Diagnosis of Fabry disease can be challenging, particularly when patients present with a non-specific sign or symptom that may be the only apparent manifestation of the disease. Diagnosis is further complicated when patients with atypical presentations harbour a GLA gene mutation with undetermined pathogenicity, or genetic variant of unknown significance (VUS).
Screening studies have shown that VUS occur frequently among patients with a single non-specific symptom of Fabry disease.1 There is increasing recognition that in these cases, biochemical testing and mutation analysis may be insufficient to provide a definitive diagnosis as it is uncertain whether the mutation is disease-causing. Organ specific diagnostic algorithms for Fabry disease have recently been developed by international expert panels to assist correct diagnosis in cases where a diagnosis of Fabry disease is uncertain.1-3
Unexplained left ventricular hypertrophy (LVH)
Left ventricular hypertrophy is a feature of Fabry disease and in some patients it may be the only manifestation.4-6 After excluding common causes, there are number of conditions that may underlie unexplained LVH.7
As a first step, a detailed history, family history, clinical examination and electrocardiogram should be undertaken. In the absence of red flags or diagnostic pointers for Fabry disease, biochemical testing and/or molecular testing for Fabry disease should still be considered if the cause of LVH remains truly unknown.
If molecular testing reveals a VUS in a patient with no other characteristic features of Fabry disease, additional testing including cardiac biopsy may be required to provide a definitive diagnosis.2
Diagnostic algorithm for unexplained left ventricular hypertrophy (LVH)
References: 1. Yousef Z, et al. Eur Heart J 2013;34:802–28. 2. Germain DP, et al. Orphanet Journal of Rare Diseases 2010, 5:30.Sanofi-Aventis Australia pty ltd trading as Sanofi Genzyme ABN 31 008 558 807. Talavera Corporate Centre, Building D, 12-24 Talavera Road, Macquarie Park, NSW 2113. GZANZ.FABR.18.05.0103(1). Date of Preparation March 2020.
Unexplained chronic kidney disease (CKD)
Renal impairment is a major complication of Fabry disease and a leading contributor to morbidity and mortality.8,9 As a first step, a detailed history, family history and clinical examination should be undertaken.
A possible diagnosis of Fabry disease should not be ruled out in the absence of other classical manifestations as renal impairment may be the first or only manifestation of the disease in some patients.10 Biochemical testing and molecular testing should be performed to confirm diagnosis of Fabry disease. In patients with unexplained CKD who harbour a VUS and do not exhibit any characteristic features of Fabry disease, it has been recommended that additional testing including renal biopsy is performed to provide definitive diagnosis.3
Diagnostic algorithm for unexplained chronic kidney disease (CKD)
Small fibre neuropathy (SFN) is a hallmark of Fabry disease, with an incidence of around 80%.11 Signs and symptoms of SFN in Fabry disease include loss of temperature sensation in hands and feet, reduced tolerance to cold and, most notably, pain.11 Neuropathic pain is a characteristic presenting feature of Fabry disease. It is experienced by 60% to 80% of affected boys and girls with SFN. Misdiagnosis of pain is common as it can be the first clinical manifestation of the disease and has a wide differential diagnosis.
Diagnosing SFN due to Fabry disease can be challenging in patients with a GLA gene mutation but without characteristic signs and symptoms of Fabry disease. Other causes of SFN neuropathy in children need to be ruled out, in particular autoimmune illnesses including rheumatoid arthritis, rheumatic fever, systemic lupus erythematosus, collagen vascular disease and Raynaud’s disease, as well as neurosis and erythromelalgia.12,13 ‘Growing pains’ is a frequent misdiagnosis in children.12 Common differential diagnoses in adulthood include celiac disease and multiple sclerosis.12
Fabry disease should always be considered as a possible cause of SFNs.14 Reduced intraepidermal nerve fibre density (IENFD) and decreased thermal sensation are Fabry-specific features of SFN that can assist in the correct diagnosis of neuropathic pain due to Fabry SFN.14
Diagnostic algorithm for Small Fibre Neuropathy (SFN)