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Different renal phenotypes in related adult males with Fabry disease with the same classic genotype.

ABSTRACT: Fabry disease related patients with classical mutation usually exhibit similar severe phenotype especially concerning renal manifestation.A dry blood spot screening (DBS) and the DNA analysis has been performed in a 48-year-old man (Patient 1) because of paresthesia.The DBS revealed absent leukocyte ?-Gal A enzyme activity while DNA analysis identified the I354K mutation. Serum creatinine and e-GFR were in normal range and also albuminuria and proteinuria were absent. The brain MRI showed ischemic lesions and a diffuse focus of gliosis in the white matter, while the echocardiogram showed a left ventricular hypertrophy. The renal biopsy performed in the case index showed a massive deposition of zebra bodies. By a familiar investigation, it was recognized that his brother (Patient 2) died 2 years before from sudden death syndrome at the age of 49. He had suffered sporadic and undiagnosed pain at the extremities, a prior cataract, bilateral neurosensorial hearing loss and left ventricular hypertrophy on Echocardiogram. His previous laboratory examinations revealed a normal serum creatinine and the absence of proteinuria. Pedigree analysis of the brothers revealed a high disease burden among family members, with an affected cousin (Patient 3) who progressed early to end-stage renal disease (ESRD) that required renal transplantation.Here we describe the clinical history of three adult male members of the same family with the same genotype who manifested different presentation and progression of the disease, particularly concerning the renal involvement.

SUBMITTER: Mignani R

PROVIDER: S-EPMC5511792 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Different renal phenotypes in related adult males with Fabry disease with the same classic genotype.

Mignani Renzo R Moschella Mariarita M Cenacchi Giovanna G Donati Ilaria I Flachi Marta M Grimaldi Daniela D Cerretani Davide D Giovanni Paola De P Montevecchi Marcello M Rigotti Angelo A Ravasio Alessandro A

Molecular genetics & genomic medicine 20170508 4

<h4>Background</h4>Fabry disease related patients with classical mutation usually exhibit similar severe phenotype especially concerning renal manifestation.<h4>Methods</h4>A dry blood spot screening (DBS) and the DNA analysis has been performed in a 48-year-old man (Patient 1) because of paresthesia.<h4>Results</h4>The DBS revealed absent leukocyte <i>α</i>-Gal A enzyme activity while DNA analysis identified the I354K mutation. Serum creatinine and e-GFR were in normal range and also albuminuri ...[more]

PMID: 28717668

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Project description:Venglustat inhibits the enzymatic conversion of ceramide to glucosylceramide, reducing available substrate for the synthesis of more complex glycosphingolipids. It offers a potential new approach to the treatment of patients with Fabry disease (α-Gal A deficiency), in whom progressive accumulation of such glycosphingolipids, including globotriaosylceramide (GL-3), in the lysosomes of a wide range of cell types often leads to vital organ complications in adulthood. An international, open-label, single-arm, Phase 2a uncontrolled 26-week clinical study (NCT02228460) and a 130-week extension study (NCT02489344) were conducted to assess the safety, pharmacodynamics, pharmacokinetics, and exploratory efficacy of 15 mg once daily oral venglustat in treatment-naïve adult male patients with classic Fabry disease. Of 11 patients (18-37 years old) who initially enrolled, nine completed the 26-week study and seven completed the extension study. A total of 169 treatment-emergent adverse events (TEAEs) were reported by nine patients, the majority being mild (73%) and unrelated to the study drug (70%). Nine serious TEAEs (serious adverse events) and 11 severe TEAEs, including a self-harm event, were reported. No deaths or treatment-related life-threatening adverse events were reported. Skin GL-3 scores in superficial skin capillary endothelium (SSCE), estimated by light microscopy, were unchanged from baseline at Week 26 in five patients, decreased in three patients, and increased in one patient. There was no significant change in GL-3 scores or significant shift in grouped GL-3 scores. Five of six patients had reductions from baseline in GL-3 score at the end of the extension study. At Weeks 26 and 156 the mean (standard deviation) changes from baseline in the fraction of the volume of SSCE cytoplasm occupied by GL-3 inclusions, measured by electron microscopy unbiased stereology, were - 0.06 (0.03) (p = 0.0010) and - 0.12 (0.04) (p = 0.0008), respectively. Venglustat treatment reduced markers in the synthetic and degradative pathway of major glycosphingolipids; proximal markers reduced rapidly and more distal markers (plasma GL-3 and globotriaosylsphingosine) reduced progressively. There were no biochemical or histological indications of progression of Fabry disease over 3 years of follow-up. These findings confirm target engagement and the pharmacodynamic effects of venglustat in adult males with classic Fabry disease. However, further clinical evaluation in larger studies is needed to determine efficacy and safety.

Dataset Information

Different renal phenotypes in related adult males with Fabry disease with the same classic genotype.

Publications

Different renal phenotypes in related adult males with Fabry disease with the same classic genotype.

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