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Thematic Area: Fabry Disease

What is Fabry Disease?

Fabry disease, also known as Anderson-Fabry disease, is a rare inherited genetic disorder classified as a lysosomal storage disorder. It is caused by mutations in the GLA gene, which leads to a deficiency or dysfunction of the enzyme alpha-galactosidase A (α-GAL A). This enzyme is responsible for breaking down a specific fatty substance called globotriaosylceramide (Gb3 or GL-3), which is normally cleared from cells.

In Fabry disease, the lack of functional α-GAL A results in the progressive accumulation of Gb3 in various cells and tissues throughout the body, particularly in the blood vessels, kidneys, heart, skin, and nervous system. This accumulation interferes with normal cellular function and can lead to a wide range of signs and symptoms.

Fabry disease is an X-linked disorder, meaning the defective gene responsible for the condition is located on the X chromosome. As a result, the disease predominantly affects males, while females can be carriers or may exhibit milder symptoms due to the presence of a second, normal X chromosome.

 

Fabry Disease Symptoms:

Symptoms of Fabry disease can vary widely and may appear at different ages. Common signs and symptoms include:

  • Pain and burning sensations in the hands and feet (acroparesthesia)
  • Skin rashes (angiokeratomas) that appear as small, dark red spots
  • Fatigue and weakness
  • Reduced sweating
  • Gastrointestinal issues
  • Kidney dysfunction and kidney failure
  • Cardiac abnormalities, such as hypertrophic cardiomyopathy
  • Hearing loss and tinnitus
  • Vision problems
  • Neurological complications, including stroke and neuropathic pain
  • Angiokeratomas (small, non-cancerous, reddish-purple elevated spots on the skin) may develop on the lower part of the trunk of the body and become more numerous with age.
     

Diagnosis:

Fabry disease is often diagnosed through a combination of clinical evaluation, family history assessment, and specific laboratory tests to measure the level of α-GAL A activity or detect genetic mutations in the GLA gene.

 

Fabry Disease Treatment:

Treatment of Fabry disease aims to alleviate symptoms, slow disease progression, and improve the quality of life.

There isn’t a cure for Fabry disease. Medications for pain and stomach problems can ease symptoms. There are two treatments that may slow down the build up of the fatty substances with the goal to prevent heart problems, kidney disease and other life-threatening complications:

Enzyme replacement therapy (ERT) is a primary treatment option for Fabry disease. ERT involves regular infusions of synthetic α-GAL A to replace the deficient enzyme and help reduce Gb3 accumulation. An intravenous (IV) infusion of lab-made agalsidase beta enzyme (Fabrazyme®) has to be administrated every two weeks. This replacement enzyme does the work of the missing alpha-GAL enzyme so that fatty substances don’t build up. PAtients may receive an antihistamine and other medications before therapy to prevent an allergic reaction.

Oral chaperone therapy: Chaperones are small molecules that repair faulty alpha-GAL enzyme. The mended enzymes can then break down the fatty substance. With this therapy, a pill (migalastat [Galafold®]) has ti be administrated every other day to stabilize the faulty alpha-GAL enzyme. Not everyone with Fabry disease can be treated with this medication. It depends on the specific genetic mutation in the GLA gene if someone is eligible for this treatment.

Researchers are actively developing several new therapies using genetic engineering and stem cell technologies.

Other supportive treatments may be prescribed to manage specific symptoms and complications associated with the disease.

Early diagnosis and proactive management are crucial to preventing irreversible organ damage and improving long-term outcomes in individuals with Fabry disease. Regular medical follow-ups and multidisciplinary care are essential to address the complex nature of the condition and provide comprehensive support for affected individuals and their families.

Experts Recommendations:

Screening, diagnosis and management of patients with Fabry disease: Conclusions from a KDIGO Controversies Conference

Reference: Schiffmann R, Hughes DA, Linthorst GE, et al. Kidney Int. (2017). doi: 10.1016/j.kint.2016.10.004

Core Recommendations:

  1. The diagnosis is established in males by a-galactosidase A–specific activity below 25-30% of control in peripheral white blood cells.
  2. There is a wide phenotypic variability even among patients with the same GLA mutation.   
  3. FD should be considered and tested in patients with chronic kidney disease (CKD) with no definitive cause of nephropathy, especially in familial cases.
  4. Common standard-of-care therapies are highly effective in alleviating symptoms and treating disease complications. There is no scientific evidence as to the optimal age of enzyme replacement therapy (ERT) initiation.
  5. Development of signs or symptoms related to FD is an indication to start ERT. For the kidney, this implies the development of CKD. The benefits of early treatment, before irreversible tissue injury occurs, should be balanced against the burden of biweekly infusions in very young individuals. There is a suggestion that ERT slows the progression of kidney involvement and results in reduction of hypertrophic cardiomyopathy, especially when started prior to established fibrosis. However, there is no reduction in the rate of stroke with ERT.

Comments by Evaluators:

  • Authors are key opinion leaders; no external reviewers available due to large number of authors.

Recommendations for initiation and cessation of enzyme replacement therapy in patients with Fabry Disease:  the European Fabry Working Group consensus document

Reference: Biegstraaten M, Arngrímsson R, Barbey F, et al. Orphanet J Rare Dis. (2015).doi: 10.1186/s13023-015-0253-6

Core Recommendations:

  1. For classically affected males, enzyme replacement therapy (ERT) is recommended as soon as there are early clinical signs of kidney, heart or brain involvement, but may be considered in patients ?16 years in the absence of clinical signs or symptoms of organ involvement.
  2. Classically affected females and males with non-classical Fabry disease (FD) should be treated as soon as there are early clinical signs of kidney, heart or brain involvement, while treatment may be considered in females with non-classical FD with early clinical signs that are considered to be due to FD.
  3. Treatment should not be withheld from patients with GFR < 45 ml/min/1.73 m2 and from those on dialysis or with cognitive decline, but carefully considered on an individual basis.
  4. Stopping ERT may be considered in patients with end stage FD or other co-morbidities, leading to a life expectancy of <1 year. In those with cognitive decline of any cause, or lack of response for 1 year when the sole indication for ERT is neuropathic pain, stopping ERT may be considered.
  5. Also, in patients with end stage renal disease, without an option for renal transplantation, in combination with advanced heart failure (NYHA class IV), cessation of ERT should be considered.

Comments by Evaluators:

  • Authors are key opinion leaders and leading experts in Fabry disease.
  • Delphi Survey among real experts on Fabry disease.  

Fabry Nephropathy:ndications for screening and guidance for diagnosis and treatment by the European Renal Best Practice 

Reference: Terryn W, Cochat P, Froissart R, et al. Nephrol Dial Transplant. (2013). doi: 10.1093/ndt/gfs526

Core Recommendations:

  1. We recommend screening for Fabry Disease in male CKD patients below 50 years of age in whom a reliable renal diagnosis is absent.
  2. We suggest screening for Fabry Disease in females with unexplained CKD, irrespective of age, with other unexplained symptoms potentially associated with Fabry Disease.
  3. We recommend discussing with the patient the implications of diagnosing a genetic disease and the possible implications for the at-risk relatives.
  4. We recommend using enzyme activity measurement for alpha-Gal A as a primary tool in males, followed by confirmation with mutation analysis when positive.
  5. We do not recommend starting enzyme replacement therapy in patients with proteinuria or eGFR <60 mL/min/1.73 m2, except for non-renal indications. 
  6. We recommend that when enzyme replacement therapy is deemed indicated, it should be started as part of a well-designed clinical trial, either observational or interventional.

Comments by Evaluators:

  • Slightly old but methodologically correct, with very clear recommendations 

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