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Anderson-Fabry disease (AFD) is a rare X-linked lysosomal storage disease, caused by defects of the alpha-galactosidase A (GLA) gene. AFD can affect the heart, brain, kidney, eye, skin, peripheral nerves, and gastrointestinal tract. Cardiology (hypertrophic cardiomyopathy), neurology (cryptogenic stroke), and nephrology (end-stage renal failure) screening studies suggest the prevalence of GLA variants is 0.62%, with diagnosis confirmation in 0.12%. OBJECTIVES: This study sought to expand screening from these settings to include ophthalmology, dermatology, gastroenterology, internal medicine, pediatrics, and medical genetics to increase diagnostic yield and comprehensively evaluate organ involvement in AFD patients. METHODS: In a 10-year prospective multidisciplinary, multicenter study, we expanded clinical, genetic, and biochemical screening to consecutive patients enrolled from all aforementioned clinical settings. We tested the GLA gene and α-galactosidase A activity in plasma and leukocytes. Inclusion criteria comprised phenotypical traits and absence of male-to-male transmission. Screening was extended to relatives of probands harboring GLA mutations. RESULTS: Of 2,034 probands fulfilling inclusion criteria, 37 (1.8%) were carriers of GLA mutations. Cascade family screening identified 60 affected relatives; clinical data were available for 4 affected obligate carriers. Activity of α-galactosidase A in plasma and leukocytes was diagnostic in male subjects, but not in female subjects. Of the 101 family members harboring mutations, 86 were affected, 10 were young healthy carriers, and 5 refused clinical evaluation. In the 86 patients, involved organs or organ systems included the heart (69%), peripheral nerves (46%), kidney (45%), eye (37%), brain (34%), skin (32%), gastrointestinal tract (31%), and auditory system (19%). Globotriaosylceramide accumulated in organ-specific and non-organ-specific cells in atypical and classic variants, respectively. CONCLUSIONS: Screening probands with clinically suspected AFD significantly increased diagnostic yield. The heart was the organ most commonly involved, independent of the clinical setting in which the patient was first evaluated. Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

While the genetic origin of Fabry disease (FD) is well known, it is still unclear why the disease presents a wide heterogeneity of clinical presentation and progression, even within the same family. Emerging observations reveal that mitochondrial impairment and oxidative stress may be implicated in the pathogenesis of FD. To investigate if specific genetic polymorphisms within the mitochondrial genome (mtDNA) could act as susceptibility factors and contribute to the clinical expression of FD, we have genotyped European mtDNA haplogroups in 77 Italian FD patients and 151 healthy controls. Haplogroups H and I, and haplogroup cluster HV were significantly more frequent in patients than controls. However, no correlation with gender, age of onset, organ involvement was observed. Our study seems to provide some evidence of a contribution of mitochondrial variation in FD pathogenesis, at least in Italy.

Background The etiologic determinants of stroke in young adults remain a diagnostic challenge in up to one-fourth of cases. Increasing evidences led to consider Fabry’s disease (FD) as a possible cause to check up. We aimed at evaluating the prevalence of unrecognized FD in a cohort of patients with juvenile stroke in northern Sardinia. Methods For this study, we enrolled 178 patients consecutively admitted to our Neurological Ward for ischemic stroke, transient ischemic attack, intracerebral haemorrhage, neuroradiological evidence of silent infarcts, or white matter lesions possibly related to cerebral vasculopathy at brain MRI, and cerebral venous thrombosis. The qualifying events have to occur between 18 and 55 years of age. Results We identified two patients with an α-galactosidase A gene variant, with a prevalence of 0.9 %. According to recent diagnostic criteria, one patient, included for the occurrence of multiple white matter lesions at brain MRI, had a diagnosis of definite FD, the other, included for ischemic stroke, had a diagnosis of uncertain FD. Conclusions Our study places in a middle position among studies that found a prevalence of FD up to 4 % and others that did not find any FD patients. Our findings confirm that FD should be considered in the differential diagnosis of patients with juvenile stroke, particularly those with a personal or familial history positive for cerebrovascular events, or evidence of combined cardiologic and/or renal impairment. All types of cerebrovascular disorders should be screened for FD, including patients with white matter lesions possibly related to cerebral vasculopathy at brain MRI.

Wernicke–Korsakoff syndrome refers to a life-threatening encephalopathy due to inadequate supply of thiamine (vitamin B1) to the brain. It is a combination of Wernicke encephalopathy (WE), an acute neuropsychiatric disorder fully responsive to prompt and adequate thiamine replacement, and Korsakoff syndrome (KS), the chronic, irreversible form of WE that does not remit with thiamine treatment. Thiamine deficiency can occur in any condition of unbalanced nutrition that lasts for 2–3 weeks. These include poor nutrition, chronic alcohol misuse, loss of thiamine owing to recurrent vomiting or malabsorption, increased thiamine requirements owing to chronic diseases, prolonged and excessive carbohydrate intake and gastrointestinal surgical procedures, in particular, patients after bariatric surgery. The diagnosis is clinical and is mainly supported by the dramatic improvement of neurological signs to parenteral thiamine. Neuroimaging studies are useful to confirm the diagnosis of both WE and KS. Patients with suspected thiamine deficiency should be treated immediately with parenteral thiamine at the doses deemed to be effective in the treatment of WE and prevention of KS. Key Concepts: Thiamine deficiency can occur in a myriad of clinical settings that include malnutrition, malabsorption and increased metabolism and in patients following bariatric surgery. A thiamine deficiency that lasts for 2 to 3 weeks leads to Wernicke encephalopathy, an acute, life-threatening disorder that is a medical emergency. Wernicke encephalopathy is fully responsive to prompt and adequate thiamine replacement. Untreated or inadequately treated Wernicke encephalopathy may lead to Korsakoff syndrome, a chronic amnesic encephalopathy that does not remit with thiamine treatment. The goal of treatment of Wernicke encephalopathy is the immediate administration of high doses of parenteral thiamine deemed sufficient to prevent Korsakoff syndrome. Keywords: thiamine deficiency; Wernicke encephalopathy; Korsakoff syndrome; Wernicke–Korsakoff syndrome; encephalopathy; vitamin B1