Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (HHH)
What else is it called?
- Ornithine translocase deficiency
- Mitochondrial Ornithine Carrier
- Ornithine Translocase Deficiency
- Triple H syndrome
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What causes it?
This disorder is caused by a problem in the SLC25A15 gene (13q14). This gene converts the mitochondrial ornithine transporter 1 (ORNT1) which plays a part in ornithine transport across the mitochondrial membrane. This process is used for breaking down arginine and lysine.
If you have a problem in the SLC25A15 gene, changes in the protein will disturb the urea cycle which means your body will be unable to process and remove the waste, ammonia.
HHH is an amino acid condition because ammonia is made when the body breaks down proteins in food into their basic building blocks (amino acids). When there is a problem with the body’s system for removing waste, dangerous amounts of ammonia start to build up in the blood.
How common is it?
HHH is a very rare disorder. Less than 100 affected people have been reported worldwide.
There is a higher prevalence in Canada (specifically Northern Saskatchewan), Italy and Japan. The male/female ratio is approximately 2:1
What are the signs and symptoms?
HHH can vary greatly in how severe it is and at what age it develops. Some babies show signs soon after they are born. Other people with HHH may not show any signs or symptoms until later in their life. However, symptoms usually start from early infancy to childhood and more rarely in adulthood. HHH that shows only later in life is usually less severe than when there are signs in infancy.
Neonatal (new-born) (12% of individuals)
Signs usually start 24-48 hours after feeding and include:
- Lethargy (exhausted)
- Refusal to feed
- Somnolence (drowsiness/ sleepiness)
- Tachypnoea (abnormally rapid breathing)
- Seizures (also known as epilepsy)
Infancy, childhood and adults (88% of individuals) signs include:
- Muscle stiffness (spasticity)
- Poorly controlled body temperature or breathing
- Refusal to eat
- Developmental delays
- Learning disabilities
- Slowed growth
- Seizures (also known as epilepsy)
- Problems with Coordination
- Hyperammonemic coma (triggered by high levels of ammonia in the blood)
If left untreated, this can lead to developmental delays, learning disabilities and muscle stiffness (spasticity).
How is it diagnosed?
Diagnosis will be determined by specific metabolic abnormalities. This is done by carrying out laboratory tests including urine and blood samples. These tests will show increased urinary excretion of orotic acid, homocitrulline and uracil. It will also show a rise in levels of plasma polyamines, ornithine, glutamine, alanine and liver transaminases. The diagnosis can be confirmed through molecular genetic testing.
Many of the serious symptoms and outcomes of HHH can be prevented by early detection through new-born screening and treatment. There is currently no newborn screening for HHH in the UK, however in some countries such as the USA and Canada, all new-borns are screened for HHH. Prenatal diagnosis is an option in families who have a known disease, causing mutation on both alleles.
Can it be treated?
Treatment includes a low protein diet with citrulline or arginine supplements. Any dietary changes require specialist dietitian’s advice and should be overseen by them. In individuals with a resistance, sodium benzoate and/or sodium or glycerol phenylbutyrate may be used for control of plasma ammonia levels. Patients should be monitored during times of stress (e.g. pregnancy, surgery, infections) and when taking certain medications (such as corticosteroids) because they can cause an episode of hyperammonaemia (a metabolic disturbance which leads to an excess of ammonia in the blood and can lead to brain injury which can be fatal).
A hyperammonemic coma is treated in a tertiary care centre where plasma ammonia levels are lowered by haemodialysis or hemofiltration. Ammonia scavenger therapy will be carried out and catabolism will be reversed (through glucose and lipid infusions). Special care must be taken to limit the risk of neurological damage.
With early diagnosis and proper treatment, the prognosis is better than that of most other urea cycle defects. However, patients remain at risk for metabolic decompensation (failure of an organ) throughout their life and if treatment is delayed, irreversible neurological complications can occur. Signs of decompensation include abnormal behaviour, drowsiness and a glazed look. Your metabolic consultant will give you an emergency regimen to follow for times when you are ill, and this will be explained to you.
Do my family need to be tested?
HHH is an inherited condition. Humans have chromosomes made up of DNA. Genes are pieces of DNA that carry the genetic information. Each chromosome may have several thousand genes. We inherit chromosomes from the egg of the mother and sperm of the father. The genes on those chromosomes carry the instructions that determine a person’s characteristics, which are a combination of the parents.
Carriers of the condition do not have the disorder because the other gene of this pair is working normally. Parents of children with HHH are carriers.
The pattern of inheritance in this condition is autosomal recessive. This means:
When both parents are carriers, the risk to the baby in each pregnancy is
- 25% chance (1 in 4) of developing the condition
- 50% chance (1 in 2) for the baby to be a carrier of the condition
- 25% chance (1 in 4) for the baby to have two working genes and neither have the condition nor be a carrier