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.