Monogenic cerebral small‐vessel diseases: diagnosis and therapy. Consensus recommendations of the European Academy of Neurology

Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene leading to deficient α-galactosidase A activity, glycosphingolipid accumulation, and life-threatening complications. Phenotypes vary from the "classic" phenotype, with pediatric onset and multi-organ involvement, to later-onset, a predominantly cardiac phenotype. Manifestations are diverse in female patients in part due to variations in residual enzyme activity and X chromosome inactivation patterns. Enzyme replacement therapy (ERT) and adjunctive treatments can provide significant clinical benefit. However, much of the current literature reports outcomes after late initiation of ERT, once substantial organ damage has already occurred. Updated monitoring and treatment guidelines for pediatric patients with Fabry disease have recently been published. Expert physician panels were convened to develop updated, specific guidelines for adult patients. Management of adult patients depends on 1) a personalized approach to care, reflecting the natural history of the specific disease phenotype; 2) comprehensive evaluation of disease involvement prior to ERT initiation; 3) early ERT initiation; 4) thorough routine monitoring for evidence of organ involvement in non-classic asymptomatic patients and response to therapy in treated patients; 5) use of adjuvant treatments for specific disease manifestations; and 6) management by an experienced multidisciplinary team. Show more

COL4A3, COL4A4, and COL4A5 are the only collagen genes that have been implicated in inherited nephropathies in humans. However, the causative genes for a number of hereditary multicystic kidney diseases, myopathies with cramps, and heritable intracranial aneurysms remain unknown. We characterized the renal and extrarenal phenotypes of subjects from three families who had an autosomal dominant hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC), which we propose is a syndrome. Linkage studies involving microsatellite markers flanking the COL4A1-COL4A2 locus were performed, followed by sequence analysis of COL4A1 complementary DNA extracted from skin-fibroblast specimens from the subjects. We identified three closely located glycine mutations in exons 24 and 25 of the gene COL4A1, which encodes procollagen type IV alpha1. The clinical renal manifestations of the HANAC syndrome in these families include hematuria and bilateral, large cysts. Histologic analysis revealed complex basement-membrane defects in kidney and skin. The systemic angiopathy of the HANAC syndrome appears to affect both small vessels and large arteries. COL4A1 may be a candidate gene in unexplained familial syndromes with autosomal dominant hematuria, cystic kidney disease, intracranial aneurysms, and muscle cramps. Copyright 2007 Massachusetts Medical Society. Show more

Strokes are an important cause of morbidity and mortality in young adults. However, in most cases the cause of the stroke remains unclear. Anderson-Fabry disease is an X-linked recessive lysosomal storage disease resulting from deficient alpha-galactosidase and causes an endothelial vasculopathy followed by cerebral ischaemia. To determine the importance of Fabry disease in young people with stroke, we measured the frequency of unrecognised Fabry disease in a cohort of acute stroke patients. Between February, 2001, and December, 2004, 721 German adults aged 18 to 55 years suffering from acute cryptogenic stroke were screened for Fabry disease. The plasma alpha-galactosidase activity in men was measured followed by sequencing of the entire alpha-GAL gene in those with low enzyme activity. By contrast, the entire alpha-GAL gene was genetically screened for mutations in women even if enzyme activity was normal. 21 of 432 (4.9%) male stroke patients and seven of 289 (2.4%) women had a biologically significant mutation within the alpha-GAL gene. The mean age at onset of symptomatic cerebrovascular disease was 38.4 years (SD 13.0) in the male stroke patients and 40.3 years (13.1) in the female group. The higher frequency of infarctions in the vertebrobasilar area correlated with more pronounced changes in the vertebrobasilar vessels like dolichoectatic pathology (42.9%vs 6.8%). We have shown a high frequency of Fabry disease in a cohort of patients with cryptogenic stroke, which corresponds to about 1.2% in young stroke patients. Fabry disease must be considered in all cases of unexplained stroke in young patients, especially in those with the combination of infarction in the vertebrobasilar artery system and proteinuria. Show more