Variable phenotypic presentations of renal involvement in Fabry disease: a case series

Sarah Mccloskey,Paul Brennan,John A Sayer

doi:10.12688/f1000research.13708.1

Abstract

Fabry disease is an X-linked genetic deficiency in the alpha-galactosidase enzyme resulting in intracellular accumulation of glycosphingolipids and multisystem organ dysfunction. Typically 50% of males and 20% of affected females have renal involvement, ranging from proteinuria or reduced renal function, renal parapelvic cysts and progressive renal disease ultimately requiring transplantation or dialysis. The phenotypic presentation of Fabry disease is incredibly varied and will even vary between family members with the same confirmed genetic mutation. In a cohort of patients affected by Fabry disease in the North East of England we examine the different phenotypic presentations of eight index cases (6 male, 2 female) with predominantly renal disease and the renal manifestations within their family members. The mean age of presentation was 40 years of age (range 23-59 years). Various multisystem manifestations were observed including cardiac, neurological, cerebrovascular and skin involvement. Two of the male index patients reached end stage renal disease (ESRD) requiring renal replacement therapy. Two female index patients had phenotypes limited to hypertension and proteinuria at presentation and the remaining patients had either stable or progressive chronic kidney disease at the time of diagnosis. We demonstrate the need for a high index of suspicion in order to consider Fabry disease as a diagnosis and the importance of cascade genetic screening to identify affected family members so that treatment can be initiated in a timely fashion.

Highlights

Fabry disease is an X-linked genetic deficiency in the alpha-galactosidase enzyme resulting in an intracellular accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids causing organ dysfunction[1]
He had been made aware that his brother had a diagnosis of Fabry disease and his diagnosis was confirmed by low serum levels of alpha-galactosidase and genetic testing
Mutational analysis of GLA revealed a nonsense mutation c.679C>T, p.Arg227*. His brother was seen the following year aged 22 and was noted to have slightly reduced renal function with no evidence of microalbuminuria but with evidence of left ventricular diastolic dysfunction on echocardiogram. Both brothers have been commenced on enzyme replacement therapy (ERT) and six other family members have been identified through cascade genetic screening

Summary

Introduction

Fabry disease ( called Anderson-Fabry disease) is an X-linked genetic deficiency in the alpha-galactosidase enzyme resulting in an intracellular accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids causing organ dysfunction[1]. A year later his brother was referred to Renal Services aged 43 years with progressive renal dysfunction (estimated Glomerular Filtration Rate (eGFR) 57 mL/min/1.73m2) and proteinuria He had been made aware that his brother had a diagnosis of Fabry disease and his diagnosis was confirmed by low serum levels of alpha-galactosidase and genetic testing (missense mutation in GLA p.Ile117Ser). F A 45 year old female presented with proteinuria and progressive CKD but developed cardiomyopathy She had initially undergone a renal biopsy which reported findings consistent with focal segmental glomerular sclerosis (FSGS) on review, the electron microscopy was found to have evidence of podocyte vacuolation in keeping with a diagnosis of Fabry disease. Both brothers have been commenced on ERT and six other family members have been identified through cascade genetic screening

Discussion

Findings

Conclusion

Germain DP