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Fabry disease
This inherited disorder primarily affects males but can also affect females, causing a range of symptoms impacting various organs including the kidneys, heart, skin, and nervous system. Early diagnosis and management are important for reducing disease progression.
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Overview
Fabry disease is a rare inherited condition caused by changes in the *GLA* gene, which is located on the X chromosome [PMID:31252112]. This genetic alteration results in a deficiency of an enzyme called alpha-galactosidase A (alpha-Gal A). The enzyme's role is to break down a specific fatty substance, globotriaosylceramide (Gb3), within the lysosomes of cells. Lysosomes are often described as the 'recycling centres' of the cell. When alpha-Gal A is deficient or not working correctly, Gb3 accumulates over time in various cells and tissues throughout the body, leading to cell damage and organ dysfunction.
Fabry disease is a progressive condition, meaning symptoms typically worsen over time if not managed. The severity and age of onset of symptoms can vary significantly between individuals, even within the same family. It is broadly categorised into 'classic' and 'later-onset' forms, though there is a spectrum of presentation [PMID:28795744]. The condition is estimated to affect between 1 in 40,000 and 1 in 117,000 live births, but the exact prevalence may be higher due to underdiagnosis, particularly of milder forms.
Symptoms & clinical features
The symptoms of Fabry disease are diverse and can affect many parts of the body, reflecting the widespread accumulation of Gb3. Early symptoms often include burning pain in the hands and feet, particularly in response to temperature changes, exercise, or fever. This pain is known as acroparesthesia [PMID:28795744]. Another common early sign is the development of angiokeratomas - small, dark red or purple spots, typically found on the skin, especially around the hips, buttocks, and thighs.
Other symptoms that can develop over time include reduced sweating (hypohidrosis), digestive issues such as abdominal pain, diarrhoea, and nausea, and corneal opacities (clouding of the cornea) that appear as spokes in the eye and do not usually affect vision. Hearing problems and tinnitus (ringing in the ears) can also occur. As the disease progresses, more serious complications involving the kidneys, heart, and brain may arise. These can include kidney failure, heart problems like cardiomyopathy or arrhythmias, and an increased risk of stroke or transient ischaemic attacks (TIAs).
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Affected organs
Fabry disease can affect a wide range of organs and body systems due to the systemic accumulation of Gb3. The kidneys are frequently affected, with early signs often including proteinuria (protein in the urine) and eventually leading to chronic kidney disease and kidney failure. Renal involvement is a significant cause of morbidity in individuals with Fabry disease.
The heart is another major organ impacted, with potential issues including left ventricular hypertrophy (thickening of the heart muscle), arrhythmias (irregular heartbeats), and valvular heart disease. These cardiac complications can lead to heart failure. The nervous system can also be affected, causing the characteristic burning pain in the extremities, but also increasing the risk of strokes and TIAs, particularly at a younger age than typically expected. Other affected areas include the skin (angiokeratomas), eyes (corneal opacities), and the gastrointestinal tract (leading to various digestive symptoms).
Risks & severity
The severity of Fabry disease can vary considerably. Males with the 'classic' form often experience severe symptoms starting in childhood or adolescence, including the characteristic pain, skin lesions, and progressive kidney and heart disease, with life-threatening complications typically emerging in adulthood. However, females, who are carriers of one altered *GLA* gene, can also develop symptoms ranging from very mild to severe, though their disease course is often more variable and can sometimes be later in onset than in males [PMID:31252112].
Individuals with 'later-onset' forms of Fabry disease may experience symptoms that begin in adulthood, often affecting a specific organ system, such as the heart or kidneys, more prominently than others. The lifetime risks include a significant chance of developing chronic kidney disease, requiring dialysis or transplant, and serious cardiac complications. There is also an increased risk of cerebrovascular events like stroke. Regular monitoring and appropriate management are crucial to mitigate these risks and improve long-term outcomes.
Genetic causes
Fabry disease is caused by pathogenic variants in the *GLA* gene. This gene provides the genetic instructions for producing an enzyme called alpha-galactosidase A (alpha-Gal A). Alpha-Gal A is found in cellular organelles called lysosomes, where its main role is to break down a specific type of fatty substance known as globotriaosylceramide (Gb3, also called GL-3 or ceramide trihexoside).
When there is a pathogenic variant in the *GLA* gene, the alpha-Gal A enzyme may be deficient, absent, or function incorrectly. This impairment means that Gb3 cannot be broken down efficiently and instead accumulates within the lysosomes of cells throughout the body [PMID:31252112]. Over time, this build-up of Gb3 disrupts normal cell function and leads to the progressive damage observed in various organs and tissues in individuals with Fabry disease. The specific type of genetic variant in *GLA* can influence the residual enzyme activity and, consequently, the clinical presentation and severity of the disease.
- GLA galactosidase alphaThe GLA gene provides instructions for creating the alpha-galactosidase A enzyme, crucial for cellular waste recycling and lipid metabolism.
Inheritance pattern
Fabry disease follows an X-linked recessive (XLR) inheritance pattern. This means the *GLA* gene is located on the X chromosome. Males have one X chromosome and one Y chromosome, while females have two X chromosomes.
For males, if their single X chromosome carries a pathogenic variant in the *GLA* gene, they will typically develop Fabry disease. For females, because they have two X chromosomes, one working copy of the *GLA* gene on the other X chromosome can sometimes compensate for the altered copy. However, due to a process called 'X-inactivation' (where one of the two X chromosomes in each cell is randomly switched off), females can still be significantly affected, with symptoms ranging from mild to severe [PMID:28795744]. A male with Fabry disease will pass the altered *GLA* gene to all of his daughters, but none of his sons. A female carrier has a 50% chance of passing the altered *GLA* gene to each child, regardless of whether the child is male or female.
X-linked recessive: sons of a carrier mother have a 50% chance of being affected. Daughters have a 50% chance of being carriers.
Diagnosis & testing
Diagnosing Fabry disease typically involves a combination of clinical suspicion based on symptoms and biochemical or genetic testing. For males, the primary diagnostic test is measuring the activity of the alpha-galactosidase A enzyme in blood or dried blood spots [PMID:31252112]. Significantly reduced enzyme activity is usually indicative of Fabry disease. For females, enzyme activity levels can be normal or only mildly reduced due to X-inactivation, making enzyme testing less reliable for diagnosis.
Therefore, genetic testing for pathogenic variants in the *GLA* gene is the most definitive diagnostic method for both males and females. This can be performed via a blood sample and is crucial for confirming the diagnosis, especially in females and in cases with atypical symptoms or later-onset forms. In the UK, genetic testing for Fabry disease would typically be requested by a clinical genetics service or specialist clinician (e.g., nephrologist, cardiologist, neurologist) through the NHS Genomic Medicine Service. Relevant R-codes for this testing would be determined by the specific clinical presentation and diagnostic pathway.
Management & lifestyle
Management of Fabry disease in the UK focuses on addressing symptoms, preventing disease progression, and improving quality of life. A multidisciplinary team of specialists, including nephrologists, cardiologists, neurologists, and geneticists, is often involved. Enzyme replacement therapy (ERT) is a key treatment, where the deficient alpha-galactosidase A enzyme is administered intravenously [PMID:32252445]. This aims to replace the missing enzyme and reduce the accumulation of Gb3 in cells. Another treatment option, for certain *GLA* gene variants, is chaperone therapy, which helps to stabilise the body's own enzyme and improve its function. Oral substrate reduction therapy (SRT) is also available and works by reducing the production of Gb3.
Beyond specific enzyme or substrate-modifying therapies, symptomatic treatment is vital. This may include pain management for acroparesthesia, medications to manage cardiac arrhythmias or hypertension, and treatments for kidney disease. Regular monitoring of kidney, heart, and neurological function is essential to track disease progression and adjust management strategies as needed. Lifestyle considerations, such as a heart-healthy diet and avoidance of smoking, may also be recommended. Individuals and families affected by Fabry disease can also benefit from support and information provided by genetic counsellors within the NHS.
UK care pathway
In the UK, individuals suspected of having Fabry disease typically enter the care pathway via referral to a specialist clinic, such as clinical genetics, nephrology, cardiology, or neurology, often prompted by suggestive symptoms or family history. Genetic testing is central to confirming the diagnosis and is performed through the NHS Genomic Medicine Service. This involves a referral from a clinician to a Genomic Laboratory Alliance (GLH) laboratory, where specific R-codes for Fabry disease (e.g., R151 for 'Lysosomal storage disorders - Enzyme deficiency/clinical features') would guide the appropriate genetic analysis. Following diagnosis, individuals are usually managed by a multidisciplinary team within specialised centres. Genetic counsellors play a vital role in explaining the inheritance pattern, discussing family planning options, and offering support to affected individuals and their relatives.
Frequently asked questions
Is Fabry disease more common in males or females?
Fabry disease is an X-linked condition, meaning males, who have only one X chromosome, are typically more severely affected. Females, with two X chromosomes, can also develop symptoms, but these can be highly variable, ranging from mild to severe.
Can Fabry disease be passed on even if someone doesn't have obvious symptoms?
Yes, individuals, particularly females, can carry the genetic change for Fabry disease and have very mild or no obvious symptoms themselves, but can still pass the condition on to their children. This is why genetic testing is important for family members of an affected individual.
What kind of treatments are available for Fabry disease?
Treatments for Fabry disease include enzyme replacement therapy (ERT) which replaces the deficient enzyme, chaperone therapy for specific genetic changes, and substrate reduction therapy (SRT) which lowers the production of the fatty substance that builds up. Symptomatic treatments for pain, heart, and kidney issues are also important.
How does Fabry disease affect my family?
Because Fabry disease is inherited, other family members may also be at risk of carrying the altered gene or developing the condition. Genetic counselling can help explain the inheritance pattern within your family and guide testing for relatives.
Are there specific dietary recommendations for Fabry disease?
While there isn't a specific 'Fabry disease diet', a generally healthy diet, often focusing on cardiovascular health and kidney support (if kidney involvement is present), is usually recommended. Your specialist team can provide personalised advice on diet and lifestyle.
References
- Chan B, Adam DN. A Review of Fabry Disease. Skin therapy letter. 2018. PMID: 29562089
- Soloway S, Lister D. Fabry's Disease. The New England journal of medicine. 2024. PMID: 39292930
- Di Toro A, Favalli V, Arbustini E. Anderson-Fabry disease. Journal of cardiovascular medicine (Hagerstown, Md.). 2018. PMID: 29538136
- Levin M. Fabry disease. Drugs of today (Barcelona, Spain : 1998). 2006. PMID: 16511611
- Balan K, Sagut P, Cowen EW. Angiokeratomas. Journal of the American Academy of Dermatology. 2026. PMID: 41692219
- Anan R. Fabry Disease and/or Hypertrophic Cardiomyopathy. International heart journal. 2017. PMID: 28539575
- Erol Ç. Artificial Intelligence, Fabry Disease…. Anatolian journal of cardiology. 2023. PMID: 36995060
- Simonetta I, Tuttolomondo A, Daidone M. Treatment of Anderson-Fabry Disease. Current pharmaceutical design. 2020. PMID: 32183665