Kiyoko Hattori

Newborn screening for Fabry disease in Japan: prevalence and genotypes of Fabry disease in a pilot study

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by a deficiency of α-galactosidase A (GLA) activity. Enzyme replacement therapy (ERT) for FD is available, and newborn mass screening for FD is being implemented. Here, we undertook a pilot study of newborn mass screening for FD in Japan. GLA activity in dried blood spots was measured using a fluorescence assay and confirmed by measurement of GLA activity in white blood cells (WBCs) in infants with abnormally low GLA activity. This was followed up by genetic testing. A total of 21 170 neonates were enrolled in the study. Of these, seven (five boys, two girls) had low GLA activities, which were verified by the WBC GLA activity assay. Thus, the initial fluorescence assay was suitable for newborn mass screening for FD. Pathogenic mutations of the GLA gene, that is, V199M and IVS4+919G>A, were found in two boys and one boy, respectively. Functional mutations, E66Q and c.−10C>T: g.1170C>T, were found in two boys and one girl, respectively. The prevalence of test-positive newborns was 1/3024, while that of those with a pathogenic mutation was 1/7057. The numbers are higher than those previously anticipated. Standardized management for FD found during newborn mass screening, including an ERT regimen, remains to be established.

Newborn screening for lysosomal storage disorders

Lysosomes are intracellular organelles containing acid hydrolases that degrade biological macromolecules. Lysosomal storage disorders (LSDs) are caused by absent activity of one or more of these enzymes due to mutations of genes encoding lysosomal hydrolases or enzymes that process, target, and transport these enzymes. The specific signs and symptoms of each LSD derive from the type of material accumulated within the lysosome, the site (organ) of accumulation and the response of the body (sometimes in the form of an inflammatory or immune response) to the accumulated material. Interest for inclusion of these disorders in newborn screening programs derives from the availability of effective therapy in the form of enzyme replacement or substrate reduction therapy and bone marrow transplant that may improve long‐term outcome especially if started prior to irreversible organ damage. Based on the availability of therapy and suitable screening methods, Gaucher disease, Fabry disease, Pompe disease, mucopolysaccharidosis I and II, Niemann–Pick disease, and Krabbe disease are candidates for newborn screening. Pilot newborn screening projects have been performed for some of these conditions that indicate the feasibility of this approach. This review will provide insight into these screening strategies and discuss their advantages and limitations.

Prevalence and cardiovascular features of Japanese hemodialysis patients with Fabry disease.

Background: Fabry disease (FD) is a rare disease and one of the causes of progressive renal dysfunction. It results from an X-linked deficiency of α-galactosidase A activity. It has been reported that its prevalence is much higher in hemodialysis patients than in the general population. However, its prevalence in Japanese hemodialysis patients and cardiovascular manifestations remain unclear. Methods: We screened the α-galactosidase A activity of 1,024 Japanese hemodialysis patients using a dried blood spot test. Patients with a low α-galactosidase A activity were assessed clinically, and a genetic study of the α-galactosidase A gene was performed for these patients. Furthermore, patients with FD underwent detailed cardiovascular examination. Results: Forty-six patients had low α-galactosidase A activity, and 1 man and 2 women had α-galactosidase A mutations (0.29%). All of these patients had a previously identified mutation (E66Q). The result of detailed cardiovascular examination showed that 2 patients had significantly impaired coronary flow reserve, reduced myocardial contraction and relaxation tissue Doppler velocities, and left ventricular hypertrophy. Conclusions: Measurement of the α-galactosidase A activity and the results of a genetic analysis indicated that the prevalence of FD in our hemodialysis patients was 0.29% (0.16% in men and 0.5% in women). Furthermore, comprehensive examination detected cardiovascular abnormalities in Japanese hemodialysis patients with FD.

Identification of a Novel Mutation and Prevalence Study for Fabry Disease in Japanese Dialysis Patients

Fabry disease—a genetic disorder characterized by the accumulation of globotriaosylceramide in cell lysosomes resulting from an X-linked deficiency of α-galactosidase A activity—presents with multiorgan manifestations, including progressive renal disease. Recently, its prevalence has been reported to be higher in hemodialysis (HD) patients than in the general population. We, therefore, examined patients on maintenance dialysis living in the Nagasaki Prefecture, Japan, to clarify the prevalence of Fabry disease. We screened 933 patients on maintenance dialysis, who were residents of Nagasaki Prefecture in Japan, for α-galactosidase A activity using a dried blood spot on filter paper. Patients with low α-galactosidase A activity were clinically assessed; subsequently, genetic analysis of the α-Galactosidase A gene (MIM:30064) was performed in these patients. Of the 933 patients, 55 had low α-galactosidase A activity; of these, one male and two females had α-Galactosidase A mutations. The prevalence of Fabry disease was thus 0.32%, which was similar to that reported previously. However, one mutation was newly identified, while the E66Q mutation observed in two patients was as previously identified. These two patients with the E66Q mutation were excluded because of the possibility of polymorphism; the prevalence of Fabry disease in the HD population was finally calculated to be 0.11%. The prevalence of Fabry disease in patients on maintenance dialysis living in Nagasaki Prefecture was 0.32%. Dried blood spot screening was considered as a simple and effective method for screening patients on maintenance dialysis for Fabry disease.

Cerebral hemorrhage in Fabry's disease

Fabrys disease is an X-linked lysosomal storage disorder resulting from α-galactosidase A deficiency. Although ischemic stroke is recognized as an important manifestation of Fabrys disease, hemorrhagic stroke is considered to be rare. Here, we report our recent clinical experience with three hemizygous male patients with Fabrys disease who developed cerebral hemorrhage. One patient had classic type Fabrys disease with p.Ala37Val mutation and others had cerebrovascular variant with p.Glu66Gln mutation. Degeneration of the cerebral small arteries secondary to deposition of glycosphingolipids and aging, in addition to hypertension and antiplatelet/anticoagulant agents, are considered to be contributing factors for hemorrhage. Fabrys disease is frequently associated with not only ischemic but also hemorrhagic stroke, especially in elderly patients.

p.E66Q mutation in the GLA gene is associated with a high risk of cerebral small-vessel occlusion in elderly Japanese males.

GLA is the causative gene of Fabry disease, an X‐linked lysosomal storage disorder resulting from α‐galactosidase A (α‐GAL) deficiency. Stroke is an important manifestation of Fabry disease, and recent epidemiological studies have indicated that up to 4.9% of young male cryptogenic stroke patients have GLA mutations. To determine the importance of GLA mutations in the general stroke population, the frequency of GLA mutations in Japanese male ischaemic stroke (IS) patients with various risk factors and ages was measured.

Prevalence of Fabry disease and GLA c.196G>C variant in Japanese stroke patients

Fabry disease is an important underlying disease in young cryptogenic stroke patients. However, little is known regarding the frequency of Fabry disease in the general stroke population, especially in elderly patients. A total of 588 stroke patients (61.7% men; average age 74.1±12.5 years) were enrolled in this prospective study. Blood samples were obtained to produce blood spots to determine α-galactosidase A (α-GalA) activity and for GLA gene analysis. One 65-year-old female patient had a known GLA gene mutation, c.2T>C (p.M1T), causing Fabry disease. Five male patients and two female patients had GLA c.196G>C (p.E66Q) variant, which is not associated with the full clinical manifestations of Fabry disease. The allele frequency of GLA c.196G>C was significantly higher in male patients with small-vessel occlusion (odds ratio 3.95, P=0.048) and non-cardioembolism (odds ratio 4.08, P=0.012) than that in the general Japanese population. Fabry disease is rare in the general Japanese stroke population. However, screening identified one elderly female patient with Fabry disease. GLA c.196G>C variant is a genetic risk factor for cerebral small-vessel occlusion and non-cardioembolism in Japanese males but not in females.

Consultants for the American Journal of Nephrology 2009

Glenn Chertow Robert Chevalier Monique Cho Kai-Ming Chow Felix Claverie-Martin Mark Cooper Fernando Cordido Daniel Coyne Farhad Danesh Robert Danziger John Daugirdas Prasad Devarajan Francis Dumler Thomas Easterling Tevfik Ecder Paul Eggers Randa El Zein Kathrin Eller Murray Epstein Sahar Fathallah-Shaykh Gal Finer Jeffrey Fink Michael Fischer Agnes Fogo Barry Freedman Eli Friedman Verica Garaj-Vrhovac Richard Glassock Glenda Gobe Stuart Goldstein Harvest Gu Krishnamurthy Gudehithlu Martha Gulati Michael Haase Melisha Hanna Peter Hart Kitamura Harumi Marion Hofmann-Bowman Yao Huang Adrian Iaina Narita Ichiei Zaid Abassi Kevin Abbott Rajiv Agarwal Adesuyi Ajayi Charambolos Antoniades Natarajan Aravindan Gema Ariceta Jose Arruda Arif Asif John Asplin Jonas Axelsson Mindy Banks Vinod Bansal Amy Barton Pai David Basile Alexei Basnakian Srinivasan Beddhu Enrico Benedetti Carsten Bergmann Daniel Berlowitz Judith Beto Rajendra Bhimma Erhard Bieberich Geoffrey Block Amy Bobrowski Neil Boudville Michael Braun Carolyn Brecklin Ellen Brooks Rebecca Brown Steve Brunelli Nigel Brunskill Emmanuel Burdmann Michel Burnier Hui Cai David Calhoun Niels Camara Vito Campese Thomas Carpenter Tak Mao Chan Arelene Chapman