Functional characterisation of alpha-galactosidase a mutations as a basis for a new classification system in fabry disease.

Fabry disease (FD) is an X-linked hereditary defect of glycosphingolipid storage caused by mutations in the gene encoding the lysosomal hydrolase α-galactosidase A (GLA, α-gal A). To date, over 400 mutations causing amino acid substitutions have been described. Most of these mutations are related to the classical Fabry phenotype. Generally in lysosomal storage disorders a reliable genotype/phenotype correlation is difficult to achieve, especially in FD with its X-linked mode of inheritance. In order to predict the metabolic consequence of a given mutation, we combined in vitro enzyme activity with in vivo biomarker data. Furthermore, we used the pharmacological chaperone (PC) 1-deoxygalacto…

Acute Cerebrovascular Disease in the Young

Background and Purpose— Strokes have especially devastating implications if they occur early in life; however, only limited information exists on the characteristics of acute cerebrovascular disease in young adults. Although risk factors and manifestation of atherosclerosis are commonly associated with stroke in the elderly, recent data suggests different causes for stroke in the young. We initiated the prospective, multinational European study Stroke in Young Fabry Patients (sifap) to characterize a cohort of young stroke patients. Methods— Overall, 5023 patients aged 18 to 55 years with the diagnosis of ischemic stroke (3396), hemorrhagic stroke (271), transient ischemic attack (1071) we…

Genotype–phenotype correlation in a new Fabry-disease-causing mutation

Background: Fabry disease (FD) is a rare X-linked inherited lysosomal storage disorder caused by α-galactosidase A deficiency leading to intracellular glycosphingolipid accumulation. FD manifestation is multisystem, and can differ depending on disease-related genetic variants. Currently, more than 700 different FD-causing mutations have been identified in the human GLA gene. We identified a novel mutation in a Lithuanian family with classical manifestations of Fabry disease, revealing severe effects to the cardiovascular systems of heterozygous women. Case presentation: A 49-year-old woman underwent echocardiography due to progressive dyspnea that lasted seven years, reduced physical a…

Repeat expansion in spinocerebellar ataxia type 17 alleles of the TATA-box binding protein gene: an evolutionary approach.

The variability and mutational changes of the CAG microsatellite in the TATA-box binding protein gene (TBP) were studied. We sequenced the microsatellite of the TBP gene of 25 unrelated individuals from northern Germany (10 SCA17 patients and 15 unaffected control individuals). In addition, the microsatellites were sequenced from individuals of 10 northern German families with at least one family member affected by SCA17. To study also the evolutionary history of this CAG/CAA microsatellite in nonhuman primates, the homologous regions were analysed from Pan troglodytes, Gorilla gorilla, Pongo pygmaeus, P. abellii, Hylobates lar, Nomascus leucogenys, Symphalangus syndactylus, Macaca mulatta,…

Basilar Artery Diameter Is a Potential Screening Tool for Fabry Disease in Young Stroke Patients

<i>Background:</i> Fabry disease (FD) is a rare hereditary lysosomal storage disease that has been highlighted as a possible etiology of stroke at a young age. Enlarged basilar artery diameters (BADs) have been demonstrated in FD, and we hypothesize that they might be useful for the screening of FD in young stroke patients. The aim of this study was to compare BADs of young stroke patients without FD to those of FD patients and of healthy age-matched controls. <i>Methods:</i> BADs were measured using MR angiography in 3 age- and gender-matched groups: 25 FD patients (aged 36.5 ± 11.0 years), 26 non-FD stroke patients and 20 healthy controls. <i>Results:</i&g…

Diagnose und Therapie des Morbus Gaucher Aktuelle Empfehlungen der deutschen Therapiezentren im Jahr 2000

Hintergrund: Beim Morbus Gaucher handelt es sich um die haufigste Sphingolipidose, deren Vorkommen zwischen 1 : 40 000 (in Zentraleuropa) und 1 : 2 000 (in einigen ausereuropaischen Landern, zum Beispiel Israel) variiert. Zugrunde liegt dieser Speichererkrankung ein autosomal-rezessiv vererbter Defekt der Glucocerebrosidase, der zu einem verminderten Abbau der Sphingolipide fuhrt. Die akuten und chronischen neuronopathischen Verlaufsformen (fruher als Gaucher-Typen 2 und 3 bezeichnet) sind mit 5 bis 10% in Mitteleuropa und Deutschland seltener als die nicht neuronopathische Variante (fruher als Gaucher-Typ 1 bezeichnet). Klinisch ist der Morbus Gaucher charakterisiert durch die Kernsymptome…

Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection

Item does not contain fulltext Cervical artery dissection (CeAD), a mural hematoma in a carotid or vertebral artery, is a major cause of ischemic stroke in young adults although relatively uncommon in the general population (incidence of 2.6/100,000 per year). Minor cervical traumas, infection, migraine and hypertension are putative risk factors, and inverse associations with obesity and hypercholesterolemia are described. No confirmed genetic susceptibility factors have been identified using candidate gene approaches. We performed genome-wide association studies (GWAS) in 1,393 CeAD cases and 14,416 controls. The rs9349379[G] allele (PHACTR1) was associated with lower CeAD risk (odds ratio…

Broad spectrum of Fabry disease manifestation in an extended Spanish family with a new deletion in the GLA gene

Background. Fabry disease (FD) is an X-linked inherited disease based on the absence or reduction of lysosomal-galactosidase (Gla) activity. The enzymatic defect results in progressive impairment of cerebrovascular, renal and cardiac function. Normally, female heterozygote mutation carriers are less strongly affected than male hemizygotes aggravating disease diagnosis. Method. Close examination of the patients by renal biopsy, echo- and electrocardiography and MRI. Blood work and subsequent DNA analysis were carried out utilizing approved protocols for PCR and Sequencing. MLPA analysis was done to unveil deletions within the GLA gene locus. Quantitative detection of Glycolipids in patient p…

Frequency of Fabry disease in patients with small-fibre neuropathy of unknown aetiology: a pilot study

Background:  Early occurrence of small-fibre neuropathy (SFN) is a common feature of Fabry disease (FD) – an X-linked storage disorder caused by reduced activity of the α-galactosidase A (α-GAL). Although SFN may result from different disorders, the cause is often unclear. Therefore, we investigated the frequency of FD in patients with SFN of unknown aetiology. Methods:  Patients with idiopathic SFN, established by sensory quantitative testing and/or skin biopsy, were examined for mutations in the α-GAL gene. Where mutations in the α-GAL gene were identified, levels of globotriaosylceramide (Gb3) were measured in urine and blood and the α-GAL activity was evaluated. When new mutations were …

Treatment and clinical survey of females with Fabry disease in Germany