Associazione Nazionale Medici Cardiologi Ospedalieri




Dall’Ospedale Valeria Parma(Parma) – Azienda ospedaliero-universitaria | Valsania Teresa Piacenza(Piacenza) – Ospedale Guglielmo da Saliceto | Di Spigno Francesco Piacenza(Piacenza) – Ospedale Guglielmo da Saliceto

Fabry disease is a genetic disorder caused by mutations in the GLA gene, which encodes alpha-galactosidase A, leading to enzyme dysfunction and subsequent accumulation of glycosphingolipids. In the classical form, it occurs in childhood or early adolescence with renal, cardiac, and neurological involvement, resulting in a poor prognosis.

The GLA D313Y is a missense mutation resulting in a significant reduction of enzyme activity in plasma, while leukocyte enzyme activity remains within normal limits, leading to a ‘pseudo-deficiency’ of enzyme activity with uncertain pathogenicity. In literature, it has been observed that individuals with this mutation may present predominantly with central neurologic manifestations, characterized by multifocal white matter lesions. Historically they do not receive indications for initiating enzyme replacement or molecular chaperone therapies.

We present the case of a man affected by arterial hypertension and history of chronic lower limb pain who experienced a lacunar stroke at the age of 35. The GLA D313Y mutation was identified and enzyme activity assay in plasma was within normal limits, precluding the initiation of enzyme replacement therapy. Over the following years, he suffered two additional ischemic strokes, a progressive decline in renal function to stage 3, and acute coronary syndrome. Transthoracic echocardiography revealed hypertrophic non-obstructive cardiomyopathy (SIVd 20 mm) with normal biventricular ejection fraction. Cardiac magnetic resonance showed late gadolinium enhancement of inferior junctional and inferior wall in middle segment (Fig.1). Considering the patient ‘s clinical conditions involving multi-organ impairment, an enzymatic activity test was performed on leukocytes, revealing a reduced activity. This prompted the decision to initiate enzyme replacement therapy.

This case report supports the hypothesis that the D313Y mutation may be associated with a later presentation and not only neurological involvement. In our experience, it’s mandatory to proceed with the determination of leukocyte enzyme activity in presence of normal enzyme activity in plasma. As an alternative, the detection of glycosphingolipids’ accumulation could be useful, but myocardial and renal biopsy poses a high bleeding risk, especially in anticoagulated or antiaggregated patients. The authors propose considering the initiation of therapy in patients with the D313Y mutation who exhibit significant organ involvement.