Between 1969 and 1978, urine amino acid screening using one dimensional paper chromatography [2
] was performed on a total of 633,331 Massachusetts infants between 4 and 6 weeks of age. Twelve infants, including one set of twins, were found to have increased argininosuccinic acid. These infants were referred to the Massachusetts General Hospital Metabolic Disorders Unit for confirmation of diagnosis and treatment. One additional infant was diagnosed shortly after birth due to an older sibling previously identified by screening.
Each patient was the healthy product of a term pregnancy, with normal anthropometric measurements. Patients were 4–6 weeks old at diagnosis and all were asymptomatic. Seven of 13 patients initially had slightly increased blood ammonia. Initial plasma ASA was 6–101 umol/l and urine ASA was 2667–81900 umol/g creatinine (). CSF ASA was increased in the three patients in whom it was measured and was more than twice as high as the corresponding level in plasma. All patients had plasma arginine levels within the normal range. Case 1 was the most severely affected patient with initial ASA levels higher than those of the others.
Following diagnosis the majority of patients were treated with a low protein diet of approximately 1.5 g protein/kg/day, consisting of a limited amount of infant formula with added lipid and carbohydrate, plus cereal, fruit, and vegetables. The patients were monitored at 1 to 3 month intervals during the first 2 years of life and less frequently thereafter. Blood ammonia, amino acids, liver function tests, BUN, urine ASA and orotic acid were measured at every follow up visit and dietary intake was adjusted.
Nine of the 13 patients were given arginine, 25–50 mg/kg /day po. Two solely breast-fed infants never received arginine. Arginine was given to one patient when weight gain began to level off at 18 months of age. In another patient, arginine supplement was discontinued at age 9 years; after one month the plasma level had dropped 19% but still remained in the normal range. One patient received a trial of sodium benzoate (1.8 g/day po) at age 11 years, which was discontinued due to increased urination.
Some families found compliance to the special low-protein diet difficult, particularly since the children appeared to have normal growth and development, and discontinued the diet when the patients were 2–5 years old. Otherwise, the low protein diet was continued throughout the follow-up period. For older children and teenagers the prescribed protein intake was in the range of 1.0 g/kg/day. Some older patients now take an essential amino acid supplement.
Serial EEGs were done routinely. IQ measurements were performed at different ages in five patients using one of the following scales: the Stanford-Binet intelligence scale, the Cattell Infant intelligence scale, WISC-III, and the Merrill-Palmer scale of mental tests. Patients who did well in school without learning difficulties were considered to have normal development. Seven patients are college students or college graduates.
None of the patients in our study group had hepatomegaly on physical exam or liver dysfunction monitored by liver function tests (ALT, AST, alkaline phosphatase, bilirubin). All had normal tyrosine and methinone levels by plasma amino acid analysis. Nor did we note brittle hair, sometimes described in AL deficiency [3
]. All patients had normal growth parameters. All our patients displayed elevations of ASA in both plasma and urine. Blood ammonia levels remained in the normal range.
None of our cases manifested hyperammonemic coma during the follow-up period; none required hospitalization for acute encephalopathy. Case 7 had two supervised uneventful pregnancies and Case 10 had two normal pregnancies. All four offspring had normal development at 5–8 years of age.
summarizes the outcome of our study group of 13 individuals. Four had a learning disability with verbal IQ range 71–95 and performance IQ range 78–132. One patient was lost to followup for over ten years. This patient went off the low protein diet at around 5–6 years of age, was in special education classes in school, and had low normal development. Six patients showed EEG abnormalities, including abnormal sharp irregular background activity, frequent bilateral paroxysms, and increased slow wave activity. In one patient, abnormal EEG was documented on 4 occasions during a six-year period when the diet was uncontrolled; over the next six years the protein intake was more strictly controlled and EEG was normal on 3 occasions. Three cases showed seizures of various types: staring spells; episodes of night distubance, vomiting, and stiffened back; and generalized tonic clonic seizure. In one case heavy alcohol consumption and noncompliance to the protein-restricted diet may have precipitated hyperammonemia and subsequent seizures. One additional patient had two febrile seizures with subsequent normal EEG. Patients with clinical seizures were treated with either carbamazepin or levetiracetam.
For comparison, we looked at two other groups of AL deficient patients: those with neonatal-onset and those with late-onset disease. Patients with neonatal onset presented with severe hyperammonemia, lethargy and vomiting in the first 10 days of life. Long-term clinical outcome was not examined in the neonatal onset group. Patients with late-onset were detected when they became symptomatic and were diagnosed between 1.5 and 15 years of age. When not acutely ill, plasma ASA in late onset patients was in the range of 107–152 umol/L and 30384–60840 umol/g creatinine in urine; blood ammonia determinations were 75–133 (N: 12–54). All late-onset patients developed mental retardation (IQ: 40-60), generalized seizures, and intermittent ataxia.