In patients with lysosomal storage disorders, biomarkers can be used to support a diagnosis.1 In Fabry disease, deficient enzymatic activity of alpha-galactosidase A, due to variants in the GLA gene, leads to an accumulation of the glycosphingolipids globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) within almost all cell types and various organs.2-5 One diagnostic biomarker is lyso-Gb3, as levels are markedly elevated in some patients with Fabry disease.5-7 To assess the extent of organ involvement in Fabry disease, numerous clinical indicators can be used.8

The international PRoposing Early Disease Indicators for Clinical Tracking in Fabry Disease (PREDICT-FD) modified Delphi initiative (funded by Shire, now part of Takeda) aimed to determine early clinical indicators that may lead to the initiation of Fabry disease-specific treatment in treatment-naïve patients. Early indicators of Fabry disease, on which consensus was reached, are presented in Figure 1.8

  • Elevated urine albumin:creatinine ratio*
  • Histological damage using kidney biopsy*
  • Microalbuminuria*
  • Abnormal glomerular filtration rate
  • Decline in iohexol glomerular filtration rate
  • Podocyte inclusions.

*The prognostic significance of this indicator is different between male and female patients
A causal relationship between this indicator and Fabry disease is required to justify treatment initiation

 

  • Markers of early systolic or diastolic dysfunction*
  • Elevated serum cardiac troponin*
  • Early indicators of left ventricular hypertrophy
  • Early indicators of histological damage using heart biopsy‡§
  • Late gadolinium enhancement on cardiac magnetic resonance imaging (MRI)
  • Elevated serum N-terminal probrain natriuretic peptide*
  • Reduced myocardial T1 relaxation time on cardiac MRI
  • Abnormal electrocardiogram†‡
  • Abnormal echocardiogram*
  • Abnormal wall motion on echocardiogram.

*A causal relationship between this indicator and Fabry disease is required to justify treatment initiation
Including decreased myocardial strain and strain rate, tissue Doppler abnormalities, enlarged left atrium or pulmonary venous flow abnormalities on echocardiogram
Including shortened PR interval, non-sustained ventricular tachycardia and symptomatic bradycardia
§Cardiac histological changes have been reported in Fabry disease; however, cardiac biopsy is too invasive to be recommended

  • Neuropathic pain*
  • Painful gastrointestinal symptoms suggestive of gastrointestinal neuropathy related to Fabry disease.*

*A causal relationship between this indicator and Fabry disease is required to justify treatment initiation

  • Pain in extremities or neuropathy
  • Stroke or transient ischaemic attack
  • Angiokeratoma
  • Organ biopsy*
  • Non-pain gastrointestinal symptoms, including diarrhoea or frequent diarrhoea, related to Fabry disease
  • Sweating abnormalities or heat or exercise intolerance.

*Including skin biopsy for small-fibre neuropathy, and kidney and heart biopsy

  • Febrile crises
  • Patient-reported progression of symptoms or signs
  • Angiokeratoma.

Figure 1.
Early clinical indicators of Fabry disease based on the PREDICT-FD initiative. Reproduced and adapted with permission from Hughes DA et al. BMJ Open 2020; 10: e035182.

C-ANPROM/INT/FAB/0016; Date of preparation: March 2021