Fabry disease (FD) (OMIM: #301500) is an X-linked lysosomal storage disorder caused by a deficiency of the enzyme alpha galactosidase A (aGAL) caused by mutations in the GLA gene (OMIM: *300644). Globotriaosylceramide (Gb3) is the main storage product in FD. In addition, lysoGb3 (or globotriaosylsphingosine), a deacylated form of Gb3 has been identified as a secondary storage product and is a useful biomarker to support the diagnosis and determine the phenotype.
The disease can be divided into an early onset, severe classical phenotype and a non-classical phenotype. Despite the X-linked inheritance pattern, women with classical FD often have signs and symptoms of FD. Four clinical subgroups can thus be distinguished.
Normal leucocyte aGAL activity in women does not rule out FD or distinguish between a classical and non-classical phenotype.
Over 900 variants in the GLA gene have so far been described, most of which appear in single families (HGMD Professional 2018.4). Individuals that are identified as carrying a GLA variant do not always display disease manifestations and the presence of a GLA variant does not necessarily equal a diagnosis of FD.
Many of the FD symptoms are non-specific (e.g. stroke, left ventricular hypertrophy and chronic kidney disease). Furthermore, even the more characteristic FD symptoms such as neuropathic pain, angiokeratoma and cornea verticillata are not pathognomonic (e.g. certain medication can induce cornea verticillata).
This poses diagnostic difficulties, for instance in patients with isolated renal or cardiac disease and a GLA variant in whom the relationship between the GLA variant and their organ involvement is unclear. Several diagnostic algorithms have been developed by experts to assist in these diagnostic dilemmas (Smid et al 2014, van der Tol et al 2014, van der Tol et al 2015). These algorithms are summarized in the following flow-chart.
For a given GLA variant it is important to distinguish whether or not the variant is pathogenic and, if pathogenic, whether or not the variant is associated with classical or non-classical Fabry disease. This latter distinction has important prognostic value and aids decisions regarding follow-up, treatment initiation and family counseling.