Histidinemia is a rare genetic disorder characterized by abnormal metabolism and accumulation of the amino acid histidine in the blood and urine.
A deficiency of the enzyme histidase, needed for the metabolism of histidine, results in an abnormal accumulation of histidine in the serum as well as its increased excretion in the urine. Most patients however, adapt to the increased levels of histidine and live a normal life without many symptoms.
This rare disease, with an autosomal recessive mode of inheritance, was originally linked to multiple developmental disorders . For many years, histidinemia was considered to be responsible for neurological symptoms such as hydrocephalus, cerebellar ataxia, seizures, emotional disturbances as well as certain non-neurological features that include multiple congenital anomalies, aplastic anemia, idiopathic thrombocytopenic purpura, growth retardation, precocious puberty and recurrent infections. Multiple studies conducted since have rejected this hypothesis, noting these findings to be coincidental  .
Histidinemia is now thought to be a benign inborn error of metabolism with the majority of patients being asymptomatic, with normal speech and mental development. However, clinical symptoms are seen in some patients and studies in newborns now consider histidinemia to be a risk factor for neurological impairment. These findings were seen to be more common in those with an adverse perinatal history  .
Atypical histidinemia is a milder form of this disorder and is seen in a minority of cases. As compared to patients with classical histidinemia, these patients usually show higher cutaneous levels of the enzyme, histidase and lower serum levels of histidine. Being clinically asymptomatic, these cases serve to illustrate the biochemical and genetic heterogeneity of histidinemia  .
Women with histidinemia deliver babies who usually do not suffer from any residual abnormalities .
Many congenital disorders were attributed to histidinemia in the past and neonatal screening programs were initiated in many countries to detect the same. However, multiple research studies over the years have refuted this linkage and screening programs performed on neonates have, therefore, been scrapped .
Histidinemia can be diagnosed by the presence of increased levels of histidine in the blood and urine. In addition, the levels of histamine and imidazole pyruvic acid may also be elevated. On the other hand, products resulting from the metabolism of histidine, such as urocanic acid, are decreased in the blood, urine, and skin cells. The normal blood levels of histidine lie in the range of 70 to 120 μM/l, with values above 290 μM/l being considered abnormally high .
Increased levels of histidine and histamine are also observed in the cerebrospinal fluid. The residual histidase activity per gram tissue of skin is decreased in patients with histidinemia.
Patients with atypical histidinemia show less pronounced elevation in the serum and urine histidine levels as well as in the cutaneous histidase activity.