RARE DISEASE
Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome
Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome
Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome
Synonyms: HHH syndrome, ORNT1 deficiency, Ornithine carrier deficiency, Ornithine translocase deficiency, Triple H syndrome
Synonyms: HHH syndrome, ORNT1 deficiency, Ornithine carrier deficiency, Ornithine translocase deficiency, Triple H syndrome
Synonyms: HHH syndrome, ORNT1 deficiency, Ornithine carrier deficiency, Ornithine translocase deficiency, Triple H syndrome
Drug discovery
3
drugs
With orphan designations
Overview
Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare autosomal recessive urea cycle disorder caused by pathogenic variants in SLC25A15, disrupting mitochondrial ornithine transport. This results in hyperammonemia, persistently elevated plasma ornithine, and homocitrullinuria. Clinical presentation spans neonatal hyperammonemic crises (lethargy, vomiting, seizures) to later-onset neurological deficits (spastic paraplegia, ataxia, intellectual disability) and chronic liver dysfunction [1][3][6]. Diagnosis relies on biochemical triad confirmation and genetic testing. Management prioritizes protein restriction, citrulline/arginine supplementation, and ammonia scavengers (e.g., sodium benzoate), with acute crises requiring hemodialysis [1][7][12].
Burden
Lifetime risk of metabolic decompensation from infections, fasting, or stressors [1][12].
Irreversible neurological sequelae (developmental delay, spasticity) despite treatment, particularly with delayed diagnosis [6][7][12].
Chronic liver dysfunction and coagulopathy in ~50% of patients, necessitating ongoing monitoring [1][6].
Therapies
Protein-restricted diet with essential amino acid supplementation [1][3][7].
Chronic citrulline/arginine to maintain urea cycle function and sodium benzoate/phenylbutyrate for ammonia control [3][7][12].
Acute hyperammonemia: Hemodialysis, intravenous nitrogen scavengers, and glucose infusions [3][7].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
39 drug discovery papers about Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
39 drug discovery papers about Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2025-11-27 | Impact of high-dose vitamins on a patient with hyperornithinemia-hyperammonemia-homocitrullinuria syndrome
Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare autosomal recessive metabolic disorder caused by a mutation of SLC25A15 encoding for the mitochondrial ornithine carrier. Recent study suggested that impaired mitochondrial function may play a major role in central nervous system impairment in HHH syndrome. We hypothesized that if the mitochondrial dysfunction was associated with neurological impairment in HHH syndrome, antioxidants might be effective to avoid aggravation of the brain injury. We presented the clinical outcome in a patient with HHH syndrome undergoing a high-dose vitamin treatment and discussed the effect of this treatment. The male patient was definitively diagnosed by compound heterogeneous pathogenic variants in the SLC25A15 gene. He was started vitamin B1, C and E therapy at age of 3 years. The blood lactate (Lac) levels gradually decreased and serum β-hydroxybutyrate/acetoacetate (β-OHB/AcAc) ratio also decreased at age of 7 years. A verbal development score in Kyoto Scale of Psychological Development was 65 at age of 3 years. However, quotient of Verbal Comprehension Index in Wechsler Intelligence Scale for Children - Fourth Edition increased to 109 at age of 7 years during this vitamin therapy. The outcome in our patient suggested that high-dose vitamin therapy might contribute to preventing cognitive disability. Moreover, the decreased blood Lac level and serum β-OHB/AcAc ratio also suggested that the effect of this therapy might be due to improving the mitochondrial function such as citric acid cycle . This case report suggest that the high-dose vitamin therapy may enhance mitochondrial function in HHH syndrome.
2025-10-23 | Liver transplantation can prevent the progression of neurological damage in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome and maintain long-term metabolic stability - The largest single-center experience.
Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) syndrome is a rare urea cycle disorder caused by mutations in the SLC25A15 gene, leading to metabolic and neurological impairments. Liver transplantation (LT) may restore urea cycle function and prevent disease progression. This retrospective study analyzed six patients with HHH syndrome who underwent LT between 2016 and 2022. Pre- and post-transplant evaluations included biochemical tests, genetic analysis, neurological assessments, and quality-of-life measures. LT successfully normalized metabolic parameters (ammonia and amino acid levels) and allowed patients to resume normal diets. Early transplantation resulted in neurological improvement in 5 of 6 patients (83.3%), including reduced lower limb spasticity and improved walking ability. Two patients (33.3%) achieved nearly normal gait, and one patient (16.7%) recovered to normal motor function within three months after LT. Quality-of-life scores improved in 2 patients (33.3%). The overall survival rate was 83.3%, with one patient dying from unrelated causes 5 years post-transplant. No significant long-term complications were observed in the surviving patients. Liver transplantation is an effective treatment for HHH syndrome, halting neurological decline and improving quality of life. Early LT before irreversible damage provides the best outcomes, making it a viable option for patients with progressive symptoms unresponsive to conventional therapies. Not applicable.
2025-09-05 | What are the effective treatments for managing symptoms of hyperornithinemia-hyperammonemia-homocitrullinuria syndrome?
Effective management of HHH syndrome involves dietary protein restriction, essential amino acid supplementation, use of nitrogen-scavenging drugs, and potentially liver transplantation.
2025-04-26 | Urea cycle defects in adulthood: clinical presentation, diagnosis and treatment in genetically encoded hepatic metabolic disorders with a potential for encephalopathy.
Hyperammonaemia is an important cause for encephalopathy. Ammonia is the waste product of amino acid degradation and cannot be excreted via urine. Ammonia is metabolized to water-soluble urea via the urea cycle. Hyperammonaemia not only occurs during acute liver failure, but also in rare genetically determined defects of enzymes or transporters involved in the urea cycle resulting in elevated ammonia concentrations. Enzyme defects include deficiency of carbamylphosphate synthase, N-acetylglutamate synthase, ornithine transcarbamylase, argininosuccinate lyase and arginase, transporter defects are citrin deficiency and HHH-syndrome. These urea cycle defects (UCD) mostly manifest for the first time during the neonatal period, infancy or childhood, however first clinical manifestations including encephalopathy may be observed in adulthood in milder forms. Therefore, physicians treating adults should be aware of clinical symptoms in UCD to make a timely diagnosis and initiate treatment. In adulthood, clinical symptoms are often uncharacteristic including headache, avoidance of high-protein food, psychiatric symptoms triggered by heavy exercise or delivery of a child, autism, attention deficit, lethargy, developmental delay and epilepsy. Elevated ammonia concentrations in blood are the biochemical hallmark. Some UCDs can be diagnosed at metabolite level, others only at genetic level. Treatment consists of eucaloric, low-protein diet supplemented with essential amino acids and vitamins/trace elements, and intake of arginine or citrulline. Pharmacological scavengers of nitrogen are benzoate and butyrate. If conservative therapy fails, hemodialysis should be considered. Prompt treatment during acute crises is essential for optimal outcome. Liver transplantation is considered in metabolically unstable patients. For arginase deficiency, enzyme replacement therapy is available.
2024-06-21 | Postoperative hyperammonemic encephalopathy due to unexpected constipation in a patient with hyperornithinemia-hyperammonemia-homocitrullinuria syndrome: a case report.
Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare autosomal recessive urea cycle disorder associated with a high risk of exacerbation of hyperammonemia during the perioperative period. Here, we describe an adult patient with HHH syndrome who developed hyperammonemic encephalopathy secondary to postoperative constipation. A 52-year-old patient with HHH syndrome underwent intrathecal baclofen pump insertion for lower limb spasticity under general anesthesia. The surgery was uneventful, without any increase in serum ammonia levels. However, after surgery, he was constipated, and on postoperative day (POD) 3, he fell into a coma with an exacerbation of hyperammonemia (894 µg/dL). After administering a glycerin enema, he defecated, leading to a rapid decrease in serum ammonia levels to 165 µg/dL. He regained consciousness, and serum ammonia levels remained stable as long as he defecated. We suggest strict management of defecation during the perioperative period to prevent hyperammonemia in patients with HHH syndrome.
2025-11-27 | Impact of high-dose vitamins on a patient with hyperornithinemia-hyperammonemia-homocitrullinuria syndrome
Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare autosomal recessive metabolic disorder caused by a mutation of SLC25A15 encoding for the mitochondrial ornithine carrier. Recent study suggested that impaired mitochondrial function may play a major role in central nervous system impairment in HHH syndrome. We hypothesized that if the mitochondrial dysfunction was associated with neurological impairment in HHH syndrome, antioxidants might be effective to avoid aggravation of the brain injury. We presented the clinical outcome in a patient with HHH syndrome undergoing a high-dose vitamin treatment and discussed the effect of this treatment. The male patient was definitively diagnosed by compound heterogeneous pathogenic variants in the SLC25A15 gene. He was started vitamin B1, C and E therapy at age of 3 years. The blood lactate (Lac) levels gradually decreased and serum β-hydroxybutyrate/acetoacetate (β-OHB/AcAc) ratio also decreased at age of 7 years. A verbal development score in Kyoto Scale of Psychological Development was 65 at age of 3 years. However, quotient of Verbal Comprehension Index in Wechsler Intelligence Scale for Children - Fourth Edition increased to 109 at age of 7 years during this vitamin therapy. The outcome in our patient suggested that high-dose vitamin therapy might contribute to preventing cognitive disability. Moreover, the decreased blood Lac level and serum β-OHB/AcAc ratio also suggested that the effect of this therapy might be due to improving the mitochondrial function such as citric acid cycle . This case report suggest that the high-dose vitamin therapy may enhance mitochondrial function in HHH syndrome.
2025-10-23 | Liver transplantation can prevent the progression of neurological damage in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome and maintain long-term metabolic stability - The largest single-center experience.
Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) syndrome is a rare urea cycle disorder caused by mutations in the SLC25A15 gene, leading to metabolic and neurological impairments. Liver transplantation (LT) may restore urea cycle function and prevent disease progression. This retrospective study analyzed six patients with HHH syndrome who underwent LT between 2016 and 2022. Pre- and post-transplant evaluations included biochemical tests, genetic analysis, neurological assessments, and quality-of-life measures. LT successfully normalized metabolic parameters (ammonia and amino acid levels) and allowed patients to resume normal diets. Early transplantation resulted in neurological improvement in 5 of 6 patients (83.3%), including reduced lower limb spasticity and improved walking ability. Two patients (33.3%) achieved nearly normal gait, and one patient (16.7%) recovered to normal motor function within three months after LT. Quality-of-life scores improved in 2 patients (33.3%). The overall survival rate was 83.3%, with one patient dying from unrelated causes 5 years post-transplant. No significant long-term complications were observed in the surviving patients. Liver transplantation is an effective treatment for HHH syndrome, halting neurological decline and improving quality of life. Early LT before irreversible damage provides the best outcomes, making it a viable option for patients with progressive symptoms unresponsive to conventional therapies. Not applicable.
2025-09-05 | What are the effective treatments for managing symptoms of hyperornithinemia-hyperammonemia-homocitrullinuria syndrome?
Effective management of HHH syndrome involves dietary protein restriction, essential amino acid supplementation, use of nitrogen-scavenging drugs, and potentially liver transplantation.
2025-04-26 | Urea cycle defects in adulthood: clinical presentation, diagnosis and treatment in genetically encoded hepatic metabolic disorders with a potential for encephalopathy.
Hyperammonaemia is an important cause for encephalopathy. Ammonia is the waste product of amino acid degradation and cannot be excreted via urine. Ammonia is metabolized to water-soluble urea via the urea cycle. Hyperammonaemia not only occurs during acute liver failure, but also in rare genetically determined defects of enzymes or transporters involved in the urea cycle resulting in elevated ammonia concentrations. Enzyme defects include deficiency of carbamylphosphate synthase, N-acetylglutamate synthase, ornithine transcarbamylase, argininosuccinate lyase and arginase, transporter defects are citrin deficiency and HHH-syndrome. These urea cycle defects (UCD) mostly manifest for the first time during the neonatal period, infancy or childhood, however first clinical manifestations including encephalopathy may be observed in adulthood in milder forms. Therefore, physicians treating adults should be aware of clinical symptoms in UCD to make a timely diagnosis and initiate treatment. In adulthood, clinical symptoms are often uncharacteristic including headache, avoidance of high-protein food, psychiatric symptoms triggered by heavy exercise or delivery of a child, autism, attention deficit, lethargy, developmental delay and epilepsy. Elevated ammonia concentrations in blood are the biochemical hallmark. Some UCDs can be diagnosed at metabolite level, others only at genetic level. Treatment consists of eucaloric, low-protein diet supplemented with essential amino acids and vitamins/trace elements, and intake of arginine or citrulline. Pharmacological scavengers of nitrogen are benzoate and butyrate. If conservative therapy fails, hemodialysis should be considered. Prompt treatment during acute crises is essential for optimal outcome. Liver transplantation is considered in metabolically unstable patients. For arginase deficiency, enzyme replacement therapy is available.
2024-06-21 | Postoperative hyperammonemic encephalopathy due to unexpected constipation in a patient with hyperornithinemia-hyperammonemia-homocitrullinuria syndrome: a case report.
Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare autosomal recessive urea cycle disorder associated with a high risk of exacerbation of hyperammonemia during the perioperative period. Here, we describe an adult patient with HHH syndrome who developed hyperammonemic encephalopathy secondary to postoperative constipation. A 52-year-old patient with HHH syndrome underwent intrathecal baclofen pump insertion for lower limb spasticity under general anesthesia. The surgery was uneventful, without any increase in serum ammonia levels. However, after surgery, he was constipated, and on postoperative day (POD) 3, he fell into a coma with an exacerbation of hyperammonemia (894 µg/dL). After administering a glycerin enema, he defecated, leading to a rapid decrease in serum ammonia levels to 165 µg/dL. He regained consciousness, and serum ammonia levels remained stable as long as he defecated. We suggest strict management of defecation during the perioperative period to prevent hyperammonemia in patients with HHH syndrome.
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Drug Discovery Landscape
3 orphan drug designations for Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, including 1 approved therapy.
3 orphan drug designations for Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Sodium benzoate | small molecules | EMA | 2016-08-29 | — | Lucane Pharma SA |
Heterologous human adult liver-derived progenitor cells | cell therapies | EMA | 2013-07-17 | — | Cellaion |
Glyceryl tri-(4-phenylbutyrate) [Ravicti] | small molecules | EMA | 2010-06-10 | 2015-12-01 | Immedica Pharma AB |
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