Clinical presentation and age at symptom onset vary largely. It has been estimated that one in eight HHH patients develop symptoms in the neonatal period, while late-onset HHH accounts for the majority of cases [10]. In this line, late-onset HHH comprises infantile, childhood and adult-onset disease. Anamnestic data don't usually reveal previous anomalies, i.e., pregnancy, perinatal period and possibly childhood have generally followed a normal course.

Neonatal HHH is clinically very similar to other urea cycle disorders; symptom onset is usually within the first four days of life. The newborn presents with feeding difficulties and vomiting, lethargy and reduced consciousness, possibly seizures and coma. Respiratory distress and hypothermia are also common. While ammonia is known to interfere with astrocytic function and maintenance of the blood-brain barrier, ornithine and homocitrulline are assumed to contribute to brain damage by disturbing the redox homeostasis of the central nervous system [13].

Late-onset HHH is often diagnosed in patients who present to their physicians because of failure to thrive, developmental delays, intellectual disability or symptoms consistent with mild encephalopathy. Hyperammonemia may cause recurrent headaches, loss of appetite, nausea, and vomiting, but is generally less pronounced than in neonatal HHH or late-onset urea cycle disorders of distinct etiology. Further symptoms comprise intolerance of protein-rich food, ataxia and spasticity, mood swings and behavioral problems. In some patients, neurological deficits worsen over time. In this context, patients may develop spastic paraparesis years after symptom onset.

• Developmental Delay

  She did have a mild developmental delay according to her family. At presentation, she was afebrile, normotensive, non-tachypnic. [shmabstracts.org]

  delay encephalopathy feeding, protein aversion or intolerance liver failure liver involvement or dysfunction seizures spastic diplegia/quadriplegia/tetraplegia spastic paraplegia strokelike episodes temperature instability vomiting apnea behavior, hyperactive [metagene.de]

  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 [hero.epa.gov]

  Alternatively, patients show a chronic course with aversion for protein rich foods, developmental delay/intellectual disability, myoclonic seizures, ataxia and pyramidal dysfunction. [pubfacts.com]

  IDENTIFICATION OF SPECIES OF ORIGIN Species of Origin Confirmed by LINE assay Remarks Clinically affected; symptom onset at age 29 months; mental retardation/developmental delay; past hyperammonemic events; HHH 5-fold elevation above mean of plasma ornithine [coriell.org]

• Poor Feeding

  […] difficulties, poor feeding growth retardation, poor growth hepatomegaly (large liver) hyperammonemia hypothermia hypotonia lactic acidosis lethargy, drowsiness, apathy mental retardation night blindness onset, adolescent onset, childhood onset, infancy [metagene.de]

  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. [hero.epa.gov]

  It is characterized by lethargy, poor feeding, vomiting, encephalopathy and liver dysfunction. [lalpathlabs.com]

  It is characterized by lethargy, poor feeding, vomiting, encephalopathy and liver dysfunction. Dr Lal PathLabs HHH SYNDROME; HYPERORNITHINEMIA - HYPERAMMONEMIA - HOMOCITRULLINURIA SYNDROME Test price in Faizabad is Rs. 7000.00. [diagnosticcentres.in]

• Hypothermia

  hyperactive, restless Coagulopathy/Coagulation factors Encephalopathic crisis, acute episodic course (clinical symptoms) failure to thrive feeding difficulties, poor feeding growth retardation, poor growth hepatomegaly (large liver) hyperammonemia hypothermia [metagene.de]

  Respiratory distress and hypothermia are also common. [symptoma.com]

  New trends and emerging therapies include the use of hypothermia in neonatal hyperammonemia. [medlink.com]

  Infants with urea cycle disorders (UCDs) develop cerebral edema, lethargy, hypothermia, neurologic signs and coma, often shortly after birth. [blueprintgenetics.com]

• Feeding Difficulties

  difficulties, poor feeding growth retardation, poor growth hepatomegaly (large liver) hyperammonemia hypothermia hypotonia lactic acidosis lethargy, drowsiness, apathy mental retardation night blindness onset, adolescent onset, childhood onset, infancy [metagene.de]

  In most cases the early symptoms appear within the first three days of life and include respiratory distress, feeding difficulty, hypotonia, lethargy, and death in untreated cases. [icd10data.com]

  The newborn presents with feeding difficulties and vomiting, lethargy and reduced consciousness, possibly seizures and coma. Respiratory distress and hypothermia are also common. [symptoma.com]

  Hyperammonemia- hyperornithinemia- homocitrullinuria (HHH) 1. first few weeks of life 2. seizures, 3. feeding difficulty, 4. altered level of consciousness. 41. [slideshare.net]

  Highly variable manifestations in infancy can include hypotonia, lethargy, failure to thrive, seizures, psychomotor delay, hepatomegaly, hepatic dysfunction (coagulopathy and elevated transaminases), hyperammonemia, feeding difficulties, and recurrent [ncbi.nlm.nih.gov]

• Tachypnea

  […] acidosis lethargy, drowsiness, apathy mental retardation night blindness onset, adolescent onset, childhood onset, infancy onset, neonatal paraparesis/paraplegia paresis photophobia or photosensitive defect in light-exposed area respiratory distress tachypnea [metagene.de]

  The neonatal presentation usually begins a few days after birth with lethargy, somnolence, refusal to feed, vomiting, tachypnea with respiratory alkalosis, and/or seizures. [orpha.net]

  Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (triple H syndrome) is a disorder of urea cycle metabolism characterized by either a neonatal-onset with manifestations of lethargy, poor feeding, vomiting and tachypnea or, more commonly, presentations [monarchinitiative.org]

  Manifestations of hyperammonemia usually begin 24-48 hours after feeding begins and can include lethargy, somnolence, refusal to feed, vomiting, tachypnea with respiratory alkalosis, and seizures. [dnalabsindia.com]

• Respiratory Distress

  distress tachypnea, hyperpnea, dyspnea, hyperventilation [metagene.de]

  In most cases the early symptoms appear within the first three days of life and include respiratory distress, feeding difficulty, hypotonia, lethargy, and death in untreated cases. [icd10data.com]

  Respiratory distress and hypothermia are also common. [symptoma.com]

  The third child was born via repeat Cesarean section and had transient respiratory distress which required mechanical ventilation. No further information was given regarding the outcome of this child. [onlinelibrary.wiley.com]

  On admission to NNU, the baby was treated for respiratory distress syndrome. He required mechanical ventilation for 3 days, 15 days of continuous positive airway pressure and further oxygen support for 52 days. [casereports.bmj.com]

• Vomiting

  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. [hero.epa.gov]

  After infancy, these individuals quickly learn to self-restrict their protein intake to avoid the malaise and vomiting that accompanies protein-rich meals. [ncbi.nlm.nih.gov]

  Carbamoylphosphate Synthetase I (CPS) Deficiency: Autosomal recessive inborn error of the urea cycle characterized by hyperammonemia (but low plasma levels of citrulline and arginine), resulting in persistent vomiting and mental confusion/coma. [accessanesthesiology.mhmedical.com]

  […] ataxia coma developmental delay encephalopathy feeding, protein aversion or intolerance liver failure liver involvement or dysfunction seizures spastic diplegia/quadriplegia/tetraplegia spastic paraplegia strokelike episodes temperature instability vomiting [metagene.de]

• Failure to Thrive

  […] to thrive feeding difficulties, poor feeding growth retardation, poor growth hepatomegaly (large liver) hyperammonemia hypothermia hypotonia lactic acidosis lethargy, drowsiness, apathy mental retardation night blindness onset, adolescent onset, childhood [metagene.de]

  There is failure to thrive, spastic paraparesis, mental retardation, myoclonus, and seizures. There may be retinal depigmentation and chorioretinal thinning. Protein restriction is beneficial. [accessanesthesiology.mhmedical.com]

  It was later found that the clinical presentations of HHH syndrome can be highly variable, and include spastic paraplegia, pyramidal and extrapyramidal signs, stroke-like episodes, hypotonia, seizures, ataxia, protein intolerance, failure to thrive, and [hkmj.org]

  […] to thrive, hepatosplenomegaly and osteoporosis. 22221392 Lysinuric protein intolerance (LPI) is an autosomal recessive disorder caused by mutations in cationic amino acid transporter gene SLC7A7. 3793440 The three most common diagnoses were ornithine [mlquery.tenwiseapps.nl]

• Nausea

  The patient was admitted for hyperammonemia, with ammonia levels recorded of 295 μmol/L (9‐45 μmol/L) and was treated as a metabolic emergency having shown physical symptoms of nausea, lethargy, and respiratory alkalosis. [onlinelibrary.wiley.com]

  Hyperammonemia may cause recurrent headaches, loss of appetite, nausea, and vomiting, but is generally less pronounced than in neonatal HHH or late-onset urea cycle disorders of distinct etiology. [symptoma.com]

  […] management of diabetes, not following the treatment plan as directed Stopping insulin or other medicines that lower glucose level Symptoms may include any of the following: Increased thirst and urination (at the beginning of the syndrome) Feeling weak Nausea [medlineplus.gov]

  Indeed, the postpartum period was only complicated by nausea (likely opiate induced) and mild hyponatraemia (likely intravenous glucose induced) on postoperative day 1. [casereports.bmj.com]

• Loss of Appetite

  Hyperammonemia may cause recurrent headaches, loss of appetite, nausea, and vomiting, but is generally less pronounced than in neonatal HHH or late-onset urea cycle disorders of distinct etiology. [symptoma.com]

  Symptoms of the disease may appear during adulthood and include lethargy (lack of energy), vomiting, loss of appetite, seizures (fits) and coma. [ema.europa.eu]

  […] of appetite, change in behaviour, confusion, irritability and seizures), in order to prevent established and irreversible cerebral oedema. [casereports.bmj.com]

  […] of appetite, or diarrhea. [medlink.com]

• Polydipsia

  Additional general biochemical indicators of follow up quantitative amino acids analysis are ketosis (high blood and urine ketones), acidosis (blood pH below 7.35) and lactic acidemia (high lactate excretion), alkalosis (blood pH above 7.45), polyuria, polydipsia [intechopen.com]

• Liver Dysfunction

  It has variable clinical presentations with episodic hyperammonemia, liver dysfunction, and chronic neurological manifestations. In this work, we report the findings of HHH syndrome in 3 Saudi siblings. [ncbi.nlm.nih.gov]

  dysfunction (unexplained elevation of liver transaminases with or without mild coagulopathy, with or without mild hyperammonemia and protein intolerance). [hero.epa.gov]

  It is characterized by lethargy, poor feeding, vomiting, encephalopathy and liver dysfunction. [lalpathlabs.com]

  It is characterized by lethargy, poor feeding, vomiting, encephalopathy and liver dysfunction. Dr Lal PathLabs HHH SYNDROME; HYPERORNITHINEMIA - HYPERAMMONEMIA - HOMOCITRULLINURIA SYNDROME Test price in Faizabad is Rs. 7000.00. [diagnosticcentres.in]

• Blurred Vision

  Adults with the disorder present with vomiting, lack of energy, coordination difficulties, confusion, and blurred vision after eating high-protein meals or during stressful times. [sema4.com]

  This rapid increase of ammonia may lead to episodes of vomiting, lack of energy (lethargy), problems with coordination (ataxia), confusion, or blurred vision. [ghr.nlm.nih.gov]

  Periodic blurred vision, confusion, and ataxia are common symptoms. Physical Eyes Retinal depigmentation and chorioretinal thinning are uncommon findings. [emedicine.medscape.com]

  This rapid increase of ammonia may lead to episodes of vomiting, lack of energy, problems with coordination, confusion, or blurred vision. [journals.plos.org]

• Transient Blindness

  Transient blindness can also occur. [2] Congenital hyperammonemia is usually due to genetic defects in one of the enzymes of the urea cycle, such as ornithine transcarbamylase deficiency, which leads to lower production of urea from ammonia. [en.wikipedia.org]

• Muscle Spasticity

  If left untreated, this can result in developmental delay, learning disabilities, or stiffness caused by abnormal tensing of muscles (spasticity). [eugenelabs.com]

  Complications of ornithine translocase deficiency may include developmental delay, learning disabilities, and stiffness caused by abnormal tensing of the muscles (spasticity). Ornithine translocase deficiency is a very rare disorder. [ghr.nlm.nih.gov]

• Abnormal Behavior

  Most patients reaching adulthood manifest variable degrees of cognitive impairment and abnormal behavior. Long-term treatment consists of a low-protein diet supplemented with citrulline, arginine, or ornithine. [oxfordmedicine.com]

• Seizure

  There is significant clinical variability, from mild learning difficulties to coma, lethargy, hepatic involvement and seizures. [shmabstracts.org]

  Mild hyperammonemic episodes and seizures during pregnancy were treated by adjustments to dietary protein intake (decrease) and anti-seizure medication (carbamazepine), respectively [Kim et al 2012, Ho et al 2019]. [ncbi.nlm.nih.gov]

  There is failure to thrive, spastic paraparesis, mental retardation, myoclonus, and seizures. There may be retinal depigmentation and chorioretinal thinning. Protein restriction is beneficial. [accessanesthesiology.mhmedical.com]

  A new disorder of amino acid metabolism associated with myoclonic seizures and mental retardation. Am J Dis Child 1969;117:83-92. Crossref 5. Al-Hassnan ZN, Rashed MS, Al-Dirbashi OY, Patay Z, Rahbeeni Z, Abu-Amero KK. [hkmj.org]

• Lethargy

  There is significant clinical variability, from mild learning difficulties to coma, lethargy, hepatic involvement and seizures. [shmabstracts.org]

  Signs and symptoms include seizures, delayed growth, behavioral changes, ataxia, lethargy, and coma. [icd10data.com]

  With dietary restriction of protein intake and supplementary administration of L-ornithine and L-arginine, the high concentration of ammonia decreased and the clinical signs of truncal ataxia and lethargy improved. [ncbi.nlm.nih.gov]

  Untreated, the result in ketoacidosis, lethargy, coma, and finally death. Camacho JA, Obie C, Biery B: Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome is caused by mutations in a gene encoding a mitochondrial ornithine transporter. [accessanesthesiology.mhmedical.com]

• Ataxia

  (disorder), energy, metabolic diseases, rats, thiobarbituric acid-reactive substances, pathophysiology, alpha-ketoglutaric acid, creatine kinase, cerebellum, aconitate hydratase, electron transport chain, nitrates Abstract: AIMS: Cerebellar ataxia is [pubag.nal.usda.gov]

  With dietary restriction of protein intake and supplementary administration of L-ornithine and L-arginine, the high concentration of ammonia decreased and the clinical signs of truncal ataxia and lethargy improved. [ncbi.nlm.nih.gov]

  It is a genetically transmitted inborn error of metabolism caused by a defect in the transport of ornithine into the mitochondrial matrix characterized clinically by early growth retardation, learning disabilities, periodic confusion, and ataxia. [accessanesthesiology.mhmedical.com]

  […] urine) L-Lysine inc (urine) Lactate/Pyruvate ratio normal/inc (urine) Ornithine inc (urine) Transaminases (ASAT/ALAT) normal/inc (serum) Uracil inc (urine) Urea normal/dec (serum) Symptoms lens opacities altered consciousness, consciousness disturbance ataxia [metagene.de]

• Encephalopathy

  She was diagnosed with acute metabolic encephalopathy due to hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. She was kept NPO and treated with IV dextrose. Her mentation improved to baseline and her ammonia level improved to normal. [shmabstracts.org]

  This progressed to severe encephalopathy requiring ventilation on day 6. Graft function, ammonia, and magnetic resonance imaging (MRI) brain were normal. Hepatic vasculature was patent, and no viremia was detected. EEG showed severe encephalopathy. [ejohg.com]

  /Pyruvate ratio normal/inc (urine) Ornithine inc (urine) Transaminases (ASAT/ALAT) normal/inc (serum) Uracil inc (urine) Urea normal/dec (serum) Symptoms lens opacities altered consciousness, consciousness disturbance ataxia coma developmental delay encephalopathy [metagene.de]

  Prior to the initiation of valproate therapy, evaluation for UCD should be considered in the following patients: 1) those with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein load, pregnancy or postpartum encephalopathy [nucdf.org]

  Clinical presentation : - neonatal period (50%): hyperammonemia with vomiting, lethargy or irritability; - childhood and adolescence: clinical picture of acute encephalopathy during stress (fever, postoperative period, protein catabolism) or progressive [sites.uclouvain.be]

• Confusion

  She was in her normal state of health according to her family and then developed confusion and erratic behavior at work. She had no history of seizures. She did have a mild developmental delay according to her family. [shmabstracts.org]

  It is a genetically transmitted inborn error of metabolism caused by a defect in the transport of ornithine into the mitochondrial matrix characterized clinically by early growth retardation, learning disabilities, periodic confusion, and ataxia. [accessanesthesiology.mhmedical.com]

  • A 39-year-old man and his 42-year-old sister, both vegetarians, had episodic confusion for many years, but their mental function was normal between those episodes. [jamanetwork.com]

  Acute clinical signs include intermittent episodes of vomiting, confusion or coma and hepatitis-like attacks. [pubfacts.com]

While neonatal hyperammonemia is highly indicative of a urea cycle disorder, HHH accounts for minimal shares of these cases. With regards to late-onset HHH, the clinical picture is more heterogeneous and hyperammonemia is not necessarily the main clinical finding. Still, laboratory analyses of blood and urine samples are the mainstays of HHH diagnosis. The following results are characteristic of this disease:

• Hyperornithinemia, i.e., serum levels of ornithine exceed physiological reference ranges (up to 200 µmol/l in pediatric patients, up to 120 µmol/l in adults). Ornithine concentrations typically don't exceed 1,000 µmol/l. The presence of neurological deficits and the absence of ophthalmological symptoms allows for a differentiation from ornithine aminotransferase deficiency [10].
• Serum glutamine and alanine concentrations may be elevated.
• Hyperammonemia, particularly after ingestion of protein-rich food. The reference range is up to 150 µmol/l in neonates and up to 50 µmol/l in elder patients.
• Enhanced concentrations of homocitrulline in urine specimens. The reference range is age-dependent and decreases from <70 nmol/mg creatinine in neonates to <15 nmol/mg creatinine in adults.
• The orotic acid may be excreted in excess since accumulating carbamoylphosphate may also be converted to this compound [1].
• Increased levels of alanine transaminase and aspartate transaminase; decreased concentrations of coagulation factors. Liver dysfunction is detected in less than half of HHH patients.

Genetic screens may be realized to confirm the diagnosis of HHH.

Neuroimaging is generally not required to this end, but may reveal brain lesions like cortical atrophy and white matter lesions.

• Ammonia Increased

  Blood ammonia increased from high normal values to 975, 990, and 750 mumol/liter (normal less than 70) and urinary orotic acid from trace to 539, 494, and 1296 mumol/mmol creatinine (normal 5-11) after the respective loads. [ncbi.nlm.nih.gov]

  Blood ammonia increased from high normal values to 975, 990, and 750μmol/liter (normal <70) and urinary orotic acid from trace to 539, 494, and 1296 μmol/mmol creatinine (normal 5-11) after the respective loads. [nature.com]

Catabolism of nitrogenous compounds may exacerbate the disease and trigger hyperammonemic crises. Although such crises are less common in HHH patients than in those individuals suffering from severe urea cycle disorders, they pose a major threat to the central nervous system. Thus, protein intake should be reduced to a minimum without inducing nutrient deficiencies. A limit of 1.2 g protein per kg and day has been proposed to this end [14]. In this context, a vegetarian diet has been associated with an attenuation of symptoms [15]. Fasting is to be avoided, too. Some patients may require long-term supplementation of L-citrulline and/or L-arginine; administration of ornithine is the subject of controversial debate [1].

Despite compliance with dietary recommendations, infectious diseases, pregnancy or any other form of stress may trigger an episode of symptoms consistent with HHH. If patients present with hyperammonemia, this condition demands immediate symptomatic treatment [16]. All protein intake should be stopped for a period of up to 36 hours. Patients should be administered dextrose, possibly plus insulin, to counteract their current metabolic state. L-citrulline and/or L-arginine may also be helpful in case of acute hyperammonemia. Provision of nitrogen scavengers like sodium benzoate, sodium phenylacetate or sodium phenylbutyrate may be indicated in patients presenting with moderate hyperammonemia. Severe hyperammonemia may require hemodialysis or hemofiltration but is rarely necessary for HHH patients. Of note, therapeutic measures described for acute hyperammonemia are not specific for HHH. In fact, drugs mentioned may not be approved for HHH therapy in all countries. However, due to the low incidence of the disease, more specific recommendations cannot be provided.

Few general statements can be made regarding the outcome of HHH. The unpredictability of a patient's prognosis is best illustrated by the example of two siblings, born to a Moroccan family, who both inherited the nonsense mutation R179X [12]. While one of the boys developed severe liver abnormalities and presented with reduced consciousness, his brother did not experience any complaints.

Recently, a retrospective study has been conducted on clinical and molecular data obtained from 111 patients: 7 patients had died from the disease; data regarding the patient's intellectual abilities was available for 86 patients, 29 of whom did present without limitations to this end, and 20, 4, and 33 of whom presented with mild, moderate, and severe disability, respectively [1]. These findings indicate that HHH have a near-to-normal life expectancy, but their life quality may be diminished due to neurological deficits.

HHH is a metabolic disorder inherited as an autosomal recessive trait. Mutations in the SLC25A15 gene, which is located on the long arm of chromosome 13, account for the biosynthesis of a defective transporter involved in the urea cycle and amino acid metabolism. In detail, this gene encodes for solute carrier family 25 member 15 or ORNT1, a citrulline-ornithine antiporter to be found in the inner mitochondrial membrane. Gene defects accounting for HHH are heterogeneous, and may lead to the synthesis of an unstable protein, of a stable yet inactive transporter, or of a shortened, dysfunctional amino acid chain [2]. To date, about two dozen mutations have been described in HHH patients [3]. The residual function of ORNT1 has been related to late-onset HHH, while a complete ORNT1 deficiency favors the onset of severe symptoms in neonates. Still, it has not been possible to predict the course of the disease in patients with a known genotype, and this observation implies that additional factors like gene redundancy and mitochondrial properties are involved in the pathogenesis of the disease [4]. The same researchers that proposed this hypothesis were able to identify a second mitochondrial transporter, ORNT2, that may be able to partially compensate for ORNT1 deficiency [5].

HHH has first been described by Vivian E. Shih and colleagues in 1969 [6], and less than 100 case reports have been published to date. Presumably, increased incidence rates in determined regions and ethnicities can be ascribed to a founder effect. This has been shown for French Canadian HHH patients, a majority of whom shows a deletion of a phenylalanine residue at position 188 [3]. In fact, the prevalence of the respective F188del mutation in northern Saskatchewan has been assessed as 1 in 19 inhabitants. Consequently, about 1 in 500 children is expected to be homozygous for this gene defect [7]. Japanese patients often carry nonsense mutation R179X, which leads to premature termination of the protein [8]. Furthermore, a considerable share of HHH patients is of Italian descent. However, the genotype underlying HHH in this ethnicity is rather heterogeneous [9].

While symptom onset may occur at any age, incidence rates decrease with age [10].

ORNT1 plays a pivotal role in the urea cycle [11], and the main symptoms of HHH, i.e., hyperornithinemia, hyperammonemia, and homocitrullinuria, result from a urea cycle disorder induced by a defective gene encoding for this transporter.

The urea cycle allows for the breakdown of proteins, amino acids, and nitrogenous compounds by detoxifying ammonia. In detail, ammonia and bicarbonate are converted to carbamoyl phosphate, before the carbamoyl group can be transferred to ornithine. These reactions are catalyzed by two mitochondrial enzymes, and an impairment of these early steps of the urea cycle causes severe hyperammonemia. The respective urea cycle disorders are carbamoyl phosphate synthetase I deficiency and ornithine transcarbamoylase deficiency. Under physiological conditions, the afore-described reactions yield citrulline and phosphate. For the urea cycle to continue, citrulline has to be transported into the cytoplasm, and this transport occurs via ORNT1. In patients suffering from HHH, the urea cycle is interrupted at this point.

Cytosolic reactions that form part of the urea cycle don't only yield urea as an easily excretable nitrogenous compound, but also arginine, a proteinogenic amino acid, and ornithine, a compound that needs to be recovered because it is required by ornithine transcarbamoylase in the proximal urea cycle. Therefore, ornithine has to be transported back into the mitochondria, and this process also depends on ORNT1.

Consequently, accumulation of citrulline and ornithine in mitochondria and cytosol, respectively, is the pathogenetic basis of HHH:

• Hyperornithinemia is the direct result of cytosolic ornithine accumulation.
• Since the urea cycle is required for ammonia detoxification, this neurotoxic compound accumulates and patients present with hyperammonemia.
• Homocitrulline is synthesized from carbamoyl phosphate and lysine. Excess production of homocitrulline, due to the accumulation of carbamoyl phosphate in hepatocytic mitochondria, results in renal excretion of this metabolite.

Affected families may benefit from genetic counseling. Firstly, carriers may be identified by means of genetic screens. On the other hand, prenatal screens may be conducted after chorionic villus sampling or amniocentesis. Parents may then be offered to opt for a premature termination of pregnancy. There is no consensus as to the assessment of serum ornithine levels shortly after birth since the possibility of ornithine concentrations within the reference range bear the risk of a false-negative diagnosis. Here, molecular biological techniques are more sensitive [14].

Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (HHH) is a very rare metabolic disease. To date, slightly more than 100 cases have been reported in the literature [1]. Its designation is derived from the disease's clinical presentation since its etiology remained largely unclear until it could be related to a defect of gene SLC25A15 [2]. This gene encodes for solute carrier family 25 member 15, which corresponds to mitochondrial ornithine transporter 1 (ORNT1). ORNT1 is sometimes also referred to as ornithine translocase and thus, ornithine translocase deficiency is an alternative denomination of HHH.

ORNT1 mediates the transport of ornithine from the cytosol across the mitochondrial membrane, and in mitochondria, it is required for the urea cycle to be completed. On the other hand, citrulline is transported in the opposite direction. After formation of argininosuccinate from citrulline and aspartate, the former is cleaved into arginine and fumarate. Thus, both the urea cycle and the biosynthesis of arginine depend on the function of ORNT1.

Symptoms may manifest at any age. Contrary to other urea cycle disorders, neonatal hyperammonemic encephalopathy accounts for minor shares of cases. Most affected individuals don't experience any symptoms until years later. Nevertheless, hyperammonemic encephalopathy is not less dangerous and may provoke irreversible brain damage and permanent neurological deficits. Late-onset HHH may also be associated with developmental delays and intellectual disability, but motor deficits like ataxia and spasticity are also common. Unfortunately, progressive worsening of neurological deficits cannot be ruled out despite an optimum management of the disease. To date, it is not possible to predict the course of the disease in an individual case.

Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (HHH) is a very rare metabolic disorder and is part of the group of diseases referred to as urea cycle disorders. Only about 100 cases have been described so far, with most patients being French-Canadians, Japanese or Italians. HHH is inherited as an autosomal recessive trait, i.e., children will develop the disease only if they inherit a defective gene from both parents. The respective gene encodes for an intracellular transporter expressed in liver cells.

Symptom onset may occur at any age, but is most frequently noted in infancy or childhood. Affected individuals frequently suffer from headaches, loss of appetite, nausea, and vomiting. Lethargy and reduced consciousness, possibly seizures and coma are further signs of an accumulation of neurotoxic metabolites like ammonia. Further symptoms comprise intolerance of protein-rich food, gait disturbances and spasticity, mood swings and behavioral problems.

Immediate treatment of acute episodes is necessary to prevent permanent brain damage. In the long term, most patients receive a dietary supplementation of amino acids whose synthesis is restricted due to the gene defect and have to adhere to a diet with low protein contents. Unfortunately, the progression of neurological deficits cannot be impeded in every patient.

1. Martinelli D, Diodato D, Ponzi E, et al. The hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. Orphanet J Rare Dis. 2015; 10:29.
2. Camacho JA, Obie C, Biery B, et al. Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome is caused by mutations in a gene encoding a mitochondrial ornithine transporter. Nat Genet. 1999; 22(2):151-158.
3. Debray FG, Lambert M, Lemieux B, et al. Phenotypic variability among patients with hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome homozygous for the delF188 mutation in SLC25A15. J Med Genet. 2008; 45(11):759-764.
4. Camacho JA, Mardach R, Rioseco-Camacho N, et al. Clinical and functional characterization of a human ORNT1 mutation (T32R) in the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome. Pediatr Res. 2006; 60(4):423-429.
5. Camacho JA, Rioseco-Camacho N, Andrade D, Porter J, Kong J. Cloning and characterization of human ORNT2: a second mitochondrial ornithine transporter that can rescue a defective ORNT1 in patients with the hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, a urea cycle disorder. Mol Genet Metab. 2003; 79(4):257-271.
6. Shih VE, Efron ML, Moser HW. Hyperornithinemia, hyperammonemia, and homocitrullinuria. A new disorder of amino acid metabolism associated with myoclonic seizures and mental retardation. Am J Dis Child. 1969; 117(1):83-92.
7. Sokoro AA, Lepage J, Antonishyn N, et al. Diagnosis and high incidence of hyperornithinemia-hyperammonemia-homocitrullinemia (HHH) syndrome in northern Saskatchewan. J Inherit Metab Dis. 2010; 33 Suppl 3:S275-281.
8. Miyamoto T, Kanazawa N, Kato S, et al. Diagnosis of Japanese patients with HHH syndrome by molecular genetic analysis: a common mutation, R179X. J Hum Genet. 2001; 46(5):260-262.
9. Salvi S, Dionisi-Vici C, Bertini E, Verardo M, Santorelli FM. Seven novel mutations in the ORNT1 gene (SLC25A15) in patients with hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome. Hum Mutat. 2001; 18(5):460.
10. Camacho J, Rioseco-Camacho N. Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews(R). Seattle (WA): University of Washington, Seattle; 2012. Available from: http://www.ncbi.nlm.nih.gov/books/NBK97260/
11. Morris SM, Jr., Kepka-Lenhart D. Hormonal induction of hepatic mitochondrial ornithine/citrulline transporter mRNA. Biochem Biophys Res Commun. 2002; 294(4):749-752.
12. Tessa A, Fiermonte G, Dionisi-Vici C, et al. Identification of novel mutations in the SLC25A15 gene in hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome: a clinical, molecular, and functional study. Hum Mutat. 2009; 30(5):741-748.
13. Amaral AU, Leipnitz G, Fernandes CG, et al. Evidence that the major metabolites accumulating in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome induce oxidative stress in brain of young rats. Int J Dev Neurosci. 2009; 27(7):635-641.
14. Lee HH, Poon KH, Lai CK, et al. Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome: a treatable genetic liver disease warranting urgent diagnosis. Hong Kong Med J. 2014; 20(1):63-66.
15. Tezcan K, Louie KT, Qu Y, et al. Adult-onset presentation of a hyperornithinemia-hyperammonemia-homocitrullinuria patient without prior history of neurological complications. JIMD Rep. 2012; 3:97-102.
16. Häberle J, Boddaert N, Burlina A, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis. 2012; 7:32.