NORD gratefully acknowledges Harvey L. Levy, MD, Senior Physician in Medicine, Children's Hospital Boston, Professor of Pediatrics, Harvard Medical School, for assistance in the preparation of this report.
Histidinemia is considered a benign condition. For years, intellectual disability and speech disorders were associated with histidinemia. However, these findings are now considered coincidental and not due to the metabolic defect of histidinemia because reports of follow-up from newborn screening have demonstrated that the majority of infants with histidinemia do not develop clinical symptoms (asymptomatic). Nevertheless, clinical symptoms have been reported in some patients with histidinemia. To reconcile this with the benign findings from newborn screening, it has been suggested that histidinemia might be a risk factor for the development of CNS problems, and that such problems might develop only in an unfavorable circumstance such as an abnormal perinatal event.
Individuals with histidinemia have elevated levels of the amino acid histidine in the blood and excessive amounts of histidine, imidazole pyruvic acid, and other imidazole metabolism products in the urine. Most people with histidinemia adapt to the presence of excessive histidine in the blood and do not suffer any ill effects.
According to the medical literature, infants born to mothers with histidinemia (maternal histinemia) have exhibited no symptoms.
Histidinemia is inherited in an autosomal recessive pattern. Genetic diseases are determined by two genes, one received from the father and one from the mother.
Recessive genetic disorders occur when an individual inherits an abnormal variant of a gene from each parent. If an individual receives one normal gene and one abnormal variant gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal variant gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Researchers believe that histidinemia is due to mutations of the human histidase (HAL) gene.
Histidinemia is one of the most common inborn errors of metabolism. Based upon newborn screening of more than 20 million infants in several countries, histidinemia is estimated to occur in about one in 11,500 births overall. The disorder appears to be most prevalent among people of French Canadian or Japanese descent. Based upon newborn screening reports, approximately one in 8,600 infants in Quebec and one in 9,500 infants in Japan are affected by the disorder. The abnormality begins at birth and affects males and females in equal numbers. Histidinemia is now thought to be a primarily benign disorder.
In some states in the United States (e.g., New York and Massachusetts) routine screening of newborns for histidinemia was conducted through blood or urine tests. However, newborn screening for histidinemia has been discontinued. A diagnosis of histidinemia may be made based upon increased levels of histidine in the blood or urine.
Histidinemia is considered a benign, asymptomatic disorder that does not require treatment. According to the medical literature, therapy consisting of a carefully monitored histidine-restricted diet was once recommended, but is no longer called for.
Genetic counseling may also be of benefit to affected individuals and their families. Treatment is symptomatic and supportive for coincidental problems.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Buist NRM, Winter SC. Histidinemia. In: NORD Guide to Rare Disorders. Philadelphia, PA: Lippincott Williams & Wilkins: 2003:459.
Levy HL, Taylor RG, McInnes RR. Disorders of histidine metabolism . Scriver CR, et al., eds.The Metabolic and Molecular Bases of Inherited Disease. 8th Ed. New York, NY; McGraw-Hill Companies, Inc; 2001:1807-20.
Lyon G, et al., eds. Neurology of Hereditary Metabolic Diseases in Childhood. 2nd ed. New York, NY: McGraw-Hill Companies; 1996:89-91.
Buyse ML, ed. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications; For: The Center for Birth Defects Information Services Inc; 1990: 875.
Lam WK, et al. Histidinaemia: a benign metabolic disorder. Arch Dis Child.1996;74:343-6.
Suchi M , et al. Molecular cloning and structural characterization of the human histidase gene (HAL). Genomics.1995;29:98-104.
Widhalm K, Virmani K. Long-term follow-up of 58 patients with histidinemia treated with a histidine-restricted diet: no effect of therapy. Pediatrics.1994;94:861-6.
Taylor RG, et al. Localization of histidase to human chromosome region 12q22-q24.1 and mouse chromosome region 10c2-d1. Cytogenet Cell Genet.1991;56:178-81.
Taylor RG, et al. Molecular characterization of histidase cdnas, and sublocalization of the human histidase gene to 12q22-23, and the mouse gene to 10c2-d1. Am J Hum Genet.1989;45:A164.
Lemieux B, et al. Newborn urine screening experience with over one million infants in the Quebec network of genetic medicine. J Inherit Metab Dis 1988;11:45-55.
Dyme IZ, et al. Histidinemia. A case of resolution of myoclonic seizures after treatment with a low-histidine diet. Am J Dis Child.1983;137:256-8.
Scriver CR, Levy HL. Histidinaemia. Part I: reconciling retrospective and prospective findings. Journal Inherited Metab Dis.1983;6:51-3.
Rosenmann A, et al. Histidinaemia. Part II: impact; a retrospective study. Journal Inherited Metab Dis.1983;6:54-7.
Coulombe JT, et al. Histidinaemia. Part III: impact; a prospective study. Journal Inherited Metab Dis.1983;6:58-61.
Tada K, et al. Intellectual development in patients with untreated histidinemia. J Pediatr. 1982;101:562-3.Snyderman SE, et al. The nutritional therapy of histidinemia. J Pediatr.1979;95:712-5.
Levy HL, Shih VE, Madigan PM. Routine newborn screening for histindinemia. Clinical and biochemical results. N Engl J Med.1974;291:1214-9.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Histidinemia. Entry No: 235800. Last Edited 11/07/2017. Available at: http://omim.org/entry/235800. Accessed March 8, 2018.
Orphanet. Histidinemia. http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=2157 Last Update: January 2015. Accessed March 8, 2018.
The information in NORD’s Rare Disease Database is for educational purposes only and is not intended to replace the advice of a physician or other qualified medical professional.
The content of the website and databases of the National Organization for Rare Disorders (NORD) is copyrighted and may not be reproduced, copied, downloaded or disseminated, in any way, for any commercial or public purpose, without prior written authorization and approval from NORD. Individuals may print one hard copy of an individual disease for personal use, provided that content is unmodified and includes NORD’s copyright.
National Organization for Rare Disorders (NORD)
55 Kenosia Ave., Danbury CT 06810 • (203)744-0100