Case 1
The patient, a male, was hospitalized at 25 months of age for vomiting, dehydration, respiratory symptoms and progressive lethargy. He was found to have metabolic acidosis with elevated lactate and ammonia (hyperammonemia at 120 µmol/L on presentation, normal 21-50). Toxicology testing was negative as well as blood and urine cultures. He was admitted to the intensive care unit (ICU) where his ammonia decreased to 43 µmol/L upon administration of intravenous fluids containing glucose and, eventually lipids, with clinical improvements of becoming more alert and engaged. During the initial hospitalization peak ammonia was 185 µmol/L. Newborn screening was reviewed and was normal at 1 and 8 days of age, with normal citrulline and glutamine/citrulline ratio. He had history of developmental delays (unable to walk, no words at 25 months of age) and had a previous hospitalization for altered mental status and dehydration with metabolic acidosis at 17 months of age at which time intussusception was suspected (ammonia was not measured at that time). A head computed tomography (CT) was normal. Otherwise, the child was growing normally and had a normal head size.
This child was the product of in vitro fertilization from sperm donor to a healthy mother. He had a 4-year-old half-sister (different sperm donor) with mild speech delay, improving with therapy.
Plasma amino acids showed elevated glutamine (peak 1448 µmol/L on admission, normal 410-700) with mildly low citrulline (9 µmol/L before supplements, normal 10-60) and arginine at low end of normal (44 µmol/L, normal 40-160). Orotic acid in the urine was mildly increased at 6.2-7.3 mmol/mol creatinine (normal 0.7-5.1) with normal orotidine (1.7-2.4 mmol/mol creatinine, normal 0.7-4.2). The child was discharged home on a low protein diet with medical food, citrulline supplements, and glycerol phenylbutyrate. Whole exome sequencing was denied by insurance. Standard genetic testing covering the exons of the OTC , CPS1 ,NAGS , and CA5A genes did not reveal pathogenic sequence variants.
Despite adherence to therapy, the child continued to have swings in ammonia and elevated glutamine in the plasma amino acids. The child was admitted again to the hospital at 26 months of age because of croup and poor intake leading to hyperammonemia (179 µmol/L). Labs and clinical status normalized with breathing treatment, dextrose containing intravenous fluids and intralipids. In view of the persistent instability, the child was tried on NCG (100 mg/kg per day) that resulted in normalization of ammonia and plasma amino acids. These remained normal even after sequentially stopping glycerol phenylbutyrate, citrulline supplements, amino acid modified medical food and the low protein diet. Clinically, his development started to improve with the initial therapies, including protein restricted diet. At 26 months, he had his first independent step and first word. He was walking independently at 31 months. By 39 months he had >100 words which he began to place in sentences.