Histidinemia

Histidinemia (also known as histidase deficiency or hyperhistidinemia) is an autosomal recessive inborn error of amino acid metabolism caused by deficiency of the enzyme histidase (histidine ammonia-lyase), which is responsible for the first step in the degradation of the amino acid histidine. The condition is caused by pathogenic variants in the HAL gene located on chromosome 12q23.1. Histidinemia results in elevated levels of histidine in the blood and urine, along with increased levels of imidazole metabolites in the urine. Histidinemia was historically considered a potentially harmful metabolic disorder when it was first identified, and early reports associated it with intellectual disability and speech disorders. However, extensive follow-up studies, including large-scale newborn screening programs (particularly in Japan and other countries), have demonstrated that the vast majority of individuals with histidinemia are clinically asymptomatic and develop normally. The condition is now widely regarded as a benign metabolic variant rather than a disease requiring treatment. The earlier associations with developmental problems are thought to have been due to ascertainment bias, as affected individuals were identified because they presented with clinical problems rather than through population screening. Because histidinemia is generally considered benign, no specific treatment is recommended for most affected individuals. Dietary restriction of histidine, which was previously attempted, is no longer advocated. Many newborn screening programs have discontinued screening for histidinemia due to its benign nature. Genetic counseling may be offered to families, and periodic developmental monitoring may be considered in rare cases where there is clinical concern, though routine follow-up is typically unnecessary.

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