Genotype-Phenotype Spectrum of 52 Mexican Patients With Fabry Disease: A Novel GLA Variant With Atypical Phenotype

Abstract

Introduction: Fabry disease (FD) is a rare lysosomal type 3 disorder with an X-linked inheritance pattern caused by pathogenic variants in the GLA gene. This study aimed to describe the genotype and phenotype of 52 Mexican patients with FD.

Methods: We included 12 patients with clinical and molecular diagnosis of FD treated at our institution and 40 FD Mexican patients already reported in the literature.

Results: The most frequent manifestations were acroparesthesias (71.2%), hypohidrosis or anhidrosis (48.1%), heat intolerance (46.2%), and proteinuria (42.3%). Renal and neurological manifestations were more prevalent in males than females. Cardiac involvement included hypertrophic cardiomyopathy and Wolf-Parkinson-White arrhythmia. Cornea verticillata was seen in 14 patients (26.9%) and angiokeratomas in 15 (28.8%). We identified 14 variants in the GLA gene in Mexican patients with FD. We found a novel variant GLA c.122C>G that causes an atypical FD phenotype with predominantly neurological involvement in two unrelated patients, one of them with a forthright clinical and radiological overlap of Multiple Sclerosis and normal biological biomarkers, thus requiring a renal biopsy that helped confirm the diagnosis of FD.

Conclusions: The genotype and phenotype of Mexican patients with FD are similar to other populations. Atypical phenotype of FD, such as the one associated with the novel variant c.122C>G, can be a diagnostic challenge, as it can be mixed up with MS. Our findings confirm the limitations of noninvasive diagnostic methods and the necessity of the renal biopsy when the clinical suspicion of FD is high.

Keywords: Fabry disease; GLA; alpha‐galactosidase A; multiple sclerosis; neurogenetics; renal biopsy.

FIGURE 1

Brain MRI of Patient 1 (A–E) and brain and spine MRI of Patient 2 (F–I) with variant c.122C>G. Patient 1 MRI in (A) T1, (B) Flair, (C) T2, and (D and E) TOF shows the absence of vascular flow in the right middle cerebral artery in its entirety with decreased flow from the extracranial left carotid artery, resulting in frontoparietoccipital infarction. Patient 2 brain MRI in (F) T1 and (G) SWAN shows juxtacortical, periventricular, and subcortical supratentorial demyelinating lesions, ovoid in shape, and those parallel to the lateral ventricles present the central vein sign. (H) The infratentorial demyelinating lesion is located in the periventricular region of the middle cerebellar peduncle and is hypointense on T1 (black hole). Patient 2 spine MRI in (I) STIR showed demyelinating lesions involving lateral portions, mainly at the level of C3‐4, C4‐5, and C5‐C6, with no data of acute inflammatory activity with contrast media.

FIGURE 2

Morphologic comparison between classic and atypical Fabry disease. Images A through C correspond to a renal biopsy of a classic case of FD, and images D through F correspond to a renal biopsy of the atypical FD case (Patient 2). Images A and D are cross‐sections of the renal cortex showing glomeruli stained with hematoxylin and eosin (H&E). Images B–F correspond to light microscopy. Classic FD is characterized by enlarged podocytes with foamy cytoplasm (A); while atypical FD lacks such characteristic changes (D and E). Ultrastructurally, classic FD is recognized for the presence of abundant zebra bodies in the cytoplasm of podocytes (B), tubular epithelial cells (C), in atypical FD there are a few zebra bodies (F). P, podocyte; US, urinary space; N, nucleus; ZB, Zebra bodies; CL, capillary lumen; BB, brush border.

FIGURE 3

Pathogenic variants in the GLA gene reported in Mexican patients with Fabry disease. Exons are numbered from 1 to 7. Splice site, missense, and frameshift variants are marked in blue, red, and green, respectively.