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Genetics of Hyperammonemia-Hyperornithinemia-Homocitrullinuria (HHH) Syndrome Clinical Presentation

  • Author: Richard E Frye, MD, PhD; Chief Editor: Maria Descartes, MD  more...
 
Updated: Oct 28, 2015
 

History

Clotting factors VII and X may be deficient in patients with hyperornithinemia-hyperammonemia-homocitrullinuria (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.

Strokelike episodes may occur.[5]

Liver failure may occur.[5, 6]

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.

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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

See the list below:

  • 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

See the list below:

  • Global motor delay
  • Speech delay
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Causes

Hyperornithinemia-hyperammonemia-homocitrullinuria 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.[7] 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-homocitrullinuria probands; these mutant alleles accounted for 21 of 22 possible mutant ORNT1 genes in the population.[8]

In individuals of French-Canadian descent with hyperornithinemia-hyperammonemia-homocitrullinuria, 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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Contributor Information and Disclosures
Author

Richard E Frye, MD, PhD Associate Professor, Department of Pediatrics, University of Arkansas for Medical Sciences

Richard E Frye, MD, PhD is a member of the following medical societies: American Academy of Neurology, Child Neurology Society, International Neuropsychological Society, American Academy of Pediatrics

Disclosure: Nothing to disclose.

Coauthor(s)

Paul J Benke, MD, PhD Director of Clinical Genetics, Joe DiMaggio Children's Hospital

Paul J Benke, MD, PhD is a member of the following medical societies: American Society of Human Genetics

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Maria Descartes, MD Professor, Department of Human Genetics and Department of Pediatrics, University of Alabama at Birmingham School of Medicine

Maria Descartes, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics, Society for Inherited Metabolic Disorders, International Skeletal Dysplasia Society, Southeastern Regional Genetics Group

Disclosure: Nothing to disclose.

Additional Contributors

Robert D Steiner, MD Chief Medical Officer, Acer Therapeutics; Clinical Professor, University of Wisconsin School of Medicine and Public Health

Robert D Steiner, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American College of Medical Genetics and Genomics, American Society of Human Genetics, Society for Inherited Metabolic Disorders, Society for Pediatric Research, Society for the Study of Inborn Errors of Metabolism

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Acer Therapeutics; Retrophin; Raptor Pharma; Veritas Genetics; Censa Pharma<br/>Received income in an amount equal to or greater than $250 from: Acer Therapeutics; Retrophin; Raptor Pharma; Censa Pharma.

References
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Important products and enzymes in ornithine metabolism (see text for pathway detail). Enzymes and transporters are highlighted in italics.
 
 
 
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