Novel compound heterozygote variants: c.4193_4206delinsG (p.Leu1398Argfs*25), c.793C > A (p.Pro265Thr), in the CPS1 gene (NM_001875.4) causing late onset carbamoyl phosphate synthetase 1 deficiency-Lessons learned

Abstract

Carbamoyl phosphate synthetase 1 (CPS1) deficiency is an autosomal recessive urea cycle disorder with varying presentations. Patients with a neonatal-onset phenotype are initially healthy but develop severe hyperammonemia days after birth and often have poor or lethal outcomes, while patients who present later in life may exhibit less severe clinical manifestations. CPS1 deficiency is rarely found on newborn screening because most states do not screen for this disease due to the technical difficulties. We report a case of an 11-year-old, previously healthy girl who presented with hyperammonemia and acute psychosis after eating large amounts of meat at summer camp. A diagnosis of carbamoyl phosphate synthetase type 1 deficiency was suspected by biochemical profiles and confirmed by molecular analysis. Subsequent follow up lab results revealed ammonia to be only 25-39 μmol/L shortly after glutamine reached levels as high as 770-1432 μmol/L with concurrent alanine elevations, highlighting the compensating mechanisms of the human body. Her initial hospital course also demonstrated the importance of continuous renal replacement therapy (CRRT) in avoiding rebound hyperammonemia and high glutamine and the benefits of intracranial pressure (ICP) monitoring, providing 3% hypertonic saline and temperature control to avoid fever in treating cerebral edema. Carglumic acid was not considered helpful in this case, with BUN levels ranging between 2 and 4 mg/dL after administration.

Keywords: Alphaketoglutarate; Carbamoyl phosphate synthetase 1 deficiency; Glutamine; Hyperammonemia; Nacetylglutamate synthetase deficiency; Urea cycle disorder.

Fig. 2

Image of brain CT on the second day of hospitalization.

Fig. 3

Image of brain CT on the third day of hospitalization. The image shows increasing cerebral and cerebellar edema with interval development of downward displacement of the cerebellar tonsils.

Fig. 4

Compensating mechanism of hyperammonemia in urea cycle disorder.

Fig. 1

Timeline of medical interventions.