Fumaric aciduria

Fumaric aciduria (also known as fumarase deficiency or fumarate hydratase deficiency) is an extremely rare autosomal recessive metabolic disorder caused by a deficiency of the enzyme fumarase (fumarate hydratase), which plays a critical role in the mitochondrial citric acid (Krebs) cycle. This enzyme catalyzes the conversion of fumarate to malate, and its deficiency leads to the accumulation of fumaric acid in body fluids, including urine, blood, and cerebrospinal fluid. The disease is caused by pathogenic variants in the FH gene located on chromosome 1q43. Fumaric aciduria primarily affects the central nervous system and is characterized by severe neurological impairment. Key clinical features include profound psychomotor delay, intellectual disability, seizures, hypotonia, microcephaly, and brain malformations such as cerebral atrophy, polymicrogyria, and enlarged ventricles. Many affected individuals also exhibit failure to thrive, feeding difficulties, and distinctive facial features including a prominent forehead, depressed nasal bridge, and widely spaced eyes. Hepatomegaly and polycythemia (excess red blood cells) have also been reported in some patients. Symptoms typically present in the neonatal or early infantile period, and the clinical course is often severe, with many affected children experiencing significant morbidity. There is currently no specific curative treatment for fumaric aciduria. Management is supportive and symptomatic, focusing on seizure control with antiepileptic medications, nutritional support, physical therapy, and management of associated complications. The prognosis is generally poor, with many affected individuals having a significantly shortened lifespan, although survival into childhood and beyond has been reported in some cases. Notably, heterozygous carriers of FH mutations have an increased predisposition to hereditary leiomyomatosis and renal cell cancer (HLRCC), which is a distinct clinical entity.

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