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Disease Profile

Ornithine translocase deficiency syndrome

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

Age of onset

Childhood

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ICD-10

E72.4

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome; HHH syndrome; HHHS;

Categories

Congenital and Genetic Diseases; Metabolic disorders; Newborn Screening

Summary

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-, IXand 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.

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.

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 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

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

      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.

        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

          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

          • 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.
          • Genetics Home Reference (GHR) contains information on Ornithine translocase deficiency syndrome. This website is maintained by the National Library of Medicine.

            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.