LATE-ONSET UREA CYCLE DISORDERS
Pathogenesis and Pathophysiology. Late-onset disease has been described in patients with CPS, OTC, ASA synthetase, AS lyase, and arginase deficiencies. They will appear from the first year of life to adulthood with abrupt episodes of acute hyperammonemia. Initial crisis will occur usually when the infant is weaned from breast milk or from low-protein formulas to cow's milk formulas. Decompensation can also occur when the patient ingests a high protein load or experiences increased catabolism (e.g., infection). These episodes readily abate with cessation of protein intake.
Epidemiology and Risk Factors. Patients with a late- onset UCD are rare. The heterozygote female for OTC deficiency is at risk of developing symptoms; and when a male infant with OTC deficiency is born, the mother has to be instructed for possible late-onset disease. Terheggen and associates, in 1969, y described argininemia in two sisters with spastic paraplegia (arginase deficiency). Arginase deficiency is rare. The mechanism for the toxicity of excess arginine is not known. Whether this is due to impaired neurotransmitter metabolism or to excess nitric oxide production from elevated arginine is not clear. Two forms of arginase are known: A-I and A-II. The A-I isozyme contributes 98 percent of the liver activity and is deficient in patients with argininemia. It is inherited as autosomal recessive.
Clinical Features and Associated Disorders. The symptoms are remarkably similar among various types of late-onset UCD. Sudden hyperammonemia leads to such neurological signs as seizures and apnea. It may be preceded by vomiting and lethargy progressing to disorientation, ataxia, amblyopia, and eventually coma. The late-onset CPS deficiency is rare. On the other hand, OTC deficiency may be mild in a male and may first manifest as early as 6 weeks or as late as 6 years. Since infections trigger hyperammonemia, late-onset OTC deficiency may be confused with Reye's syndrome. In symptomatic heterozygotes or mild OTC deficiency, growth and mental retardation are seen in half of patients. The use of valproate in OTC carriers may also cause liver toxicity. Late-onset OTC deficiency causes high mortality.
ASA synthetase deficiency was first reported in a 9- month-old girl with mental retardation. In Japan, a variant form of this disease is found to occur as late as 48 years of age. The symptoms in such cases are nonspecific and include bizarre behavior, psychotic episodes, delusions, hallucinations, insomnia, and endocrine disturbances, such as delayed menarche. ASA lyase deficiency may also occur late in infancy or adults. These cases present as mental retardation or ataxia, or the patient might be totally asymptomatic. This heterogeneity might be explained by the studies of McInnes and colleagues, which indicated at least 12 allelic mutations leading to extensive genetic heterogeneity. y Immunoblot analysis shows a wide variation in size and amount of enzyme protein in patients. The presentation of arginase deficiency is heterogeneous. Early development is usually unremarkable, but developmental delay and psychomotor retardation will definitely appear by 3 years. Progressive spastic diplegia is by far the most common motor deficit, seen by 5 years. y Seizures are present in half of the patients and are often generalized tonic-clonic. These symptoms improve or regress on dietary restriction of arginine.
Differential Diagnosis. The clinical presentations of all
of late-onset UCDs are alike, because only the laboratory findings will identify exact diseases. Oroticaciduria is a common feature except for partial CPS I deficiency. By definition, the mother of a patient with OTC deficiency is a carrier; the presence of the mutant gene in other females related to the mother must be ruled out by allopurinol testing, provided that other diseases that give a positive result are absent. y Although it is the most common presenting symptom of arginase deficiency, spastic diplegia has many other causes (e.g., periventricular hemorrhage in a premature infant or hypoxic brain injury). In these conditions, spasticity is either static or progresses slowly. When spastic diplegia is progressive, familial spastic paraplegia, worsening of an existing hydrocephalus, spinal cord cysts, or tumors should be ruled out.
Hyperammonemia is encountered in other disorders. Reye's syndrome can be differentiated by the elevated transaminase and high plasma lysine levels. Patients with liver failure usually have elevated plasma methionine and tyrosine levels, which are not observed in UCDs of various types. Patients with valproate toxicity have elevated valproylcarnitine levels and deficiency of free carnitine in studies with tandem mass spectrometry.
Any infant or child who develops sudden lethargy or coma after a high-protein meal, infection, and prodrome of vomiting should be immediately evaluated for changes in blood gases, ammonia, lactic acid, and ketones. Arginase deficiency should be ruled out in all children with spastic diplegia. The definite diagnosis of a UCD, or an organic acidemia, will be reached by using high-pressure liquid chromatography, gas chromatography/mass spectrometry, and tandem mass spectrometry techniques in blood and urine samples. Any infant or child with psychomotor retardation or seizures with no clear cause, or with progressive encephalopathy, should be studied by measurement of plasma amino acids and in some cases by the study of urinary organic acids.
Evaluation. The laboratory findings are the same as those described for neonatal onset UCD, except the hyperammonemia and elevation of specific amino acid and orotic acid levels are only prominent during the acute metabolic crisis. Both ASA synthetase and ASA lyase deficiencies are readily diagnosed by the plasma amino acid profile during the acute episode. Plasma arginine is elevated 2 to 10 times normal in arginase deficiency, and arginase in red blood cells is deficient. Hyperammonemia is not a constant feature of arginase deficiency but is found during a catabolic event (e.g., an infection or consumption of high protein diet). A urine sample may show oroticaciduria and increased excretion of arginine.
Management. The treatment is approximately the same as that for UCD in the neonatal period: protein restriction, sodium phenylbutyrate, and L-arginine in doses previously described. Such patients should receive low protein diets. No specific treatment exists for arginase deficiency. Reduction of protein intake might lead to improvement of the continued disease progression and at times dramatic resolution of the symptoms. Cognitive dysfunction appears to be amenable to diet therapy, and improvement of spasticity has been observed in 30 percent of patients with arginase deficiency. Late-onset UCDs show the same complications as described for the acute neonatal form.
Prognosis and Prevention. Prognosis depends on rapid identification and adequate management. A survey of 12 patients with late-onset ASA lyase deficiency indicated no eventual impairment in intellectual and psychomotor development. Arginase deficiency may be managed with success and arrest of the disease. All subsequent newborns of a family with UCD should be investigated for the disease. The maternally related female members of the extended family with OTC deficiency must be investigated for the presence of the mutated gene either by molecular genetic studies or by allopurinol loading.
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