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Fabry disease in a Japanese population-molecular and biochemical characteristics.

ABSTRACT: We had experienced 117 Japanese Fabry patients (72 males and 45 females) from 1977 to 2006, and then we generated an improved Fabry analysis system in 2007 and have found 196 ones (95 males and 101 females) since then. In this study, we summarized the data of the patients and tried to elucidate the molecular and biochemical characteristics of Japanese Fabry patients. Gene analysis revealed various GLA mutations, including missense mutations (56.5%, 48 types); nonsense mutations (15.9%, 13 types); deletions (12.6%, 13 types); splicing defects (10.1%, 6 types); insertions (1.0%, 2 types), and insertions/deletions (0.5%, 1 type), in the patients that were tested. Amino acid substitutions resulting from the missense mutations found in the classic form patients tended to be localized in the core of the GLA protein, and those in the later-onset ones in the peripheral region. The most commonly identified pathogenic mutations are c.888G?>?A (p.M296I), c.936?+?919G?>?A, c.679C?>?T (p.R227X), c.335G?>?A (p.R112H), c.334C?>?T (p.R112C), and c.902G?>?A (p.R301Q). Among them, c.888G?>?A (p.M296I) is unique to Japanese Fabry patients. On the other hand, c.936?+?919G?>?A is a variant that has been frequently detected in Taiwan Chinese Fabry patients, and c.335G?>?A (p.R112H) in various countries. These are found in later-onset patients, and c.679C?>?T (p.R227X) and c.334C?>?T (p.R112C) classic ones. c.902G?>?A (p.R301Q) is found in both classic and later-onset form patients. A possible functional polymorphism, c.196G?>?C (p.E66Q), was identified in 0.4% of the subjects who underwent high-risk screening. The biochemical findings including leukocyte ?-galactosidase A activity, plasma globotriaosylsphingosine level and urinary globotriaosylceramide in the individual phenotypic groups well reflected the phenotypic differences in this disease. The results will be useful for understanding the basis of Fabry disease in Japan.

SUBMITTER: Sakuraba H

PROVIDER: S-EPMC6205336 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Fabry disease in a Japanese population-molecular and biochemical characteristics.

Sakuraba Hitoshi H Tsukimura Takahiro T Togawa Tadayasu T Tanaka Toshie T Ohtsuka Tomoko T Sato Atsuko A Shiga Tomoko T Saito Seiji S Ohno Kazuki K

Molecular genetics and metabolism reports 20181026

We had experienced 117 Japanese Fabry patients (72 males and 45 females) from 1977 to 2006, and then we generated an improved Fabry analysis system in 2007 and have found 196 ones (95 males and 101 females) since then. In this study, we summarized the data of the patients and tried to elucidate the molecular and biochemical characteristics of Japanese Fabry patients. Gene analysis revealed various <i>GLA</i> mutations, including missense mutations (56.5%, 48 types); nonsense mutations (15.9%, 13 ...[more]

PMID: 30386727

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Project description:BackgroundFabry disease (FD) results from X-linked inheritance of a mutation in the GLA gene, encoding for alpha galactosidase A, and is characterized by heterogeneous clinical manifestations. Two phenotypes have been described "Classic" and "late onset" which cannot be predicted exclusively by genotype. The latter has been considered an attenuated form of the disease often affecting a single organ system commonly the heart. Recent studies have demonstrated that cardiac outcomes are similar in patients with classic and late onset mutations. In this study we investigate the relationship between clinical heterogeneity and plasma lyso-Gb3 in a large single centre cohort of N215S patients and compare this to patients with other mutations.MethodsIn this single-centre, retrospective, cross-sectional study we analysed a cohort of 251 FD patients: 84 N215S mutation (37 males) and 167 non-N215S mutations (58 males). The Mainz severity score index (MSSI) was used as an index of overall disease severity. Cardiac function and morphology were assessed by electrocardiogram and echocardiogram. Left ventricular mass was calculated using the Devereux formula and the left ventricular mass index (LVMI) calculated to adjust for height (g/m2.7). The presence of white matter lesions was assessed by cerebral MRI or computed tomography (CT). GFR was measured by radio-isotope (chromium-EDTA) method and adjusted for patient height (ml/min/m2.7), and urinary protein quantification was undertaken by 24 hour urine collection. Plasma globotriaosylsphingosine (lyso-Gb3) was analysed prior to ERT in 84 patients.ResultsN215S patients showed later symptom onset (males: p< 0.0001, females: p<0.03), later development of left ventricular hypertrophy (LVH) (median survival without LVH: 41 (non-N215S) vs. 64 (N215S) years, p< 0.0001), later development of proteinuria (median survival without proteinuria 43 (non-N215S) vs 71 years (N215S), p< 0.0001), later occurrence of cerebrovascular events (stroke/ Transient Ischaemic Attacks (TIA); median survival without stroke: 74 years (non-N215S) vs. not reached (N215S), p< 0.02), later decline in renal function to GFR <60 ml/min/1.73m2 (median survival: 56 (non-N215S) vs. 72 (N215S) years, p< 0.01), and greater overall survival (median survival 81 (N215S) vs. 66 (non-N215S) years, p< 0.0006). Lyso-Gb3 was found to be less elevated in N215S compared to non-N215S male and female patients. However, the N215S population eventually reached an overall severity measured by MSSI comparable to the non-N215S without equivalent elevation of lyso-Gb3 (means: 6.7 vs. 74.3 nmol/L, p < 0.001). In addition, N215S patients showed strong correlations between lyso-Gb3 levels and LVMI, GFR, and MSSI. These associations became stronger when we investigated individuals' life time exposure to lyso-Gb3 (calculated as [lyso-Gb3]*age): MSSI (r2 = 0.88, p< 0.0001), LVMI (r2 = 0.59, p< 0.005), and GFR (r2 = 0.75, p = 0.0001).ConclusionThese results demonstrate that the N215S mutation results in a late onset phenotype involving the heart and other organs. Correlations between clinical manifestations and plasma lyso-Gb3 variations in this group suggest a Fabry-relevant disease mechanism for the heterogeneity observed in this group.

Project description:Fabry disease (FD) is a progressive, X-linked inherited disorder of glycosphingolipid metabolism due to deficient or absent lysosomal α-galactosidase A activity. FD is pan-ethnic and the reported annual incidence of 1 in 100,000 may underestimate the true prevalence of the disease. Classically affected hemizygous males, with no residual α-galactosidase A activity may display all the characteristic neurological (pain), cutaneous (angiokeratoma), renal (proteinuria, kidney failure), cardiovascular (cardiomyopathy, arrhythmia), cochleo-vestibular and cerebrovascular (transient ischemic attacks, strokes) signs of the disease while heterozygous females have symptoms ranging from very mild to severe. Deficient activity of lysosomal α-galactosidase A results in progressive accumulation of globotriaosylceramide within lysosomes, believed to trigger a cascade of cellular events. Demonstration of marked α-galactosidase A deficiency is the definitive method for the diagnosis of hemizygous males. Enzyme analysis may occasionnally help to detect heterozygotes but is often inconclusive due to random X-chromosomal inactivation so that molecular testing (genotyping) of females is mandatory. In childhood, other possible causes of pain such as rheumatoid arthritis and 'growing pains' must be ruled out. In adulthood, multiple sclerosis is sometimes considered. Prenatal diagnosis, available by determination of enzyme activity or DNA testing in chorionic villi or cultured amniotic cells is, for ethical reasons, only considered in male fetuses. Pre-implantation diagnosis is possible. The existence of atypical variants and the availability of a specific therapy singularly complicate genetic counseling. A disease-specific therapeutic option - enzyme replacement therapy using recombinant human α-galactosidase A - has been recently introduced and its long term outcome is currently still being investigated. Conventional management consists of pain relief with analgesic drugs, nephroprotection (angiotensin converting enzyme inhibitors and angiotensin receptors blockers) and antiarrhythmic agents, whereas dialysis or renal transplantation are available for patients experiencing end-stage renal failure. With age, progressive damage to vital organ systems develops and at some point, organs may start to fail in functioning. End-stage renal disease and life-threatening cardiovascular or cerebrovascular complications limit life-expectancy of untreated males and females with reductions of 20 and 10 years, respectively, as compared to the general population. While there is increasing evidence that long-term enzyme therapy can halt disease progression, the importance of adjunctive therapies should be emphasized and the possibility of developing an oral therapy drives research forward into active site specific chaperones.

Dataset Information

Fabry disease in a Japanese population-molecular and biochemical characteristics.

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Fabry disease in a Japanese population-molecular and biochemical characteristics.

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