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Fabry Disease

November 10, 2017

Clinical features

Fabry disease is a lysosomal storage disorder which will typically lead to the accumulation of the sphingolipid globotriaosylceramide (Gb3) in numerous organs of the body 1, 2. The patients may presents with isolated symptoms (e.g. only pain or cerebrovascular disorders) or with multiple symptoms which can differ in severity. In particular, these include pain (acroparasthesias), cardiac arrhythmias or neurological symptoms. If left untreated, Fabry disease not only impairs the quality of life, but also strongly reduces patient´s life expectancy. Fabry disease affects an estimated 1 in 40,000 to 60,000 males 1-3. This disorder also occurs in females, although less frequently. Milder, late-onset forms of the disorder are probably more common than the classic, severe form.

Fabry disease is caused by pathogenic variants in the GLA gene that encodes an enzyme alpha-galactosidase A. Pathogenic variants in the GLA gene alter the structure and function of the enzyme, resulting in progressive accumulation of Gb3 in cells, leading to the varied signs and symptoms of Fabry disease 3. Nearly 98% of male patients with a clinical diagnosis of Fabry disease have an identifiable mutation 3.

Fabry disease should be considered in males and females with the following signs 1-3:

  • Periodic crises of severe pain in the extremities (acroparesthesias)
  • Vascular cutaneous lesions (angiokeratomas)
  • Sweating abnormalities (anhydrosis, hypohydosis, and rarely hyperhidrosis)
  • Characteristic corneal and lenticular opacities
  • Unexplained stroke
  • Unexplained left ventricular hypertrophy
  • Renal insufficiency of unknown etiology

The most efficient and reliable method for the diagnosis of Fabry disease in affected males is the demonstration of deficient α-galactosidase A (α-Gal A) enzyme activity in plasma, isolated leukocytes, and/or cultured cells. Males with classic Fabry disease have less than 1% α-Gal A enzyme activity.

In CENTOGENE, over 500 variants have been detected in GLA gene, which include missense, frameshift, nonsense, splicing variants and others. For a proportion of pathogenic variants, we have also confirmed the pathogenicity via our valid biomarker/enzymatic assay.

Enzyme replacement therapy is available for the treatment of Fabry disease 5. It can reduce lipid storage, ease pain, and preserve organ function in affected patients. The pain that accompanies the disease may be treated with anticonvulsants such as phenytoin and carbamazepine. Gastrointestinal hyperactivity may be treated with metoclopramide. Some individuals may require dialysis or kidney transplantation.

Both males and females can be diagnosed by enzyme assay testing. Due to X-inactivation, female carriers may present normal levels of the alpha-GAL enzyme or may be affected. For this reason genetic testing should be considered together with clinical manifestation as well as enzyme activity.

Differential diagnosis

The differential diagnosis of Fabry disease and GLA-related disorders – depending on the major symptoms in the initial case – includes the following diseases:

  • Rheumatoid arthritis
  • Erythromelalgia
  • Systemic lupus erythematosus
  • Petechiae, Raynaud syndrome
  • Early-onset stroke

Testing strategy

CENTOGENE offers an extensive Fabry screening program, including biochemical, genetic and biomarker testing for effective disease diagnosing and monitoring. Measuring biomarkers is essential when treating patients with Fabry disease. Lyso-Gb3 in Fabry disease is able to reflect the burden of the disease and any potential need of correcting the course of treatment. Tracking biomarkers helps in follow-up of the disease progress and estimation of the efficiency of treatment. We recommend measuring the biomarker at least once every three months.

To confirm/establish the diagnosis, we offer biochemical, genetic and biomarker testing. Standard testing includes biochemical assays for enzyme activity and following steps include GLA gene sequencing and deletion/duplication testing. We are also offering a broad selection of NGS panels that are designed for the molecular diagnostics of related conditions/phenotypes i.e. the Cardiomyopathy hypertrophic panel.

For males:

Step 1: α-Gal A enzyme analysis

Step 2: If enzyme is deficient, Lyso Gb3 biomarker analysis + GLA gene sequencing.

Step 3: If sequencing is negative, GLA deletion/duplication analysis.

For females:

Step 1: GLA gene sequencing

Step 2: If no mutation identified, GLA gene deletion/duplication analysis.

Step 3: If a pathogenic mutation is identified, then follow up with Lyso-Gb3 biomarker analysis.

Referral reasons

The following individuals are candidates for this particular gene testing:

  • Individuals with a known or suspected family history of disease and presentation of the most common symptoms
  • Individuals without a positive family history, but with symptoms resembling this disease

Test utility

Biochemical testing, sequencing and deletion/duplication of this gene should be performed in all individuals suspected for this particular phenotype. Confirmation of a clinical diagnosis through genetic testing may direct medical management.

Genetic counseling is recommended and can provide a patient and/or family with the natural history of the condition, identify at-risk family members, provide reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.