Identification of fifteen novel mutations and genotype-phenotype relationship in Fabry disease

Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
Clinical Genetics (Impact Factor: 3.93). 08/2001; 60(1):46-51. DOI: 10.1034/j.1399-0004.2001.600107.x
Source: PubMed


Fabry disease is an X-linked recessive disorder caused by a deficiency in the lysosomal enzyme alpha-galactosidase A, which results in a progressive multisystem disease. Most families have private mutations and no general correlation between genotype and disease manifestations has been described to date. Forty-nine patients (47 males and 2 females) from 36 affected families were selected for the study. Their evaluation included clinical examination, identification of alpha-galactosidase A gene mutations and residual enzymatic activity. For mutation detection, each exon with flanking intronic sequences was amplified by polymerase chain reaction (PCR) from the patient's genomic DNA and sequenced. Analysis of the resulting sequences was conducted to identify structural defects in the gene. Each of the Fabry patients carried a mutation in the alpha-galactosidase A gene. Fifteen mutations were novel. They included missense mutations (M51K, Y123M, G261D), nonsense point mutations (E251X) and small insertions or deletions creating a premature translational termination signal (P6X, D93X, W162X, K240X, H302X, I303X, L403X, S345X, G375X, F396X). Residual alpha-galactosidase A activity was significantly lower in patients with neuropathic pain (p=0.01) and in patients with mutations leading to a nonconservative amino acid change (p=0.04). Our findings emphasize the wide variety of genetic mechanisms leading to Fabry disease. A significant genotype-phenotype relationship was found.

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    • "However, according to recent studies, a correlation between the mutation of particular exon codes, such as exons 3 and 7, and the most severe disease phenotypes is being reported. There appears to be a correlation between clinical phenotypes and three-dimensional structural changes in protein cores or functionally important regions by various mutations5,6. "
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    ABSTRACT: A 28-year-old Asian male was referred for dermatologic evaluation of diffuse bluish-red maculopapules in the lower trunk and genital regions. There was no family history, and with the exception of dispersed skin lesions and hypohidrosis, no other complaints or symptoms were present. Histological evaluation of the skin lesions revealed angiokeratomas. When this combination of clinical and histological findings is observed, Fabry disease is suspected. Biochemical examination performed for definitive diagnosis did not show any activity of the α-galactosidase A enzyme. Through identification of a c.182_183ins(GA) mutation of the GLA gene, Fabry disease was diagnosed. However, there was no particular abnormal finding with regard to the evaluation of non-cutaneous manifestations, a symptom that can occur in the progress of this disease. We reported a case of Fabry disease, restricted to the dermatologic presentation, involving a novel frameshift mutation in the GLA gene.
    Full-text · Article · Feb 2013 · Annals of Dermatology
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    • "It has been suggested that the severity of the clinical course of Fabry disease, and particularly the extend of renal involvement, at least partly, depends on the amount of residual a-Gal A activity [1]. Twelve of our patients had minimum residual enzyme activity, as is typical in classically affected Fabry patients [5]. "
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    ABSTRACT: Fabry disease is a progressive metabolic disorder with a clinical course characterized by different phases and a variety of disease manifestations. The first symptoms generally appear in childhood or early adolescence and are followed by late life-threatening complications involving vascular, renal, cardiac, and cerebral systems. We report the clinical and biochemical characteristics of 16 male patients from 10 unrelated families who represent almost the entire cohort of known Fabry patients in Greece. Despite the presence of early symptoms in almost every patient (mean age at onset of symptoms 15.6 years), the diagnosis was delayed for a mean of about 18 years (mean age of diagnosis 36 years). Patients are currently monitored and the majority (15 out 16 patients) treated with Enzyme Replacement Therapy.
    Full-text · Article · Jan 2010 · Clinical nephrology
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    • "However, it was recently reported that disease-associated mutations were more common in exons 3 and 7 of the GLA gene [49]. We found particularly high urinary excretion levels of Gb 3 in patients with a nonsense mutation (Q386X) in exon 7. We observed that the truncated protein resulting from this particular mutation leads to massive excretion of Gb 3 in children, as well as in adults, suggesting that mutations in exons 3 and 7 code for important functional domains or cause unusually marked instability of the gene product [12] [21]. The results also suggest that the effect of missense mutations is unpredictable and variable, since the variability of Gb 3 excretion among people with missense mutations is greater than among people with nonsense mutations. "
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    ABSTRACT: Fabry disease is a complex, multisystemic and clinically heterogeneous disease, in which the urinary excretion of globotriaosylceramide (Gb3), the principal substrate of the deficient enzyme, alpha-galactosidase A, is more prominent than the increased concentrations of the lipid in the plasma of affected hemizygotes and heterozygotes. We have developed and validated a simultaneous analysis of Gb3 and creatinine in a 2.6-min run using filter paper discs saturated with urine and analyzed by LC-MS/MS. Using this method, we studied the relationship between urinary levels of total Gb3/creatinine excretion and four types of mutations in the GLA gene (missense, nonsense, frameshift, and splice-site defects) in 32 children and 78 adult patients with Fabry disease. Forty-one patients were treated by enzyme replacement therapy and 69 were untreated. Our results show that the mean recoveries of Gb3 and creatinine from the urine filter paper standards were 91% and 97%, respectively, with precision, reproducibility, and linearity within acceptable ranges. Statistical analysis using the independent variables of sex, age, types of mutations and treatment showed that the mutation factor has a statistically significant impact on urinary Gb3 excretion (p = 0.0007). This means that the levels of urinary excretion of Gb3/creatinine in children and adults with Fabry disease are directly related to the types of mutations. The same correlation was found for the sex (p < 0.0001) and treatment (p = 0.0011). In conclusion, we studied 35 mutations in 110 children and adults with Fabry disease and found a significant correlation between the types of mutations and total Gb3 excretion in Fabry patients.
    Full-text · Article · Mar 2008 · Molecular Genetics and Metabolism
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