Diagnostic dilemmas in Fabry disease: a case series study on GLA mutations of unknown clinical significance.

[fabry disease]

Fabry disease ' (FD ) phenotype is heterogeneous : alpha-galactosidase A gene mutations (GLA ) can lead to classical or non-classical FD , or no FD . The aim of this study is to describe pitfalls in diagnosing non-classical FD and assess the diagnostic value of plasma globotriaosylsphingosine . This is a case series study . Family 1 (p .A 143 T ) presented with hypertrophic cardiomyopathy (HCM ), absent classical FD signs , high residual alpha-galactosidase A activity (AGAL-A ) and normal plasma globotriaosylsphingosine . Co -segregating sarcomeric mutations were found . Cardiac biopsy excluded FD . In family 2 (p .P 60 L ), FD was suspected after kidney biopsy in a female with chloroquine use . Males had residual AGAL-A , no classical FD signs and minimally increased plasma globotriaosylsphingosine , indicating that p .P 60 L is most likely non-pathogenic . Non-specific complications and histology can be explained by chloroquine and alternative causes . Males of two unrelated families (p .R 112 H ) show AGAL-A <5 %, but slightly elevated plasma globotriaosylsphingosine (1 .2 -2 .0 classical males >50 nmol /l ). Histological evidence suggests a variable penetrance of this mutation . Patients with GLA mutations and non-specific findings such as HCM may have non-classical FD or no FD . Other (genetic ) causes of FD -like findings should be excluded , including medication inducing FD -like storage . Plasma globotriaosylsphingosine may serve as a diagnostic tool , but histology of an affected organ is often mandatory .