Angiokeratoma corporis diffusum

Signs and symptoms

Symptoms typically first appear in early childhood and can be difficult to diagnose, often leading to misdiagnosis due to the condition's rarity. Manifestations generally increase in number and severity with age. Patients commonly experience full-body or localized pain in the extremities, known as acroparesthesia, and gastrointestinal tract pain. The extremity pain 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 frequent and serious; chronic kidney disease and kidney failure may worsen over time, with foamy urine from proteinuria often being the first sign. End-stage kidney failure typically occurs in the third decade of life and is a common cause of death. Cardiac involvement includes abnormal thickening of heart muscle (hypertrophy) leading to hypertrophic cardiomyopathy and shortness of breath, as well as electrical conduction abnormalities causing slow or rapid heart rhythms, 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—commonly appear 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 is caused by a mutation in the GLA gene, leading to insufficient functioning of the enzyme alpha-galactosidase A. This deficiency results in 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, as well as homozygous and many heterozygous females, are affected. Males typically experience severe symptoms, while females may range from asymptomatic to severely affected, a variability thought to be due 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 not reliable for diagnosing females due to random X-inactivation. Molecular genetic analysis of the GLA gene is the most accurate method for 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. Since 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 is accurate for assessing 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 show low T1 signal due to sphingolipid storage even without ventricular hypertrophy in 40% of affected individuals.

Treatment

Treatments for Fabry disease are divided into therapies that correct the underlying enzyme deficiency to reduce organ damage risk, and therapies that improve symptoms and life expectancy after organ damage has occurred. Enzyme replacement therapy provides the missing enzyme and can partially prevent disease progression and potentially reverse some symptoms, though it is not a cure. 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 by intravenous infusion 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.