A Genetic Cause of Hyperammonemic Encephalopathy in an Infant

Carbonic anhydrase-VA (CA-VA) deficiency is a rare autosomal recessive disorder resulting from a homozygous mutation in the CA5A gene. With only 26 reported cases, 71% are from the Indian subcontinent. CA-VA deficiency affects bicarbonate supply for mitochondrial enzymes, impairing urea cycle, TCA cycle, and gluconeogenesis. The condition manifests as hyperammonemia, hyperlactatemia, and ketonuria.

A previously healthy 3-month-old girl presented with a one-day history of vomiting, lethargy, and a generalized seizure. She had no fever or loose stools.

A thorough history revealed that the baby was born to non-consanguineous parents.

The child exhibited encephalopathy (Glasgow Coma Scale: E2V1M4), effortless tachypnea (respiratory rate: 72/min), and moderate hepatomegaly on examination. Central nervous system (CNS) examination revealed normal tone.

Initial investigations showed normal blood counts, sugar, electrolytes, negative C-reactive protein (CRP), hyperammonemia (460 µmol/L), metabolic acidosis (pH: 7.36, pCO2: 7.2 mmHg, HCO3−: 8 mmol/L), lactate: 8.3 mmol/L (normal range: 0.7–2.1), ketonuria (4+), elevated aspartate aminotransferase (AST) - 135 U/L, and alanine transaminase (ALT) - 85 U/L.

The patient underwent ventilation, received fluids, sodium benzoate, carnitine, and underwent peritoneal dialysis with bicarbonate-based fluid.

Within 36 hours, her sensorium improved, ammonia levels dropped to 17 µmol/L, and lactate normalized to 2.5 mmol/L. MRI brain, plasma amino acids, acyl carnitine, and urine organic acids results were normal.

The infant was discharged on sodium benzoate and carnitine. Genetic testing confirmed a pathogenic homozygous missense mutation in exon 6 of the CA5A gene, indicating carbonic anhydrase VA (CA-VA) deficiency. At 1.6 years old, she remains biochemically and developmentally normal.

Low pCO2 in blood gas, deviating from expected compensation, is indicative of CA-VA deficiency. Long-term treatment involves sodium benzoate, carnitine, prompt recognition, and treatment of metabolic crises, while avoiding specific medications. The prognosis is generally favorable, with one-third experiencing recurrent metabolic decompensation and the majority achieving good neurological outcomes, possibly due to overlapping CA-VB function.

Source: Ganesh R, Karthik Narayanan R.  Indian Journal of Pediatrics. 2024 Jan;91(1):88-.