Fabry disease

Signs and symptoms

Symptoms typically begin in early childhood and are often difficult to diagnose, leading to frequent misdiagnoses. The number and severity of manifestations increase with age. Patients commonly experience full-body or localized pain in the extremities, known as acroparesthesia, and gastrointestinal tract pain. Acroparesthesia is thought to result from damage to peripheral nerve fibers that transmit pain, while GI pain likely arises from lipid accumulation in small blood vessels of the GI tract, obstructing blood flow.

Kidney complications are serious and common; chronic kidney disease and kidney failure may progress over time. Foamy urine due to protein in the urine is often the first sign of kidney involvement. End-stage kidney failure typically occurs in the third decade of life and is a frequent cause of death. Cardiac effects include abnormal thickening of heart muscle (hypertrophy), leading to stiff, non-relaxing muscle and hypertrophic cardiomyopathy with shortness of breath.

Electrical conduction abnormalities can cause slow rhythms such as complete heart block or rapid rhythms like ventricular tachycardia, resulting in blackouts, palpitations, or sudden cardiac death. Sphingolipid buildup in heart valves can cause thickening, leading to regurgitation or stenosis, most often affecting the aortic and mitral valves. Angiokeratomas—tiny, painless papules—appear predominantly on the thighs, around the navel, buttocks, lower abdomen, and groin.

Anhidrosis (lack of sweating) is common, and hyperhidrosis (excessive sweating) occurs less often. Patients may also exhibit Raynaud's disease-like symptoms with neuropathy, particularly burning extremity pain.

Causes

Fabry disease results from a mutation in the GLA gene, leading to insufficient functioning of the enzyme alpha-galactosidase A. This deficiency causes accumulation of the glycolipid globotriaosylceramide (Gb3, GL-3, or ceramide trihexoside) within blood vessels, tissues, and organs, impairing their function. At least 443 disease-causing mutations in the GLA gene have been identified.

The condition is X-linked recessive with incomplete penetrance in heterozygous females. Hemizygous males, homozygous females, and many heterozygous females are affected. Males typically experience severe symptoms, while females may range from asymptomatic to severely affected, likely due to X-inactivation patterns during embryonic development.

Diagnosis

Diagnosing Fabry disease often begins with a doctor suspecting it from a patient’s symptoms. A standard test measures alpha-galactosidase enzyme activity in white blood cells, but this method is not reliable for women because of random X-chromosome inactivation. For females, the most accurate approach is genetic testing of the GLA gene, especially if a male relative’s mutation is already known. A kidney biopsy can also point to the disease if it shows excessive fat buildup.

Both pediatricians and internists frequently miss the diagnosis. Since all blood relatives in a family carry the same mutation, once one person’s DNA change is identified, other family members can be tested with a faster, cheaper targeted analysis. One study found that for every first diagnosis, about five additional relatives are later diagnosed. MRI is useful for detecting heart involvement: it can measure left ventricular mass and thickness, and late gadolinium enhancement often reveals a bright signal in the mid wall of the lower left ventricle’s side wall, even without thickening.

T1-weighted imaging shows a low signal from sphingolipid storage in 40% of patients before hypertrophy appears, enabling early detection.

Treatment

Treatments for Fabry disease aim either to correct the underlying enzyme deficiency and reduce organ damage risk, or to improve symptoms and life expectancy after organ damage has occurred. Enzyme replacement therapy provides the missing enzyme but is not a cure; it can partially prevent disease progression and potentially reverse some symptoms. As of 2022, three enzyme replacement drugs are available: agalsidase alfa (Replagal, by Takeda), approved in the EU in 2001 but not FDA-approved; agalsidase beta (Fabrazyme, by Sanofi), approved in the EU in 2001 and by the FDA in 2003; and pegunigalsidase alfa (Elfabrio), approved in the EU in May 2023.

Agalsidase alfa and beta are generally similar in effectiveness and safety, though never directly compared in a randomized trial; both are given intravenously every two weeks. Pharmacological chaperone therapy assists correct folding of alpha-galactosidase despite mutations; as of 2022, one chaperone drug is available for Fabry disease.

Did You Know?

• Newborn screening in Italy found a prevalence as high as one in about 3,100 newborns, and in Taiwan around one in 1,500 newborn males.
• Research approaches include enzyme replacement, substrate synthesis inhibition, chaperone therapy, and gene editing.