Late-onset Fabry disease due to a new (p.Pro380Leu) pathogenic variant of GLA Gene

Metab Brain Dis. 2022 Dec;37(8):3023-3026. doi: 10.1007/s11011-022-01079-1.

PMID: 36178639

Vittoria Cianci, Angelo Pascarella, Sara Gasparini

Highlights: p.Pro380Leu novel pathogenic variant of GLA gene should be considered as pathogenic and associated with a late-onset variant of Fabry disease with a predominant neurological phenotype.

Abstract

Background: Due to pathogenic variants of the galactosidase alpha (GLA) gene, which result in a deficiency of alpha-galactosidase A, Fabry disease is a rare X-linked lysosomal storage disorder. Insufficient enzymatic activity causes gradual glycosphingolipid buildup within tissues and ensuing multisystemic dysfunction, with the heart, kidneys, and nervous system being most commonly affected. The classic type and the late-onset type are recognized as two kinds.

Objective: This study discusses the clinical features of a patient with Fabry disease of late onset who carries a novel GLA gene variant.

Results: This 50-year-old man had an acute ischemic stroke, which sent him to the hospital. He had angiokeratomas in the back and nape, and he also complained of acroparesthesia. Low alpha-galactosidase A activity in blood, borderline plasmatic lyso-Gb3 levels, cardiac fibrosis findings in the MRI, cerebrovascular disease in the brain MRI, and small fiber neuropathy without globotriaosylceramide-3 skin deposits were all seen. Targeted next-generation sequencing analysis used in genetic research revealed the missense substitution c.1139C>T (p.Pro380Leu) in the GLA gene.

Conclusion: This study contends that this novel variant ought to be regarded as pathogenic and connected to a late-onset Fabry disease variant with a predominance of neurological symptoms.

Keywords: GLA pathogenic variant, Late-onset Fabry Disease, Small fiber neuropathy, Stroke