HHH syndrome

Roland Posset MD (Dr. Posset of the University Center for Child and Adolescent Medicine in Heidelberg has no relevant financial relationships to disclose.)
Georg F Hoffmann MD (Dr. Hoffmann of the University Center for Child and Adolescent Medicine in Heidelberg has no relevant financial relationships to disclose.)
Tyler Reimschisel MD, editor. (Dr. Reimschisel of Vanderbilt University has received contracted research grants from Shire.)
Originally released June 22, 2016; last updated June 10, 2017; expires June 10, 2020

This article includes discussion of HHH syndrome, hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, and triple H syndrome. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.


HHH syndrome is an inherited urea cycle disorder caused by deficiency of the mitochondrial 1 ornithine transporter (ORNT1) transferring ornithine from the cytosol to hepatic mitochondria for the ornithine transcarbamylase reaction.

HHH syndrome. Ammonia is detoxified through its conversion to urea by the enzymes in the small boxes. Ornithine transporter 1 (ORNT1) catalyzes the transport of ornithine from the cytosol into the mitochondrion and in return the transport of citrulline from the mitochondrion into the cytosol. Deficiency of ORNT1 (highlighted in red) causes hyperornithinemia, hyperammonemia, and homocitrullinuria as well as normal to low normal plasma lysine, citrulline, and arginine levels. Urinary orotic acid might be increased. Image: HHH syndrome
Thus, the ornithine transporter is essential for function of the urea cycle. Absence or deficiency of the transporter leads to a hyperammonemia disorder, specifically hyperornithinemia, hyperammonemia, and homocitrullinuria. Affected individuals suffer progressive neurologic sequelae and mental impairment or even early death in some severely affected individuals. Severe neonatal forms are rare but may result in hyperammonemic coma within the neonatal period (28 days or younger; neonatal- or early-onset), whereas presentations in later life (older than 28 days; late-onset) during infancy, childhood, adolescence, or adulthood cause variable progressive neurologic disease. Biochemical markers include elevated plasma glutamine and ornithine and normal to low-normal plasma lysine, citrulline, and arginine as well as orotic aciduria and especially homocitrullinuria. Diagnosis is confirmed by molecular genetic analysis or, rarely, by enzymatic testing. Treatment consists of long-term dietary therapy supplemented with L-citrulline/L-arginine and, if necessary, ammonia scavengers. Intercurrent infections, vaccinations, or conditions that are likely to induce a catabolic state might lead to metabolic decompensations and hyperammonemic crises. In case of hyperammonemia, transient stop of protein intake, adequate fluid, glucose substitution, and first-line medications must be administered. Currently, international networks for rare metabolic diseases (UCDC, E-IMD, JUCDC) aim to more completely describe the natural history, especially the initial and evolving clinical phenotypes of urea cycle disorders (UCDs) such as HHH syndrome. These networks collect systematic data to improve the clinical knowledge, develop guidelines, and provide patients and professionals with reliable data on disease manifestation, complications, and long-term outcomes of urea cycle disorders. They include the Urea Cycle Disorders Consortium (UCDC; established in 2003), the European Registry and Network for Intoxication Type Metabolic Diseases (E-IMD; established in 2011), and the Japanese Urea Cycle Disorders Consortium (JUCDC; established in 2012) (Summar et al 2014).

Key points


• HHH syndrome is a rare disorder of the urea cycle with variable clinical phenotype.


• Hyperammonemia must be avoided and determines the neurologic outcome.


• Biochemical, enzymatic, or molecular genetic analyses are necessary for confirmation of the diagnosis.


• Emergency and long-term treatment protocols, as suggested by Haberle and colleagues (Haberle et al 2012), should be available in all specialized pediatric hospitals.

Historical note and terminology

A 3-year-old boy with cognitive impairment and myoclonic seizures as well as intermittent hyperammonemia, abnormally high plasma ornithine levels, and homocitrullinuria was described by Shih and colleagues in 1969 (Shih et al 1969). The term “hyperornithinemia-hyperammonemia-homocitrullinuria syndrome” (HHH syndrome) was coined to characterize the specific biochemical pattern that has been observed.

The content you are trying to view is available only to logged in, current MedLink Neurology subscribers.

If you are a subscriber, please log in.

If you are a former subscriber or have registered before, please log in first and then click select a Service Plan or contact Subscriber Services. Site license users, click the Site License Acces link on the Homepage at an authorized computer.

If you have never registered before, click Learn More about MedLink Neurology  or view available Service Plans.