Anderson–Fabry disease

Signs and symptoms

Symptoms typically begin in early childhood and can be difficult to diagnose, often leading to misdiagnosis due to the condition's rarity. Manifestations increase in number and severity with age. Pain, either full-body or localized to the extremities (acroparesthesia) or the gastrointestinal tract, is common; acroparesthesia is thought to result from damage to peripheral nerve fibers that transmit pain, while GI pain likely stems from lipid accumulation in small blood vessels obstructing flow.

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

Electrical conduction abnormalities can cause slow rhythms like complete heart block or rapid rhythms like ventricular tachycardia, resulting in blackouts, palpitations, or sudden cardiac death. Sphingolipids may also thicken heart valves, causing leakage (regurgitation) or restricted forward flow (stenosis), most often affecting the aortic and mitral valves. Angiokeratomas—tiny, painless papules—commonly appear on the thighs, navel, buttocks, lower abdomen, and groin.

Anhidrosis (lack of sweating) is frequent, 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 the glycolipid globotriaosylceramide (Gb3, GL-3, or ceramide trihexoside) to accumulate 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 range from asymptomatic to severe, a variability attributed to X-inactivation patterns during embryonic development.

Diagnosis

Fabry disease is suspected based on clinical presentation and can be diagnosed by an enzyme assay measuring alpha-galactosidase activity, usually on leukocytes. However, enzyme assay is unreliable for females due to random X-inactivation. Molecular genetic analysis of the GLA gene is the most accurate method for diagnosing females, especially if mutations have been identified in male family members. Kidney biopsy may suggest Fabry disease if excessive lipid buildup is noted.

Pediatricians and internists commonly misdiagnose the condition. Because all immediate and extended family members share the same family mutation, once one member has DNA sequence analysis, others can be diagnosed with targeted sequencing, which is quicker and less expensive. MRI accurately assesses left ventricular mass, thickness, and hypertrophy; late gadolinium enhancement shows increased signal at the mid wall of the inferolateral left ventricular base, and T1-weighted imaging can reveal low T1 signal from sphingolipid storage even without ventricular hypertrophy in 40% of affected individuals, aiding early diagnosis.

Treatment

Treatments for Fabry disease fall into two categories: therapies that address the underlying enzyme deficiency to reduce organ damage risk, and therapies that manage symptoms and improve 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 agalsidase 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 is another strategy that assists correct folding of alpha-galactosidase despite mutations; as of 2022, one chaperone drug is available.

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 therapy, substrate synthesis inhibition (substrate reduction therapy), chaperone therapy, and gene editing.