Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome is a very rare urea cycle disorder. It is provoked by a mutation of the gene encoding for the mitochondrial ornithine transporter 1, which plays a crucial role in citrulline and ornithine transport across the mitochondrial membrane.
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 . 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 .
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.
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:
Genetic screens may be realized to confirm the diagnosis of HHH.
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 . In this context, a vegetarian diet has been associated with an attenuation of symptoms . 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 .
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 . 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 . 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 . 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 . To date, about two dozen mutations have been described in HHH patients . 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 . 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 .
HHH has first been described by Vivian E. Shih and colleagues in 1969 , 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 . 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 . Japanese patients often carry nonsense mutation R179X, which leads to premature termination of the protein . Furthermore, a considerable share of HHH patients is of Italian descent. However, the genotype underlying HHH in this ethnicity is rather heterogeneous .
While symptom onset may occur at any age, incidence rates decrease with age .
ORNT1 plays a pivotal role in the urea cycle , 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:
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 .
Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (HHH) is a very rare metabolic disease. To date, slightly more than 100 cases have been reported in the literature . 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 . 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.