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Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome

Synonyms: HHH Syndrome, Mitochondrial Ornithine Transporter Deficiency

, MD and , BA.

Author Information
, MD
University of California-Irvine
Irvine, California
, BA
University of California-Irvine
Irvine, California

Initial Posting: .

Summary

Disease characteristics. Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is characterized by variable clinical presentation and age of onset.

Neonatal onset (~12% of affected individuals). Infants are normal for the first 24-48 hours followed by onset of symptoms related to hyperammonemia (poor feeding, vomiting, lethargy, low temperature, rapid breathing). Information on long-term outcome is limited.

Infancy, childhood, and adult presentation (~88%). Affected individuals may present with:

  • Chronic neurocognitive deficits (including developmental delay, ataxia, spasticity, learning disabilities, cognitive deficits and/or unexplained seizures);
  • Acute encephalopathy secondary to hyperammonemic crisis precipitated by a variety of factors; and
  • Chronic liver dysfunction (unexplained elevation of liver transaminases with or without mild coagulopathy, with or without mild hyperammonemia and protein intolerance).

Neurologic findings and cognitive abilities can continue to deteriorate despite early metabolic control that prevents hyperammonemia.

Diagnosis/testing. HHH syndrome is caused by mutations in SLC25A15, the gene that encodes ORNT1 (mitochondrial ornithine transporter 1), which is involved in the urea cycle and the ornithine degradation pathway. The metabolic triad of persistent hyperornithinemia, episodic or postprandial hyperammonemia, and urinary excretion of homocitrulline establishes the diagnosis of HHH syndrome.

Management. Treatment of manifestations: Acute and long-term management is best performed in conjunction with a metabolic specialist. Of primary importance is the use of established protocols to rapidly control hyperammonemic episodes by discontinuation of protein intake, intravenous infusion of glucose and, as needed, infusion of supplemental arginine and the ammonia removal drugs, sodium benzoate and sodium phenylacetate. Hemodialysis is performed if hyperammonemia persists and/or the neurologic status deteriorates.

Prevention of primary manifestations: Individuals with HHH syndrome should be maintained on an age-appropriate protein-restricted diet, citrulline supplementation, and sodium phenylbutyrate to maintain plasma concentrations of ammonia, glutamine, arginine, and essential amino acids within normal range. Note: Liver transplantation is not indicated: Although it may correct the hyperammonemia, it will not correct the neurologic pathology.

Surveillance: Routine assessment of height, weight and head circumference from the time of diagnosis to adolescence. Routine assessment of plasma ammonia concentration, plasma and urine amino acid concentrations, urine organic acids, and urine orotic acid based on age and history of compliance and metabolic control. Attention to subtle changes in mood, behavior, and eating, and/or the onset of vomiting which may suggest that plasma concentrations of glutamine and ammonia are increasing. Periodic neurologic evaluation to monitor for neurologic deterioration even when metabolic control is optimal.

Agents/circumstances to avoid: Excess dietary protein intake; non-prescribed protein supplements such as those used to during exercise regimens; prolonged fasting during an illness or weight loss; use of intravenous steroids; and valproic acid which exacerbates hyperammonemia in urea cycle disorders

Evaluation of relatives at risk: If the disease-causing mutations in a family are known, use molecular genetic testing to clarify the genetic status of at-risk relatives to allow early diagnosis and treatment, perhaps even before symptoms occur.

Pregnancy management: Pregnancy in a woman with symptomatic HHH syndrome has not been reported. There are no well-controlled epidemiologic studies of the fetal effects of sodium benzoate, phenylacetate or phenylbutyrate during human pregnancy.

Genetic counseling. HHH syndrome is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutations in the family have been identified. Of note, given the marked phenotypic variability that exists among individuals with the same SLC25A15 mutations it is possible that two affected sibs may have completely different clinical outcomes.

Diagnosis

Clinical Diagnosis

Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is caused by mutations in SLC25A15, the gene that encodes ORNT1 (mitochondrial ornithine transporter 1), which is involved in the urea cycle and the ornithine degradation pathway.

Clinical Presentation

Neonatal onset (~12% of individuals). Findings that result from hyperammonemia usually begin 24-48 hours after the start of feeding and can include lethargy, somnolence, refusal to feed, vomiting, tachypnea with respiratory alkalosis, and/or seizures.

Infantile, childhood, and adult onset (~88% of individuals). Individuals with HHH syndrome may present with any of the following:

  • Chronic neurocognitive deficits including developmental delay, ataxia, spasticity, learning disabilities, cognitive deficits, and/or unexplained seizures
  • Acute encephalopathy secondary to hyperammonemic crisis, which can be precipitated by infection, fasting, or injury (or occur for no apparent reason) and can manifest as lethargy, decreased appetite, nausea, vomiting, increased respiratory rate and seizures
  • Chronic liver dysfunction characterized by unexplained elevation of liver enzymes (AST and ALT) with or without mild coagulopathy and with or without mild hyperammonemia and protein intolerance.

Testing

The metabolic triad of episodic or postprandial hyperammonemia, persistent hyperornithinemia, and urinary excretion of homocitrulline establishes the diagnosis of HHH syndrome.

Note: An incomplete metabolic triad may be observed because: (1) individuals whose protein intake was restricted during early childhood may never have experienced hyperammonemia; (2) affected individuals who come to medical attention because of learning disabilities or school difficulties may only have isolated persistent hyperornithinemia at the time of evaluation; or (3) a low-protein diet can be associated with little to no homocitrulline in the urine.

Episodic or postprandial mild to moderate hyperammonemia. The plasma ammonia concentrations in 42 individuals with HHH syndrome at the time of diagnosis (between 2006 and 2011) are summarized in Table 1 [Camacho et al 2006, Fecarotta et al 2006, Al-Hassnan et al 2008, Debray et al 2008, Mhanni et al 2008, Tessa et al 2009, Tezcan et al 2011].

In HHH syndrome the degree of hyperammonemia is usually significantly less than in other urea cycle disorders such as OTC, ASS, or CPS-I deficiency (see Urea Cycle Disorders).

Note: Once an affected individual is placed on a protein-restricted diet and treated with sodium phenylbutyrate (see Management), plasma ammonia concentrations return to normal.

Table 1. Plasma Ammonia Concentrations Observed in HHH Syndrome by Age of Onset

StudyPlasma Ammonia Concentration in µmol/L by Age of Onset 1
Neonatal (n=4)1st 3 years of life (n=21)Childhood (n=9)Adolescence to Adulthood (n=8)
Fecarotta et al [2006]141
Camacho et al [2006] 45 43
 55
100
 40
Debray et al [2008]173 49
 54
 58
100
109
120
217
315
119
139
216
325
 64
125
250
Mhanni et al [2008] 98
186
Tessa et al [2009]100
400
700
 62
 75
 96
125
137
200
321
370
235222
306
Al-Hassnan et al [2008]532 54 77
Tezcan et al [2011]140

1. The upper limit of normal for plasma ammonia can vary among laboratories, but values of 50 μmol/L or less are usually considered normal for most neonates, infants, children, and adults. However, higher normal upper limits of plasma ammonia concentration for neonates (100 μmol/L) have been reported (see Argininosuccinate Lyase Deficiency).

Hyperornithinemia (increased plasma concentration of ornithine). At the time of initial diagnosis, plasma concentration of ornithine can range from 200 to 1100 μmol/L (normal: 30-110 μmol/L).

Note: While plasma concentration of ornithine decreases significantly with a protein-restricted diet, it very rarely normalizes.

Homocitrullinuria (urinary excretion of homocitrulline). In persons with HHH syndrome homocitrullinuria is a key feature of the disease; however, exceptions exist: some infants with neonatal-onset HHH syndrome do not excrete homocitrulline in significant amounts and individuals with HHH syndrome who self-restrict protein intake may excrete minimal or no homocitrulline in the urine [Korman et al 2004, Valle & Simell 2001]. In unaffected individuals, homocitrulline is not detected in the urine.

Note: (1) Homocitrulline may be found in infant formulas due to the carbamylation of lysine during manufacture and, thus, may cause a false positive result. (2) For laboratories that do not measure homocitrulline directly, an increase in urinary excretion of methionine (with normal methionine plasma concentrations) may indicate homocitrullinuria, because the peaks of homocitrulline and methionine overlap [Camacho et al 2006].

Additional clinical biochemical abnormalities that may be observed include:

  • Elevations in plasma glutamine concentration. During periods of hyperammonemia, significant elevations in plasma glutamine concentrations are expected. However, as plasma ammonia concentrations return to normal, plasma glutamine concentrations may remain mildly elevated (1.5- to twofold the upper limits of control values).
  • Low normal or low plasma concentrations of lysine
  • Increased urinary excretion of:
    • Ornithine. Tthe degree of urinary ornithine excretion does not seem to correlate with the plasma concentration of ornithine [Valle & Simell 2001].
    • Orotic acid. Increased urinary excretion of orotic acid (orotic aciduria) may vary from person to person independent of the level of hyperammonemia and metabolic control.
    • Organic acids. An increase in the urinary excretion of components of the Krebs cycle (succinate, citrate, fumaric, α-ketoglutaric) and lactate has been documented in a few reports [Korman et al 2004, Fecarotta et al 2006].

Cellular mitochondrial transport of radiolabelled 14C-ornithine in cultured skin fibroblasts. Cultured fibroblasts from persons with null alleles demonstrate an approximately 75%-80% reduction in ornithine transport, thus suggesting that residual transport is present and most likely mediated by redundant transporters [Camacho et al 1999, Camacho et al 2003]. No correlation exists between ornithine transport capacity, genotype, and phenotype [Camacho et al 1999, Camacho et al 2006]. The diagnosis of HHH syndrome may be confirmed by studying the cellular mitochondrial transport of radiolabelled 14C-ornithine in cultured skin fibroblasts.

Molecular Genetic Testing

Gene. SLC25A15 (previously known as ORNT1) is the only gene in which mutations are known to cause the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome [Camacho et al 1999].

Clinical testing

Table 2. Summary of Molecular Genetic Testing Used in Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
SLC25A15Sequence analysisSequence variants 499%
Targeted mutation analysisc.562_564delTTC 5100% for target variant
Deletion / duplication analysis 6Exonic or whole-gene deletionsSee footnote 7

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3. p.Phe188del (c.562_564delTTC) is the predominant mutant allele found in ~50% of affected individuals, most of whom are of French Canadian descent.

5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5. One exonic-intronic microdeletion (~4.5 kb) has been reported [Camacho et al 1999].

Testing Strategy

To confirm/establish the diagnosis in a symptomatic proband, the initial work-up should include plasma ammonia concentration and plasma amino acid analysis; urine amino acid analysis; urine organic acid analysis; and urine orotic acid analysis.

  • The finding of the classic metabolic triad of episodic or postprandial hyperammonemia, persistent hyperornithinemia, and urinary excretion of homocitrulline establishes the diagnosis of HHH syndrome.
  • When biochemical findings are equivocal, SLC25A15 molecular genetic testing can be used to confirm the diagnosis: sequence analysis is performed first, followed by deletion/duplication analysis if only one or no mutant SLC25A15 alleles are identified.

Newborn screening (NBS). In the US, testing for HHH syndrome is included in some newborn screening programs (California, Oregon, Massachusetts, Mississippi, Nebraska, New York, North Dakota, Pennsylvania, South Dakota, and Tennessee). However, tandem mass spectrometry (MS/MS), the standard newborn screening methodology, is probably not reliable in detecting newborns with HHH syndrome. In a recent study of newborns in Canada in an isolated population in northern Saskatchewan which is a mixture of French-Canadian and Aboriginal descendants at high risk for the p.Phe188del (c.562_564delTTC) SLC25A15 mutation, the newborn screening samples of infants with HHH syndrome identified by molecular genetic testing did not demonstrate elevated plasma ornithine levels by MS/MS [Sokoro et al 2010]. This finding suggests that the rise of plasma ornithine levels occurs after the first few days of life when NBS blood samples are typically obtained.

Note: It is likely that HHH syndrome has been included in some NBS programs because measurement of plasma concentration of ornithine (like arginine) is technically easy. Until publication of the study of Sokoro et al [2010], the ineffectiveness of NBS in screening for HHH syndrome was unknown. Future retrospective studies of the plasma ornithine concentration of NBS samples of persons with confirmed HHH syndrome are needed.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Heterozygotes (e.g., parents and carrier sibs) do not exhibit biochemical abnormalities in plasma or urine; therefore, molecular genetic testing is the only reliable method of carrier detection.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis for at-risk pregnancies can be performed by molecular genetic testing if the disease-causing mutations have been identified in the family.

Preimplantation genetic diagnosis (PGD) for at-risk pregnancies requires prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

In general, the age of onset and clinical presentation of individuals with hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome vary.

Onset can be divided into four different age periods: neonatal, first three years of life, childhood, and adolescence to adulthood.

Neonatal onset accounts for about 12% of affected individuals. Usually the prenatal and perinatal courses are uncomplicated. The neonatal-onset presentation is indistinguishable from that of other neonatal-onset urea cycle disorders: the infant is asymptomatic for the first 24-48 hours and, thereafter, has episodes of poor feeding, vomiting, lethargy, low temperature, and/or rapid breathing related to hyperammonemia (see Table 1).

Little is known about the long-term outcome of individuals with the neonatal onset form of HHH syndrome:

  • One child with neonatal-onset who had an initial plasma ammonia concentration of 317 μmol/L had normal growth, development, and neuroimaging studies at age 18 months. Follow-up brain imaging at age six was normal [Salvi et al 2001].
  • By age six years female twins who appeared to have had lethargy and coma during the neonatal period had developed pyramidal signs [Tessa et al 2009]. The twin with the higher plasma ammonia concentration (700 μmol/L) had seizures and significant intellectual disability, whereas the twin with the lower plasma concentration of ammonia (100 μmol/L) had only mild cognitive impairment.
  • Two other neonatal-onset cases evaluated in their late teens had pyramidal signs of the lower limbs (hyperreflexia, clonus, tip-toe gait, and/or spastic ataxia) and moderate cortical atrophy on neuroimaging [Salvi et al 2001].

Infancy, childhood, and adult presentation account for approximately 88% of affected individuals. Onset at or before age three years occurs in about 40%, childhood onset in about 29%, and adolescent to adult onset in about 19% [Salvi et al 2001, Korman et al 2004, Fecarotta et al 2006, Al-Hassnan et al 2008, Debray et al 2008, Mhanni et al 2008, Tessa et al 2009, Tezcan et al 2011].

Affected individuals in this group come to medical attention for findings related to a mild degree of hyperammonemia with or without liver dysfunction or for evaluation of developmental delay, intellectual disability, learning disabilities, recurring vomiting, school difficulties, ataxia, and/or seizure activity.

Even when ammonia levels are normal, a history of protein intolerance or neurologic symptoms suggestive of hyperammonemia (periods of lethargy, nausea, vomiting, decreased appetite, headaches, changes in mood, or altered behavior) may sometimes be elicited during the initial evaluation of a patient. A college-educated male age 35 years with adult onset disease who had no history of learning disabilities, liver disease, psychiatric illness, or neurologic deficits was diagnosed with HHH syndrome after deviating from a vegetarian diet [Tezcan et al 2011]. Two previous accounts of sibs with adult-onset HHH syndrome attributed the mildness of the phenotype, in part, to adherence to a vegetarian diet [Tuchman et al 1990].

The cognitive development of persons with HHH syndrome ranges from normal to severe impairment, with the majority having mild neurocognitive impairment. In some reports persons with adolescent-onset and adult-onset disease have significant neurologic deficits such as spasticity and ataxia without cognitive impairment. Of note, pyramidal signs of the lower extremities (hyperreflexia, clonus, tip-toe gait, and/or spastic ataxia) may develop years after the initial diagnosis [Salvi et al 2001, Debray et al 2008].

Despite early detection and adequate metabolic control (i.e., absence of hyperammonemia), some individuals with HHH syndrome continue to worsen neurologically with progressive pyramidal tract disease and cognitive deterioration [Debray et al 2008]. In some individuals with early childhood onset, gait abnormalities and spasticity are the predominant findings.

Liver dysfunction, present in 20%-25% of affected individuals, generally manifests as mild coagulopathy and elevated liver enzymes (AST and ALT) with or without hyperammonemia. In a few reports acute liver failure prompted consideration of liver transplantation [Fecarotta et al 2006, Mhanni et al 2008]. However, the liver dysfunction that may occur during the initial clinical presentation does not appear to cause long-term complications. Once the hyperammonemia is treated with standard intravenous infusion of dextrose and arginine and protein intake is restricted, the liver dysfunction subsides [Korman et al 2004, Camacho et al 2006, Fecarotta et al 2006, Debray et al 2008, Mhanni et al 2008, Tessa et al 2009].

Neuroimaging in HHH syndrome has revealed evidence of cortical or subtentorial atrophy, demyelinization, stroke-like lesions, and/ or calcifications of the basal ganglia [Salvi et al 2001, Camacho et al 2006, Al-Hassnan et al 2008].

Genotype-Phenotype Correlations

The SLC25A15 (ORNT1) genotype does not correlate with the clinical or biochemical phenotype of HHH syndrome. Functional studies of SLC25A15 mutations using in vitro cell culture and liposome reconstitution studies revealed no genotype-phenotype correlation [Fiermonte et al 2003, Camacho et al 2006]: some SLC25A15 missense and nonsense mutations (p.Phe188del, p.Thr32Arg, and p.Gly190Asp) had mild residual function and others (p.Gly220Arg, p.Arg179*, p.Gly27Arg, p.Arg275Gln, and p.Arg275*) had no function. Individuals with completely nonfunctional SLC25A15 mutations did not have neonatal hyperammonemia.

Nomenclature

The name hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome was coined by Vivian Shih, MD in 1969 for the disorder in which a "block in the ornithine metabolic pathway" has biochemical findings "not concordant with those in patients with proven hepatic ornithine transcarbamylase deficiency"

In 1999 after ORNT1 (now known as SLC25A15), the gene encoding ORNT1, was identified, the term ORNT1 deficiency was introduced and used interchangeably with HHH syndrome.

Prevalence

Since the description of the first individual with HHH syndrome by Shih et al [1969] approximately 85 persons with HHH syndrome have been reported in the literature.

Although the frequency of HHH syndrome in the general population is not known, its incidence is highest in individuals of French Canadian ancestry because of the SLC25A15 founder mutation c.562_564delTTC (p.Phe188del) in this population [Camacho et al 1999, Debray et al 2008]. A recent study suggested that the incidence of HHH syndrome in an isolated northern Saskatchewan population of mixed French-Canadian and Aboriginal descent is 1:5500 [Sokoro et al 2010].

Persons of Japanese and Italian ancestry diagnosed with HHH syndrome, who make up the next-largest cohorts, have a variety of different SLC25A15 mutations.

Differential Diagnosis

Hyperammonemia. Most commonly, neonates with hyperammonemia and neonatal onset HHH syndrome are initially suspected of having sepsis.

Like urea cycle disorders, HHH syndrome should be included in the differential diagnosis of any individual with hyperammonemia, including women who experience hyperammonemia during or following pregnancy. The onset and severity of findings in HHH syndrome are more variable and less severe when compared to urea cycle disorders like ornithine transcarbamylase (OTC) deficiency or carbamyl phosphate synthase (CPS-I) deficiency. Urea cycle disorders usually present with isolated elevation in plasma ammonia concentration and metabolic alkalosis. Plasma amino acid analysis, urine amino acid analysis, organic acid analysis, and urine orotic acid measurements allow diagnosis of the specific urea cycle disorder (see Urea Cycle Disorders) or HHH syndrome.

A complete chemistry panel, lactate/pyruvate determination, arterial blood gases, and urinalysis should always be included in the evaluation of any person with an elevated plasma ammonia concentration to evaluate for conditions including the following:

Hyperornithinemia. The only other condition that causes chronic elevations in plasma ornithine concentration is deficiency of ornithine amino transferase (OAT), a mitochondrial matrix enzyme involved in the ornithine degradation pathway. However, OAT deficiency never presents with the neurologic and clinical biochemical features of HHH syndrome (e.g., elevation in plasma ammonia concentration and glutamine, urinary excretion of homocitrulline and/or orotic acid). OAT deficiency presents mostly with ophthalmologic findings known as hyperornithinemia with gyrate atrophy of the choroid and retina that manifest as chorioretinal degeneration with loss of peripheral vision, night blindness, and often posterior subcapsular cataracts [Valle & Simell 2001].

Given that the neurologic non-acute presentation for HHH syndrome may be indistinguishable from primary mitochondrial disease, urine organic acid analysis should also be ordered. In some cases of HHH syndrome, urinary excretion of Krebs cycle components (succinate, fumarate, citrate and α-ketoglutarate) and lactate have been reported [Korman et al 2004]. This pattern of excretion of organic acids, which is commonly seen in children and adults with defects in the mitochondrial complex I or III, may create the impression that persons with HHH syndrome have a primary rather than a secondary mitochondrial defect.

Homocitrullinuria. Other conditions in which homocitrullinuria can be observed should be included in the differential diagnosis of HHH syndrome:

  • Homocitrulline is a by-product of canned milk production that arises from the reaction of cyanate and the terminal ε-amino group of lysine. In canned formulas, cyanate is produced from heat-induced urea breakdown. When homocitrulline is consumed in the diet from sources such as these, it is absorbed in the small intestine via a transport system similar to that of cationic amino acids and excreted in the urine [Valle & Simell 2001]. In contrast, homocitrullinuria detected in neonates given IV glucose only (and no dietary source of protein) indicates the presence of a metabolic disorder.
  • Some individuals with lysinuric protein intolerance (LPI) have been shown to excrete homocitrulline [Palacin et al 2004]. Although these individuals may also have hyperammonemia, their clinical biochemical profile demonstrates low concentrations of plasma ornithine, lysine, and arginine and persistent urinary excretion of lysine, ornithine, and arginine.
  • Homocitrullinuria has also been observed in arginase deficiency; however, in this disorder, the plasma concentration of arginine is increased and homoarginine is excreted in the urine [Valle & Simell 2001].

Neurologic findings. In those individuals with early childhood onset in whom gait abnormalities and spasticity predominate, the differential diagnosis includes cerebral palsy and early-onset inherited spastic paraplegia.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, the following evaluations are recommended:

  • Neurocognitive evaluation of the affected individual including brain imaging
  • Evaluation of school performance with attention to possible learning disabilities

Treatment of Manifestations

Of primary importance in the management of individuals with HHH syndrome is rapid control of the hyperammonemic episodes that may result from changes in diet (e.g., protein intake), infection, fasting, or injury, or have no apparent cause. Long-term management of affected individuals focuses on the prevention of episodes of hyperammonemia and attempts to lower the level of plasma ornithine concentration.

It is critical that the acute and long-term management of individuals with HHH syndrome be performed in conjunction with a metabolic specialist.

Treatment of acute hyperammonemic episodes. Assess plasma ammonia concentration, complete chemistry panel, arterial blood gases (ABGs), CBC and differential (to evaluate for an infectious process), urinalysis, urine and plasma amino acids, and urine orotic acid.

Plasma ammonia concentrations ≥100-125 μmol/L (~2 times control values) should be treated immediately.

Discontinue all oral intake until the patient’s condition is stabilized because vomiting may be induced by hyperammonemia and/or some of the drugs given intravenously to promote ammonia removal (e.g., as part of nitrogen scavenging therapy). This approach also stops all protein intake.

Initial intravenous infusion should be 10% dextrose (with 1/4 normal saline and 20mEq/liter KCl) at twice maintenance; ammonia and glucose/Na/K/Cl/CO2 concentrations should be monitored every two hours or when neurologic status changes. It is important to note that patients respond neurologically differently to rising ammonia concentrations: an individual with HHH syndrome is more likely to respond to the initial IV infusion of dextrose and to normalize his/her plasma ammonia concentration when compared to an individual with a urea cycle disorder such as OTC deficiency or ASS deficiency. If clinical status does not improve, infusion of supplemental arginine and ammonia removal drugs is added to the regimen.

Follow published protocols for treatment of acute hyperammonemic episodes similar to those instituted for OTC deficiency [Brusilow & Horwich 2001]. These protocols consist of arginine supplementation and use of intravenous bolus and maintenance infusions of the ammonia removal drugs sodium benzoate and sodium phenylacetate. The New England Consortium of Metabolic Programs has a complete set of treatment protocols and algorithms that are freely available and easily accessible.

An initial priming dose of arginine, benzoate, and phenylacetate is given (see Table 3).

Table 3. Initial Priming Dose of Arginine, Benzoate, and Phenylacetate by Age Group

Infusion 1Infants and ChildrenAdolescents and Adults
10% arginine HCl210 mg/kg/day4.0 g/m2
Sodium benzoate250 mg/kg/day5.5 g/m2
Sodium phenylacetate250 mg/kg/day5.5 g/m2

1. Mix solutions of arginine, benzoate, and phenylacetate in a 10% dextrose solution at a dose of 25 mL of 10% dextrose/kg and infuse over 90 min. The solutions containing arginine, benzoate, and phenylacetate should be given in conjunction with 10% dextrose + one quarter normal saline + 20 mEq/L KCL solution.

If ammonia levels stabilize, the same arginine, benzoate, and phenylacetate solution is infused over 24 hrs.

Note: All preparations of arginine and ammonia removal drugs should be double- or triple-checked given the potential for drug intoxication if high doses are given or continued CNS ammonia toxicity if low doses are given. If sodium benzoate or sodium phenylacetate solutions are not available, infusion of arginine should be started.

Table 4. Mechanisms of Drug Action in Treatment of Hyperammonemia

DrugAction
Glucose• Raises insulin levels
• Induces anabolic state
• Causes protein sparing effect from skeletal muscle amino acids
Arginine 1 • Needs to be supplemented in those with a urea cycle disorder
• Stimulates secretion of insulin
• Plays a role in the first step of the synthesis of creatine 2
Sodium benzoate 3• Forms benzoate-glycine (hippurate) via the benzoylCoA:glycine acyltransferase reaction 4
• Eliminates one amino group in the urine
Sodium phenylacetate 3• Forms a phenylacetate-glutamine compound via the phenylacetateCoA:glutamine acetyl-transferase reaction 4
• Eliminates two amino groups in the urine

1. A non-essential amino acid in humans

2. Interruption in the synthesis of brain creatine secondary to hyperammonemia has been proposed as a contributing factor to the neurologic findings in affected individuals.

3. Initially esterified to its CoA-ester via the medium chain fatty acid enzyme, acyl-CoA ligase

4. Reaction takes place in the mitochondrial matrix (liver and kidney) [Brusilow & Horwich 2001]

Hemodialysis. If the patient fails to respond to the above treatment of hyperammonemia, if the plasma ammonia concentration increases, and/or if the neurologic status deteriorates, hemodialysis should be started promptly to remove ammonia from the circulation. Infusion of arginine, benzoate, and phenylacetate should continue during hemodialysis.

Dialysis may be prolonged if the catabolic state persists.

Nutrition. Twenty-four to 36 hours after initial admission the patient should start receiving intravenous alimentation including daily doses of only essential amino acids, carnitine, vitamins, and lipids to help avoid a catabolic state which will prolong hyperammonemia. Note: Non-essential amino acids (i.e., glutamine, proline, and glycine) should be avoided since they increase the nitrogen load to an already compromised urea cycle.

Prevention of Primary Manifestations

Depending on their age, individuals with HHH syndrome should be maintained on a protein-restricted diet. For infants and children the dietary protein needs to be restricted to control hyperammonemia, but sufficient for normal growth and development.

  • Dietary supplementation with Cyclinex®-1 (infants and children) or Cyclinex®-2 (adult) formulas that provide only essential amino acids and other nutritional supplements have been helpful for some affected individuals.
  • Citrulline supplementation at 0.17 g/kg/day or 3.8 g/m2/day is preferred to arginine because citrulline accepts an aspartate (via the arginosuccinate synthase reaction) and therefore eliminates two amino groups per cycle. Moreover, there may be a possible association between arginine supplementation and progression of lower limb spasticity [HHH International Round Table, Roma 2006, unpublished].
  • Sodium phenylbutyrate (Buphenyl®) is given at 450-600 mg/kg/day in three divided doses. Sodium phenylbutyrate initially is imported into the mitochondria where it undergoes β-oxidation to produce phenylacetate.
  • Lysine supplementation is indicated when plasma lysine concentrations are low. Low plasma lysine concentrations have been associated with delayed growth and development.
  • Plasma concentrations of ammonia, glutamine, arginine, and essential amino acids should be maintained within the normal range.

    Note: (1) Although elevated plasma ornithine concentrations may decrease significantly if dietary management is followed, complete normalization of plasma ornithine concentration is rarely observed. (2) Even in the absence of hyperammonemic episodes, affected individuals may continue to develop neurologic complications such as spasticity or learning disabilities. Maintaining as low a level of plasma ornithine concentration as possible by restricting protein intake could help prevent some of the progressive neurologic complications seen in these individuals.

Liver transplantation is not indicated for persons with HHH syndrome. Because SLC25A15 and the ornithine degradation pathway are expressed in all tissues (i.e., brain, kidney) and most cell types (i.e. astrocytes, fibroblasts), liver transplantation may correct the hyperammonemia, but it will not correct tissue-specific metabolic abnormalities that also contribute to the neurologic pathology.

Three individuals with HHH syndrome who had acute fulminant hepatic failure and coagulopathy rapidly stabilized after protein restriction and arginine or citrulline supplementation [Fecarotta et al 2006, Mhanni et al 2008].

Surveillance

All surveillance of patients with HHH syndrome should be a combined effort of the general pediatrician or adult practitioner and a metabolic specialist.

  • Height, weight, and head circumference should be assessed routinely in children from the time of diagnosis to adolescence.
  • Plasma ammonia concentration, plasma and urine amino acid concentrations, urine organic acids, and urine orotic acid need to be monitored routinely, based on age and history of compliance and metabolic decompensation.
    • Low plasma concentrations of essential amino acids could trigger a catabolic state, requiring readjustment of the diet/formulas.
    • Low plasma concentrations of lysine may lead to delays in growth and development in infants.
  • Parents of infants and small children should be alert to subtle changes in mood, behavior, and eating and/or the onset of vomiting, which may suggest that plasma concentrations of glutamine and ammonia are increasing.
  • School performance should be monitored since poor school performance may lead to low self-esteem and/or behavioral problems that could influence compliance with a protein-restricted diet.
  • Periodic neurologic evaluation is warranted to monitor for neurologic deterioration even when metabolic control is optimal.

Agents/Circumstances to Avoid

Avoid the following:

  • Excess dietary protein intake
  • Non-prescribed protein supplements such as those used to increase size of skeletal muscle during exercise regimens
  • Prolonged fasting during an illness or weight loss
  • Use of intravenous steroids
  • Valproic acid, which exacerbates hyperammonemia in urea cycle disorders
  • Exposure to communicable diseases

Evaluation of Relatives at Risk

If the disease-causing mutations in a family are known, use molecular genetic testing to clarify the genetic status of at-risk relatives to allow for early diagnosis and treatment, perhaps even before symptoms occur. Note: Plasma concentrations of ornithine and urinary excretion of orotic acid and homocitrulline may be unreliable in asymptomatic persons.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Pregnancy in a woman with HHH syndrome has not been published. Rebecca Mardach, MD (Kaiser Permanente, Los Angeles) provided information to the authors about a healthy boy born after an uneventful pregnancy to a clinically asymptomatic woman in her early 20s who had been diagnosed with HHH syndrome at age 13 years in the course of evaluation of her affected five-year-old sib [Camacho et al 2006]. During her pregnancy the mother was maintained on a protein and citrulline regimen that allowed normal fetal development and maternal health; plasma and urine amino acids, orotic acid, plasma ammonia, and urine organic acids were monitored.

There are no well-controlled epidemiologic studies of the fetal effects of sodium benzoate, phenylacetate, or phenylbutyrate during human pregnancy. However, sodium benzoate has been reported to lead to malformations and neurotoxicity/nephrotoxicity in zebrafish larvae [Tsay et al 2007] and to possible teratogenicity in rats [Minor & Becker 1971, Onodera et al 1978]. As a known differentiating agent, sodium phenylbutyrate also functions as a histone deacetylase (HDAC) inhibitor with potential teratogenicity given its ability to alter gene expression in fetal mice [Di Renzo et al 2007].

The FDA has assigned sodium benzoate and sodium phenylacetate to pregnancy category C (“potential benefits may warrant use of the drug in pregnant women despite potential risks”). Theoretically, the use of benzoate/phenylacetate and in particular sodium phenylbutyrate should be avoided during pregnancy, especially during the first trimester. The use of these medications should be carefully evaluated for each individual (benefit/risk ratio) in consultation with a metabolic genetics specialist. Despite the report of successful administration of sodium phenybutyrate to an OTC-deficient woman throughout her 11-33 week gestation period, caution is advised and the alternate use of sodium benzoate, if deemed necessary, is recommended [Redonnet-Vernhet et al 2000]. Mendez-Figueroa et al [2010] reported a small number of females with OTC deficiency who successfully completed their pregnancies without need of ammonia removal medications. This study also reported the use of sodium benzoate to manage a pregnant woman with OTC deficiency who developed mild hyperammonemia during induction of labor.

No specialized care for a fetus known to have HHH syndrome is warranted.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e. carriers of one mutant allele).
  • Heterozygotes (carriers) do not have any of the clinical biochemical changes seen in homozygotes; therefore, they are clinically asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.
  • Given the marked phenotypic variability that exists among individuals with the same SLC25A15 mutations, it is possible that two affected sibs may have completely different clinical outcomes.

Offspring of a proband. The offspring of an individual with HHH syndrome are obligate heterozygotes (carriers) for a disease-causing mutation in SLC25A15.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible if the disease-causing mutations in the family have been identified.

Carrier testing using clinical biochemical parameters is unreliable.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Parents should be advised of the marked phenotypic variability that exists among sibs that have the same disease-causing SLC25A15 mutations [Camacho et al 2006, Debray et al 2008, Tessa et al 2009].

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing SLC25A15 mutations in the family must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions which (like HHH syndrome) have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although decisions about prenatal testing are the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • Children Living with Inherited Metabolic Diseases (CLIMB)
    Climb Building
    176 Nantwich Road
    Crewe CW2 6BG
    United Kingdom
    Phone: 0800-652-3181 (toll free); 0845-241-2172
    Fax: 0845-241-2174
    Email: info.svcs@climb.org.uk
  • National Urea Cycle Disorders Foundation
    75 South Grand Avenue
    Pasadena CA 91105
    Phone: 800-386-8233 (toll-free); 626-578-0833
    Fax: 626-578-0823
    Email: info@nucdf.org
  • European Registry and Network for Intoxication Type Metabolic Diseases (E-IMD)
  • Urea Cycle Disorders Consortium Registry
    Children's National Medical Center
    Phone: 202-306-6489
    Email: jseminar@childrensnational.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
SLC25A1513q14​.11Mitochondrial ornithine transporter 1SLC25A15 @ LOVDSLC25A15

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome (View All in OMIM)

238970HYPERORNITHINEMIA-HYPERAMMONEMIA-HOMOCITRULLINURIA SYNDROME
603861SOLUTE CARRIER FAMILY 25 (MITOCHONDRIAL CARRIER, ORNITHINE TRANSPORTER), MEMBER 15; SLC25A15

Molecular Genetic Pathogenesis

Decreased ornithine transport across the inner mitochondrial membrane in the periportal region of the liver (hepatocytes in the area of the portal vein, artery, and bile duct) disrupts the function of the urea cycle at the level of the ornithine transcarbamylase (OTC) reaction thus causing episodic or postprandial hyperammonemia (Figure 1). In spite of the impermeability of the inner mitochondrial membrane to solutes, persons with HHH syndrome come to medical attention mostly during infancy and childhood and tend to exhibit mild or no elevations in plasma ammonia concentration when initially diagnosed [Brusilow & Horwich 2001, Valle & Simell 2001, Palmieri 2008].

Figure 1

Figure

Figure 1. Compartmentalization of the biochemical pathways involved in HHH syndrome as a result of deficiency of the mitochondrial ornithine transporter (ORNT1; encoded by SLC25A15), leading to abnormal accumulation of the metabolites marked in black (more...)

The chronic elevation in plasma ornithine concentration (150-1,200 μmol/L) occurs because SLC25A15 is also expressed in the pericentral region of the liver (hepatocytes surrounding the central vein) and most peripheral tissues (i.e., brain, kidney, testis) and cells (i.e., skin fibroblasts, astrocytes) where ornithine is normally catabolized into proline and glutamate via the intramitochondrial enzyme, ornithine amino transferase (OAT). Increased cytoplasmic ornithine leads to hyperornithinemia and increased polyamine biosynthesis (Figure 1). The elevated concentration of plasma ornithine on occasion may be similar to that seen in individuals with gyrate atrophy (OAT deficiency), a genetic disorder with mostly ophthalmologic symptoms [Valle & Simell 2001].

The homocitrullinuria occurs when intramitochondrial carbamyl phosphate is underused and accumulates in the presence of deficient ornithine transport into the mitochondrial matrix. Excess carbamyl phosphate either condenses with intramitochondrial lysine to form homocitrulline or is shunted through the cytosolic pyrimidine biosynthetic pathway leading to increased urinary excretion of orotic acid and uracil (Figure 1) [Valle & Simell 2001].

Given that the inner mitochondrial membrane is impermeable to solutes, it is thought that additional mitochondrial carrier proteins with redundant function to ORNT1 (mitochondrial ornithine transporter 1) are, in part, responsible for the late onset and variable clinical phenotype of HHH syndrome. The residual ornithine transport in cultured fibroblasts and liver of affected individuals reinforces the notion of gene redundancy in HHH syndrome. SLC25A2 (ORNT2) and SLC25A29 (ORNT3), two additional mitochondrial ornithine transporters, are thought to mediate the residual ornithine transport in HHH syndrome and may serve as modifying genes [Camacho et al 2003, Camacho & Rioseco-Camacho 2009]. These ornithine transporters have additional functions such as the transport of D- and L-histidine, L-homoarginine, D- and L-amino acids (ORNT2) [Fiermonte et al 2003], and carnitine/acylcarnitine (ORNT3) [Camacho & Rioseco-Camacho 2009].

Given that HHH syndrome is in part a disorder of the urea cycle, the central nervous system (CNS) cellular pathophysiology has been attributed to the toxic effects of elevated ammonia and glutamine on the astrocyte, including osmotic swelling, abnormalities in creatine metabolism, changes in cellular bioenergetics, mitochondrial dysfunction, and alterations in glutamine-glutamate cycling [Braissant 2010, Sofroniew & Vinters 2010]. These cellular pathophysiologic changes may lead to CNS alterations including atrophy, demyelinization, or stroke-like lesions [Enns 2008, Gropman 2010]. However, it is unlikely that hyperammonemia is solely responsible for the pathophysiology of HHH syndrome since affected individuals who are diagnosed early and maintain good metabolic control nonetheless develop progressive neurologic dysfunction (e.g., progressive spastic paraparesis) years after their initial diagnosis. Of note, this progressive pyramidal tract involvement is reminiscent of arginase deficiency [Rodes et al 1987, Debray et al 2008].

Since ORNT1 also functions as a cationic amino acid transporter, it is reasonable to propose that the pathophysiology of HHH syndrome may also be dependent on the interruption of the physiologic functions of ORNT1, including its role in mitochondrial protein synthesis, metabolism of arginine and lysine, and synthesis of polyamines [Palmieri 2008]. Of note, recent work has demonstrated that excessive ornithine and homocitrulline can cause protein and lipid oxidation, as well as negatively interfere in cellular bioenergetics, oxidative phosphorylation, and Krebs cycle function of the rat brain [Viegas et al 2011].

Another factor that may contribute to the mechanisms of disease in HHH syndrome is the synthesis of creatine: it has been observed that ornithine negatively regulates the activity of L-arginine:glycine amidinotransferase (AGAT), the enzyme that catalyzes the first step in the synthesis of creatine [Valle & Simell 2001]. Though low creatine excretion was previously reported in two persons with HHH syndrome, this negative effect of ornithine on AGAT function may not be as significant in HHH syndrome as in OAT deficiency given the differences in the localization and activity of the mitochondrial and cytoplasmic isoforms of AGAT [Humm et al 1997]. (See also Creatine Deficiency Syndromes.)

Normal allelic variants. SLC25A15 (previously ORNT1) comprises eight exons (NM_014252.3).

The open reading frame (ORF) is encoded by exons 2 through 7 [Tsujino et al 2000, Camacho et al 2006]. Exon 1 encodes part of the 5’UTR and exon 8 encodes only part of the 3’UTR.

At least eight non-processed SLC25A15 pseudogenes are located on different chromosomes: chromosome 3 (AC073022.12), 10 (AC027723.2), 13 (AC018739.4 & AL356259.11), 16 (AC141274.1), 21 (AF254982.4), 22 (NW_001838735.2), and Y (AC019099). Although these non-processed SLC25A15 pseudogenes have truncations of several exons, they consistently have more than 90% conserved regions of exons 6 and 7.

Pathologic allelic variants. Approximately 20 SLC25A15 pathogenic allelic variants that produce missense and nonsense mutations, plus an in-frame deletion, have been reported. Ten other allelic variants that cause splicing errors, microdeletions, and insertions have been described [Debray et al 2008, Tessa et al 2009]. Almost all mutations have occurred in exons 2 through 7, which correspond to the SLC25A15 coding region.

Exon 5 has the highest mutational frequency. Importantly, exon 5 encodes for the fourth transmembrane domain, a region that forms part of the solute (ornithine, lysine, and arginine) recognition site of the SLC25A15 transporter [Palmieri 2008]. The two most common mutations occur in this region [Camacho & Rioseco-Camacho 2009]:

  • c.562_564delTTC (p.Phe188del), found predominately in persons of French Canadian descent, accounts for the majority of individuals (~50%) reported with HHH syndrome.
  • c.535C>T (p.Arg179*), appears to be prevalent in individuals of Japanese heritage and Middle Eastern heritage [Miyamoto et al 2001, Tessa et al 2009].

See Table 5 (pdf) for additional variants.

Table 6. Selected Pathologic SLC25A15 Allelic Variants =

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.95C>Gp.Thr32Arg 1, 2NM_014252​.3
NP_055067​.1
c.535C>Tp.Arg179* 3
c.562_564delTTCp.Phe188del 1, 3
c.569G>Ap.Gly190Asp 1, 3
c.658G>Ap.Gly220Arg 3, 4
c.824G>Ap.Arg275Gln 4

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Residual function

2. Targets normally to mitochondria

3. SLC25A15 (ORNT1) mutations associated with neonatal onset

4. No residual function

Normal gene product. Mitochondrial ornithine transporter 1 (ORNT1) is a member of the mitochondrial carrier family (MCF) of proteins that transports solutes across the inner mitochondrial membrane and has at least 45 members including CITRIN (aspartate/glutamate transporter), carnitine/acylcarnitine translocator (CACT), and the ADP/ATP-1 and citrate transporters. ORNT1 belongs to a subfamily that transports charged amino compounds. ORNT1 subfamily members include ORNT2, ORNT3 (also transports carnitine/acylcarnitine), CACT, and SLC25A45.

Structurally, ORNT1 is a 301-amino acid, six-transmembrane domain carrier protein inserted in the inner mitochondrial membrane with its amino and carboxy terminal domains facing the cytoplasm [Camacho et al 2006].

Biochemical studies have demonstrated that in pericentral hepatocytes and peripheral tissues, ORNT1 transports ornithine, lysine, and arginine into the mitochondrial matrix in exchange for an intramitochondrial hydrogen ion (H+). In periportal hepatocytes that express components of the urea cycle, ORNT1 exchanges intramitochondrial citrulline and H+ for cytoplasmic ornithine. Given ORNT1's role in the catabolism of ornithine via the OAT reaction and its transport of arginine and lysine into the mitochondrion, it is anticipated that ORNT1 plays a complex biochemical role in tissues (liver, brain, pancreas, and kidney) and cells (astrocytes, fibroblasts) where it is expressed.

Abnormal gene product

  • Several SLC25A15 missense and nonsense mutations and the in-frame deletion have been analyzed by in vitro cell culture and lipid reconstitution studies to determine if the observed amino acid change alters basic transporter function; many exhibited residual ability to transport ornithine.
  • The ORNT1 protein with the most common mutation, p.Phe188del, produces an unstable protein of 300 amino acids with 10%-15% residual function when compared to controls [Camacho et al 1999, Fiermonte et al 2003, Morizono et al 2005]. Thus, it is possible that in some affected individuals other factors involved in regulating protein stability may allow a significant level of expression that influences the neurologic phenotype.
  • The protein with the nonsense mutation p.Arg179* produces a truncated and non-functional ORNT1 protein [Tsujino et al 2000, Fiermonte et al 2003] that is associated with both neonatal- and late-onset disease.
  • A protein with the substitution p.Gly190Asp had approximately 33% residual activity and was associated with a neonatal-onset phenotype.
  • The p.Thr32Arg SLC25A15 amino acid substitution produces a transporter protein that targets normally to the mitochondria and has approximately 50% residual function. This mutant transporter protein was found in five related individuals with HHH syndrome with late-onset disease.
  • The non-functional protein with the p.Gly220Arg substitution targets normally to the mitochondria and was observed in a family in which the proband had stroke-like lesions of the frontal lobe and two other affected sibs had a mild phenotype consisting of learning disabilities.

References

Literature Cited

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  35. Valle D, Simell O. The hyperornithinemias. In Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Basis of Inherited Disease. 8 ed. Vol 2. New York, NY: McGraw Hill; 2001:1857-96.
  36. Viegas CM, Busanello EN, Tonin AM, de Moura AP, Grings M, Ritter L, Schuck PF, Ferreira Gda C, Sitta A, Vargas CR, Wajner M. Dual mechanism of brain damage induced in vivo by the major metabolites accumulating in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. Brain Res. 2011;1369:235–44. [PubMed: 21059345]

Suggested Reading

  1. Gray RG, Green A, Hall S, McKeown C. Prenatal exclusion of the HHH syndrome. Prenat Diagn. 1995;15:474–6. [PubMed: 7644438]

Chapter Notes

Acknowledgments

We would like to acknowledge Drs William Nyhan, Rebecca Mardach, Steve Cederbaum, Yong Qu, and Kamer Tezcan for referring patients affected with HHH syndrome.

Dr José A Camacho's work was supported by a Robert Wood Johnson Foundation-Dr Harold Amos Faculty Development Award.

Revision History

  • 31 May 2012 (me) Review posted live
  • 17 June 2011 (jac) Original submission
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