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1.
《Genetics in medicine》2010,12(7):440-445
PurposeGlycogen Storage Disease Type III, also known as debrancher deficiency or Cori disease, is an autosomal recessive disorder recognized for both its hepatic and muscle manifestations. The neuromuscular manifestations of Glycogen Storage Disease Type III are not well characterized. In this study, we attempt to better define the disorder.MethodsThe medical records of 40 patients with Glycogen Storage Disease Type III seen at Duke University during 1990–2009 were reviewed. The medical records of all patients with nerve conduction studies and/or electromyography were examined.ResultsTwelve patients with Glycogen Storage Disease Type III (aged 5–55 years) had undergone nerve conduction studies ± electromyography. Three of these cases are presented in detail. Nine patients had Glycogen Storage Disease Type IIIa, two patients had Glycogen Storage Disease Type IIIb, and the clinical subtype of one patient was unknown. All had nerve conduction studies and of those nerves tested, abnormalities in the median motor response were most common, corresponding to previously described, intrinsic hand muscle weakness. Electromyography was performed in eight patients and myopathic findings were present in six individuals. Abnormal electrodiagnostic findings were more common in older patients. The two patients with Glycogen Storage Disease Type IIIb had electrodiagnostic evidence of nerve involvement with minor myopathic findings.ConclusionsThe neuromuscular manifestations of Glycogen Storage Disease Type III include myopathy and neuropathy and are more likely to occur with increasing age, even in those diagnosed with Glycogen Storage Disease Type IIIb. Intrinsic hand muscle weakness is likely due to a combination of nerve and muscle dysfunction, a finding that may have implications for treatment. 相似文献
2.
《Genetics in medicine》2010,12(7):413-423
PurposeGlycogen Storage Disease Type III, glycogen debranching enzyme deficiency, causes accumulation of glycogen in liver, skeletal, and cardiac muscle. Some patients develop increased left ventricular thickness by echocardiography, but the rate of increase and its significance remain unclear.MethodsWe evaluated 33 patients with Glycogen Storage Disease Type III, 23 with IIIa and 10 with IIIb, ages 1 month to 55.5 years, by echocardiography for wall thickness, left ventricular mass, shortening and ejection fractions, at 1 time point (n = 33) and at 2 time points in patients with more than 1 echocardiogram (13 of the 33).ResultsOf 23 cross-sectional patients with type IIIa, 12 had elevated left ventricular mass, 11 had elevated wall thickness. One type IIIb patient had elevated left ventricular mass but four had elevated wall thickness. For those with multiple observations, 9 of 10 with type IIIa developed increased left ventricular mass over time, with three already increased at first measurement. Shortening and ejection fractions were generally normal.ConclusionElevated left ventricular mass and wall thickness is more common in patients with type IIIa but develops rarely in type IIIb, although ventricular systolic function is preserved. This suggests serial echocardiograms with attention to left ventricular thickness and mass are important for care of these patients. 相似文献
3.
The autosomal recessive disorder Glycogen Storage Disease Type II (GSDII) is caused by a deficiency in the lysosomal enzyme acid α-glucosidase. We have optimised a procedure to use fluorescent DNA sequencing technology to screen for mutations within the α-glucosidase gene from UK patients with GSDII. Five previously unknown mutations in six patients (4 early onset infantile and 2 late onset adult) have been found. The mutations are an insertion of a C residue in exon 2 (InsC258), an insertion of a G residue in exon 16 (InsG2242), a deletion of 20 nucleotides in exon 4 Δ, and a nonsense mutation in exon 16 (G2237A - Trp746Stop). All will result in the introduction of a premature stop codon in the coding region, predicting a truncated and non-functional protein. The final mutation is a duplication of 18 nucleotides in exon 19 (Ins18nt2776) and will result in the insertion of an additional six amino acids into the protein chain after Asn925 (Gly-Val-Pro-Val-Ser-Asn). Hum Mutat 11:413, 1998. © 1998 Wiley-Liss, Inc. 相似文献
4.
Total or partial lack of glycogen debranching enzyme (GDE or AGL, amylo-1,6-glucosidase, 4-alpha-glucanotransferase) is responsible for Glycogen Storage Disease type III (GSDIII), a rare autosomal recessive disorder of glycogen metabolism. The clinical and biochemical features of GSDIII subjects are quite heterogeneous, and this mirrors the genotype-phenotype heterogeneity among patients. In this paper, we report the molecular characterisation of five unrelated subjects, four Italian and one Tunisian. The following new mutations are described and confirm the genetic heterogeneity of this disease: p.R864X, p.R428K, c.3911 insA, p.G1087R and c.3512_3549dup+c.3512_3519del. The functional relevance of these mutations is discussed on the basis of the recently acquired knowledge about the boundaries and structures of the two catalytic domains. 相似文献
5.
The autosomal recessive disorder Glycogen Storage Type II (GSDII) is caused by a deficiency in the lysosomal enzyme acid alpha-glucosidase. We have optimised a procedure to use fluorescent DNA sequencing technology to screen for mutations within the alpha-glucosidase gene from UK patients with GSDII. Five previously unknown mutations in six patients (4 early onset infantile and 2 late adult) have been found. The mutations are an insertion of a C residue in exon 2 (InsC258), an insertion of a G residue in exon 16 (InsG2242), a deletion of 20 nucleotides in exon 4 delta, and a nonsense mutation in exon 16 (G2237A-Trp746Stop). All will result in the introduction of a premature stop codon in the coding region, predicting a truncated and non-functional protein. The final mutation is a duplication of 18 nucleotides in exon 19 (Ins18nt2776) and will result in the insertion of an additional six amino acids into the protein chain after Asn925 (Gly-Val-Pro-Val-Ser-Asn). 相似文献
6.
Lucchiari S Donati MA Parini R Melis D Gatti R Bresolin N Scarlato G Comi GP 《Human mutation》2002,20(6):480
Deficiency of amylo-1,6-glucosidase, 4-alpha-glucanotransferase enzyme (AGL or glycogen debranching enzyme) is causative of Glycogen Storage Disease type III, a rare autosomal recessive disorder of glycogen metabolism. The disease has been demonstrated to show clinical and biochemical heterogeneity, reflecting the genotype-phenotype heterogeneity among different subjects. The aim of this study was the molecular characterisation of eight unrelated patients from an ethnically heterogeneous population (six Italians, one from India and another one from Tunisia). We describe six novel mutations responsible for the disease (C234R, R675W, 2547delG, T38A, W1327X, IVS6 +3 A>G) and the presence in two Italian subjects of a splice variant (IVS21(+1) G>A) already described elsewhere. This last one is confirmed to be the most frequent mutation among the Italian patients come to our observation, accounting for 28% of 21 patients. One subject was found to be a compound heterozygous. Our data confirm the substantial genetic heterogeneity of this disease. Consequently, the strategy of mutation finding based on screening of recurrent common mutations is limited, as far as regards Italian GSD III patients, to check for the presence of IVS21(+1) G>A. 相似文献
7.
《Genetics in medicine》2010,12(7):446-463
PurposeGlycogen storage disease type III is a rare disease of variable clinical severity affecting primarily the liver, heart, and skeletal muscle. It is caused by deficient activity of glycogen debranching enzyme, which is a key enzyme in glycogen degradation. Glycogen storage disease type III manifests a wide clinical spectrum. Individuals with glycogen storage disease type III present with hepatomegaly, hypoglycemia, hyperlipidemia, and growth retardation. Those with type IIIa have symptoms related to liver disease and progressive muscle (cardiac and skeletal) involvement that varies in age of onset, rate of disease progression, and severity. Those with type IIIb primarily have symptoms related to liver disease. This guideline for the management of glycogen storage disease type III was developed as an educational resource for health care providers to facilitate prompt and accurate diagnosis and appropriate management of patients.MethodsAn international group of experts in various aspects of glycogen storage disease type III met to review the evidence base from the scientific literature and provided their expert opinions. Consensus was developed in each area of diagnosis, treatment, and management.ResultsThis management guideline specifically addresses evaluation and diagnosis across multiple organ systems (cardiovascular, gastrointestinal/nutrition, hepatic, musculoskeletal, and neuromuscular) involved in glycogen storage disease type III. Conditions to consider in a differential diagnosis stemming from presenting features and diagnostic algorithms are discussed. Aspects of diagnostic evaluation and nutritional and medical management, including care coordination, genetic counseling, hepatic transplantation, and prenatal diagnosis, are addressed.ConclusionsA guideline that will facilitate the accurate diagnosis and appropriate management of individuals with glycogen storage disease type III was developed. This guideline will help health care providers recognize patients with all forms of glycogen storage disease type III, expedite diagnosis, and minimize stress and negative sequelae from delayed diagnosis and inappropriate management. It will also help identify gaps in scientific knowledge that exist today and suggest future studies. 相似文献
8.
Lam CW Lee AT Lam YY Wong TW Mak TW Fung WC Chan KC Ho CS Tong SF 《Molecular genetics and metabolism》2004,83(3):271-275
Glycogen storage disease type III (GSD III) is an inborn error of glycogen metabolism caused by a deficiency of glycogen debranching enzyme (AGL). Here, we investigate two unrelated Hong Kong Chinese GSD III patients and identify a novel 5-base pair deletional mutation, 2715_2719delTCAGAin exon 22, in one patient and a nonsense mutation, 1222C>T (R408X) in exon 11, in another patient. Since GSD IIIb is only caused by mutation in exon 3 of the AGL gene, we diagnose our patients to have GSD IIIa, which is consistent with the clinical diagnosis. Until now, R408X has only been reported in Faroe Islands GSDIII patients and was thought to demonstrate a founder effect. In this study, haplotyping of the disease-bearing chromosomes in the AGL locus by 19 intragenic single nucleotide polymorphisms shows that R408X is linked with IVS16+8T and IVS23-21T in our patient while R408X is linked with IVS16+8C and IVS23-21A in the Faroe Islands. The different haplotypes of R408X in Chinese and Faroese indicated that R408X is a recurrent mutation. 相似文献
9.
Mili A Ben Charfeddine I Amara A Mamaï O Adala L Ben Lazreg T Bouguila J Saad A Limem K Gribaa M 《Clinical genetics》2012,82(6):534-539
Mili A, Ben Charfeddine I, Amara A, MamaÏ O, Adala L, Ben Lazereg T, Bougulia J, Saad A, Limem K, Gribaa M. A c.3216_3217delGA mutation in AGL gene in Tunisian patients with a glycogen storage disease type III: evidence of a founder effect. Glycogen storage disease type III (GSD III) is an autosomal recessive disorder characterized by excessive accumulation of abnormal glycogen in the liver and muscles and caused by deficiency in the glycogen debranching enzyme, the amylo‐1,6‐glucosidase (AGL). In this study, we report the clinical, biochemical and genotyping features of five unrelated GSD III patients coming from the same region in Tunisia. The concentration of erythrocyte glycogen and AGL activity were measured by colorimetric and fluorimetric methods, respectively. Four CA/TG microsatellite markers flanking the AGL gene in chromosome 1 were amplified with fluoresceinated primers. The full coding exons and their relevant exon–intron boundaries of the AGL gene were directly sequenced for the patients and their parents. All patients showed a striking increase of erythrocytes glycogen content. No AGL activity was detected in peripheral leukocytes. Sequencing of the AGL gene identified a c.3216_3217delGA (p.Glu1072AspfsX36) mutation in the five patients which leads to a premature termination, abolishing the AGL activity. Haplotype analysis showed that the mutation was associated with a common homozygote haplotype. Our results suggested the existence of a founder effect responsible for GSD III in this region of Tunisia. 相似文献
10.
Endo Y Horinishi A Vorgerd M Aoyama Y Ebara T Murase T Odawara M Podskarbi T Shin YS Okubo M 《Journal of human genetics》2006,51(11):958-963
Glycogen storage disease type III (GSD III) is an autosomal recessive disorder characterized by excessive accumulation of abnormal glycogen in the liver and/or muscles and caused by deficiency in the glycogen debranching enzyme (AGL). Previous studies have revealed that the spectrum of AGL mutations in GSD III patients depends on ethnic grouping. We investigated nine GSD III patients from Germany, Canada, Afghanistan, Iran, and Turkey and identified six novel AGL mutations: one nonsense (W255X), three deletions (1019delA, 3202–3203delTA, and 1859–1869del11-bp), and two splicing mutations (IVS7 + 5G > A and IVS21 + 5insA), together with three previously reported ones (R864X, W1327X, and IVS21 + 1G > A). All mutations are predicted to lead to premature termination, which abolishes enzyme activity. Our molecular study on GSD III patients of different ethnic ancestry showed allelic heterogeneity of AGL mutations. This is the first AGL mutation report for German, Canadian, Afghan, Iranian and Turkish populations.Electronic Supplementary Material Supplementary material is available in the online version of this article at and is accessible for authorized users. 相似文献
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Megumu Hino Makiko Shimodahira Toshio Iwakura Takashi Ishihara Katsuji Ikekubo Yoshihiro Ogawa Kazuwa Nakao Hiroyuki Kurahachi 《American journal of medical genetics. Part A》2002,107(1):26-29
We report a new Japanese family with tricho‐rhino‐phalangeal syndrome type III (TRPS III) who have a missense mutation (Arg908Gln) of theTRPS1 gene (TRPS1) in affected individuals of the family. This study supports the notion that TRPS III results from missense mutations in exon 6 of TRPS1. © 2001 Wiley‐Liss, Inc. 相似文献
13.
Mili A Ben Charfeddine I Mamaï O Abdelhak S Adala L Amara A Pagliarani S Lucchiarri S Lucchiari S Ayadi A Tebib N Harbi A Bouguila J H'Mida D Saad A Limem K Comi GP Gribaa M 《Journal of human genetics》2012,57(3):170-175
Glycogen storage disease type III (GSD III) is an autosomal recessive inborn error of metabolism caused by mutations in the glycogen debranching enzyme amylo-1,6-glucosidase gene, which is located on chromosome 1p21.2. GSD III is characterized by the storage of structurally abnormal glycogen, termed limit dextrin, in both skeletal and cardiac muscle and/or liver, with great variability in resultant organ dysfunction. The spectrum of AGL gene mutations in GSD III patients depends on ethnic group. The most prevalent mutations have been reported in the North African Jewish population and in an isolate such as the Faroe Islands. Here, we present the molecular and biochemical analyses of 22 Tunisian GSD III patients. Molecular analysis revealed three novel mutations: nonsense (Tyr1148X) and two deletions (3033_3036del AATT and 3216_3217del GA) and five known mutations: three nonsense (R864X, W1327X and W255X), a missense (R524H) and an acceptor splice-site mutation (IVS32-12A>G). Each mutation is associated to a specific haplotype. This is the first report of screening for mutations of AGL gene in the Tunisian population. 相似文献
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15.
《Genetics in medicine》2012,14(8):737-741
PurposeThe aim of this study was to characterize the pathogenesis of low bone mineral density in glycogen storage disease type Ia and Ib.MethodsA retrospective chart review performed at the University of Florida Glycogen Storage Disease Program included patients with glycogen storage disease type Ia and Ib for whom dual-energy X-ray absorptiometry analysis was performed. A Z-score less than −2 SD was considered low. Analysis for association of bone mineral density with age, gender, presence of complications, mean triglyceride and 25-hydroxyvitamin D concentrations, erythrocyte sedimentation rate, duration of granulocyte colony–stimulating factor therapy, and history of corticosteroid use was performed.ResultsIn glycogen storage disease Ia, 23/42 patients (55%) had low bone mineral density. Low bone mineral density was associated with other disease complications (P = 0.02) and lower mean serum 25-hydroxyvitamin D concentration (P = 0.03). There was a nonsignificant trend toward lower mean triglyceride concentration in the normal bone mineral density group (P = 0.1).In patients with glycogen storage disease type Ib, 8/12 (66.7%) had low bone mineral density. We did not detect an association with duration of granulocyte colony–stimulating factor therapy (P = 0.68), mean triglyceride level (P = 0.267), erythrocyte sedimentation rate (P = 0.3), or 25-hydroxyvitamin D (P = 0.63) concentration, and there was no evidence that corticosteroid therapy was associated with lower bone mineral density (P = 1).ConclusionIn glycogen storage disease type Ia, bone mineral density is associated with other complications and 25-hydroxyvitamin D status. In glycogen storage disease type Ib, bone mineral density was not associated with any covariates analyzed, suggesting multifactorial etiology or reflecting a small sample.Genet Med 2012:14(8):737–741 相似文献
16.
Crouzon syndrome: mutations in two spliceoforms of FGFR2 and a common point mutation shared with Jackson--Weiss syndrome 总被引:5,自引:0,他引:5
Gorry Michael C.; Preston Robert A.; White Gregory J.; Zhang Yingze; Singhal Virender K.; Losken H.Wolgang; Parker Michael G.; Nwokoro Ngozi A.; Post J.Christopher; Ehrlich Garth D. 《Human molecular genetics》1995,4(8):1387-1390
Dominant mutations in the fibroblast growth factor receptor2 (FGFR2) gene have been recently identified as causes of fourphenotypically distinct craniosynostosis syndromes, includingCrouzon, JacksonWeiss, Pfeiffer, and Apert syndromes.These data suggest that the genetics of the craniosynostosissyndromes is more complex than would be expected from theirsimple autosomal-dominant inheritance pattern. Identical mutationsin the FGFR2 gene have been reported to cause both Pfeifferand Crouzon syndrome phenotypes. We now report the finding ofa mutation in exon Illc of the FGFR2 gene in a kindred affectedwith Crouzon syndrome (C1043 to G; Ala344Gly) that is identicalto the mutation previously associated with JacksonWeisssyndrome. We also report finding in a Crouzon kindred a mutationin the 3' end of exon Illu (formerly referred to as exon 5,exon 7, or exon U) (A878 to C; Gln289Pro) which encodes theamino terminal portion of the lg-like III domain of the FGFR2protein. This exon is common to both the FGFR2 and the KGFRspliceoforms of the FGFR2 gene, unlike all previously reportedCrouzon mutations, which have been found only in the FGFR2 spliceoform.These findings reveal further unexpected complexity in the moleculargenetics of these craniosynostosis syndromes. The data impliesthat second-site mutations in FGFR2 itself (outside of exonIllc) or in other genes may determine specific aspects of thephenotypes of craniosynostosis syndromes. 相似文献
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Zeynep Tümer Birgitte BertelsenOle Gredal Melinda MagyariKaren Cecilie Nielsen LuCampKaren Grønskov Karen Brøndum-Nielsen 《Neurobiology of aging》2012,33(1):208
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder. About 10% of ALS cases are familial (FALS) and the genetic defect is known only in approximately 20%-30% of these cases. The most common genetic cause of ALS is SOD1 (superoxide dismutase 1) mutation. Very recently, mutations of the optineurin gene (OPTN), which is involved in open-angle glaucoma, were identified in 3 Japanese patients/families with ALS, and subsequently in a few FALS patients of European descent. We found a heterozygous nonsense mutation (c.493C>T, p.Gln165X, exon 6) in the OPTN gene in a Danish patient with ALS, and the mutation segregated from his affected father. The p.Gln165X mutation could not be detected in 1070 healthy Danish controls, in 1000 Danish individuals with metabolic phenotypes or in 64 sporadic ALS (SALS) cases. The p.Gln165X mutation described in this study is the first mutation reported in a Danish family and is likely involved in disease pathogenesis. Until now, only few OPTN mutations have been associated with ALS. As the underlying genetic defect is known only in approximately 20%-30% of FALS families, further screening of these cases is necessary for establishing the contribution of OPTN mutations in disease pathogenesis. 相似文献
19.
Akagi M Inui K Nakajima S Shima M Nishigaki T Muramatsu T Kokubu C Tsukamoto H Sakai N Okada S 《Journal of human genetics》2000,45(1):60-62
Fanconi-Bickel syndrome (FBS), or glycogen storage disease type XI, is a rare autosomal recessive disorder characterized
by hepatorenal glycogen accumulation, Fanconi nephropathy, and impaired utilization of glucose and galactose. Recently, this
disease was elucidated to link mutations in the glucose transporter 2 (GLUT2) gene. Only three mutations in three FBS families have been reported. Therefore, it is important to elucidate mutations in
the GLUT2 gene in FBS by answering the question of whether the syndrome is a single gene disease. In this report, we describe two patients
in two unrelated families clinically diagnosed with FBS. No mutation in the entire protein coding region of the GLUT2 gene was detected in patient 1, which suggested that no mutation existed in the GLUT 2 gene, or that some mutations had affected the expression of the GLUT 2 gene. In patient 2, a novel homozygous nonsense mutation (W420X, Trp at codon 420 to stop codon) was detected. These results
support the correlation between GLTU2 gene mutation and FBS syndrome. However, many patients must be analyzed to determine whether other genes are involved in
FBS.
Received: July 16, 1999 / Accepted: September 3, 1999 相似文献
20.
Kyoung Chan Park Sang Kyu Park Yong Suk Lee Sang Woong Youn Byung Soon Park Kyu Han Kim Seung Taek Lee 《Journal of human genetics》1996,41(3):299-305
Summary Oculocutaneous albinism (OCA) is an inherited disorder of the melanin pigmentary system, characterized by a decrease or an absence of melanin in the skin, hair, and eyes. Type I (tyrosinase-deficient) OCA results from mutations of thetyrosinase (TYR) gene encoding tyrosinase, the enzyme that catalyzes at least the first two steps of melanin biosynthesis. We have analyzed theTYR gene in three Korean patients with severe type I OCA. Two patients were compound heterozygotes for the Arg (CGG) to Gln (CAG) mutation at position 77 and a C insertion mutation at position 310. The other was a compound heterozygote for a C insertion mutation at position 310 and the Asp (GAT) to Asn (AAT) mutation at position 383. These mutations were easily detected by restriction enzyme digestion or by SSCP analysis. Such methods of mutation analysis thus provide a basis for a screening system for theTYR gene mutations in Korean patients with type I OCA. 相似文献