NEWLY DETECTED MISSENSE VARIANT IN FABRY DISEASE

Fabry disease (FD) is an inherited X-linked lysosomal storage disorder. De novo mutations present a clinical challenge in the diagnosis of FD.  We present the case of a  57 year-old symptomatic woman,  with abnormal enzymatic test and renal biopsy proven FD. A new missense variant c.731A>T(p.Asp244Val) associated with FD is detected. In addition we detected the same variant in her 22 year-old asymptomatic son, starting treatment and preventing disease progression.

Therefore, this novel variant was detected in two patients with FD.  There is no evidence of this missense variant in literature or database. The description of new and rare mutations as well as their clinical evolution helps to better understand FD and facilitate new genetic diagnosis.  Performing a renal biopsy confirmed FD and allowed the identification of the VUS as a pathogenic variable despite the fact that the patient had mild proteinuria, avoiding an endomyocardial biopsy. The discovery of this variant allowed the diagnosis of  an asymptomatic young male, preventing disease progresión and comorbidities, as well as his mother, improving her life expectancy.  Furthermore it is unusual for a female patient to present symptoms and to have an enzymatic test compatible with FD.

Fabry disease (FD) is an inherited X-linked lysosomal storage disorder (Xq22.1), due to the deficiency of alpha-galactosidase A (α-GLA) enzyme activity involved in the degradation of glycosphingolipids with consequent accumulation of globotriaosylceramide (Gb3) inside the cells.  It is caused by mutations in the GLA gene and is characterized by a large genotypic and phenotypic spectrum such as renal failure, stroke and cardiomyopathy . Typically female patients remain  asymptomatic throughout a normal life span, although they can be as severely affected as much as the male patients carrying the same mutation.

The diagnosis in females is stablished through a genetic test as their enzymatic tests are unreliable if normal. A heterozygous female has a 50% chance of transmitting the GLA pathogenic variant in each pregnancy. Symptomatic women and asymptomatic men have indication for treatment with enzyme replacement therapy: agalsidase alfa and agalsidase beta, as well as migalastat.

We present the case of a 57-year-old woman being under Nephrology follow-up for kidney stones, with 172 mg/24h proteinuria, 0.82 mg/dl creatinine, 82 glomerular filtration rate (GFR), and no other personal history. She began Cardiology follow-up for chest pain, identifying severe ventricular hypertrophy with hyperrefringence of the interventricular septum  on the echocardiogram (Image 1), and bradycardia with a short PR segment on the electrocardiogram.

A year later she was admitted to Neurology  ward due to cryptogenic parieto-occipital ischemic stroke. Given the thrombotic finding, proteinuria and cardiac alterations, FD was suspected by Nephrology service and dry gout was requested.

The result of the enzymatic test was α-GLA 1.5umol/L/h (reference values: 2-11.7) and  Gb3 14.5ng/mL (reference value <4), compatible with FD. The genetic test showed a hemizygous variant of unknown significance  (VUS) c.731A>T(p.Asp244Val) in GLA gene, probably pathogenic in the clinical context.

Cardiac magnetic resonance was performed, with endocardial late enhancement (Image 2) and shortened T1 maps (Image 3). The ophthalmological study revealed cornea verticillata.

A renal biopsy was performed to verify deposit and confirm the pathogenicity of VUS, observing intracytoplasmic inclusions in the podocytes and myelinated bodies inside the cytoplasm (Image 4).

With a diagnosis of classic symptomatic FD in a woman, enzyme replacement therapy was started with algalsidase beta 70 mg intravenously every 15 days, with no adverse reaction and stable since then, with resolution of proteinuria.

A genetic study was performed on her 22-year-old asymptomatic son, finding the same missense variant and starting treatment with agalsidase beta at a dose of 1 mg/kg.

Conclusions