Alternative titles; symbols
SNOMEDCT: 30287008; ICD10CM: E72.4; ORPHA: 415; DO: 0050720;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 13q14.11 | Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome | 238970 | Autosomal recessive | 3 | SLC25A15 | 603861 |
A number sign (#) is used with this entry because of evidence that the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome (HHHS) is caused by homozygous mutation in the SLC25A15 gene (603861), which encodes the mitochondrial ornithine transporter, on chromosome 13q14.
Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (HHHS) is an autosomal recessive, chronic and progressive disorder of the urea cycle with typical age of onset in early life. The acute phase is characterized by hyperammonemia accompanied by vomiting, ataxia, lethargy, confusion, and coma. Chronically, aversion to protein-rich foods, coagulation abnormalities, hypotonia, developmental delay, progressive encephalopathy with mental regression, and signs of motor dysfunction are present. About 95% of patients survive after diagnosis and therapy is established. However, in early adulthood most patients develop signs of pyramidal tract dysfunction (summary by Tessa et al., 2009).
Shih et al. (1969) reported a child with mental retardation and myoclonic seizures associated with hyperornithinemia, hyperammonemia, and homocitrullinemia. The findings were consistent with an inherited disorder of amino acid metabolism.
Rodes et al. (1987) reported a family in which 2 brothers and a sister were affected with HHH syndrome. One patient had progressive spastic paraparesis. At least 2 of the individuals voluntarily avoided a high protein diet.
Dionisi Vici et al. (1987) found reports of 23 patients with HHH syndrome in the literature, only 1 of whom showed symptoms as a neonate.
Koike et al. (1987) reported Japanese brothers, aged 13 and 19 years, with HHH syndrome. The clinical picture included protein intolerance, mental retardation, seizures, and stuporous episodes. One patient had cerebellar ataxia, myoclonus, convulsive seizure, and muscular weakness in both legs. The older brother had refused to eat fish and meat, and had episodes of vomiting when fed a high-protein formula. Both brothers also had myoclonus epilepsy.
Nakajima et al. (1988) reported a Japanese child, born of healthy first-cousin parents, with HHH syndrome. Development was delayed in late infancy, and spastic paraplegia was noted at the age of 3 years. The patient always avoided the intake of meat, milk, and eggs. At age 10, he had an episode of lethargy and hyperammonemia. Brain CT showed diffuse white matter low density and atrophy of the cerebellar vermis.
Tuchman et al. (1990) described this disorder in a 39-year-old man and his 42-year-old sister, both vegetarians, who had had episodic confusion for many years, but normal mental function between these episodes. Hyperammonemia was documented during an episode of confusion in the male sib but not in his sister. During therapy with citrulline and phenylbutyrate sodium, plasma ornithine levels increased in both patients, while plasma levels of glutamine and alanine decreased to normal. With therapy, their clinical conditions improved and no recurrent neurologic dysfunction was observed over a follow-up period of 20 months.
Miyamoto et al. (2001) reported a 52-year-old woman who had spastic gait and cerebellar signs, including dysmetria, dysdiadochokinesis, and scanning speech, since adolescence, but did not have mental retardation. She had spastic paraparesis of the arms since age 27. Hyperammonemia was noted at the age of 36 years, and a protein-restricted diet and kanamycin were prescribed. At age 37, she had surgery to elongate Achilles tendons in both legs. The diagnosis of HHH syndrome was made at the age of 52, on the basis of hyperornithinemia and homocitrullinuria.
Salvi et al. (2001) reported a follow-up on 8 Italian patients who had been diagnosed with HHH syndrome. Age at onset ranged from infancy to 18 years. The predominant neurologic finding was spastic paraparesis, seen in 5 patients. The remaining 3 patients showed signs of pyramidal dysfunction, which the authors suggested may progress to spastic paraparesis later in life. Mental retardation and clonic movements were variably present.
Debray et al. (2008) reviewed the medical records of 16 French Canadian patients with HHH syndrome, 15 of whom were homozygous for the common F188del founder mutation in the SLC25A15 gene (603861.0001). Six of the patients had previously been reported by Lemay et al. (1992). The median age at presentation was 2.7 years (range, 3 months to 16 years). Common features included failure to thrive, developmental delay, liver dysfunction with secondary coagulation defects, hyperammonemia, hyperornithinemia, and abnormally increased liver enzymes.
Batshaw et al. (2014) reported the results of an analysis of 614 patients with urea cycle disorders (UCDs) enrolled in the Urea Cycle Disorders Consortium's longitudinal study protocol. HHH syndrome occurred in 9 patients (1.5%), 8 of whom had a late-onset form.
Hommes et al. (1986) reported what they considered to be the twelfth documented case of HHH syndrome. They showed that the uptake of ornithine by the particulate fraction of the patient's fibroblasts was abnormally low, but still measurable. This suggested a partial impairment of uptake of ornithine by mitochondria.
Rodes et al. (1987) found that cultured skin fibroblasts derived from patients with HHH syndrome showed 6 times less incorporation of labeled ornithine into protein as compared to control cells. Further studies were consistent with a defect in the transport of ornithine into the mitochondria.
Koike et al. (1987) found that isolated liver mitochondria in a patient with HHH syndrome showed decreased ornithine transport and citrulline synthesis, but urea cycle enzymes and ornithine aminotransferase were normal. Ornithine metabolism was also decreased in cultured skin fibroblasts.
Dionisi Vici et al. (1987) reported 2 unrelated patients with neonatal onset of HHH syndrome. One of their patients also had deficiency of clotting factors VII (F7; 613878) and X (F10; 613872), both of which are linked to chromosome 13q. The same association had been described by Gatfield et al. (1975) and by Simell et al. (1985). Dionisi Vici et al. (1987) suggested that the mutation responsible for the HHH syndrome is located on 13q.
Smith et al. (1992), who stated that over 30 patients had been described, reported a 5-year-old French-Canadian girl with HHH syndrome who presented a clinical picture suggesting hepatitis associated with coagulopathy, initially thought to be acute viral hepatitis.
Lemay et al. (1992) described the clinical, electrophysiologic, ophthalmologic, and neuropsychologic features of 6 patients. Pyramidal signs, decreased vibration sense, buccofaciolingual dyspraxia, and learning difficulties or subnormal intelligence were found in most. Anomalies of peripheral nerve conduction velocity and of evoked potentials were common. In 1 patient, markedly abnormal white matter was demonstrated on cranial MRI. One patient had retinal depigmentation and chorioretinal thinning. Only 2 of the patients had had episodes of symptomatic hyperammonemia. The relationship of hyperammonemia to the chronic neuropsychologic problems of these patients was unclear. However, in a follow-up to these patients, Debray et al. (2008) noted that these patients showed no clinical signs of peripheral neuropathy. In addition, the patient with retinal depigmentation and chorioretinal thinning showed no deterioration and had normal visual function at age 22 years.
Autosomal recessive inheritance was supported by the large Canadian pedigree of Gatfield et al. (1975), with 6 affected persons of both sexes.
Prenatal Diagnosis
Chadefaux et al. (1989) suggested that the first-trimester diagnosis of HHHS can be achieved by study of the incorporation of (14)C-ornithine into proteins of chorionic villi. They referred to a case of untreated HHH syndrome in the mother being associated with a mentally retarded offspring.
Shih et al. (1992) described neonatal death in the HHH syndrome and successful prenatal diagnosis of the disorder in a subsequent pregnancy in this family. Thus, the severity ranges from minimal neurologic dysfunction in adulthood (Tuchman et al., 1990) to neonatal death. Diagnostic of the condition in amniotic cells was the combination of normal OAT activity and the inability of the cells to utilize ornithine.
In the first case of HHH syndrome reported from Norway, Gjessing et al. (1986) found that a low protein diet initiated early in life permitted normal development.
Rodes et al. (1987) found that ornithine supplementation and restricted protein intake appeared to be useful in treatment of HHH syndrome.
Wong et al. (1989) treated a woman with this disorder during pregnancy with lactulose and arginine to reduce blood ammonia. A normal offspring resulted, who developed normally and showed a full-scale IQ of 130 at age 5 years.
Among 11 patients with the HHH syndrome, Camacho et al. (1999) identified 2 mutations in the ORNT1 gene (see, e.g., F188del; 603861.0001 and E180K; 603861.0002), and a larger deletion. The F188del mutation accounted for 19 of 20 possible mutant ORNT1 alleles among French Canadian patients, consistent with a founder effect in that population.
In 2 unrelated Japanese patients with HHH syndrome, Miyamoto et al. (2001) identified a homozygous mutation in the SLC25A15 gene (R179X; 603861.0003) substitution. One of the patients had previously been reported by Nakajima et al. (1988).
In 8 Italian patients with HHH syndrome, Salvi et al. (2001) identified 9 different mutations in the SLC25A15 gene, 7 of which were novel (see, e.g., 603861.0004).
Debray et al. (2008) noted that 22 different mutations of the SLC25A15 gene had been described in 49 patients from 31 unrelated families with HHH syndrome to date.
In 16 patients from 13 unrelated families with HHH syndrome, Tessa et al. (2009) identified 13 different mutations in the SLC25A15 gene, including 11 novel mutations (see, e.g., 603861.0003; 603861.0006-603861.0008). In vitro functional expression assays showed mutant proteins with decreased transport activity between 4 and 19% of control values. There were no apparent genotype/phenotype correlations.
Genetic Modifiers
Camacho et al. (2003) identified ORNT2 (SLC25A2; 608157), an intronless gene encoding a protein 88% identical to ORNT1. ORNT2 targets to mitochondria and is expressed in human liver, pancreas, kidney, and cultured fibroblasts from control and HHH patients. When ORNT2 was overexpressed transiently in cultured fibroblasts from HHH patients, it rescued the deficient ornithine metabolism in those cells. Camacho et al. (2003) suggested that expression of ORNT2 may in part be responsible for the milder phenotype in HHH patients secondary to a gene redundancy effect.
Camacho et al. (2006) identified a homozygous mutation in the SLC25A15 gene (T32R; 603861.0009) in 5 affected members of 2 related families of Mexican descent with HHH syndrome. Overexpression studies showed that the mutant protein targeted normally to the mitochondrial and retained some residual activity. However, basal ornithine transport of primary untransfected patient fibroblasts showed loss of function; the observations were important, since they showed a discordance between the clinical and cellular phenotype in patients with HHH syndrome. The patients showed phenotypic variability, with 1 patient in particular having neurologic involvement, including poor school performance, low IQ (55), dysarthria, hyperreflexia, and cortical atrophy on MRI. This patient died from complications of hyperammonemic encephalopathy. The other patients had mild learning disabilities, but no neurologic deficits. Two patients with the mildest defects were found to be carriers for a gain of function val181-to-gly (V181G) polymorphism in the ORNT2 gene, whereas the members of the family who had the patient with the more severe phenotype had the wildtype val181 ORNT2 variant. The mitochondrial haplotypes of the 2 families also differed. Camacho et al. (2006) suggested that the genotype of HHH patients cannot predict the clinical course of the disease, and that other modifying factors, such as gene redundancy or mitochondrial background may further influence the phenotype.
Camacho and Rioseco-Camacho (2009) found that mouse and human SLC25A29 (615064), a mitochondrial carnitine/acylcarnitine transporter, rescued defective ornithine metabolism in skin fibroblasts cultured from patients with HHH syndrome.
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Camacho, J. A., Mardach, R., Rioseco-Camacho, N., Ruiz-Pesini, E., Derbeneva, O., Andrade, D., Zaldivar, F., Qu, Y., Cederbaum, S. D. Clinical and functional characterization of a human ORNT1 mutation (T32R) in the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome. Pediat. Res. 60: 423-429, 2006. [PubMed: 16940241] [Full Text: https://doi.org/10.1203/01.pdr.0000238301.25938.f5]
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