On this page
HHH syndrome
HHH syndrome, or hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome, is a genetic condition that impacts the urea cycle, leading to a build-up of ammonia in the blood. This can affect the brain and other organs, typically presenting in infancy or early childhood.
Available at Jeen Health
Clinical tests that include this
Overview
HHH syndrome, also known as hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome, is a rare inherited metabolic disorder. It affects the urea cycle, a crucial process in the body responsible for converting toxic ammonia into urea, which can then be safely removed from the body [PMID:33678000]. When this cycle doesn't work correctly, ammonia can build up in the blood, a condition known as hyperammonaemia. High levels of ammonia are particularly harmful to the brain.
The syndrome typically manifests in infancy or early childhood, though in some cases, symptoms may appear later. The severity can vary greatly between individuals, even within the same family. Early diagnosis and management are important to help reduce the impact of the condition.
Symptoms & clinical features
The symptoms of HHH syndrome can be varied, depending on the severity of the metabolic disruption. In infants, feeding difficulties, vomiting, lethargy (lack of energy), and developmental delays are common initial signs. Some infants may experience seizures or periods of unconsciousness (coma) due to high ammonia levels [PMID:33678000].
In older children and adults, symptoms might include intellectual disabilities, balance and coordination problems (ataxia), muscle weakness (myopathy), and episodes of confusion or behavioural changes, particularly after eating high-protein meals. Headaches, vision problems, and liver enlargement have also been reported in some individuals. Recognising these symptoms and seeking medical advice is important for timely diagnosis.
Video: Genetics 101
Affected organs
The primary organ affected by HHH syndrome is the brain, due to its vulnerability to high ammonia levels. Ammonia is neurotoxic, meaning it can damage nerve cells and impair brain function. This can lead to a range of neurological symptoms, including developmental delay, intellectual disability, seizures, and ataxia.
Other organs can also be impacted. The liver may show some changes, though severe liver disease is not typically a primary feature. Muscle weakness (myopathy) can also occur, suggesting an effect on muscle tissue. The kidneys are involved in excreting homocitrulline, which accumulates in the urine (homocitrullinuria).
Risks & severity
HHH syndrome has a variable spectrum of severity. Some individuals experience severe symptoms from infancy, including life-threatening episodes of hyperammonaemic crises, while others may have milder, later-onset presentations. The long-term outlook is closely linked to the degree of ammonia control; sustained high ammonia levels can lead to irreversible neurological damage.
The exact prevalence of HHH syndrome is not well established, but it is considered a very rare condition globally. There is no specific age of onset that is universally predictable; symptoms can emerge at any point from the neonatal period into adulthood, though childhood onset is more common. Early intervention and consistent management are key to improving outcomes and reducing the risk of severe complications.
Genetic causes
HHH syndrome is caused by pathogenic variants in the SLC25A15 gene [PMID:19640473]. This gene provides instructions for making a protein called ornithine translocase, which is located in the inner membrane of the mitochondria. Mitochondria are often called the 'powerhouses' of the cell, responsible for producing energy.
Ornithine translocase plays a critical role in the urea cycle by transporting ornithine into the mitochondria. Ornithine is essential for the function of an enzyme called ornithine transcarbamylase, which is part of the urea cycle. When the SLC25A15 gene has a pathogenic variant, the ornithine translocase protein either doesn't work correctly or isn't produced in sufficient amounts. This disrupts the transport of ornithine, leading to a build-up of ammonia and ornithine in the blood, and the excretion of homocitrulline in the urine.
- SLC25A15 solute carrier family 25 member 15The SLC25A15 gene provides instructions for mitochondrial ornithine transporter 1, a protein vital for nitrogen waste processing in the urea cycle, with variants associated with hyperornithinaemia-hyperammonaemia-homocitrullinuria (HHH) syndrome.
Inheritance pattern
HHH syndrome is inherited in an autosomal recessive pattern. This means that a person must inherit two altered copies of the SLC25A15 gene - one from each parent - to develop the condition. Individuals who inherit only one altered copy are called carriers. Carriers typically do not show symptoms of HHH syndrome because their single working copy of the gene is sufficient to produce enough functional ornithine translocase.
If both parents are carriers of a pathogenic variant in the SLC25A15 gene, there is a 25% (1 in 4) chance with each pregnancy that their child will inherit two altered copies and develop HHH syndrome. There is a 50% (2 in 4) chance their child will be a carrier, and a 25% (1 in 4) chance their child will inherit two working copies of the gene and not be affected or a carrier.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
Diagnosis of HHH syndrome typically involves a combination of clinical observations and specific biochemical tests. Blood tests may reveal elevated levels of ammonia and ornithine, while urine tests often show high levels of homocitrulline [PMID:33678000]. These biochemical markers are key indicators of the condition. Elevated ornithine in the cerebrospinal fluid may also be observed.
Confirmation of the diagnosis is made through genetic testing, which identifies pathogenic variants in the SLC25A15 gene. In the UK, genetic testing for suspected metabolic disorders, including HHH syndrome, is typically requested by a specialist metabolic consultant. Referrals to clinical genetics services can also be made for diagnostic testing following initial biochemical findings. The NHS Genomic Medicine Service provides comprehensive genetic testing, often referenced by specific R-codes.
Management & lifestyle
Management of HHH syndrome focuses on reducing ammonia levels in the blood and preventing metabolic crises. This primarily involves dietary modifications, especially restricting protein intake, as protein breakdown produces ammonia. Special low-protein formulas and medical foods may be prescribed. Some individuals may also benefit from supplements like L-citrulline or L-arginine, which can help support the urea cycle, or ammonia scavengers, which help remove ammonia from the body.
Regular monitoring of blood ammonia and amino acid levels is crucial. In the UK, care for individuals with HHH syndrome is usually coordinated by a specialist metabolic team, including dietitians, metabolic consultants, and genetic counsellors. Management plans are individualised and adjusted based on the person's age, symptoms, and biochemical results. During acute crises, hospitalisation may be necessary for intensive medical management to rapidly lower ammonia levels.
UK care pathway
In the UK, individuals with suspected or diagnosed HHH syndrome are managed within the NHS Genomic Medicine Service. If a metabolic disorder is suspected, a general practitioner (GP) will typically refer to a paediatrician or an adult specialist, who can then involve a metabolic consultant. These specialists will guide diagnostic investigations, including biochemical and genetic testing. Genetic testing for HHH syndrome, often requested through specific NHS R-codes, confirms the diagnosis by identifying variants in the SLC25A15 gene.
Following diagnosis, individuals and their families are usually referred to a regional clinical genetics service and have access to genetic counselling. Genetic counsellors provide information about the condition, its inheritance pattern, and discuss implications for family members. Multidisciplinary teams, including metabolic consultants, dietitians, and specialist nurses, provide ongoing care and support.
Frequently asked questions
What is ammonia, and why is it harmful in HHH syndrome?
Ammonia is a waste product generated when the body breaks down protein. In HHH syndrome, the body cannot effectively convert ammonia into a less toxic substance called urea, leading to its build-up in the blood. High levels of ammonia are particularly damaging to the brain and can cause various neurological problems.
Can HHH syndrome be cured?
There is currently no cure for HHH syndrome. However, the condition can be managed effectively through dietary changes, such as restricting protein intake, and sometimes with medications that help remove ammonia from the body. These treatments aim to prevent or reduce the severity of symptoms and improve long-term outcomes.
How is HHH syndrome inherited?
HHH syndrome is inherited in an autosomal recessive manner. This means that an individual must inherit a faulty copy of the SLC25A15 gene from each parent to develop the condition. Parents who carry one faulty copy typically do not have symptoms but can pass the gene on to their children.
What kind of diet is recommended for HHH syndrome?
A low-protein diet is typically recommended for individuals with HHH syndrome to minimise ammonia production. This diet must be carefully planned and monitored by a specialist dietitian to ensure adequate nutrition and prevent complications. Special medical foods and supplements may also be part of the dietary management.
How often do people with HHH syndrome need to see a doctor?
Individuals with HHH syndrome usually require regular follow-up appointments with a specialist metabolic team, including a metabolic consultant and dietitian. The frequency of these appointments depends on the individual's age, symptoms, and how well their ammonia levels are controlled. Regular blood tests are often necessary to monitor biochemical markers.
References
- Adam MP, Bick S, Mirzaa GM. Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome. 1993. PMID: 22649802
- Martinelli D, Diodato D, Ponzi E. The hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. Orphanet journal of rare diseases. 2015. PMID: 25874378
- Nguyen KN, Tran VK, Nguyen NL. Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome in Vietnamese Patients. Medicina (Kaunas, Lithuania). 2024. PMID: 39597062
- Panza E, Martinelli D, Magini P. Hereditary Spastic Paraplegia Is a Common Phenotypic Finding in ARG1 Deficiency, P5CS Deficiency and HHH Syndrome: Three Inborn Errors of Metabolism Caused by Alteration of an Interconnected Pathway of Glutamate and Urea Cycle Metabolism. Frontiers in neurology. 2019. PMID: 30853934
- Martinelli D, Fiermonte G, Häberle J. CUGC for hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome. European journal of human genetics : EJHG. 2020. PMID: 32242103
- Sokoro AA, Lepage J, Antonishyn N. Diagnosis and high incidence of hyperornithinemia-hyperammonemia-homocitrullinemia (HHH) syndrome in northern Saskatchewan. Journal of inherited metabolic disease. 2010. PMID: 20574716
- Camacho JA, Mardach R, Rioseco-Camacho N. Clinical and functional characterization of a human ORNT1 mutation (T32R) in the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome. Pediatric research. 2006. PMID: 16940241
- Camacho JA, Rioseco-Camacho N. The human and mouse SLC25A29 mitochondrial transporters rescue the deficient ornithine metabolism in fibroblasts of patients with the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome. Pediatric research. 2009. PMID: 19287344