Cerebral Small Vessel Disease as the Predominant Manifestation of Fabry Disease Caused by a Hemizygous GLA Frameshift Variant: A Case Report

Introduction. Cerebral small vessel disease (SVD) is an early but nonspecific manifestation of Fabry disease. We describe a middle-aged patient with severe SVD in whom recognition of long-standing systemic disease ultimately led to the detection of a likely pathogenic GLA variant and enabled initiation of enzyme replacement therapy before advanced renal involvement developed. Methods. The patient underwent clinical evaluation, brain MRI, whole-genome sequencing, biochemical analysis of dried blood spots, and Sanger sequencing. Results. A 41-year-old man presented with recurrent lacunar strokes, progressive gait impairment, pseudobulbar syndrome, cognitive decline, and bladder dysfunction. Brain MRI revealed severe SVD with confluent white matter hyperintensities, multiple lacunes, and microbleeds. From early adulthood, he had arterial hypertension, hypohidrosis, acroparesthesias, and mild proteinuria. Later, he developed a cataract and an acute dissection of the ascending aorta. Whole-genome sequencing identified a hemizygous GLA frameshift variant (c.1095dup), predicted to truncate alpha-galactosidase A (p.Thr366TyrfsTer9) and classified as likely pathogenic. The diagnosis was confirmed by Sanger sequencing, markedly reduced alpha-galactosidase A activity, and elevated lyso-Gb3 in dried blood spots. Discussion. This case expands the neurologic phenotype of Fabry disease and supports its inclusion in the differential diagnosis of severe early-onset SVD, even when the classic systemic phenotype is incomplete.