Ornithine translocase deficiency syndrome

Title

Other Names:

Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome; HHH syndrome; HHHS; Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome; HHH syndrome; HHHS; HHH; Ornithine translocase deficiency See More

Categories:

Congenital and Genetic Diseases; Metabolic disorders; Newborn Screening

This disease is grouped under:

Urea cycle disorders

Summary Summary

The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.

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

Symptoms Symptoms

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 deficiency Mental retardation Mental retardation, nonspecific 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 seizures		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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Do you have more information about symptoms of this disease? We want to hear from you.

Last updated: 2/1/2020

Do you have updated information on this disease? We want to hear from you.

Diagnosis Diagnosis

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.

Treatment Treatment

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.

Find a Specialist Find a Specialist

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

To find a medical professional who specializes in genetics, you can ask your doctor for a referral or you can search for one yourself. Online directories are provided by the American College of Medical Genetics and the National Society of Genetic Counselors. If you need additional help, contact a GARD Information Specialist. You can also learn more about genetic consultations from Genetics Home Reference.

Research Research

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

The Urea Cycle Disorders Consortium is a team of doctors, nurses, research coordinators, and research labs throughout the US, working together to improve the lives of people with Urea Cycle Disorders. The Urea Cycle Disorders Consortium maintains a registry for patients who wish to be contacted about clinical research opportunities.
For more information on the registry see: http://rarediseasesnetwork.epi.usf.edu/ucdc/takeaction/index.htm

Organizations Organizations

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

Metabolic Support UK
5 Hilliards Court
Sandpiper Way
Chester Business Park
Chester, CH4 9QP United Kingdom
Toll-free: 0800 652 3181
Telephone: 0845 241 2173
E-mail: https://www.metabolicsupportuk.org/contact-us
Website: https://www.metabolicsupportuk.org
National Urea Cycle Disorders Foundation
75 South Grand Avenue
Pasadena, CA 91105
Toll-free: 800-38-NUDCF (386-8233)
Telephone: +1-626-578-0833
E-mail: info@nucdf.org
Website: http://www.nucdf.org

Do you know of an organization? We want to hear from you.

Living With Living With

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.

Learn More Learn More

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 & Events News & Events

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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