National Center for Advancing and Translational Sciences Genetic and Rare Diseases Information Center, a program of the National Center for Advancing and Translational Sciences

Ornithine translocase deficiency syndrome


Other Names:
Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome; HHH syndrome; HHHS; Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome; HHH syndrome; HHHS; HHH; Ornithine translocase deficiency See More
Categories:
This disease is grouped under:
The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.
orphanet

Orpha Number: 415

Definition
A rare, genetic disorder of urea cycle metabolism characterized by either a neonatal-onset with manifestations of lethargy, poor feeding, vomiting and tachypnea or, more commonly, presentations in infancy, childhood or adulthood with chronic neurocognitive deficits, acute encephalopathy and/or coagulation defects or other chronic liver dysfunction.

Epidemiology
More than 100 cases have been reported in the literature to date. The prevalence in Northern Saskatchewan, Canada is especially high due to a founder effect and is estimated in this population at 1/1550 live births.

Clinical description
Age of onset can range from the neonatal period to adulthood and a wide phenotypic spectrum is noted. The neonatal presentation usually begins a few days after birth with lethargy, somnolence, refusal to feed, vomiting, tachypnea with respiratory alkalosis, and/or seizures. Onset of symptoms (ranging from mild to severe) in the majority of patients occurs in infancy, childhood and adulthood with episodes of confusion, forgetfulness, hyperammonemic coma, intellectual disability, developmental delay, spastic paraplegia, cerebellar ataxia, learning difficulties, unexplained seizures, liver dysfunction (rarely failure) and coagulopathy with factor VII-, IX- and X-deficiencies. An aversion to protein-rich foods before diagnosis is often reported.

Etiology
The syndrome is due to mutations in the SLC25A15 gene (13q14) encoding the mitochondrial ornithine transporter 1 (ORNT1) which plays a role in ornithine transport across the mitochondrial membrane and consecutively in mitochondrial protein synthesis, metabolism of arginine and lysine, and synthesis of polyamines. Mutations in this protein disrupt the urea cycle, resulting in hyperornithinemia, hyperammonemia and homocitrullinuria. Patients with a complete ORNT1 deficiency present in the neonatal period with severe hyperammonemia whereas those with a partial deficiency present later, between infancy to adulthood.

Diagnostic methods
Diagnosis is based on clinical findings and specific metabolic abnormalities. Laboratory tests usually reveal increased urinary excretion of orotic acid, homocitrulline and uracil, and a rise in the levels of plasma polyamines, ornithine, glutamine, alanine, and liver transaminases. Plasma ammonia levels are elevated episodically or postprandially and plasma ornithine is chronically elevated and is a hallmark of the disease as is the presence of homocitrulline in urine. Molecular genetic testing confirms diagnosis.

Differential diagnosis
Differential diagnosis includes other urea cycle disorders as well as lysinuric protein intolerance. Hyperinsulinism-hyperammonemia syndrome, pyruvate carboxylase deficiency and secondary causes of hyperammonemia should also be considered.

Antenatal diagnosis
Prenatal diagnosis is possible in families with a known disease causing mutation on both alleles.

Genetic counseling
The pattern of inheritance is autosomal recessive; where both parents are unaffected carriers, there is a 25% risk of inheriting the disease.

Management and treatment
Treatment involves the adherence to a low protein diet along with citrulline or arginine supplementation. In resistant cases, sodium benzoate and/or sodium or glycerol phenylbutyrate may be necessary for control of plasma ammonia levels. Patients should be monitored during times of stress (e.g. pregnancy, surgery, intercurrent infections) and when taking certain medications (i.e. corticosteroids) as they can trigger an episode of hyperammonemia. Hyperammonemic coma is treated in a tertiary care center where plasma ammonia levels must be lowered (by hemodialysis or hemofiltration), ammonia scavenger therapy implemented, catabolism reversed (with glucose and lipid infusions) and special care taken to reduce the risk of neurological damage.

Prognosis
With early diagnosis and proper adherence to treatment protocol the prognosis is better than for most other urea cycle defects. However, patients remain at risk for metabolic decompensation throughout life and irreversible neurological complications can occur if treatment is delayed.

Visit the Orphanet disease page for more resources.
Last updated: 10/1/2019

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

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Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Abnormal circulating citrulline concentration 0011965
Cognitive impairment
Abnormality of cognition
Cognitive abnormality
Cognitive defects
Cognitive deficits
Intellectual impairment
Mental impairment
[ more ] 		0100543
Hyperammonemia
High blood ammonia levels
0001987
Hyperornithinemia
High blood ornithine levels
0012026
Neurodevelopmental delay 0012758
30%-79% of people have these symptoms
Abnormal pyramidal sign 0007256
Acute encephalopathy 0006846
Cerebral cortical atrophy
Decrease in size of the outer layer of the brain due to loss of brain cells
0002120
Clonus 0002169
Confusion
Disorientation
Easily confused
Mental disorientation
[ more ] 		0001289
Elevated hepatic transaminase
High liver enzymes
0002910
Episodic vomiting 0002572
Failure to thrive
Faltering weight
Weight faltering
[ more ] 		0001508
Feeding difficulties
Feeding problems
Poor feeding
[ more ] 		0011968
Generalized hypotonia
Decreased muscle tone
Low muscle tone
[ more ] 		0001290
Hepatitis
Liver inflammation
0012115
Hepatomegaly
Enlarged liver
0002240
Impaired vibratory sensation
Decreased vibration sense
Decreased vibratory sense
Diminished vibratory sense
Impaired vibratory sense
[ more ] 		0002495
Intellectual disability
Mental retardation, nonspecific
Mental deficiency
Mental retardation
Mental-retardation
[ more ] 		0001249
Lethargy 0001254
Oroticaciduria
High urine orotic acid levels
0003218
Poor coordination 0002370
Progressive cerebellar ataxia 0002073
Protein avoidance 0002038
Spastic paraplegia 0001258
Specific learning disability 0001328
Speech apraxia 0011098
Tachypnea
Increased respiratory rate or depth of breathing
0002789
5%-29% of people have these symptoms
Abnormality of the coagulation cascade 0003256
Coma 0001259
Generalized myoclonic seizure 0002123
Multifocal cerebral white matter abnormalities 0007052
Respiratory alkalosis 0001950
Spastic gait
Spastic walk
0002064
1%-4% of people have these symptoms
Chorioretinal atrophy 0000533
Chorioretinal hypopigmentation 0040030
Hepatic failure
Liver failure
0001399
Percent of people who have these symptoms is not available through HPO
Acute hepatitis
Acute liver inflammation
0200119
Autosomal recessive inheritance 0000007
Decreased liver function
Liver dysfunction
0001410
Decreased nerve conduction velocity 0000762
Global developmental delay 0001263
Hypopigmentation of the fundus 0007894
Morphological abnormality of the pyramidal tract 0002062
Psychomotor retardation 0025356
Spastic paraparesis 0002313
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Last updated: 7/1/2020

Making a diagnosis for a genetic or rare disease can often be challenging. Healthcare professionals typically look at a person’s medical history, symptoms, physical exam, and laboratory test results in order to make a diagnosis. The following resources provide information relating to diagnosis and testing for this condition. If you have questions about getting a diagnosis, you should contact a healthcare professional.

Testing Resources

  • The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

Newborn Screening

  • The Newborn Screening Coding and Terminology Guide has information on the standard codes used for newborn screening tests. Using these standards helps compare data across different laboratories. This resource was created by the National Library of Medicine.

The resources below provide information about treatment options for this condition. If you have questions about which treatment is right for you, talk to your healthcare professional.

Management Guidelines

  • GeneReviews provides a current, expert-authored, peer-reviewed, full-text article urea cycle disorders in general that you may find helpful. GeneReview articles describe the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
  • Orphanet Emergency Guidelines is an article which is expert-authored and peer-reviewed that is intended to guide health care professionals in emergency situations involving this condition.  

If you need medical advice, you can look for doctors or other healthcare professionals who have experience with this disease. You may find these specialists through advocacy organizations, clinical trials, or articles published in medical journals. You may also want to contact a university or tertiary medical center in your area, because these centers tend to see more complex cases and have the latest technology and treatments.

If you can’t find a specialist in your local area, try contacting national or international specialists. They may be able to refer you to someone they know through conferences or research efforts. Some specialists may be willing to consult with you or your local doctors over the phone or by email if you can't travel to them for care.

You can find more tips in our guide, How to Find a Disease Specialist. We also encourage you to explore the rest of this page to find resources that can help you find specialists.

Healthcare Resources

Research helps us better understand diseases and can lead to advances in diagnosis and treatment. This section provides resources to help you learn about medical research and ways to get involved.

Patient Registry

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

Living with a genetic or rare disease can impact the daily lives of patients and families. These resources can help families navigate various aspects of living with a rare disease.

Education Resources

  • The Genetics Education Materials for School Success (GEMSS) aims to assure that all children with genetic health conditions succeed in school-life. Their Web site offers general and condition-specific education resources to help teachers and parents better understand the needs of students who have genetic conditions.

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

  • Genetics Home Reference (GHR) contains information on Ornithine translocase deficiency syndrome. This website is maintained by the National Library of Medicine.
  • MedlinePlus.gov provides more information on urea cycle disorders in general. MedlinePlus is a Web site designed by the National Library of Medicine to help you research your health questions.

In-Depth Information

  • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
  • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
  • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
  • PubMed is a searchable database of medical literature and lists journal articles that discuss Ornithine translocase deficiency syndrome. Click on the link to view a sample search on this topic.

News

Other Conferences

  • Reaching for a Cure: 2011 NUCDF Annual Conference, July 8 2011 - July 10, 2011 
    Location: Sheraton Denver Downtown, Denver, Colorado
    Description: This conference offers the unique opportunity to meet other UCD families, stay informed, and learn about new advances in research, treatment and management to improve the lives of children and adults with UCD. Working together, our NUCDF families and community of committed researchers and medical professionals are making a major impact with advances in the understanding of UCDs, accelerating research, and improved outcomes in children and adults with UCD. In the past four years, research for UCDs has increased by 400%! Let's continue the momentum and end the devastating effects of UCD.

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