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Last updated: 10/31/2024
Years published: 2024
NORD gratefully acknowledges Josephine Gao, MS, LCGC, Perinatal Genetic Counselor, Stanford Children’s Hospital and Jose Camacho, MD, Clinical Geneticist, University of California Irvine Medical Center, for the preparation of this report.
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Hyperornithinemia–Hyperammonemia-Homocitrullinuria (HHH) syndrome is characterized by high ammonia and ornithine levels in blood (hyperammonemia and hyperornithinemia) and high homocitrulline levels in the urine (homocitrullinuria). These metabolic abnormalities lead to the symptoms of HHH syndrome.
Symptoms can show at any age, but typically start in infancy or childhood. Hyperammonemia can cause vomiting, low energy (lethargy), confusion, coordination problems (ataxia), rapid breathing, feeding difficulties, seizures and coma. Triggers include illness, protein intake, fasting, surgery, pregnancy and certain medications. HHH syndrome can also cause liver dysfunction and bleeding abnormalities. Chronic symptoms of the disorder affect the brain and may result in learning difficulties, behavior problems, movement disorders, muscle stiffness and weakness.
HHH syndrome is caused by changes (variants) in the SLC25A15 gene. Inheritance is autosomal recessive.
HHH syndrome is treated with a low-protein diet balanced with nutritional supplements and medications to prevent hyperammonemia.
Introduction
HHH syndrome was first described by the team of Dr. Vivian Shih in 1969. HHH syndrome was named after the metabolite differences that characterize the condition: high ammonia and ornithine levels in blood and high homocitrulline levels in the urine. The causative gene, SLC25A15, was discovered in 1999 by the team of Dr. Jose Camacho. This gene provides instructions for a protein called ORNT1 that transports ornithine into a part of the cell called the mitochondria and it is an important part of the urea cycle and important for liver function.
HHH syndrome is considered as a disorder of the urea cycle. The condition has also been called “ornithine transporter (ORNT1) deficiency ” or “ornithine translocase deficiency.”
Symptoms of HHH syndrome can start at any age, but most often begin in infancy or childhood. Symptoms may happen during acute episodes of hyperammonemia, or they may be chronic and progress over time. There is clinical variability, meaning the symptoms and how severe they are can be different for each person. The spectrum can range from learning difficulties and mild brain involvement to life-threatening crises.
High levels of ammonia in the blood (hyperammonemia) may cause:
Triggers include illness, excessive protein intake, fasting, surgery, pregnancy and certain medications. People with HHH syndrome may naturally avoid high-protein foods.
Chronic symptoms of HHH syndrome include:
People with HHH syndrome may have brain damage or loss of brain tissue that can be seen on brain imaging such as an MRI or CT scan. The parts of the brain and nervous system that are affected control muscle tone and reflexes, balance and coordinated movement.
In addition to the brain, HHH syndrome can also affect the function of the liver. The liver may be enlarged (hepatomegaly) and liver function tests may be abnormal.
Other symptoms may include bleeding abnormalities such as bleeding near the brain (subdural hematoma) and inside the body that results in dark stools (melena).
HHH syndrome is caused by variants in the SLC25A15 gene. The protein produced by this gene called ORNT1 is important for transporting ornithine into a part of the cell called the mitochondria. When ornithine cannot be transported, it builds up in the blood (hyperornithinemia) and disrupts a process called the urea cycle. The urea cycle is how the body gets rid of nitrogen, which comes from breaking down proteins. When this process is not working properly, nitrogen builds up in the body in the form of ammonia. A high level of ammonia in the blood (hyperammonemia) is dangerous for the body, especially the brain.
HHH syndrome is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
HHH syndrome is classified as a urea cycle disorder. Over 120 patients have been reported in the medical literature to have HHH syndrome. The estimated frequency of urea cycle disorders collectively is 1 in 35,000. HHH syndrome accounts for 1% – 3.8% of all urea cycle disorders. In the U.S., the frequency of HHH syndrome is less than 1 in 2,000,000 live births.
The frequency of HHH syndrome is highest in people with French-Canadian ancestry because there is a founder variant in this population. A founder variant is a gene variant that is relatively common in a specific population because a common ancestor carried it. There is also a founder variant for people of Japanese and Middle Eastern ancestries.
HHH syndrome should be considered as a possible diagnosis based on symptoms, laboratory studies, brain imaging and family history. HHH syndrome can be diagnosed based on laboratory studies, genetic testing, or both. HHH syndrome is characterized by high levels of ammonia in the blood (hyperammonemia), ornithine in the blood (hyperornithinemia) and homocitrulline in the urine (homocitrullinemia) but these findings are not found in all people with HHH syndrome and may be subtle. This is especially true depending on the person’s diet. There may also be other abnormal findings on blood plasma amino acid and urine organic acid profiles. Abnormalities on brain imaging and liver function tests may help lead to the diagnosis.
HHH syndrome may also be diagnosed based on genetic testing for variants in the SLC25A15 gene, also known as ORNT1.
HHH syndrome is not currently on the Recommended Uniform Screening Panel (RUSP) for newborn screening.
With treatment, people with HHH syndrome can have a normal lifespan and metabolic stability. Treatment can fix liver symptoms and prevent episodes of hyperammonemia. Treatment may not fix neurologic and cognitive symptoms, such as stiffness (spasticity).
The main treatment for HHH syndrome is a low-protein diet. Proteins are made up of amino acids; some amino acids are essential for growth and development. Special formulas and supplements may be recommended to make sure the person receives the essential amino acids, calories and other nutrients their body needs to function. Some of these supplements may include citrulline, arginine, creatine and/or carnitine. There are also medications called ammonia scavengers that can remove ammonia from the body. It is important for the diet and medications to be managed by a dietician and care team that specialize in metabolic genetic disorders.
People with HHH syndrome should avoid high levels of protein in their diet, prolonged fasting, exposure to infectious/contagious diseases and certain medications such as valproic acid and steroids that can trigger or worsen symptoms.
Hyperammonemic crises should be managed in a hospital by a metabolic specialty care team. In these situations, people with HHH syndrome are recommended to stop protein intake and may instead be provided with fluids containing sugar and fats (intralipids) through the vein (intravenously). They will also be given ammonia scavenging medications. If this is not effective, ammonia may need to be filtered from the blood in a process called hemodialysis.
Other management for HHH syndrome is based on symptoms. Growth, development and behavior should be monitored. Metabolic status can be monitored based on blood and urine tests such as plasma ammonia, plasma amino acids, urine amino acids, urine organic acids and urine orotic acid.
People with HHH syndrome should have brain imaging through MRI/MRS, and EEG if they have seizures. They should have a liver ultrasound and laboratory studies to test liver function and blood clotting (coagulation) profile.
People with HHH syndrome may be followed by a specialty care team that includes metabolic genetics, nutrition, neurology, neuropsychology and hepatology. They may benefit from therapies such as occupational, physical and speech therapies. Children may benefit from an individualized education plan (IEP) at school.
Patients who are pregnant should continue their management, including the diet and supplements, and to monitor their ammonia and amino acid levels in the blood regularly. It is important to balance the low protein diet with protein needs for growth of the fetus.
Genetic counseling is recommended for individuals with HHH syndrome and their families.
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For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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For information about clinical trials sponsored by private sources, contact:
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TEXTBOOK
Nyhan WL, Hoffmann GF. Hyperammonemia and Disorders of the Urea Cycle. In: Nyhan WL, Hoffmann GF, eds. Atlas of Inherited Metabolic Diseases. 4th ed. Copyright 2020.
JOURNAL ARTICLE
Martinelli D, Diodato D, Ponzi E, et al. The hyperornithinemia–hyperammonemia-homocitrullinuria syndrome. Orphanet Journal of Rare Diseases. 2015;10(1):29. doi:10.1186/s13023-015-0242-9
INTERNET
Camacho J, Rioseco-Camacho N. Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome. 2012 May 31 [Updated 2020 Feb 13]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK97260/ Accessed Oct 24, 2024.
HHH Syndrome. Baby’s First Test: https://www.babysfirsttest.org/newborn-screening/conditions/hyperornithinemia-hyperammonemia-homocitrullinuria-syndrome Accessed Oct 24, 2024.
Ornithine Translocase Deficiency. Health Resources and Services Administration: https://newbornscreening.hrsa.gov/conditions/ornithine-translocase-deficiency Accessed Oct 24, 2024.
Ornithine Translocase Deficiency. MedlinePlus August 1, 2019. https://medlineplus.gov/genetics/condition/ornithine-translocase-deficiency/ Accessed Oct 24, 2024.
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