Ornithine translocase deficiency syndrome

Alternate names

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

Definition

Ornithine translocase deficiency is an inherited disorder that causes ammonia and other substances to build up (accumulate) in the blood. Ammonia, which is formed when proteins are broken down in the body, is toxic if the levels become too high. The nervous system is especially sensitive to the effects of excess ammonia.

Onset

• Ornithine translocase deficiency varies widely in its severity and age of onset.
• Affected infants show signs and symptoms of ornithine translocase deficiency within days after birth.
• In most affected individuals, however, signs and symptoms of ornithine translocase deficiency do not appear until later in life, with health problems first appearing anytime from childhood to adulthood.
• Later-onset forms of ornithine translocase deficiency are usually less severe than the infantile form.

Epidemiology

Ornithine translocase deficiency is a very rare disorder. More than 100 affected individuals have been described in the scientific literature.

Cause

• Mutations in the SLC25A15 gene cause ornithine translocase deficiency.
• The SLC25A15 gene provides instructions for making a protein called mitochondrial ornithine transporter 1. This protein participates in the urea cycle, which is a sequence of biochemical reactions that occurs in liver cells.
• The urea cycle breaks down excess nitrogen, made when protein is broken down by the body, to make a compound called urea that is excreted by the kidneys in urine.
• Mitochondrial ornithine transporter 1 is located within the mitochondria (the energy-producing centers in cells), where the protein transports a molecule called ornithine so it can participate in the urea cycle.
• Another version of the mitochondrial ornithine transporter protein is produced by a different gene. While this protein is not as abundant as mitochondrial ornithine transporter 1, it is thought that this other version of the protein may partially compensate for the loss of mitochondrial ornithine transporter 1 and contribute to the late age of onset and mild signs and symptoms in some affected individuals.
• Other factors, many unknown, also contribute to the variable severity of ornithine translocase deficiency.
• Because ornithine translocase deficiency is caused by problems with the urea cycle, it belongs to a class of genetic diseases called urea cycle disorders.

Gene mutations

• Mutations in the SLC25A15 gene cause the production of a mitochondrial ornithine transporter 1 with reduced or absent function. As a result, ornithine transport is impaired and the urea cycle cannot proceed normally.
• This causes, nitrogen to accumulate in the bloodstream in the form of toxic ammonia instead of being converted to less toxic urea and being excreted. A
• mmonia is especially damaging to the brain, and excess ammonia causes neurological problems and other signs and symptoms of ornithine translocase deficiency.
• Byproducts of impaired ornithine transport in people with this condition include the accumulation of a substance called ornithine in the blood (hyperornithinemia) and the excretion of a substance called homocitrulline in the urine (homocitrullinuria).

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

• Infants with ornithine translocase deficiency may lack energy (be lethargic), refuse to eat, vomit frequently, or have poorly controlled breathing or body temperature.
• Seizures or unusual body movements are common in these individuals.
• Some people with this condition have intellectual disability or developmental delay, but others have normal intelligence. Severe cases may result in coma.
• Some people with later-onset ornithine translocase deficiency have episodes of vomiting, lethargy, problems with coordination (ataxia), vision problems, episodes of brain dysfunction (encephalopathy), developmental delay, learning disabilities, or stiffness caused by abnormal tensing of the muscles (spasticity). Affected individuals may have chronic liver problems and mild abnormal bleeding.
• Individuals with ornithine translocase deficiency often cannot tolerate high-protein foods, such as meat. Occasionally, high-protein meals or stress caused by illness or periods without food (fasting) may cause ammonia to accumulate more quickly in the blood. This rapid increase of ammonia likely leads to the signs and symptoms of ornithine translocase deficiency.
• While the signs and symptoms of ornithine translocase deficiency can vary greatly among affected individuals, proper treatment can prevent some complications from occurring and may improve quality of life.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Abnormal circulating citrulline concentration
• Cognitive impairment(Abnormality of cognition)
• Hyperammonemia(High blood ammonia levels)
• Hyperornithinemia(High blood ornithine levels)
• Neurodevelopmental delay

30%-79% of people have these symptoms

• Abnormal pyramidal sign
• Acute encephalopathy
• Cerebral cortical atrophy(Decrease in size of the outer layer of the brain due to loss of brain cells)
• Clonus
• Confusion(Disorientation)
• Elevated hepatic transaminase(High liver enzymes)
• Episodic vomiting
• Failure to thrive(Faltering weight)
• Feeding difficulties(Feeding problems)
• Generalized [[hypotonia](Decreased muscle tone)
• Hepatitis(Liver inflammation)
• Hepatomegaly(Enlarged liver)
• Impaired vibratory sensation(Decreased vibration sense)
• Intellectual disability(Mental deficiency)
• Lethargy
• Oroticaciduria(High urine orotic acid levels)
• Poor coordination
• Progressive cerebellar ataxia
• Protein avoidance
• Spastic paraplegia
• Specific learning disability
• Speech apraxia
• Tachypnea(Increased respiratory rate or depth of breathing)

5%-29% of people have these symptoms

• Abnormality of the coagulation cascade
• Coma
• Generalized myoclonic seizure
• Multifocal cerebral white matter abnormalities
• Respiratory alkalosis
• Spastic gait(Spastic walk)

1%-4% of people have these symptoms

• Chorioretinal atrophy
• Chorioretinal hypopigmentation
• Hepatic failure(Liver failure)

Diagnosis

• 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.

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.

NIH genetic and rare disease info

• NIH info on Ornithine translocase deficiency syndrome

Ornithine translocase deficiency syndrome is a rare disease.

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