Sign Up for a Free Account
  • Updated 02.27.2024
  • Released 06.22.2016
  • Expires For CME 02.27.2027

HHH syndrome



HHH syndrome is an inherited urea cycle disorder caused by deficiency of the mitochondrial ornithine transporter 1 (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 ci...

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 cessation of protein intake, adequate fluid, glucose substitution, and first-line medications must be administered as soon as possible.

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 manifestations, complications, and long-term outcomes of urea cycle disorders. They include the Urea Cycle Disorders Consortium (UCDC), established in 2006; 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 (55).

Key points

• HHH syndrome is one of the rarest disorders of the urea cycle with variable clinical phenotypes.

• 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 (24), should be available in all specialized pediatric hospitals.

• Neurologic outcome depends on noninterventional parameters, eg, intrinsic disease severity (reflected by onset type and initial peak plasma ammonia concentration during the first metabolic decompensation). The impact of interventional measures, eg, diagnostic and therapeutic interventions, on clinical outcome remains to be elucidated.

Historical note and terminology

A 3-year-old boy with cognitive impairment and myoclonic seizures as well as intermittent hyperammonemia, abnormally high plasma L-ornithine levels, and homocitrullinuria was described by Shih and colleagues in 1969 (52). The term “hyperornithinemia-hyperammonemia-homocitrullinuria syndrome” (HHH syndrome) was coined to characterize the specific biochemical pattern that was observed.

This is an article preview.
Start a Free Account
to access the full version.

  • Nearly 3,000 illustrations, including video clips of neurologic disorders.

  • Every article is reviewed by our esteemed Editorial Board for accuracy and currency.

  • Full spectrum of neurology in 1,200 comprehensive articles.

  • Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660



ISSN: 2831-9125