Fabry disease: symptoms, causes, diagnosis and treatment

Symptoms vary in age of onset, severity and speed of progression, as NICE notes. In the classic form in males, Contact (with specialist input from Royal Free London) says symptoms usually become apparent in childhood or adolescence. Males with higher enzyme activity are more mildly affected and show features later in life, mostly with heart or kidney problems and few of the other symptoms.

Kidney Care UK notes that the pain in the hands and feet is often worse after sudden changes in temperature and can be triggered by tiredness, stress and exercise. NICE calls pain that spreads through the body a Fabry crisis.

Fabry disease, also called Anderson-Fabry disease, is a rare genetic metabolic condition. Contact explains that it is caused by changes (mutations) in the GLA gene, which provides instructions for making the enzyme alpha-galactosidase A. Without enough working enzyme, a fatty substance (Gb3, also written GL-3) builds up in cells throughout the body, particularly in cells lining blood vessels in the skin and in the kidneys, heart and nervous system.

NICE says the build-up leads to irreversible organ damage, resulting in progressive kidney and heart disease and an increased risk of stroke at a relatively young age, and that the condition can reduce life expectancy and have a profound effect on quality of life. It also notes the company estimate of 855 people with Fabry disease in England, a prevalence of about 0.002%.

Contact says that in males, low alpha-galactosidase A activity in blood, or in cultured skin cells, can make the diagnosis. In females, measuring enzyme activity is unreliable, and molecular genetic testing of the GLA gene is the most reliable way to identify Fabry disease.

Kidney Care UK adds that urine and blood tests are used to check for signs of kidney damage, and that the main clues of pain in the hands and feet, an inability to sweat and reddish-purple spots on the abdomen are key indicators. Diagnosis often follows because of a family member with the condition or because organ changes, such as an enlarged heart or kidney problems at a young age, prompt the question.

NICE says there is no cure. Current options are enzyme replacement therapy (ERT), using agalsidase alfa or agalsidase beta given by infusion every 2 weeks, or supportive care to manage symptoms and complications. ERT is a lifelong treatment that reduces symptoms and slows disease progression. Contact says ERT has been shown to clear Gb3 deposits, stabilise kidney function, reduce heart size and significantly improve pain and quality of life, and that in the UK most patients receive it at home.

Kidney Care UK says the first few doses are given in hospital to monitor for side effects, and that if treatment starts early the complications normally seen are unlikely to occur, whereas damage already done will not be reversed but should not get worse.

Chaperone therapy with migalastat is a tablet taken every other day that stabilises the damaged enzyme. NICE highly specialised technology guidance HST4 recommends migalastat as an option for people over 16 with an amenable mutation, only if ERT would otherwise be offered. Whether you have an amenable change depends on your specific GLA variant.

Other treatments relieve symptoms. Contact lists antiepileptic drugs such as gabapentin and carbamazepine for nerve pain, laser treatment or removal for angiokeratomas, and standard therapies such as aspirin, antihypertensives, ACE inhibitors for protein in the urine and cholesterol-lowering medicines for the kidney, cardiovascular and vascular effects. Kidney Care UK says dialysis or a transplant may be needed if kidney failure occurs.

Fabry disease is X-linked, which is why males are usually more severely affected. Kidney Care UK describes women with one changed gene as carriers. Contact, written by a specialist, is more cautious: females typically have milder symptoms and a later onset than males, but this is very variable. Some females may have no symptoms throughout a normal lifespan, while others may have symptoms as severe as those seen in males.

The practical point is that a woman in an affected family should not be told she is only a carrier without being offered assessment, because organ involvement can occur and enzyme tests can be falsely reassuring. Genetic testing is the reliable way to confirm.

Yes. It is caused by a variant in the GLA gene on the X chromosome. Kidney Care UK explains that a woman with one affected gene has a one in two chance of passing it to each child. An affected man cannot pass it to his sons, because they inherit his Y chromosome, but he will pass the changed gene to all of his daughters.

Contact says affected families should be referred to a genetics centre for information and support, and that prenatal testing by chorionic villus sampling or amniocentesis is available. Preimplantation genetic diagnosis may be available when the family variant has been identified.

Because Fabry disease raises the risk of stroke at a relatively young age, the NHS stroke advice applies. Call 999 now if you think you are having or have had a stroke, even if the signs have stopped. The NHS lists face drooping, arm weakness or numbness, slurred or confused speech, blurred vision or loss of sight, dizziness and a severe headache. Do not drive yourself to A&E.

Chest pain that does not go away, a new irregular or racing heartbeat, or breathlessness also need urgent assessment through 999, NHS 111 or A&E. Between flare-ups, contact your specialist centre about new or worsening symptoms rather than waiting for the next scheduled review.

Fabry disease is managed in specialist lysosomal storage disorder centres, which NICE says number 8 in England (5 adult and 3 paediatric). A GP or hospital specialist usually refers you, often after a suspicious finding such as unexplained kidney or heart disease, or after a relative is diagnosed.

Enzyme replacement and migalastat are specialist-prescribed treatments funded through NHS specialised services. Private assessment can help with an early opinion or genetic testing, but long-term treatment decisions are usually coordinated with the specialist centre, so it helps to bring any private results to that team.