eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Hyperammonemia-Hyperornithinemia-Homocitrullinemia Syndrome

Author: Richard E Frye, MD, PhD, Assistant Professor, Departments of Pediatrics and Neurology, University of Texas Health Science Center at Houston
Coauthor(s): Paul J Benke, MD, PhD, Director of Clinical Genetics, Joe DiMaggio Children's Hospital
Contributor Information and Disclosures

Updated: Oct 30, 2009

Introduction

Background

Hyperornithinemia-hyperammonemia-homocitrullinemia (HHH) syndrome is a very rare inborn error of metabolism; the age at presentation and long-term prognosis widely vary among affected individuals. Growth and developmental delays, learning disabilities (especially speech delay), and periodic confusion and ataxia are typical presenting symptoms. In this syndrome, a defect in the transport of ornithine into the mitochondrial matrix significantly inhibits the urea cycle, thereby impeding nitrogen disposal. Early detection and treatment may lead to favorable outcome.

Pathophysiology

The urea cycle maintains the concentration of the toxic ammonium ion in a narrow, tolerable range despite a 10-fold variation in the dietary intake of its precursor, nitrogen. A total of 5 enzymes in 2 subcellular compartments (mitochondrial matrix and cytosol) convert ammonia into urea, which is excreted by the kidney (see Media file 1).

The first 2 steps of the urea cycle occur in the mitochondrial matrix. Carbamoyl phosphate is produced from ammonia and bicarbonate by carbamoylphosphate synthetase I. This reaction is stimulated by ornithine. An inner mitochondrial membrane transporter directs ornithine to the transcarbamoylase enzyme to keep intramatrix ornithine levels low. The specifics of the liver transporter have recently been identified.

Cationic L-ornithine is electroneutrally transported into the matrix in exchange for a proton and citrulline. The inner membrane pH gradient and the availability of proton-yielding anions may affect the transport rate. As with other mitochondrial carrier family proteins, the ornithine carrier is composed of 300 amino acids that constitute 3 repeated motifs of approximately 100 amino acids each. These motifs contain 2 hydrophobic alpha-helical segments connected by an extensive hydrophilic sequence, resulting in 6 transmembrane portions of the protein.

The transporter was identified by probing a mammalian-expressed sequence tag database with 2 fungal mitochondrial ornithine carrier protein sequences. Ornithine incorporation was restored in fibroblasts derived from patients with hyperornithinemia-hyperammonemia-homocitrullinemia syndrome by transforming the fibroblasts with transporter complementary DNA (cDNA). Incorporation was traced using ornithine labeled with radioactive carbon (¹⁴ C).

Following incorporation of ornithine into the mitochondrial matrix, carbamoyl phosphate and ornithine are condensed to form citrulline by ornithine transcarbamoylase. Citrulline is believed to passively diffuse across the inner mitochondrial matrix to the cytosol. The contribution of the ornithine/citrulline antiporter to citrulline transport from the mitochondria to the cytosol is not known.

The next 3 steps of the urea cycle occur in the cytosol. Argininosuccinic acid is produced from the condensation of citrulline and aspartate by a synthetase enzyme. It is then cleaved to produce fumarate and arginine by a lyase enzyme. Urea and ornithine are produced by arginase. Under normal circumstances, the ornithine produced outside the mitochondrial matrix is transported into the mitochondrial matrix, where it is reused in the urea cycle.

This transport of ornithine across the inner mitochondrial membrane is essential to the urea cycle. Ornithine can also be produced in the matrix by aminotransferase, but this enzyme is active in pericentral venous hepatocytes rather than in periportal hepatocytes.

In hyperornithinemia-hyperammonemia-homocitrullinemia syndrome, the mitochondrial ornithine transporter ORNT1 is defective. The carrier protein and gene sequence have only recently been identified; before its identification, the carrier's dysfunction was deduced biochemically because a patient with hyperornithinemia-hyperammonemia-homocitrullinemia syndrome has abnormally high ornithine levels despite normal ornithine transcarbamoylase function. Because the urea cycle cannot continue without ornithine inside the mitochondria, ammonia disposal slows, and blood ammonia levels rise. A second mitochondrial ornithine transporter, ORNT2, has been suggested and may account for a mild variation of hyperornithinemia-hyperammonemia-homocitrullinemia syndrome in French-Canadian probands. In some individuals, a gain in ORNT2 transporter function may compensate for the ORNT1 deficit.

Ornithine transcarbamoylase within the mitochondrial matrix may convert lysine to homocitrulline in the absence of ornithine, causing high blood levels of homocitrulline and homocitrullinuria. However, this theory is controversial because some studies have shown no correlation between lysine supplementation and homocitrulline levels; moreover, the role of the lysine transcarbamoylase that lies outside the inner mitochondrial membrane is not known.

Frequency

International

Only about 50 cases have been reported.

Mortality/Morbidity

Neonatal death has been reported but is rare. Some patients have progressive neurologic and cognitive deterioration, whereas other patients demonstrate good function if metabolic anomalies are well controlled. Clearly, this is a very serious disorder that is potentially life-threatening and often life-shortening.

Race

Most reported cases have been in the French-Canadian population in the Quebec Province of Canada.

Sex

The male-to-female ratio is unknown.

Age

The severity ranges from minimal neurologic dysfunction in adulthood to neonatal death. Age at diagnosis also widely varies, probably, in part, because of variation in the degree of residual enzyme activity and because of the nonspecific symptoms of this disorder.

Clinical

History

• Clotting factors VII and X may be deficient in patients with hyperornithinemia-hyperammonemia-homocitrullinemia (HHH) syndrome. 
• A sibling with the disorder or consanguinity is not uncommon. 
• Ask about a history of previous neonatal deaths or miscarriages.
• Common presenting signs include the following:
  • Developmental delays
  • School difficulties
  • Recurrent liver dysfunction
  • Increased levels of transaminases with mild coagulopathy detected on laboratory tests
• Episodic lethargy and vomiting may be presenting signs.
• The history varies depending on age of onset, as follows:
  • Neonatal onset
    • Vomiting and lethargy following feeding of high-protein formula suggests formula intolerance.
    • The neonatal period may be uneventful if the neonate is breastfed.
    • Symptoms may be mild and may include only bottle refusal. 
    • Severe hyperammonemia with rapidly progressive deterioration after formula feeding is rare but has occurred.
  • Infant onset
    • Symptoms may coincide with the introduction of high-protein solid food around the time of weaning. 
    • Choreoathetosis episodes may occur, with normal neurological function between episodes. 
    • Hypotonia may progress to spasticity. 
    • Seizures may resemble infantile spasms.
    • Developmental milestones are typically delayed. 
    • Growth may be retarded.
  • Childhood onset
    • Ataxia or choreoathetosis episodes may occur, with normal neurological function between episodes.
    • The child may refuse to eat meat and fish or to drink milk.
    • Other signs may include seizures, developmental delays, polyneuropathy, episodic confusion, gait disturbance, learning disabilities, a below-average intelligent quotient (IQ) score, attention deficit hyperactivity disorder (ADHD), conduct disorder, and failure to thrive.
  • Adult onset 
    • Patients may experience learning disabilities.
    • Patients may avoid high-protein foods and possibly have a vegetarian diet. 
    • Periodic blurred vision, confusion, and ataxia are common symptoms.

Physical

• Eyes: Retinal depigmentation and chorioretinal thinning are uncommon findings. In contrast, chorioretinal atrophy with punched-out lesions is a standard finding in patients with gyrate atrophy.
• Abdomen: The liver and spleen may be enlarged.
• Neurologic
  • Pyramidal syndrome characterized by increased deep tendon reflexes, spasticity, positive Babinski reflex, and nonpersistent clonus
  • Decreased vibration sensation
  • Buccofaciolingual dyspraxia
  • Poor visuomotor function
  • Poor hand coordination
  • Poor fine-motor coordination
  • Dysdiadochokinesia
• Development
  • Global motor delay
  • Speech delay

Causes

Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome is a genetic/metabolic disorder caused by a defect in the mitochondrial ornithine transporter ORNT1.

• The ORNT1 gene has been mapped to band 13q14. This gene is also identified as SLC25A15 because of its membership in the solute mitochondrial carrier protein family.¹ Its expression is similar to that of other urea-cycle enzyme genes; it is expressed at high levels in hepatocytes, and an increase in dietary protein can promote its expression.
• Three ORNT1 mutant alleles were identified in a survey of 11 hyperornithinemia-hyperammonemia-homocitrullinemia probands; these mutant alleles accounted for 21 of 22 possible mutant ORNT1 genes in the population.²
  • In individuals of French-Canadian descent with hyperornithinemia-hyperammonemia-homocitrullinemia, a 3-base-pair (bp) in-frame deletion of codon 188 for phenylalanine, which causes an unstable carrier protein, is common. Ten patients were tested for this mutation; 9 were homozygous, and one was heterozygous. The mutation responsible for the dysfunction of the heterozygote's remaining allele was not identified.
  • A missense mutation at codon 189, resulting from a G → A transition at bp 538, impaired carrier activity without affecting targeting or stability in a non–French-Canadian patient. The patient was heterozygous for this mutation and had a microdeletion on chromosome 13 that, presumably, accounted for dysfunction in the corresponding allele.
• Genotyping studies have repeatedly confirmed that genotype has a poor correlation with phenotype.
• Inheritance is autosomal recessive.
• Although the genes for clotting factors VII and X are also located on chromosome arm 13q, these genes are believed to be too distant from the ornithine transporter gene to be part of a contiguous gene syndrome.

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