The pattern of inheritance of each of these disorders is autosomal recessive except for OTC deficiency, which is X-linked dominant. Their clinical manifestations are a common expression of an accumulation of ammonia or of urea cycle intermediates in the brain; they differ only in severity, in accordance with the degree of completeness of the enzymatic deficiency and with the age of the affected individual. The one exception is arginase deficiency, which commonly appears during later childhood as a progressive spastic paraplegia with mental retardation. Clinically, it has been convenient to divide the hyperammonemias into two groups—one that presents in the neonatal period and another that becomes evident in the weeks or months thereafter. This division is somewhat artificial, the clinical presentation being more in the nature of a continuous spectrum governed by the biologic factors mentioned above and even extending to rare cases that have their first symptoms during adulthood.
In the most severe forms of the hyperammonemic disorders, the infants are asymptomatic at birth and during the first day or two of life, after which they refuse their feedings, vomit, and rapidly become inactive and lethargic, soon lapsing into an irreversible coma. Profuse sweating, focal or generalized seizures, rigidity with opisthotonos, hypothermia, and hyperventilation have been observed in the course of the illness. These symptoms constitute a medical emergency, but even with measures to reduce serum ammonia, the disease is usually fatal.
In less severely affected infants, hyperammonemia develops some months later, when protein feeding is increased. There is a failure to thrive, and attempts to enforce feeding or during periods of constipation (both of which increase ammonia production in the bowel) may result in bouts of vomiting, lethargy, hyperirritability, and screaming. Respiratory alkalosis is a consistent feature. Other manifestations are periods of alternating hypertonia and hypotonia, seizures, ataxia, blurred vision, and of confusion, stupor, and coma. During episodes of stupor, often precipitated by dehydration, an alimentary protein load, or minor surgery, brain edema may be seen by CT and MRI; with repeated relapses, the brain edema gives way to atrophy, which appears as symmetrical areas of decreased attenuation in the cerebral white matter. Between attacks, some patients with partial deficiency may be normal or show only a slight hyperbilirubinemia (DiMagno et al; Rowe et al). With decompensation, the bilirubin rises, as does ammonia, but neither reaches exceedingly high levels. After repeated attacks, signs of developmental delay with motor and mental retardation become evident, and the patient is vulnerable to recurrent infections. Two adult male patients in our care, who were married (but with azoospermia, which is common) and working at technically demanding jobs, came to medical attention because of bouts of visual blurring followed by stupor that evolved over hours (Shih et al, 1999). They had displayed an aversion to protein and milk products as children; in later life, after meals high in protein, they became encephalopathic, one with severe brain swelling. There are few phenotypic differences among the late-onset hyperammonemias except for argininosuccinic aciduria, in which excessive dryness and brittleness of the hair (trichorrhexis nodosa) are notable features, and the aforementioned arginase deficiency with spastic diplegia.
Diagnosis is established by the finding of hyperammonemia, often as high as 1,500 mg/dL. The precise diagnosis requires genetic testing. The primary hyperammonemias must be distinguished from the organic acidurias, including methylmalonic aciduria (see above), in which hyperammonemia can occur as a secondary metabolic abnormality.