Ornithine Transcarbamylase Deficiency, Hyperammonemia Due To
A number sign (#) is used with this entry because ornithine transcarbamylase deficiency is caused by mutation in the gene encoding ornithine carbamoyltransferase (OTC; 300461) on chromosome Xp11.
DescriptionOrnithine transcarbamylase deficiency is an X-linked inborn error of metabolism of the urea cycle which causes hyperammonemia. The disorder is treatable with supplemental dietary arginine and low protein diet.
Urea cycle disorders are characterized by the triad of hyperammonemia, encephalopathy, and respiratory alkalosis. Five disorders involving different defects in the biosynthesis of the enzymes of the urea cycle have been described: OTC deficiency, carbamyl phosphate synthetase deficiency (237300), argininosuccinate synthetase deficiency, or citrullinemia (215700), argininosuccinate lyase deficiency (207900), and arginase deficiency (207800).
Clinical FeaturesRussell et al. (1962) described 2 cousins with chronic ammonia intoxication and mental deterioration. By liver biopsy, the activity of hepatic OTC was shown to be very low. A defect was presumed to be present in urea synthesis at the level of conversion of ornithine to citrulline.
Levin et al. (1969) reported an affected female infant whose mother had an aversion to protein and raised plasma ammonia levels, whereas the father was normal. In another infant, a male, Levin et al. (1969) found what they considered a variant of the usual hyperammonemia caused by OTC deficiency, presumably due to a different enzymatic change. Enzyme activity was 25% of normal, rather than 5 to 7% of normal as in other cases, and other properties of the enzyme showed differences from the normal. The clinical picture was milder than in the usual cases. Holmes et al. (1987) also described a mild variant of OTC deficiency.
Campbell et al. (1971, 1973) reported lethal neonatal hyperammonemia due to complete ornithine transcarbamylase deficiency. They suggested that mutation in the gene encoding the enzyme may lead to partial deficiency in heterozygous females and to complete deficiency in hemizygous males.
Thaler et al. (1974) described a 'novel protein tolerant variant' of OTC deficiency in a child with encephalopathy with fatty visceral degeneration suggestive of Reye syndrome. Krieger et al. (1979) reported a male infant with OTC deficiency who was relatively symptom free for 4 months, but gradually developed severe spasticity due to cerebral atrophy, and died at 13 months of age. Liver OTC activity was 1.5% of normal. The authors noted that the clinical picture of OTC deficiency during acute exacerbations with microvesicular fat accumulation in the liver may suggest Reye syndrome.
Bruton et al. (1970) described astrocyte transformation to Alzheimer type II glia, a feature of any form of hyperammonemia. Kornfeld et al. (1985) reported neuropathologic findings in 2 cases of OTC deficiency. A 3-day-old boy showed gliosis mainly in the brainstem, and a 2-year-old girl showed widespread gliosis and ulegyria of the cerebral cortex, as well as atrophy in the internal granular layer of the cerebellum.
Drogari and Leonard (1988) described 6 affected boys with relatively late onset of clinical symptoms. One of them was a boy who during childhood was considered a 'very difficult child, introverted with volcanic tempers.' At the age of 12 years, he had an episode of confusion for which he was admitted to hospital, but no cause was found. At the age of 14 years, he was admitted to hospital deeply unconscious after a high protein meal the night before admission. Urine orotic acid excretion was raised, and his mother was found to be a carrier. Thereafter, he was treated with a low protein diet, arginine supplements, and sodium benzoate. He had further episodes of hyperammonemia, however, particularly precipitated by energy restriction. At the age of 18 years he performed commendably in examinations and was accepted for medical school. Finkelstein et al. (1989, 1990) described 21 male patients who presented after age 28 days with what the authors defined as late-onset OTC deficiency. The patients appeared normal at birth, but irritability, vomiting and lethargy, which were often episodic, developed later. The age of presentation ranged from 2 months to 44 years.
Partial deficiency in the male, a presumably allelic form, was reported by Matsuda et al. (1971) and by Oizumi et al. (1984). Oizumi et al. (1984) reported the case of a 6-year-old boy who had intermittent coma with hyperammonemia precipitated by infections. Liver biopsy showed OTC activity 16% of normal. The mother showed elevated orotic acid excretion in the urine following protein load. Supplementation of dietary arginine abolished the episodes of hyperammonemia in the boy. Matsuda et al. (1991) described the clinical and laboratory features of 32 Japanese patients with OTC deficiency. They divided their patients into 3 groups, based on clinical manifestations and age of onset: group 1 (0 to 28 days), group 2 (29 days to 5 years), and group 3 (greater than 5 years). The lowest mortality and incidence of mental retardation was among the group 2 patients. Patients in groups 1 and 3 had similar mortality rates and enzyme activities. These patients had the highest citrulline levels and were asymptomatic prior to their first episode of hyperammonemia. The authors emphasized that the incidence of late-onset OTC deficiency is higher than previously recognized.
Anadiotis et al. (2001) reported a 15-year-old male patient with OTC deficiency who developed pancreatitis while taking a low protein diet, citrulline, and sodium phenylbutyrate.
Lee et al. (2002) noted that there have been several reports of acrodermatitis enteropathica-like dermatosis in association with inborn errors of the urea cycle, in citrullinemia associated with argininosuccinate synthase deficiency (Goldblum et al., 1986), and in carbamoyl phosphate synthetase deficiency (Kline et al., 1981). Lee et al. (2002) speculated that since arginine represents such a large proportion of the amino acid composition of epidermal keratins, arginine deficiency associated with urea cycle defects may contribute to compromised epidermal barrier function and skin lesions in affected infants.
Lien et al. (2007) reported a 52-year-old man who died suddenly of hyperammonemia after routine surgery for removal of a throat polyp. Eight days after surgery, he developed confusion, ataxia, and paranoia, which progressed to seizures, cerebral edema, coma, and death within 3 days. Prior medical history was unremarkable. The patient's asymptomatic 20-year-old daughter presented for prenatal evaluation, and her twin boys were both found to be carriers of a mutation in the OTC gene. The mother was heterozygous for the mutation, but DNA analysis on autopsy samples from her father were unsuccessful. Both baby boys were healthy on a low protein diet. Lien et al. (2007) emphasized the late onset and unusual presentation of OTC deficiency in the older man.
In a review of inherited metabolic disorders and stroke, Testai and Gorelick (2010) noted that patients with urea cycle defects, including CPS1 deficiency (237300), OTC deficiency, and citrullinemia (215700) can rarely have strokes.
Batshaw et al. (2014) reported the results of an analysis of 614 patients with urea cycle disorders (UCDs) enrolled in the Urea Cycle Disorders Consortium's longitudinal study protocol. The most common disorder was ornithine transcarbamylase deficiency, accounting for more than half of the participants. The overall prevalence of UCDs in the population was calculated as 1 per 35,000, with two-thirds presenting initial symptoms after the neonatal period. Batshaw et al. (2014) found the mortality rate to be 24% in neonatal-onset cases and 11% in late-onset cases. The most common precipitant of clinical hyperammonemic episodes in the post-neonatal period was intercurrent infections. Elevations in both blood ammonia and glutamine appeared to be biomarkers for neurocognitive outcome. In terms of chronic treatment, low protein diet appeared to result in normal weight but decreased linear growth, while nitrogen scavenger therapy with phenylbutyrate resulted in low levels of branched chain amino acids. Batshaw et al. (2014) found an unexpectedly high risk for hepatic dysfunction in patients with ornithine transcarbamylase deficiency.
Heterozygous Females
Rowe et al. (1986) reviewed 13 symptomatic female heterozygotes. They presented as early as the first week of life or as late as the sixth year. Symptoms before diagnosis were nonspecific: episodic extreme irritability (100%), episodic vomiting and lethargy (100%), protein avoidance (92%), ataxia (77%), stage II coma (46%), delayed growth (38%), developmental delay (38%), and seizures (23%). Onset at the time of weaning from breast milk was frequent. Including the proband, 42% of females in the 13 families had symptoms.
Gilchrist and Coleman (1987) reported 2 heterozygous females who had late onset of severe symptoms. Encephalopathy and focal neurologic deficits began at age 36 years in 1 and at age 38 years in the other. The second had increased urine orotate after a protein meal and had had a lifelong aversion to eating meat, which usually precipitated headaches.
Arn et al. (1989) discussed phenotypic effects of heterozygosity for mutations at the OTC locus. Arn et al. (1990) reported that otherwise normal women who are carriers of a mutant OTC allele are at increased risk for hyperammonemic coma, especially during puerperium. They recommended that any woman who presents with an episode of progressive lethargy and stupor, evidence of acute cortical dysfunction, or coma, especially during pregnancy, be examined for OTC deficiency by pedigree analysis, a search for a history of previous episodes, and the measurement of plasma ammonium and, if immediately available, plasma glutamine levels. The early identification of hyperammonemia provides an opportunity to correct plasma ammonium levels by intravenous therapy with sodium benzoate, sodium phenylacetate, and arginine hydrochloride.
Lee et al. (2002) reported a female infant with skin lesions resembling acrodermatitis enteropathica who was subsequently found to have OTC deficiency. Infectious causes and zinc deficiency were ruled out, and resolution of the eruption occurred after arginine and citrulline supplementation was instituted.
Valproate Sensitivity
In males with OTC deficiency, sodium valproate may precipitate acute liver failure (Tripp et al., 1981). Hjelm et al. (1986) concluded that the vulnerability of toxic effects of valproate extends to heterozygotes as well. They described a family in which 2 daughters and a son died in childhood, all with clinical features suggesting a metabolic disorder; in one, valproate seemed to have accelerated death. They concluded that the mother was a heterozygote for OTC deficiency. Valproate sensitivity in OTC deficiency is comparable to vincristine neuropathy in Charcot-Marie-Tooth disease (118200).
Honeycutt et al. (1992) reported a previously undiagnosed heterozygous woman who had symptomatic hyperammonemia during initiation of valproate therapy. Kay et al. (1986) had reported a similar patient. Valproate inhibits ureagenesis and can be toxic to mitochondria.
There is a recognizable congenital phenotype, the fetal valproate syndrome (609442; Winter et al., 1987), which may not be related to OTC deficiency. The features are epicanthic folds, flat nasal bridge, broad nasal base, anteverted nostrils, shallow philtrum, thin upper lip with thick lower lip, and, in some cases, ridging of the metopic suture, congenital heart defect, postaxial polydactyly, and hypospadias. Ardinger et al. (1988) provided verification of the fetal valproate syndrome phenotype. Clayton-Smith and Donnai (1995) reviewed and illustrated the facial features and other clinical findings in sibs whose mother took 1.2 grams of valproate per day while pregnant. While studying the genetic basis of valproate teratogenicity in the mouse, Faiella et al. (2000) discovered that parental factors influence fetal susceptibility to induced malformations. They found that many of these malformations were homeotic transformations. In pluripotent human embryonal carcinoma cells treated with valproate, they found altered expression of specific HOX (see 142950) genes.
InheritanceScott et al. (1972) presented 2 kindreds that supported X-linked recessive inheritance of OTC deficiency. Short et al. (1973) studied 4 families, all consistent with X-linked inheritance. In the liver of a woman heterozygous for OTC deficiency, Ricciuti et al. (1976) demonstrated 2 classes of cells, one deficient and one normal in enzyme activity. The findings of cellular mosaicism confirmed that the gene for OTC is X-linked. Thus, the evidence of X-linked dominant inheritance is based on (1) the severe nature of the disorder in males with almost complete absence of enzyme in most cases; (2) wide variation in clinical severity and in enzyme level in heterozygous women; (3) demonstration of the Lyon phenomenon in the liver of heterozygous females; and (4) demonstration of X-linkage in the mouse (see DeMars et al., 1976).
MappingBurdakin and Norum (1981) observed at least 1 recombinant in 3 opportunities for the linkage of OTC deficiency and G6PD (305900) on the X chromosome. The loci were later found to be at opposite ends of the X chromosome.
DiagnosisRowe et al. (1986) suggested that family history, dietary history, episodic nonspecific symptoms, response to withdrawal of protein, and other characteristics should permit early diagnosis. In 5 patients tested, IQ was below 70 at the time of diagnosis.
OTC is expressed in the liver and in the mucosa of the small intestine. Hamano et al. (1988) described the identification of a carrier of OTC deficiency by means of immunocytochemical examination of a biopsy specimen from the duodenal mucosa. OTC-negative cells were distributed around 1 side of some villi, whereas OTC-positive cells were located on the other side. The epithelial cells of the intestine arise from the division of the crypt cells and then move up along the sides of the villi. The epithelium of individual crypts is thought to be composed of cells of a single parental type.
About 15% of heterozygous females have life-threatening hyperammonemic comas. Both symptomatic and asymptomatic carriers show increased orotic acid excretion, especially under protein loading tests. Pelet et al. (1990) found that the test is rarely negative in obligate carriers, perhaps no more often than in 8% of carriers.
Hauser et al. (1990) described a test that can be substituted for nitrogen loading for identification of heterozygous females. In the nitrogen loading test, there is intramitochondrial accumulation of carbamoyl phosphate. The excess carbamoyl phosphate is diffused into the cytosol where it functions as a substrate to enhance the biosynthesis of pyrimidine, resulting in the accumulation and excretion of orotic acid. In the test proposed by Hauser et al. (1990), a single oral dose of allopurinol substitutes for the nitrogen load. The effectiveness of the method depends on the inhibitory effect of oxypurinol ribonucleotide (a metabolite of allopurinol) on orotidine monophosphate decarboxylase, which leads to the accumulation of orotidine monophosphate and its precursor orotic acid, and ultimately to orotic aciduria and orotidinuria.
Grompe et al. (1991) offered a diagnostic algorithm for OTC deficiency. Although the accuracy of prenatal and carrier detection of OTC deficiency has been greatly improved by linkage analysis since the cloning of the gene, RFLP-based diagnosis is limited in this disorder in which many of the cases represent new mutations.
Yudkoff et al. (1996) developed a new technique that monitors metabolic competence in female heterozygotes for OTC deficiency. They concluded that the test effectively monitors in vivo nitrogen metabolism and may obviate the need for liver biopsy to measure enzyme activity in OTC deficiency. Asymptomatic OTC deficiency carriers form urea at a normal rate, indicating that ureagenesis can be competent even though enzyme activity is below normal. Although ostensibly asymptomatic OTC deficiency carriers form urea at a normal rate, their nitrogen metabolism is still abnormal, as reflected in their increased production of 5-(15)N-glutamine. The new test may be important for monitoring the efficacy of novel treatments for OTC deficiency, e.g., liver transplantation and gene therapy. The method uses mass spectrometry to measure conversion of (15)NH(4)Cl to (15)N-urea and 5-(15)N-glutamine following an oral load of (15)NH(4)Cl.
Bowling et al. (1999) reported a family with 2 consecutive males with OTC deficiency caused by mutation in the OTC gene. The mother had normal biochemical studies. Genotyping of the mother was performed on peripheral blood leukocytes and skin fibroblasts and showed no mutation, strongly suggesting gonadal mosaicism. The authors noted that gonadal mosaicism needs to be considered when counseling couples in which the mother has had a previously affected child with OTC deficiency but does not appear to be a carrier.
Prenatal Diagnosis
In a report of prenatal diagnosis of OTC deficiency, Pembrey et al. (1985) suggested that regardless of the predicted outcome as far as the fetus is concerned, the biochemical status of the carrier mother should be monitored because hyperammonemia and arginine deficiency might have a deleterious effect on the fetus, perhaps particularly if a female fetus is heterozygous for the OTC deficiency gene.
Fox et al. (1986, 1986) discussed the use of DNA polymorphisms in the prenatal diagnosis of OTC deficiency.
Clinical ManagementBatshaw et al. (1982) reported on therapy of 26 patients with inborn errors of urea synthesis by activation of alternative pathways of waste nitrogen synthesis and excretion. In 7 with deficiency of argininosuccinate synthetase (citrullinemia) and 10 with deficiency of argininosuccinate lyase (argininosuccinic aciduria), excretion of citrulline and argininosuccinate served as waste nitrogen products because they contain nitrogen normally destined for urea synthesis; synthesis and excretion of these substances was enhanced by arginine supplementation. Administration of sodium benzoate further diverted ammonium nitrogen from the defective urea pathway to hippurate synthesis by way of the glycine cleavage complex in the above 2 disorders, as well as in ornithine transcarbamylase deficiency and hyperammonemia due to carbamoyl phosphate synthetase deficiency.
Brusilow et al. (1984) reported the successful treatment of episodic hyperammonemia in children with carbamoyl phosphate synthetase deficiency, ornithine transcarbamylase deficiency, and citrullinemia. Treatment made use of intravenous sodium benzoate, sodium phenylacetate and arginine, nitrogen-free intravenous alimentation, and, when other measures failed, dialysis.
Michels et al. (1982) reported survival to over 4 years of age in a male with OTC deficiency who was treated with a very low protein diet supplemented with essential amino acids and keto acid analog of essential amino acids. Korson et al. (1989) described the successful use of liver transplantation in the treatment of OTC deficiency.
Maestri et al. (1991) described a diagnostic and therapeutic protocol designed to prevent clinical expression of inborn errors of urea synthesis in the neonatal period. In 7 of 32 affected infants with carbamoyl phosphate synthetase deficiency, argininosuccinate synthetase deficiency, and argininosuccinate lyase deficiency, therapy was effective in avoiding neonatal hyperammonemic coma and death. When treated prospectively, 5 of 8 patients with OTC deficiency avoided severe hyperammonemia and survived the neonatal period. Two of the patients with OTC deficiency subsequently died; 3 others had received orthotopic liver transplants. The experience with all of the surviving patients suggested a more favorable neurologic outcome than that achieved in patients rescued from neonatal hyperammonemic coma. Maestri et al. (1996) reported on the long-term outcome of 32 girls with OTC deficiency enrolled in a treatment protocol who had at least 1 episode of encephalopathy. The authors reported a survival rate greater than 90% at 5 years of age. The frequency of hyperammonemic episodes decreased with increasing age and with sodium phenylacetate or sodium phenylbutyrate treatment. Although mean IQ before treatment was in the low average range, 19 of the 23 girls in whom intelligence was tested longitudinally had stable test scores.
Wilson et al. (2001) reviewed the plasma ammonia and glutamine concentrations during long-term management of 7 patients with OTC deficiency and 3 patients with citrullinemia. Patients with citrullinemia tended to have higher plasma ammonia concentrations for a given plasma glutamine concentration compared to those with OTC deficiency, and there was not a simple linear relationship between glutamine and ammonia in either condition.
Molecular GeneticsRozen et al. (1985) gave the first reported example of an OTC gene deletion that could be identified cytogenetically in a patient with OTC deficiency. In a boy with a mild form of OTC deficiency, Maddalena et al. (1988) found somatic mosaicism for an intragenic deletion of the OTC gene (300461.0001). In 3 of 24 unrelated patients with OTC deficiency, Maddalena et al. (1988) identified 2 different point mutations in the same codon of the OTC gene (300461.0002-300461.0003). The patients included 2 males with severe neonatal onset and a female patient with mild disease. In 5 unrelated patients with OTC deficiency, Grompe et al. (1989) identified 4 mutations and a polymorphism in the OTC gene (300461.0004-300461.0009).
In a catalog of mutations in the OTC gene, Tuchman (1993) reported that approximately 10 to 15% of all molecular alterations associated with OTC deficiency were large deletions involving all or part of the OTC gene. Tuchman et al. (1996) estimated that approximately 90 different mutations associated with OTC deficiency had been defined.
X-Inactivation
To understand the correlation between X-inactivation status and the clinical phenotype of carrier females (which can vary from asymptomatic to severe hyperammonemia), Yorifuji et al. (1998) analyzed the X-inactivation pattern of peripheral blood leukocytes in a family consisting of a clinically normal mother and 2 daughters with a severe manifestation. In addition, they obtained tissue samples from various parts of the liver of one of the daughters and analyzed X-inactivation patterns and residual OTC activities. The X inactivation of peripheral blood leukocytes was nearly random in these carrier females and showed no correlation with the disease phenotype; however, the X inactivation of the liver was much more skewed and correlated well with the OTC activity of all samples. The degree of X inactivation varied considerably, even within the same liver.
Genotype/Phenotype CorrelationsMcCullough et al. (2000) examined the genotype/phenotype correlations of 157 probands with OTC deficiency, including 57 heterozygous females. In patients with mutations that abolished enzyme activity, the severe clinical and biochemical phenotype was homogeneous. The males in this group presented within the first few days of life with high mortality and morbidity. Most patients with the late-onset form had missense mutations in the OTC gene, although a few had 3-bp deletions, and late-onset patients had residual enzyme activity ranging from 26 to 74% of normal control values. Mutations in manifesting females were primarily of the neonatal-onset type. Substitutions occurring in CpG dinucleotides accounted for approximately 31% of all mutations.
Population GeneticsNagata et al. (1991) estimated that OTC deficiency has a frequency of 1 in 80,000 births in Japan. The total frequency of this and the other urea cycle enzymopathies, carbamoyl phosphate synthetase deficiency, argininosuccinate synthetase deficiency, argininosuccinate lyase deficiency, and arginase deficiency, in Japan was 1 in 46,000.
Testai and Gorelick (2010) estimated the prevalence of OTC to range from 1 in 40,000 to 1 in 80,000.
Animal ModelThe trait 'sparse fur' (spf) in the mouse is due to OTC deficiency. X-linkage was confirmed indirectly by the demonstration of DeMars et al. (1976) that the same enzyme deficiency is X-linked in the mouse.
Extracts of liver from hemizygous affected mice with the X-linked spf(ash) (sparse fur, abnormal skin and hair) mutation have 5 to 10% of normal OTC activity, yet the homogeneous enzyme isolated from these extracts is identical to that in controls. Rosenberg et al. (1983) found that the mRNA from mutant livers programs the synthesis of 2 distinct OTC precursor polypeptides: one normal in size, the other elongated. Only the normal one is assembled into the active trimeric enzyme. The novel phenotype likely results from a mutation in the structural gene for OTC, leading to aberrant splicing of mRNA and formation of an altered precursor that cannot undergo proper posttranslational modification.
In the 'sparse fur' mouse, Veres et al. (1987) identified a mutation in the OTC gene (see also Ohtake et al., 1986).
Cavard et al. (1988) successfully corrected OTC deficiency in the mouse by injection of rat OTC cDNA linked to the SV40 early promoter into fertilized eggs.
Morsy et al. (1996) achieved significant improvement of OTC deficiency in a mouse model through adenovirus-mediated gene transfer of the human OTC cDNA. Substantial reduction in orotic aciduria was observed within 24 hours of treatment. Metabolic correction was later associated with phenotypic correction and moderate increase in enzymatic activity. In an effort to identify the level of gene expression required to achieve wildtype levels of enzyme activity, Morsy et al. (1996) uncovered a dominant-negative effect of the endogenous mutant protein on the activity of the delivered recombinant wildtype protein. The authors stated that this phenomenon is relevant to homomultimeric protein defects, such as OTC deficiency.