...

  13. Neonatal Screening Tests.

    ERIC Educational Resources Information Center

    Vigue, Charles L.

    1986-01-01

    Describes several laboratory experiments that are adaptations of clinical tests for certain genetic diseases in babies. Information and procedures are provided for tests for phenylketonuria (PKU), galactosemia, tyrosinemia, cystinuria, and mucopolysaccharidosis. Discusses the effects of each disease on the infants' development. (TW)

  14. Clinical and molecular spectra in galactosemic patients from neonatal screening in northeastern Italy: structural and functional characterization of new variations in the galactose-1-phosphate uridyltransferase (GALT) gene.

    PubMed

    Viggiano, E; Marabotti, A; Burlina, A P; Cazzorla, C; D'Apice, M R; Giordano, L; Fasan, I; Novelli, G; Facchiano, A; Burlina, A B

    2015-04-01

    Classical galactosemia is an autosomal recessive inborn error of metabolism due to mutations of the GALT gene leading to toxic accumulation of galactose and derived metabolites. With the benefit of early diagnosis by neonatal screening and early therapy, the acute presentation of classical galactosemia can be prevented. However, despite early diagnosis and treatment, the long term outcome for these patients is still unpredictable because they may go on to develop cognitive disability, speech problems, neurological and/or movement disorders and, in females, ovarian dysfunction. The objectives of the current study were to report our experience with a group of galactosemic patients identified through the neonatal screening programs in northeastern Italy during the last 30years. No neonatal deaths due to galactosemia complications occurred after the introduction of the neonatal screening program. However, despite the early diagnosis and dietary treatment, the patients with classical galactosemia showed one or more long-term complications. A total of 18 different variations in the GALT gene were found in the patient cohort: 12 missense, 2 frameshift, 1 nonsense, 1 deletion, 1 silent variation, and 1 intronic. Six (p.R33P, p.G83V, p.P244S, p.L267R, p.L267V, p.E271D) were new variations. The most common variation was p.Q188R (12 alleles, 31.5%), followed by p.K285N (6 alleles, 15.7%) and p.N314D (6 alleles, 15.7%). The other variations comprised 1 or 2 alleles. In the patients carrying a new mutation, the biochemical analysis of GALT activity in erythrocytes showed an activity of <1%. In silico analysis (SIFT, PolyPhen-2 and the computational analysis on the static protein structure) showed potentially damaging effects of the six new variations on the GALT protein, thus expanding the genetic spectrum of GALT variations in Italy. The study emphasizes the difficulty in establishing a genotype-phenotype correlation in classical galactosemia and underlines the importance of

  15. Galactose oxidation using (13)C in healthy and galactosemic children.

    PubMed

    Resende-Campanholi, D R; Porta, G; Ferrioli, E; Pfrimer, K; Ciampo, L A Del; Junior, J S Camelo

    2015-03-01

    Galactosemia is an inborn error of galactose metabolism that occurs mainly as the outcome of galactose-1-phosphate uridyltransferase (GALT) deficiency. The ability to assess galactose oxidation following administration of a galactose-labeled isotope (1-(13)C-galactose) allows the determination of galactose metabolism in a practical manner. We aimed to assess the level of galactose oxidation in both healthy and galactosemic Brazilian children. Twenty-one healthy children and seven children with galactosemia ranging from 1 to 7 years of age were studied. A breath test was used to quantitate (13)CO2 enrichment in exhaled air before and at 30, 60, and 120 min after the oral administration of 7 mg/kg of an aqueous solution of 1-(13)C-galactose to all children. The molar ratios of (13)CO2 and (12)CO2 were quantified by the mass/charge ratio (m/z) of stable isotopes in each air sample by gas-isotope-ratio mass spectrometry. In sick children, the cumulative percentage of (13)C from labeled galactose (CUMPCD) in the exhaled air ranged from 0.03% at 30 min to 1.67% at 120 min. In contrast, healthy subjects showed a much broader range in CUMPCD, with values from 0.4% at 30 min to 5.58% at 120 min. The study found a significant difference in galactose oxidation between children with and without galactosemia, demonstrating that the breath test is useful in discriminating children with GALT deficiencies. PMID:25608239

  16. Origins, distribution and expression of the Duarte-2 (D2) allele of galactose-1-phosphate uridylyltransferase

    PubMed Central

    Carney, Amanda E.; Sanders, Rebecca D.; Garza, Kerry R.; McGaha, Lee Anne; Bean, Lora J. H.; Coffee, Bradford W.; Thomas, James W.; Cutler, David J.; Kurtkaya, Natalie L.; Fridovich-Keil, Judith L.

    2009-01-01

    Duarte galactosemia is a mild to asymptomatic condition that results from partial impairment of galactose-1-phosphate uridylyltransferase (GALT). Patients with Duarte galactosemia demonstrate reduced GALT activity and carry one profoundly impaired GALT allele (G) along with a second, partially impaired GALT allele (Duarte-2, D2). Molecular studies reveal at least five sequence changes on D2 alleles: a p.N314D missense substitution, three intronic base changes and a 4 bp deletion in the 5′ proximal sequence. The four non-coding sequence changes are unique to D2. The p.N314D substitution, however, is not; it is found together with a silent polymorphism, p.L218(TTA), on functionally normal Duarte-1 alleles (D1, also called Los Angeles or LA alleles). The HapMap database reveals that p.N314D is a common human variant, and cross-species comparisons implicate D314 as the ancestral allele. The p.N314D substitution is also functionally neutral in mammalian cell and yeast expression studies. In contrast, the 4 bp 5′ deletion characteristic of D2 alleles appears to be functionally impaired in reporter gene transfection studies. Here we present allele-specific qRT–PCR evidence that D2 alleles express less mRNA in vivo than their wild-type counterparts; the difference is small but statistically significant. Furthermore, we characterize the prevalence of the 4 bp deletion in GG, NN and DG populations; the deletion appears exclusive to D2 alleles. Combined, these data strongly implicate the 4 bp 5′ deletion as a causal mutation in Duarte galactosemia and suggest that direct tests for this deletion, as proposed here, could enhance or supplant current tests, which define D2 alleles on the basis of the presence and absence of linked coding sequence polymorphisms. PMID:19224951

  17. Overview of the current attempts toward the medical treatment of cataract

    SciTech Connect

    Kador, P.F.

    1983-04-01

    A variety of agents are currently available that claim to either prevent, delay, or reverse cataracts associated with aging (senile cataracts), radiation, or diabetes and galactosemia (sugar cataracts). Senile cataract therapy includes formulation containing inorganic salts, nutritional supplements, natural product extracts, sulfhydryl, and sulfonic acid containing compounds and miscellaneous redox and nonsteroidal anti-inflammatory compounds. Agents associated with the treatment of radiation cataracts include antioxidants and free radial scavengers. Aldose reductase inhibitors have been effective in the prevention of sugar cataracts. A summary of these agents and their potential ocular effects are presented.

  18. Rare case of homozygous epimerase deficiency and heterozygous of duarte 2 variant.

    PubMed

    Koliofoti, Eleana Georgia; Gkentzi, Despoina; Varvarigou, Anastasia; Trigka, Maria; Schulpis, Kleopatra

    2014-09-01

    We present a rare case of galactosemia identified by a positive screening test. A 20-day-old female infant was admitted with jaundice and bloody stained diarrhea. There was no history of fever, convulsions, abdominal distention, or bleeding from other sites. Laboratory findings indicated elevated total billirubin, alanine transaminase, aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyl transferase. International normalized ratio (INR), prothrombin time (PT) and activated partial thromboplastin time (aPTT) were prolonged. Total vitamin D was low. Quantitative assay for GALT in hemolysates of RBC: 17 μmol/min/mg protein (normal values: 20-35) (compound heterozygous for D2/N: 16-19). GALE level in RBC hemolysate: 11.5 μmol/h/g Hb (normal values 19-35). Our patient was homozygous for the peripheral form of epimerase deficiency galactosemia, as well as heterozygous for GALT/(D2) deficiency. She was started on galactose restricted diet and vitamin supplementation. At the age of 10 months, the patient appeared normal with no signs of developmental delay or eye-cataract. PMID:24859500

  19. The Rapid and Sensitive Quantitative Determination of Galactose by Combined Enzymatic and Colorimetric Method: Application in Neonatal Screening.

    PubMed

    Kianmehr, Anvarsadat; Mahrooz, Abdolkarim; Ansari, Javad; Oladnabi, Morteza; Shahbazmohammadi, Hamid

    2016-05-01

    The quantitative measurement of galactose in blood is essential for the early diagnosis, treatment, and dietary monitoring of galactosemia patients. In this communication, we aimed to develop a rapid, sensitive, and cost-effective combined method for galactose determination in dry blood spots. This procedure was based on the combination of enzymatic reactions of galactose dehydrogenase (GalDH), dihydrolipoyl dehydrogenase (DLD), and alkaline phosphates with a colorimetric system. The incubation time and the concentration of enzymes used in new method were also optimized. The analytical performance was studied by the precision, recovery, linearity, and sensitivity parameters. Statistical analysis was applied to method comparison experiment. The regression equation and correlation coefficient (R (2)) were Y = 0.0085x + 0.032 and R (2) = 0.998, respectively. This assay exhibited a recovery in the range of 91.7-114.3 % and had the limit detection of 0.5 mg/dl for galactose. The between-run coefficient of variation (CV) was between 2.6 and 11.1 %. The within-run CV was between 4.9 and 9.2 %. Our results indicated that the new and reference methods were in agreement because no significant biases exist between them. Briefly, a quick and reliable combined enzymatic and colorimetric assay was presented for application in newborn mass screening and monitoring of galactosemia patients. PMID:26821257

  20. Structure activity relationships of human galactokinase inhibitors.

    PubMed

    Liu, Li; Tang, Manshu; Walsh, Martin J; Brimacombe, Kyle R; Pragani, Rajan; Tanega, Cordelle; Rohde, Jason M; Baker, Heather L; Fernandez, Elizabeth; Blackman, Burchelle; Bougie, James M; Leister, William H; Auld, Douglas S; Shen, Min; Lai, Kent; Boxer, Matthew B

    2015-02-01

    Classic Galactosemia is a rare inborn error of metabolism that is caused by deficiency of galactose-1-phosphate uridyltransferase (GALT), an enzyme within the Leloir pathway that is responsible for the conversion of galactose-1-phosphate (gal-1-p) and UDP-glucose to glucose-1-phosphate and UDP-galactose. This deficiency results in elevated intracellular concentrations of its substrate, gal-1-p, and this increased concentration is believed to be the major pathogenic mechanism in Classic Galactosemia. Galactokinase (GALK) is an upstream enzyme of GALT in the Leloir pathway and is responsible for conversion of galactose and ATP to gal-1-p and ADP. Therefore, it was hypothesized that the identification of a small-molecule inhibitor of human GALK would act to prevent the accumulation of gal-1-p and offer a novel entry therapy for this disorder. Herein we describe a quantitative high-throughput screening campaign that identified a single chemotype that was optimized and validated as a GALK inhibitor. PMID:25553891

  1. Intracerebroventricular D-galactose administration impairs memory and alters activity and expression of acetylcholinesterase in the rat.

    PubMed

    Rodrigues, André Felipe; Biasibetti, Helena; Zanotto, Bruna Stela; Sanches, Eduardo Farias; Pierozan, Paula; Schmitz, Felipe; Parisi, Mariana Migliorini; Barbé-Tuana, Florencia; Netto, Carlos Alexandre; Wyse, Angela T S

    2016-05-01

    Tissue accumulation of galactose is a hallmark in classical galactosemia. Cognitive deficit is a symptom of this disease which is poorly understood. The aim of this study was to investigate the effects of intracerebroventricular administration of galactose on memory (inhibitory avoidance and novel object recognition tasks) of adult rats. We also investigated the effects of galactose on acetylcholinesterase (AChE) activity, immunocontent and gene expression in hippocampus and cerebral cortex. Wistar rats received a single injection of galactose (4mM) or saline (control). For behavioral parameters, galactose was injected 1h or 24h previously to the testing. For biochemical assessment, animals were decapitated 1h, 3h or 24h after galactose or saline injection; hippocampus and cerebral cortex were dissected. Results showed that galactose impairs the memory formation process in aversive memory (inhibitory avoidance task) and recognition memory (novel object recognition task) in rats. The activity of AChE was increased, whereas the gene expression of this enzyme was decreased in hippocampus, but not in cerebral cortex. These findings suggest that these changes in AChE may, at least in part, to lead to memory impairment caused by galactose. Taken together, our results can help understand the etiopathology of classical galactosemia. PMID:26948151

  2. Arginine Functionally Improves Clinically Relevant Human Galactose-1-Phosphate Uridylyltransferase (GALT) Variants Expressed in a Prokaryotic Model.

    PubMed

    Coelho, Ana I; Trabuco, Matilde; Silva, Maria João; de Almeida, Isabel Tavares; Leandro, Paula; Rivera, Isabel; Vicente, João B

    2015-01-01

    Classic galactosemia is a rare genetic disease of the galactose metabolism, resulting from deficient activity of galactose-1-phosphate uridylyltransferase (GALT). The current standard of care is lifelong dietary restriction of galactose, which however fails to prevent the development of long-term complications. Structural-functional studies demonstrated that the most prevalent GALT mutations give rise to proteins with increased propensity to aggregate in solution. Arginine is a known stabilizer of aggregation-prone proteins, having already shown a beneficial effect in other inherited metabolic disorders.Herein we developed a prokaryotic model of galactose sensitivity that allows evaluating in a cellular context the mutations' impact on GALT function, as well as the potential effect of arginine in functionally rescuing clinically relevant variants.This study revealed that some hGALT variants, previously described to exhibit no detectable activity in vitro, actually present residual activity when determined in vivo. Furthermore, it revealed that arginine presents a mutation-specific beneficial effect, particularly on the prevalent p.Q188R and p.K285N variants, which led us to hypothesize that it might constitute a promising therapeutic agent in classic galactosemia. PMID:25814382

  3. Experience of the Manitoba Perinatal Screening Program, 1965-85.

    PubMed Central

    Fox, J G

    1987-01-01

    The Manitoba Perinatal Screening Program is guided by a committee of medical specialists with skills in the diagnosis and management of disorders of metabolism in the newborn. The program is voluntary and is centralized at Cadham Provincial Laboratory, in Winnipeg. A filter card blood specimen is collected from newborns on discharge from hospital, and a filter card urine sample is collected and mailed to the laboratory by the mother when the infant is about 2 weeks of age. The overall compliance rates for the blood and urine specimens are approximately 100% and 84% respectively. The blood specimen is screened for phenylalanine and other amino acids, thyroxine, galactose, galactose-1-phosphate and biotinidase. The urine specimen is screened for amino acids, including cystine, as well as methylmalonic acid and homocystine. Between 1965 and 1985, 83 cases of metabolic disorders were detected, including 23 cases of primary hypothyroidism, 14 of classic phenylketonuria, 5 of galactosemia variants, 3 of galactosemia, 2 of maple syrup urine disease and 1 of hereditary tyrosinemia. The direct cost per infant screened is $5.50, and the cost:benefit ratio is approximately 7.5:1. Maternal serum alpha-fetoprotein screening is being made available as the necessary supporting clinical facilities become available. On the basis of this experience, the author outlines the components that are important for an effective screening program. PMID:3676929

  4. Quantification of Galactose-1-Phosphate Uridyltransferase Enzyme Activity by Liquid Chromatography–Tandem Mass Spectrometry

    PubMed Central

    Li, Yijun; Ptolemy, Adam S.; Harmonay, Lauren; Kellogg, Mark; Berry, Gerard T.

    2013-01-01

    Background The diagnosis of galactosemia usually involves the measurement of galactose-1-phosphate uridyltransferase (GALT) activity. Traditional radioactive and fluorescent GALT assays are nonspecific, laborious, and/or lack sufficient analytical sensitivity. We developed a liquid chromatography–tandem mass spectrometry (LC-MS/MS)–based assay for GALT enzyme activity measurement. Method Our assay used stable isotope-labeled α-galactose-1-phosphate ([13C6]-Gal-1-P) as an enzyme substrate. Sample cleanup and separation were achieved by reversed-phase ion-pair chromatography, and the enzymatic product, isotope-labeled uridine diphosphate galactose ([13C6]-UDPGal), was detected by MS/MS at mass transition (571 > 323) and quantified by use of [13C6]-Glu-1-P (265 > 79) as an internal standard. Results The method yielded a mean (SD) GALT enzyme activity of 23.8 (3.8) µmol · (gHgb)−1 · h−1 in erythrocyte extracts from 71 controls. The limit of quantification was 0.04 µmol · (g Hgb)−1 · h−1 (0.2% of normal control value). Intraassay imprecision was determined at 4 different levels (100%, 25%, 5%, and 0.2% of the normal control values), and the CVs were calculated to be 2.1%, 2.5%, 4.6%, and 9.7%, respectively (n = 3). Interassay imprecision CVs were 4.5%, 6.7%, 8.2%, and 13.2% (n = 5), respectively. The assay recoveries at the 4 levels were higher than 90%. The apparent Km of the 2 substrates, Gal-1-P and UDPGlc, were determined to be 0.38 mmol/L and 0.071 mmol/L, respectively. The assay in erythrocytes of 33 patients with classical galactosemia revealed no detectable activity. Conclusions This LC-MS/MS–based assay for GALT enzyme activity will be useful for the diagnosis and study of biochemically heterogeneous patients with galactosemia, especially those with uncommon genotypes and detectable but low residual activities. PMID:20348403

  5. Neonates with inborn errors of metabolism: spectrum and short-term outcomes at a tertiary care hospital.

    PubMed

    Gündüz, Mehmet; Ünal, Sevim; Okur, İlyas; Ayrancı Sucaklı, İclal; Güzel, Fatma; Koç, Nevra

    2015-01-01

    We aimed to evaluate the neonates diagnosed as IEM in our neonatal intensive care unit and their outcomes. Among 2994 neonates hospitalized, 51 were diagnosed as IEM (1.7%). Admission complaints were poor feeding, decreased activity, jaundice, seizures, abnormal screening and respiratory problems. Phenylketonuria (11), organic acidemias (8), maple syrup urine disease (5), citrullinemia (5), galactosemia (4), nonketotic hyperglycinemia (4) and tyrosinemia (2) were the most commonly diagnosed IEMs. The follow-up period was 2.5-43 months. Among the 33 neonates followed, 19 had normal development, 9 had developmental delays and 5 had cerebral palsy according to the Guide for Monitoring Child Development. Postnatal age on admission, Apgar score at 5 minutes, being transferred, peritoneal dialysis, cranial ultrasonographic findings, consanguinity and sibling history had significant effects on outcome. Early diagnosis through expanded neonatal screening in countries with high rates of consanguinity, enabling the initiation of early treatment, is essential for achieving low mortality rates and good prognoses. PMID:26613220

  6. Safety of soy-based infant formulas containing isoflavones: the clinical evidence.

    PubMed

    Merritt, Russell J; Jenks, Belinda H

    2004-05-01

    Soy protein has been used in infant feeding in the West for nearly 100 y. Soy protein infant formulas have evolved in this interval to become safe and effective alternatives for infants whose nutritional needs are not met with human milk or formulas based on cow's milk. Modern soy formulas meet all nutritional requirements and safety standards of the Infant Formula Act of 1980. They are commonly used in infants with immunoglobulin E-mediated cow's milk allergy (at least 86% effective), lactose intolerance, galactosemia, and as a vegetarian human milk substitute. Largely as a result of research in animal models, concerns have been voiced regarding isoflavones in soy infant formulas in relation to nutritional adequacy, sexual development, neurobehavioral development, immune function, and thyroid disease. We discuss the available clinical evidence regarding each of these issues. Available evidence from adult human and infant populations indicates that dietary isoflavones in soy infant formulas do not adversely affect human growth, development, or reproduction. PMID:15113975

  7. Cloning of a human galactokinase gene (GK2) on chromosome 15 by complementation in yeast.

    PubMed Central

    Lee, R T; Peterson, C L; Calman, A F; Herskowitz, I; O'Donnell, J J

    1992-01-01

    A human cDNA encoding a galactokinase (EC 2.7.1.6) was isolated by complementation of a galactokinase-deficient (gal1-) strain of Saccharomyces cerevisiae. This cDNA encodes a predicted protein of 458 amino acids with 29% identity to galactokinase of Saccharomyces carlsbergensis. Previous studies have mapped a human galactokinase gene (GK1) to chromosome 17q23-25, closely linked to thymidine kinase. The galactokinase gene that we have isolated (GK2) is located on chromosome 15. The relationship between the disease locus for galactokinase deficiency galactosemia, which is responsible for cataracts in newborns and possibly presenile cataracts in adults, and the two galactokinase loci is unknown. Images PMID:1438294

  8. [Hepatoblastoma, Etiology, Case Reports].

    PubMed

    Puchmajerová, A; Křepelová, A; Indráková, J; Sítková, R; Balaščak, I; Kruseová, J; Švojgr, K; Kodet, R; Kynčl, M; Vícha, A; Macek, M

    2016-01-01

    Hepatoblastoma is an uncommon malignant neoplasm in general, yet, it is the most common liver malignancy in children with the incidence about one per milion children. This type of liver tumor usually occurs before the age of three years. The etiology of hepatoblastoma remains unknown. However, there are some genetic conditions known to be associated with an increased risk of developing hepatoblastoma such as Beckwith-Wiedemann syndrome, hemihypertrophy, APC-associated polyposis, α-1-antitrypsin defficiency and some metabolic disorders including tyrosinemia, galactosemia and glycogen storage disease type 1. There is a higher risk of hepatoblastoma in children with very low birthweight, children who acquire hepatitis B at an early age and children with congenital biliary atresia. PMID:26691946

  9. Ultra Fast and Sensitive Liquid Chromatography Tandem Mass Spectrometry Based Assay for Galactose-1-Phosphate Uridylyltransferase and Galactokinase Deficiencies

    PubMed Central

    Li, Yijun; Ptolemy, Adam S.; Harmonay, Lauren; Kellogg, Mark; Berry, Gerard T.

    2013-01-01

    The diagnosis of transferase and galactokinase deficiency galactosemia usually involves the measurement of erythrocyte galactose-1-phosphate uridylyltransferase (GALT) and galactokinase (GALK) enzyme activity, respectively. The current gold standard assays for these enzymes are radioactive assays, which are laborious and/or incapable of measuring low enzyme activities. To further our knowledge of genotype-phenotype relationships, we had developed an assay for GALT activity alone using LC-MS/MS. In this study we generated a robust and sensitive LC-MS/MS based GALT and GALK assay using a novel normal phase chromatographic condition. We improved upon our earlier assay by drastically reducing the instrument run time and eliminating the use of an ion pairing reagent. Stable isotope labeled substrates were utilized in the GALT and GALK assays. The enzymatic products ([13C6]-uridine diphosphate galactose in GALT assay and [13C6]-galactose-1-phosphate in GALK assay) were quantified in a 3 min LC-MS/MS run. The assays were sensitive enough to allow for the quantification of enzyme activities as low as 0.2% and 0.3% of normal control values in the GALT and GALK assays, respectively. Thirty-three samples from non-galactosemic patients were assayed to have erythrocyte GALT activity of 23.4 ± 4.2 and GALK activity of 1.8 ± 0.47 (mean ± SD) µmol·(g Hgb) −1·hr−1. Erythrocyte GALT activities in a cohort of 16 patients with classic galactosemia were measured: 4 patients had GALT activity less than 1% of normal control values and the remaining 12 had no detectable GALT activity. No GALK activity was detected in a GALK deficient sample we analzyed. Lastly, we tested the feasibility of adapting this LC-MS/MS based GALT/GALK assay as a newborn screening (NBS) test. PMID:20863731

  10. Ultra fast and sensitive liquid chromatography tandem mass spectrometry based assay for galactose-1-phosphate uridylyltransferase and galactokinase deficiencies.

    PubMed

    Li, Yijun; Ptolemy, Adam S; Harmonay, Lauren; Kellogg, Mark; Berry, Gerard T

    2011-01-01

    The diagnosis of transferase and galactokinase deficiency galactosemia usually involves the measurement of erythrocyte galactose-1-phosphate uridylyltransferase (GALT) and galactokinase (GALK) enzyme activity, respectively. The current gold standard assays for these enzymes are radioactive assays, which are laborious and/or incapable of measuring low enzyme activities. To further our knowledge of genotype-phenotype relationships, we had developed an assay for GALT activity alone using LC-MS/MS. In this study we generated a robust and sensitive LC-MS/MS based GALT and GALK assay using a novel normal phase chromatographic condition. We improved upon our earlier assay by drastically reducing the instrument run time and eliminating the use of an ion pairing reagent. Stable isotope labeled substrates were utilized in the GALT and GALK assays. The enzymatic products ([(13)C(6)]-uridine diphosphate galactose in GALT assay and [(13)C(6)]-galactose-1-phosphate in GALK assay) were quantified in a 3 min LC-MS/MS run. The assays were sensitive enough to allow for the quantification of enzyme activities as low as 0.2% and 0.3% of normal control values in the GALT and GALK assays, respectively. Thirty-three samples from non-galactosemic patients were assayed to have erythrocyte GALT activity of 23.4±4.2 and GALK activity of 1.8±0.47 (mean±SD) μmol⋅(g Hgb)(-1) h(-1). Erythrocyte GALT activities in a cohort of 16 patients with classic or severe galactosemia were measured: 4 patients had GALT activity less than 1% of normal control values and the remaining 12 had no detectable GALT activity. No GALK activity was detected in a GALK deficient sample we analyzed. Lastly, we tested the feasibility of adapting this LC-MS/MS based GALT/GALK assay as a newborn screening (NBS) test. PMID:20863731

  11. Subfertility and growth restriction in a new galactose-1 phosphate uridylyltransferase (GALT) - deficient mouse model

    PubMed Central

    Tang, Manshu; Siddiqi, Anwer; Witt, Benjamin; Yuzyuk, Tatiana; Johnson, Britt; Fraser, Nisa; Chen, Wyman; Rascon, Rafael; Yin, Xue; Goli, Harish; Bodamer, Olaf A; Lai, Kent

    2014-01-01

    The first GalT gene knockout (KO) mouse model for Classic Galactosemia (OMIM 230400) accumulated some galactose and its metabolites upon galactose challenge, but was seemingly fertile and symptom free. Here we constructed a new GalT gene-trapped mouse model by injecting GalT gene-trapped mouse embryonic stem cells into blastocysts, which were later implanted into pseudo-pregnant females. High percentage GalT gene-trapped chimera obtained were used to generate heterozygous and subsequently, homozygous GalT gene-trapped mice. Biochemical assays confirmed total absence of galactose-1 phosphate uridylyltransferase (GALT) activity in the homozygotes. Although the homozygous GalT gene-trapped females could conceive and give birth when fed with normal chow, they had smaller litter size (P=0.02) and longer time-to-pregnancy (P=0.013) than their wild-type littermates. Follicle-stimulating hormone levels of the mutant female mice were not significantly different from the age-matched, wild-type females, but histological examination of the ovaries revealed fewer follicles in the homozygous mutants (P=0.007). Administration of a high-galactose (40% w/w) diet to lactating homozygous GalT gene-trapped females led to lethality in over 70% of the homozygous GalT gene-trapped pups before weaning. Cerebral edema, abnormal changes in the Purkinje and the outer granular cell layers of the cerebellum, as well as lower blood GSH/GSSG ratio were identified in the galactose-intoxicated pups. Finally, reduced growth was observed in GalT gene-trapped pups fed with normal chow and all pups fed with high-galactose (20% w/w) diet. This new mouse model presents several of the complications of Classic Galactosemia and will be useful to investigate pathogenesis and new therapies. PMID:24549051

  12. Subfertility and growth restriction in a new galactose-1 phosphate uridylyltransferase (GALT) - deficient mouse model.

    PubMed

    Tang, Manshu; Siddiqi, Anwer; Witt, Benjamin; Yuzyuk, Tatiana; Johnson, Britt; Fraser, Nisa; Chen, Wyman; Rascon, Rafael; Yin, Xue; Goli, Harish; Bodamer, Olaf A; Lai, Kent

    2014-10-01

    The first GalT gene knockout (KO) mouse model for Classic Galactosemia (OMIM 230400) accumulated some galactose and its metabolites upon galactose challenge, but was seemingly fertile and symptom free. Here we constructed a new GalT gene-trapped mouse model by injecting GalT gene-trapped mouse embryonic stem cells into blastocysts, which were later implanted into pseudo-pregnant females. High percentage GalT gene-trapped chimera obtained were used to generate heterozygous and subsequently, homozygous GalT gene-trapped mice. Biochemical assays confirmed total absence of galactose-1 phosphate uridylyltransferase (GALT) activity in the homozygotes. Although the homozygous GalT gene-trapped females could conceive and give birth when fed with normal chow, they had smaller litter size (P=0.02) and longer time-to-pregnancy (P=0.013) than their wild-type littermates. Follicle-stimulating hormone levels of the mutant female mice were not significantly different from the age-matched, wild-type females, but histological examination of the ovaries revealed fewer follicles in the homozygous mutants (P=0.007). Administration of a high-galactose (40% w/w) diet to lactating homozygous GalT gene-trapped females led to lethality in over 70% of the homozygous GalT gene-trapped pups before weaning. Cerebral edema, abnormal changes in the Purkinje and the outer granular cell layers of the cerebellum, as well as lower blood GSH/GSSG ratio were identified in the galactose-intoxicated pups. Finally, reduced growth was observed in GalT gene-trapped pups fed with normal chow and all pups fed with high-galactose (20% w/w) diet. This new mouse model presents several of the complications of Classic Galactosemia and will be useful to investigate pathogenesis and new therapies. PMID:24549051

  13. Breast is best for babies.

    PubMed Central

    Leung, Alexander K. C.; Sauve, Reginald S.

    2005-01-01

    Breastfeeding is the optimal method of infant feeding. Breast milk provides almost all the necessary nutrients, growth factors and immunological components a healthy term infant needs, Other advantages of breastfeeding include reduction of incidences and severity of infections; prevention of allergies; possible enhancement of cognitive development; and prevention of obesity, hypertension and insulin-dependent diabetes mellitus. Health gains for breastfeeding mothers include lactation amenorrhea, early involution of the uterus, enhanced bonding between the mother and the infant, and reduction in incidence of ovarian and breast cancer. From the economic perspective, breastfeeding is less expensive than formula feeding. In most cases, maternal ingestion of medications and maternal infections are not contraindications to breastfeeding. Breastfeeding, however, is contraindicated in infants with galactosemia. The management of common breastfeeding issues, such as breast engorgement, sore nipples, mastitis and insufficient milk, is discussed. Breastfeeding should be initiated as soon after delivery as possible. To promote, protect and support breastfeeding, the World Health Organization (WHO) and the United Nations Children's Fund (UNICEF) developed the Baby-Friendly Hospital Initiative (BFHI) 10 Steps to Successful Breastfeeding. Healthcare professionals have an important role to play in promoting and protecting breastfeeding. PMID:16080672

  14. Allelic variation, aneuploidy, and nongenetic mechanisms suppress a monogenic trait in yeast.

    PubMed

    Sirr, Amy; Cromie, Gareth A; Jeffery, Eric W; Gilbert, Teresa L; Ludlow, Catherine L; Scott, Adrian C; Dudley, Aimée M

    2015-01-01

    Clinically relevant features of monogenic diseases, including severity of symptoms and age of onset, can vary widely in response to environmental differences as well as to the presence of genetic modifiers affecting the trait's penetrance and expressivity. While a better understanding of modifier loci could lead to treatments for Mendelian diseases, the rarity of individuals harboring both a disease-causing allele and a modifying genotype hinders their study in human populations. We examined the genetic architecture of monogenic trait modifiers using a well-characterized yeast model of the human Mendelian disease classic galactosemia. Yeast strains with loss-of-function mutations in the yeast ortholog (GAL7) of the human disease gene (GALT) fail to grow in the presence of even small amounts of galactose due to accumulation of the same toxic intermediates that poison human cells. To isolate and individually genotype large numbers of the very rare (∼0.1%) galactose-tolerant recombinant progeny from a cross between two gal7Δ parents, we developed a new method, called "FACS-QTL." FACS-QTL improves upon the currently used approaches of bulk segregant analysis and extreme QTL mapping by requiring less genome engineering and strain manipulation as well as maintaining individual genotype information. Our results identified multiple distinct solutions by which the monogenic trait could be suppressed, including genetic and nongenetic mechanisms as well as frequent aneuploidy. Taken together, our results imply that the modifiers of monogenic traits are likely to be genetically complex and heterogeneous. PMID:25398792

  15. Amniocentesis and fetoscopy.

    PubMed

    Hopkins, E L; Carey, J; Moye, R

    1982-01-01

    Amniocentesis and fetoscopy are two of several modalities used to offer information during the prenatal period of the status of the fetus. Amniocentesis is most frequently used and with continuing research is becoming an invaluable aid to prenatal diagnosis. With the recent studies of DNA characteristics of globin chains of cells obtained at amniocentesis, the need to obtain blood directly from fetal vessels to diagnose major hemoglobinopathies prenatally is rapidly diminishing. Open neural tube defects are diagnosable with alpha feto protein analysis. All chromosomal defects are accurately quantitated and more than 100 inborn errors of metabolism are predictable. Fetoscopy is a technique which has a limited utility. It should be confined to major centers where adequate midtrimester abortions are done in order to provide training for those who aspire to pursue this method. With fetal blood sampling the following conditions are detected: beta thalassemia major, Hemophilia A, sickle cell anemia, chronic granulomatous disease, galactosemia and Tay Sachs disease, all of which may be diagnosed directly. Alpha and beta thalassemia, Hemophilia B and homozygous Von Willenbrand's disease may be excluded. With fetal biopsy one can diagnose congenital bullous ichthyosiform erythroderma ichthyosis. During the last ten years the amount of information brought to our attention has also brought the expectation that the next decade will be the most fruitful period in our history in this discipline. PMID:7146020

  16. Health-Related Quality of Life in Patients with MPS II.

    PubMed

    Needham, Mary; Packman, Wendy; Quinn, Natasha; Rappoport, Maxwell; Aoki, Christa; Bostrom, Alan; Cordova, Matthew; Macias, Sandra; Morgan, Cynthia; Packman, Seymour

    2015-08-01

    Mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome, is a chronic and progressive X-linked lysosomal disease that mainly affects males. The National MPS Society (2013) reports that MPS II affects 1 in 100,000 to 1 in 150,000 males worldwide. Two distinct forms of the disease are based on age of onset and clinical course: attenuated and severe. MPS II affects many organ systems including the nervous, cardiovascular, gastrointestinal and respiratory systems. Clinical manifestations can include progressive hearing loss, mental impairment, and enlarged liver and spleen. This study focuses on the health-related quality of life of individuals (HRQOL) with MPS II as measured by the parent and self-report versions of the Pediatric Quality of Life Inventory (PedsQL™). Both parents of patients with MPS II as well as patients themselves reported lower scores on all domains of the PedsQL™ (physical, emotional, social and school functioning) indicating that children with MPS II have an overall lower HRQOL when compared to a healthy sample. When compared with patients with other chronic illnesses (cancer, MSUD, galactosemia,), the MPS II sample had significantly lower scores on a number of PedsQL™ scales, suggesting an overall lower HRQOL. No significant relationships were found using scores from parent or self report PedsQL™ measures and length of time on ERT. PMID:25395377

  17. Diet in dermatology: revisited.

    PubMed

    Kaimal, Sowmya; Thappa, Devinder Mohan

    2010-01-01

    Diet has an important role to play in many skin disorders, and dermatologists are frequently faced with the difficulty of separating myth from fact when it comes to dietary advice for their patients. Patients in India are often anxious about what foods to consume, and what to avoid, in the hope that, no matter how impractical or difficult this may be, following this dictum will cure their disease. There are certain disorders where one or more components in food are central to the pathogenesis, e.g. dermatitis herpetiformis, wherein dietary restrictions constitute the cornerstone of treatment. A brief list, although not comprehensive, of other disorders where diet may have a role to play includes atopic dermatitis, acne vulgaris, psoriasis vulgaris, pemphigus, urticaria, pruritus, allergic contact dermatitis, fish odor syndrome, toxic oil syndrome, fixed drug eruption, genetic and metabolic disorders (phenylketonuria, tyrosinemia, homocystinuria, galactosemia, Refsum's disease, G6PD deficiency, xanthomas, gout and porphyria), nutritional deficiency disorders (kwashiorkar, marasmus, phrynoderma, pellagra, scurvy, acrodermatitis enteropathica, carotenemia and lycopenemia) and miscellaneous disorders such as vitiligo, aphthous ulcers, cutaneous vasculitis and telogen effluvium. From a practical point of view, it will be useful for the dermatologist to keep some dietary information handy to deal with the occasional patient who does not seem to respond in spite of the best, scientific and evidence-based therapy. PMID:20228538

  18. Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency in Korean Infants

    PubMed Central

    Ko, Jae Sung; Song, Jung Han; Park, Sung Sup

    2007-01-01

    Citrin is a liver-type mitochondrial aspartate-glutamate carrier encoded by the SLC25A13 gene, and its deficiency causes adult-onset type II citrullinemia and neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). Here, the authors investigated clinical findings in Korean infants with NICCD and performed mutation analysis on the SLC25A13 gene. Of 47 patients with neonatal cholestasis, three infants had multiple aminoacidemia (involving citrulline, methionine, and arginine) and galactosemia, and thus were diagnosed as having NICCD. Two of these three showed failure to thrive. The laboratory findings showed hypoproteinemia and hyperammonemia, and liver biopsies revealed micro-macrovesicular fatty liver and cholestasis. The three patients each harbored compound heterozygous 1,638-1,660 dup/ S225X mutation, compound heterozygous 851del4/S225X mutation, and heterozygous 1,638-1,660 dup mutation, respectively. With nutritional manipulation, liver functions were normalized and catch-up growth was achieved. NICCD should be considered in the differential diagnosis of cholestatic jaundice in Korean infants. PMID:18162705

  19. Functional correction by antisense therapy of a splicing mutation in the GALT gene.

    PubMed

    Coelho, Ana I; Lourenço, Sílvia; Trabuco, Matilde; Silva, Maria João; Oliveira, Anabela; Gaspar, Ana; Diogo, Luísa; Tavares de Almeida, Isabel; Vicente, João B; Rivera, Isabel

    2015-04-01

    In recent years, antisense therapy has emerged as an increasingly important therapeutic approach to tackle several genetic disorders, including inborn errors of metabolism. Intronic mutations activating cryptic splice sites are particularly amenable to antisense therapy, as the canonical splice sites remain intact, thus retaining the potential for restoring constitutive splicing. Mutational analysis of Portuguese galactosemic patients revealed the intronic variation c.820+13A>G as the second most prevalent mutation, strongly suggesting its pathogenicity. The aim of this study was to functionally characterize this intronic variation, to elucidate its pathogenic molecular mechanism(s) and, ultimately, to correct it by antisense therapy. Minigene splicing assays in two distinct cell lines and patients' transcript analyses showed that the mutation activates a cryptic donor splice site, inducing an aberrant splicing of the GALT pre-mRNA, which in turn leads to a frameshift with inclusion of a premature stop codon (p.D274Gfs*17). Functional-structural studies of the recombinant wild-type and truncated GALT showed that the latter is devoid of enzymatic activity and prone to aggregation. Finally, two locked nucleic acid oligonucleotides, designed to specifically recognize the mutation, successfully restored the constitutive splicing, thus establishing a proof of concept for the application of antisense therapy as an alternative strategy for the clearly insufficient dietary treatment in classic galactosemia. PMID:25052314

  20. Newborn Screening: What Does the Emergency Physician Need to Know?

    PubMed

    Lavin, Lindsay Roofe; Higby, Nicholas; Abramo, Thomas

    2015-09-01

    Newborn screening programs were established in the United States in the early 1960s. Newborn screening programs were then developed by states and have continued to be the responsibility of the state. All states require a newborn screening, but what is required of these programs and screening panels has differed greatly by state. Historically, the most commonly screened disorders are the following: congenital hypothyroidism, congenital adrenal hyperplasia, sickle cell disease and associated hemoglobinopathies, biotinidase deficiency, galactosemia, cystic fibrosis and phenylketonuria, maple syrup urine disease, and homocystinuria. However, under new guidelines in 2006 and with new advances in technology, the scope of newborn screening programs has expanded to include at a minimum 9 organic acidurias, 5 fatty acid oxidation disorders, 3 hemoglobinopathies, and 6 other conditions. This CME article reviews the logistics of newborn screening and explores the effect of new technology and recent policy on state screens and what that means for providers. This article also highlights several of the disorders most relevant to emergency room physicians and discusses future considerations of newborn screening. PMID:26335232

  1. UDP-hexose 4-epimerases: a view on structure, mechanism and substrate specificity.

    PubMed

    Beerens, Koen; Soetaert, Wim; Desmet, Tom

    2015-09-23

    UDP-sugar 4-epimerase (GalE) belongs to the short-chain dehydrogenase/reductase (SDR) superfamily of proteins and is one of enzymes in the Leloir pathway. They have been shown to be important virulence factors in a number of Gram-negative pathogens and to be involved in the biosynthesis of different polysaccharide structures. The metabolic disease type III galactosemia is caused by detrimental mutations in the human GalE. GalE and related enzymes display unusual enzymologic, chemical, and stereochemical properties; including irreversible binding of the cofactor NAD and uridine nucleotide-induced activation of this cofactor. These epimerases have been found active on UDP-hexoses, the N-acetylated and uronic acid forms thereof as well as UDP-pentoses. As they are involved in different pathways and functions, a deeper understanding of the enzymes, and their substrate promiscuity and/or selectivity, could lead to drug and vaccine design as well as antibiotic and probiotic development. This review summarizes the research performed on UDP-sugar 4-epimerases' structure, mechanism and substrate promiscuity. PMID:26162744

  2. GALT protein database: querying structural and functional features of GALT enzyme.

    PubMed

    d'Acierno, Antonio; Facchiano, Angelo; Marabotti, Anna

    2014-09-01

    Knowledge of the impact of variations on protein structure can enhance the comprehension of the mechanisms of genetic diseases related to that protein. Here, we present a new version of GALT Protein Database, a Web-accessible data repository for the storage and interrogation of structural effects of variations of the enzyme galactose-1-phosphate uridylyltransferase (GALT), the impairment of which leads to classic Galactosemia, a rare genetic disease. This new version of this database now contains the models of 201 missense variants of GALT enzyme, including heterozygous variants, and it allows users not only to retrieve information about the missense variations affecting this protein, but also to investigate their impact on substrate binding, intersubunit interactions, stability, and other structural features. In addition, it allows the interactive visualization of the models of variants collected into the database. We have developed additional tools to improve the use of the database by nonspecialized users. This Web-accessible database (http://bioinformatica.isa.cnr.it/GALT/GALT2.0) represents a model of tools potentially suitable for application to other proteins that are involved in human pathologies and that are subjected to genetic variations. PMID:24990533

  3. Cholestane-3β,5α,6β-triol: high levels in Niemann-Pick type C, cerebrotendinous xanthomatosis, and lysosomal acid lipase deficiency.

    PubMed

    Pajares, Sonia; Arias, Angela; García-Villoria, Judit; Macías-Vidal, Judit; Ros, Emilio; de las Heras, Javier; Girós, Marisa; Coll, Maria J; Ribes, Antonia

    2015-10-01

    Niemann-Pick type C (NPC) is a progressive neurodegenerative disease characterized by lysosomal/endosomal accumulation of unesterified cholesterol and glycolipids. Recent studies have shown that plasma cholestane-3β,5α,6β-triol (CT) and 7-ketocholesterol (7-KC) could be potential biomarkers for the diagnosis of NPC patients. We aimed to know the sensitivity and specificity of these biomarkers for the diagnosis of NPC compared with other diseases that can potentially lead to oxysterol alterations. We studied 107 controls and 122 patients including 16 with NPC, 3 with lysosomal acid lipase (LAL) deficiency, 8 with other lysosomal diseases, 5 with galactosemia, 11 with cerebrotendinous xanthomatosis (CTX), 3 with Smith-Lemli-Opitz, 14 with peroxisomal biogenesis disorders, 19 with unspecific hepatic diseases, 13 with familial hypercholesterolemia, and 30 with neurological involvement and no evidence of an inherited metabolic disease. CT and 7-KC were analyzed by HPLC-ESI-MS/MS as mono-dimethylglycine derivatives. Levels of 7-KC were high in most of the studied diseases, whereas those of CT were only high in NPC, LAL, and CTX patients. Consequently, although CT is a sensitive biomarker of NPC disease, including those cases with doubtful filipin staining, it is not specific. 7-KC is a very unspecific biomarker. PMID:26239048

  4. Molecular Diagnosis of Hereditary Fructose Intolerance: Founder Mutation in a Community from India.

    PubMed

    Bijarnia-Mahay, Sunita; Movva, Sireesha; Gupta, Neerja; Sharma, Deepak; Puri, Ratna D; Kotecha, Udhaya; Saxena, Renu; Kabra, Madhulika; Mohan, Neelam; Verma, Ishwar C

    2015-01-01

    Hereditary fructose intolerance (HFI) is a difficult-to-confirm diagnosis, requiring either invasive liver biopsy-enzyme assay or potentially hazardous fructose challenge test or expensive molecular genetic analysis. Therefore, worldwide there has been a trend towards finding "common mutations" in distinct ethnic groups to simplify the process of diagnosis. The nonspecific presentation of the disease often leads to diagnostic confusion with other metabolic liver disorders such as glycogenoses, galactosemia, and tyrosinemia. This leads to much delay in diagnosis with consequent harm to the patient.We report mutations in the ALDOB gene, from eleven Indian patients, seven of whom belong to the Agarwal community. Six patients from the Agarwal community and two non-Agarwal patients harbored one novel mutation, c.324+1G>A (five homozygous and one heterozygous), in the ALDOB gene. Haplotyping performed in families confirmed a founder effect. The community has been known to harbor founder mutations in other genes such as the MLC1, PANK2, and CAPN3 genes, thus providing another evidence for a founder effect in the community in case of HFI. This may pave the path for a simpler and quicker test at least for this community in India. In addition to the founder mutation, we report four other novel mutations, c.112+1delG, c.380-1G>A, c.677G>A, and c.689delA, and a previously reported mutation, c.1013C>T, in the cohort from India. PMID:25595217

  5. Differential Proteomics of Urinary Exovesicles from Classical Galactosemic Patients Reveals Subclinical Kidney Insufficiency.

    PubMed

    Staubach, Simon; Pekmez, Murat; Hanisch, Franz-Georg

    2016-06-01

    Classical galactosemia is caused by a nearly complete deficiency of galactose-1-phosphate uridyltransferase (GALT; EC 2.7.712), resulting in a severely impaired galactose metabolism with galactose-1-phosphate and galactitol accumulation. Even on a galactose-restricted diet, patients develop serious long-term complications of the central nervous system and ovaries that may result from chronic cell-toxic effects exerted by endogenous galactose. To address the question of whether disease-associated cellular perturbations could affect the kidney function of the patients, we performed differential proteomics of detergent-resistant membranes from urinary exovesicles. Galactosemic samples (showing drastic shifts from high-mannose to complex-type N-glycosylation on exosomal N-glycoproteins) and healthy, sex-matched controls were analyzed in quadruplex iTRAQ experiments performed in biological and technical replicates. Particularly in the female patient group, the most striking finding was a drastic increase of abundant serum (glyco)proteins, like albumin, leucine-rich α-2-glycoprotein, fetuin, immunoglobulins, prostaglandin H2 d-isomerase, and α-1-microglobulin protein (AMBP), pointing to a subclinical failure of kidney filter function in galactosemic patients and resulting in a heavy overload of exosomal membranes with adsorbed serum (glyco)proteins. Several of these proteins are connected to TBMN and IgAN, proteinuria, and renal damage. The impairment of renal protein filtration was also indicated by increased protein contents derived from extracellular matrices and lysosomes. PMID:27103203

  6. [How much nutrition matters for children].

    PubMed

    Catassi, Carlo; Gatti, Simona

    2015-02-01

    Overweight/obesity is a growing epidemic in the Western world and a leading cause of morbidity and mortality, mainly from cardiovascular disease. Doctors are going to play a major role as they are being called on to adapt their practices to confront it. In particular, nutrition seems to be at the core of obesity in children. The ascending trend of this phenomenon in pediatric age, with inherent healthcare implications, was already reported in epidemiological studies of the mid '90s. Public health programs of primary prevention should be stimulated and recommended, with the aim of promoting diet and lifestyle changes in the general population. In addition, accurate anthropometric measurements should be performed for use by pediatricians, who should focus efforts on preventing obesity during infancy and childhood. Nutrition plays such a pivotal role that it may be considered a valuable treatment strategy for multiple pediatric conditions, including celiac disease, Crohn's disease, short bowel syndrome, galactosemia, congenital deficiency of urea cycle enzymes. In view of all this, it would be advisable that food science be given higher relevance in medical education. PMID:25734596

  7. Etiopathogenesis of cataract: An appraisal

    PubMed Central

    Gupta, Varun B; Rajagopala, Manjusha; Ravishankar, Basavaiah

    2014-01-01

    Natural eye lens is a crystalline substance to produce a clear passage for light. Cataract is opacity within the clear lens of the eye and is the dominant cause of socio-medical problem i.e., blindness worldwide. The only available treatment of cataract is surgery. However, insufficient surgical facilities in poor and developing countries and post-operative complications inspire researchers to find out other modes of treatment for cataract. In this review, an attempt has been made to appraise various etiological factors of cataract to make their perception clear to build up counterpart treatment. Present study is an assortment of various available literatures and electronic information in view of cataract etiopathogenesis. Various risk factors have been identified in development of cataracts. They can be classified in to genetic factors, ageing (systemic diseases, nutritional and trace metals deficiencies, smoking, oxidative stress etc.), traumatic, complicated (inflammatory and degenerative diseases of eye), metabolic (diabetes, galactosemia etc.), toxic substances including drugs abuses, alcohol etc., radiation (ultraviolet, electromagnetic waves etc.) are implicated as significant risk factors in the development of cataract. PMID:24618482

  8. Allelic Variation, Aneuploidy, and Nongenetic Mechanisms Suppress a Monogenic Trait in Yeast

    PubMed Central

    Sirr, Amy; Cromie, Gareth A.; Jeffery, Eric W.; Gilbert, Teresa L.; Ludlow, Catherine L.; Scott, Adrian C.; Dudley, Aimée M.

    2015-01-01

    Clinically relevant features of monogenic diseases, including severity of symptoms and age of onset, can vary widely in response to environmental differences as well as to the presence of genetic modifiers affecting the trait’s penetrance and expressivity. While a better understanding of modifier loci could lead to treatments for Mendelian diseases, the rarity of individuals harboring both a disease-causing allele and a modifying genotype hinders their study in human populations. We examined the genetic architecture of monogenic trait modifiers using a well-characterized yeast model of the human Mendelian disease classic galactosemia. Yeast strains with loss-of-function mutations in the yeast ortholog (GAL7) of the human disease gene (GALT) fail to grow in the presence of even small amounts of galactose due to accumulation of the same toxic intermediates that poison human cells. To isolate and individually genotype large numbers of the very rare (∼0.1%) galactose-tolerant recombinant progeny from a cross between two gal7Δ parents, we developed a new method, called “FACS-QTL.” FACS-QTL improves upon the currently used approaches of bulk segregant analysis and extreme QTL mapping by requiring less genome engineering and strain manipulation as well as maintaining individual genotype information. Our results identified multiple distinct solutions by which the monogenic trait could be suppressed, including genetic and nongenetic mechanisms as well as frequent aneuploidy. Taken together, our results imply that the modifiers of monogenic traits are likely to be genetically complex and heterogeneous. PMID:25398792

  9. [Breastfeeding: health benefits for child and mother].

    PubMed

    Turck, D; Vidailhet, M; Bocquet, A; Bresson, J-L; Briend, A; Chouraqui, J-P; Darmaun, D; Dupont, C; Frelut, M-L; Girardet, J-P; Goulet, O; Hankard, R; Rieu, D; Simeoni, U

    2013-11-01

    The prevalence of breastfeeding in France is one of the lowest in Europe: 65% of infants born in France in 2010 were breastfed when leaving the maternity ward. Exclusive breastfeeding allows normal growth until at least 6 months of age, and can be prolonged until the age of 2 years or more, provided that complementary feeding is started after 6 months. Breast milk contains hormones, growth factors, cytokines, immunocompetent cells, etc., and has many biological properties. The composition of breast milk is influenced by gestational and postnatal age, as well as by the moment of the feed. Breastfeeding is associated with slightly enhanced performance on tests of cognitive development. Exclusive breastfeeding for at least 3 months is associated with a lower incidence and severity of diarrhoea, otitis media and respiratory infection. Exclusive breastfeeding for at least 4 months is associated with a lower incidence of allergic disease (asthma, atopic dermatitis) during the first 2 to 3 years of life in at-risk infants (infants with at least one first-degree relative presenting with allergy). Breastfeeding is also associated with a lower incidence of obesity during childhood and adolescence, as well as with a lower blood pressure and cholesterolemia in adulthood. However, no beneficial effect of breastfeeding on cardiovascular morbidity and mortality has been shown. Maternal infection with hepatitis B and C virus is not a contraindication to breastfeeding, as opposed to HIV infection and galactosemia. A supplementation with vitamin D and K is necessary in the breastfed infant. Very few medications contraindicate breastfeeding. Premature babies can be breastfed and/or receive mother's milk and/or bank milk, provided they receive energy, protein and mineral supplements. Return to prepregnancy weight is earlier in breastfeeding mothers during the 6 months following delivery. Breastfeeding is also associated with a decreased risk of breast and ovarian cancer in the

  10. Newborn screening conditions: What we know, what we do not know, and how we will know it.

    PubMed

    Levy, Harvey L

    2010-12-01

    Expanding newborn screening beyond that for phenylketonuria was always the goal of Guthrie once phenylketonuria screening was on solid ground. He succeeded in this effort to an extent, adding screening for galactosemia, maple syrup urine disease, and homocystinuria. Screening for congenital hypothyroidism, congenital adrenal hyperplasia, biotinidase deficiency, and a few additional disorders was added by others over the years. However, a very large expansion of covered metabolic disorders eluded Guthrie despite his best efforts. This required a new screening technology, tandem mass spectrometry, which was not available until recently. Now, almost all developed newborn screening program use tandem mass spectrometry to cover the 29 metabolic disorders recommended for coverage by the American College of Medical Genetics and additional secondary disorders. The results have in some cases been spectacular in preventing or greatly reducing the burden of disease imposed by many of the screened disorders. However, expanded newborn screening has also brought problems that need to be addressed. These include lack of knowledge about the natural history of some of the disorders, absence of effective preventive therapy for others, identification of seemingly benign disorders or benign variants of severe disorders, and the resulting parental anxiety. To address these and other issues brought by expanded newborn screening, a national effort led by the American College of Medical Genetics has been developed. This effort known as the Newborn Screening Translational Research Network seeks to stimulate research, advocate pilot screening programs for proposed new additions to screening, and develop a protocol-based systematic long-term follow-up of infants identified in expanded screening programs. Upon the outcome, this critical effort will depend on the health and well-being of children throughout the United States. PMID:21150366

  11. Hint, Fhit and GalT: Function, Structure, Evolution and Mechanism of Three Branches of the Histidine Triad Superfamily of Nucleotide Hydrolases and Transferases

    PubMed Central

    Brenner, Charles

    2008-01-01

    HIT (histidine triad)1 proteins, named for a motif related to the sequence HφHφHφφ, (φ a hydrophobic amino acid) are a superfamily of nucleotide hydrolases and transferases, which act on the α-phosphate of ribonucleotides, and contain a ∼30 kDa domain that is typically either a homodimer of ∼15 kDa polypeptides with two active-sites or an internally, imperfectly repeated polypeptide that retains a single HIT active site. On the basis of sequence, substrate specificity, structure, evolution and mechanism, HIT proteins can be classified into the Hint branch, which consists of adenosine 5′-monophosphoramide hydrolases, the Fhit branch, which consists of diadenosine polyphosphate hydrolases, and the GalT branch, which consists of specific nucleoside monophosphate transferases including galactose-1-phosphate uridylyltransferase, diadenosine tetraphosphate phosphorylase, and adenylylsulfate:phosphate adenylytransferase. At least one human representative of each branch is lost in human diseases. Aprataxin, a Hint branch hydrolase, is mutated in ataxia-oculomotor apraxia syndrome. Fhit is lost early in development of many epithelially derived tumors. GalT is deficient in galactosemia. Additionally, ASW is an avian Hint family member that has evolved to have unusual gene expression properties and the complete loss of its nucleotide binding-site. The potential roles of ASW and Hint in avian sexual development are discussed in an accompanying manuscript. Here we review what is known about biological activities of HIT proteins, the structural and biochemical bases for their functions, and propose a new enzyme mechanism for Hint and Fhit that may account for the differences between HIT hydrolases and transferases. PMID:12119013

  12. Assessing Psychological Functioning in Metabolic Disorders: Validation of the Adaptive Behavior Assessment System, Second Edition (ABAS-II), and the Behavior Rating Inventory of Executive Function (BRIEF) for Identification of Individuals at Risk.

    PubMed

    Waisbren, Susan E; He, Jianping; McCarter, Robert

    2015-01-01

    Long-term follow-up of neuropsychological functioning in metabolic disorders remains difficult due to limited opportunities for comprehensive neuropsychological evaluations. This study examined the validity of using the Adaptive Behavior Assessment System, Second Edition (ABAS-II), and the Behavior Rating Inventory of Executive Function (BRIEF) for assessing developmental status in metabolic disorders and for identifying individuals at risk for cognitive deficits. Results from individuals with urea cycle disorders, phenylketonuria, galactosemia, and fatty acid oxidation disorders were obtained on the ABAS-II and BRIEF and were compared to results obtained from neuropsychological testing performed on the same day. Correlations between scores on the ABAS-II and developmental or IQ tests for individuals with urea cycle disorders ranged from 0.48 to 0.72 and concordance rates for scores greater than a standard deviation below the normative mean ranged from 69 to 89%. Correlations ranged from 0.20 to 0.68 with concordance ranging from 73 to 90% in the other metabolic disorders. For the BRIEF, correlations with other tests of executive functioning were significant for urea cycle disorders, with concordance ranging from 52 to 80%. For the other metabolic disorders, correlations ranged from -0.09 to -0.55. Concordance rates for at-risk status on the BRIEF and executive functioning tests ranged from 55% in adults to 80% in children with other metabolic disorders. These results indicate that the ABAS-II and BRIEF together can confidently be used as an adjunct or supplementary method for clinical follow-up and for research on functional status involving infants, children, and adults with metabolic disorders. PMID:25712381

  13. A retrospective drug use evaluation of cabergoline for lactation inhibition at a tertiary care teaching hospital in Qatar

    PubMed Central

    AlSaad, Doua; ElSalem, Samah; Abdulrouf, Palli Valapila; Thomas, Binny; Alsaad, Tayseer; Ahmed, Afif; AlHail, Moza

    2016-01-01

    Background Breastfeeding is considered as gold standard for infant nutrition and should be interrupted only when a compelling indication exists. Certain medical conditions such as abortion, stillbirth, HIV infection, or infant galactosemia and certain medications such as chemotherapy necessitate lactation inhibition to protect the health of mother and infant. Drug use evaluation (DUE) studies are done to explore the current practice in a setting and help to identify areas in which further information and education may be needed by clinicians. Objective The aim of this study was to conduct a DUE of cabergoline to assess indications for lactation inhibition, dosage regimen, and its safety. Method A retrospective cross-sectional DUE study was conducted over a period of 4 months from September 1, 2013, till December 31, 2013, at the Women’s Hospital, Qatar. All cabergoline prescriptions written for lactation inhibition within 10 days of delivery or abortion were included in the study. A descriptive data analysis was undertaken. Results Of the 85 patients included, stillbirth (50.6%) was considered as the main reason for lactation inhibition, followed by abortion (27.1%) and neonatal death (12.9%). The remaining 9.4% of the patients had live baby, and the majority of them were prescribed cabergoline for lactation inhibition because their maternal medical conditions required the use of drugs with insufficient safety data (n=6). Seventy-four percent of patients received cabergoline at accurate time and dose. However, 14% of the patients had preexisting hypertensive disorder and 58.3% of them were diagnosed as uncontrolled hypertension. Conclusion The current DUE study found that cabergoline was mainly used to inhibit lactation for patients with stillbirth, abortion, and neonatal death. In mothers who use medications for other medical conditions, benefits and risks of breastfeeding should be carefully balanced before prescribing cabergoline. Current prescribing pattern

  14. Expression and response surface optimization of the recovery and purification of recombinant D-galactose dehydrogenase from Pseudomonas fluorescens.

    PubMed

    Azar, Shadi Rokhsartalab; Naiebi, Raika; Homami, Ameneh; Akbari, Zahra; Kianmehr, Anvarsadat; Mahdizadehdehosta, Rahman; Najafzadeh, Faezeh

    2015-02-01

    The enzyme D-galactose dehydrogenase (GalDH) has been used in diagnostic kits to screen blood serum of neonates for galactosemia. It is also a significant tool for the measurement of β-D-galactose, α-D-galactose and lactose as well. In this study, response surface methodology (RSM) was used to identify the suitable conditions for recovery of recombinant GalDH from Pseudomonas fluorescens in aqueous two-phase systems (ATPS). The identified GalDH gene was amplified by PCR and confirmed by further cloning and sequencing. E. coli BL-21 (DE3) containing the GalDH gene on a plasmid (pET28aGDH) was used to express and purify the recombinant enzyme. The polyethylene glycol (PEG) and ammonium sulfate concentrations and pH value were selected as variables to analyze purification of GalDH. To build mathematical models, RSM with a central composite design was applied based on the conditions for the highest separation. The recombinant GalDH enzyme was expressed after induction with IPTG. It showed NAD'-dependent dehydrogenase activity towards D-Galactose. According to the RSM modeling, an optimal ATPS was composed of PEG-2000 14.0% (w/w) and ammonium sulfate 12.0% (w/w) at pH 7.5. Under these conditions, GalDH preferentially concentrated in the top PEG-rich phase. The enzyme activity, purification factor (PF) and recovery (R) were 1400 U/ml, 60.0% and 270.0%, respectively. The PEG and salt concentrations were found to have significant effect on the recovery of enzyme. Briefly, our data showed that RSM could be an appropriate tool to define the best ATPS for recombinant P. fluorescens GalDH recovery. PMID:26040113

  15. Preparation of low galactose yogurt using cultures of Gal(+) Streptococcus thermophilus in combination with Lactobacillus delbrueckii ssp. bulgaricus.

    PubMed

    Anbukkarasi, Kaliyaperumal; UmaMaheswari, Thiyagamoorthy; Hemalatha, Thiagarajan; Nanda, Dhiraj Kumar; Singh, Prashant; Singh, Rameshwar

    2014-09-01

    Streptococcus thermophilus is an important lactic starter used in the production of yogurt. Most strains of S. thermophilus are galactose negative (Gal(-)) and are able to metabolize only glucose portion of lactose and expel galactose into the medium. This metabolic defect leads to the accumulation of free galactose in yogurt, resulting in galactosemia among consumers. Hence there is an absolute need to develop low galactose yogurt. Therefore, in this study, three galactose positive (Gal(+)) S. thermophilus strains from National Collection of Dairy Cultures (NCDC) viz. NCDC 659 (AJM), NCDC 660 (JM1), NCDC 661 (KM3) and a reference galactose negative (Gal(-)) S. thermophilus NCDC 218 were used for preparation of low galactose yogurt. In milk fermented using S. thermophilus isolates alone, NCDC 659 released less galactose (0.27 %) followed by NCDC 661 (0.3 %) and NCDC 660 (0.45 %) after 10 h at 42 °C. Milk was fermented in combination with Gal(-) L. delbrueckii subsp. bulgaricus NCDC 04, in which NCDC 659 released least galactose upto 0.49 % followed by NCDC 661 (0.51 %) and NCDC 660 (0.60 %) than reference Gal(-) NCDC 218(0.79 %). Low galactose yogurt was prepared following standard procedure using Gal(+) S. thermophilus isolates and Gal(-) L. delbrueckii subsp. bulgaricus NCDC 04 in 1:1 ratio. Among which low galactose yogurt by NCDC 659 combination contained less galactose 0.37 % followed by NCDC 661 (0.51 %), NCDC 660 (0.65 %) and reference Gal(-) NCDC 218 (0.98 %) after 4 h of fermentation. This study clearly reveals that Gal(+) S. thermophilus isolates can be paired with Gal(-) L. delbrueckii subsp. bulgaricus for developing low galactose yogurt. PMID:25190881

  16. Extensions to the Speech Disorders Classification System (SDCS)

    PubMed Central

    Shriberg, Lawrence D.; Fourakis, Marios; Hall, Sheryl D.; Karlsson, Heather B.; Lohmeier, Heather L.; McSweeny, Jane L.; Potter, Nancy L.; Scheer-Cohen, Alison R.; Strand, Edythe A.; Tilkens, Christie M.; Wilson, David L.

    2010-01-01

    This report describes three extensions to a classification system for pediatric speech sound disorders termed the Speech Disorders Classification System (SDCS). Part I describes a classification extension to the SDCS to differentiate motor speech disorders from speech delay and to differentiate among three subtypes of motor speech disorders. Part II describes the Madison Speech Assessment Protocol (MSAP), an approximately two-hour battery of 25 measures that includes 15 speech tests and tasks. Part III describes the Competence, Precision, and Stability Analytics (CPSA) framework, a current set of approximately 90 perceptual- and acoustic-based indices of speech, prosody, and voice used to quantify and classify subtypes of Speech Sound Disorders (SSD). A companion paper, Shriberg, Fourakis, et al. (2010) provides reliability estimates for the perceptual and acoustic data reduction methods used in the SDCS. The agreement estimates in the companion paper support the reliability of SDCS methods and illustrate the complementary roles of perceptual and acoustic methods in diagnostic analyses of SSD of unknown origin. Examples of research using the extensions to the SDCS described in the present report include diagnostic findings for a sample of youth with motor speech disorders associated with galactosemia (Shriberg, Potter, & Strand, 2010) and a test of the hypothesis of apraxia of speech in a group of children with autism spectrum disorders (Shriberg, Paul, Black, & van Santen, 2010). All SDCS methods and reference databases running in the PEPPER (Programs to Examine Phonetic and Phonologic Evaluation Records; [Shriberg, Allen, McSweeny, & Wilson, 2001]) environment will be disseminated without cost when complete. PMID:20831378

  17. Present status of amniocentesis in intrauterine diagnosis of genetic defects.

    PubMed

    Nadler, H L; Gerbie, A

    1971-11-01

    Practical and scientific aspects of prenatal detection of genetic disorders is discussed. The indications for intrauterine detection of familial biochemical and particular chromosomal disorders require assessment of the risks of transabdominal amniocentesis and of the reliability of diagnosis. A high degree of experience in cultivating amniotic fluid cells and in performing diagnostic tests is required. The obstetrician performing the amniocentesis should be responsible for referring the family to a physician who will perform the abortion. A high-risk group for which amniocentesis may be especially important includes families in which 1 parent is a carrier of a chromosomal rearrangement and in which the woman is a known carrier of an X-linked recessive disorder so that sex determination is important. A moderate-risk group includes women who become pregnant after age 40 in which the risk of having a child with a chromosomal aberration is greater than 1%. A low-risk group includes women over 35 and women who have previously borne a child with trisomic Down's syndrome. The experience gained in over 300 patients suggests that transabdominal aminocentesis carries minimal risks to mother and fetus. Analyses of amniotic fluid obtained by amniocentesis have resulted in antenatal diagnoses of Pompe's disease (deficient alpha-1, 4-glucosidase), Tay-Sachs disease (deficient hexosaminidase A), mucopolysaccharidosis (quantitative and qualitative changes in mucopolysaccharides), methylmalonic aciduria (increased methylamlonate), and adrenogenital syndrome (increase 17-ketosteroids and pregnanetriol). There is a lack of consensus on the reliability of several of these diagnoses resulting from the direct analysis of amniotic fluid. Analyses of uncultured amniotic fluid cells have resulted in diagnoses of Pompe's disease (ultrastructural changes) and Tay-Sachs disease. Analyses of cultivated amniotic fluid cells have enabled diagnoses of galactosemia (deficient galactose-1

  18. Medical management of chronic liver diseases in children (part I): focus on curable or potentially curable diseases.

    PubMed

    El-Shabrawi, Mortada H F; Kamal, Naglaa M

    2011-12-01

    The management of children with chronic liver disease (CLD) mandates a multidisciplinary approach. CLDs can be classified into 'potentially' curable, treatable non-curable, and end-stage diseases. Goals pertaining to the management of CLDs can be divided into prevention or minimization of progressive liver damage in curable CLD by treating the primary cause; prevention or control of complications in treatable CLD; and prediction of the outcome in end-stage CLD in order to deliver definitive therapy by surgical procedures, including liver transplantation. Curative, specific therapies aimed at the primary causes of CLDs are, if possible, best considered by a pediatric hepatologist. Medical management of CLDs in children will be reviewed in two parts, with part I (this article) specifically focusing on 'potentially' curable CLDs. Dietary modification is the cornerstone of management for galactosemia, hereditary fructose intolerance, and certain glycogen storage diseases, as well as non-alcoholic steatohepatitis. It is also essential in tyrosinemia, in addition to nitisinone [2-(nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione] therapy, as well as in Wilson disease along with copper-chelating agents such as D-penicillamine, triethylenetetramine dihydrochloride, and ammonium tetrathiomolybdate. Zinc and antioxidants are adjuvant drugs in Wilson disease. New advances in chronic viral hepatitis have been made with the advent of oral antivirals. In children, currently available drugs for the treatment of chronic hepatitis B virus infection are standard interferon (IFN)-α-2, pegylated IFN-α-2 (PG-IFN), and lamivudine. In adults, adefovir and entecavir have also been licensed, whereas telbivudine, emtricitabine, tenofovir disoproxil fumarate, clevudine, and thymosin α-1 are currently undergoing clinical testing. For chronic hepatitis C virus infection, the most accepted treatment is PG-IFN plus ribavirin. Corticosteroids, with or without azathioprine, remain the basic

  19. Metabolic correlates of learning disability.

    PubMed

    Nyhan, W L; Wulfeck, B B; Tallal, P; Marsden, D L

    1989-01-01

    prognosis for cognitive development. In summary, a multidisciplinary center has been established at UCSD to study the neurologic basis of disorders of language, learning and behavior in infants and children. The center draws together a group of researchers from many fields including neurology, biochemistry, pediatrics, cognitive and developmental neuropsychology, psycholinguistics, neurophysiology and communicative disorders. Because of the diverse interests and expertise of our group, it is hoped to forge a synthesis of the behavioral and neurosciences to study populations of children with a variety of neurologic, metabolic, and language/learning disorders. Disorders currently under study include Lesch-Nyhan disease, oculocutaneous tyrosinemia, propionic acidemia, carnitine palmityl transferase deficiency, Schwachman-Diamond syndrome, histidinemia, Hartnup disease, citrullinemia, galactosemia, maple syrup urine disease, and methylmalonic acidemia.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:2605319

  20. Main Report

    PubMed Central

    2006-01-01

    . Using the validated evidence base and expert opinion, each condition that had previously been assigned to a category based on scores gathered through the data collection instrument was reconsidered. Again, the factors taken into consideration were: 1) available scientific evidence; 2) availability of a screening test; 3) presence of an efficacious treatment; 4) adequate understanding of the natural history of the condition; and 5) whether the condition was either part of the differential diagnosis of another condition or whether the screening test results related to a clinically significant condition. The conditions were then assigned to one of three categories as previously described (core panel, secondary targets, or not appropriate for Newborn Screening). Among the 29 conditions assigned to the core panel are three hemoglobinopathies associated with a Hb/S allele, six amino acidurias, five disorders of fatty oxidation, nine organic acidurias, and six unrelated conditions (congenital hypothyroidism (CH), biotinidase deficiency (BIOT), congenital adrenal hyperplasia (CAH), classical galactosemia (GALT), hearing loss (HEAR) and cystic fibrosis (CF)). Twenty-three of the 29 conditions in the core panel are identified with multiplex technologies such as tandem mass spectrometry (MS/MS) or high pressure liquid chromatography (HPLC). On the basis of the evidence, six of the 35 conditions initially placed in the core panel were moved into the secondary target category, which expanded to 25 conditions. Test results not associated with potential disease in the infant (e.g., carriers) were also placed in the secondary target category. When newborn screening laboratory results definitively establish carrier status, the result should be made available to the health care professional community and families. Twenty-seven conditions were determined to be inappropriate for newborn screening at this time. Conditions with limited evidence reported in the scientific literature were more