Spatial distribution of brain ceramides in an acid ceramidase deficient murine model: Subsequent histological manifestations and functional deficits

Background: Fabry disease (FD) is an innate error of glycosphingolipid catabolism due to a genetic defect in the gene which codifies for alphagalactosidase A (α-Gal A) production (GLA gene). Mutations affecting the GLA gene result in deficiency of this lysosomal enzyme, which in turn leads to progressive accumulation of neutral glycosphingolipids, primarily globotriaosylceramide (GL-3), in different cell types throughout the body, including renal glomerular and tubular epithelial cells, myocardial cells and valvular fibrocytes, and nervous system. FD has an X linked inheritance. Currently, more than 600 disease-causing mutations in the GLA gene have been described. Most of these mutations are private, restricted to an individual family. De novo mutations are rare; population reports establish their frequency between 4 and 7%. We present the case of a pediatric male patient with a previously unreported de novomutation, which during family tree analysis, revealed a positive sibling, but nomutation found in the mother. Case presentation: A 17 year old male patient from Durango, Mexico with a negative family history presented at our ward. His initial symptoms began at 10 years of age and were primarily neurological: recurrent and progressive acroparesthesias several times a week, upper and lower extremity weaknesswithmovement limitations and fainting spells; he also complained of intermittent fever, hypohidrosis, abdominal pain and diarrhea. Clinical evaluation of the patient revealed tortuosity of retinal vessels, sinus bradycardia and hypotension and distal hyperesthesia in arms and legs. Fabry disease was suspected; αGal A enzyme activity, GLA gene analysis and lysoGL-3 measurement confirmed the diagnosis. Family tree evaluation was carried out; one six-year-old brother also had the mutation; however no mutation was found in the mother’s molecular analysis. FD specific evaluation of the index case revealed positive 24-hour proteinuria (6.5 mg/kg/h reference b4 ml/kg/h); CNSMRI was normal. Kidney biopsy was conducted; electron microscopy analysis of specimens revealed dense lamellar bodies corresponding to lipid material deposits in all cell groups, confirming the presence of a pathological mutation. Conclusions: De novo onset mutations in FD are rare; however, even more infrequent is the presence of germline mutations, which have been reported only periodically in case reports. Unfortunately, female germline cells are difficult to obtain to confirm this diagnosis. doi:10.1016/j.ymgme.2014.12.069