Recurrent Hypoglycemic Seizures Resolved by Whole Exome Sequencing as Malonyl-CoA Decarboxylase Deficiency

Background: Malonyl-CoA decarboxylase deficiency is an ultra-rare inborn error of metabolism (IEM), with approximately 30 patients described in the literature to date. This autosomal-recessive disorder may present with hypoglycemia, ketosis, metabolic acidosis, seizures, developmental delay, abdominal pain, hypotonia, and in some cases changes in the cerebral white matter and hypertrophic cardiomyopathy.

Case presentation: We describe the evaluation of a five years-old child with a history of hypoglycemic episodes after birth, hyperinsulinism in infancy, recurring abdominal pain and hypotonia. The child was admitted to the Pediatrics Department following a tonic-clonic seizure with hypoglycemia (serum glucose level of 20 mg/dl) which persisted after reaching normal glucose levels. A thorough neurological, endocrinologic, metabolic and ophthalmologic evaluation was performed during hospitalization. In parallel, genetic testing was pursued, including targeted gene panel sequencing for glycogen storage diseases and Whole Exome Sequencing (WES) for the child and his parents. While the gene panel results were negative, trio WES revealed the proband to harbor a homozygous variant in the MLYCD gene, establishing the diagnosis of Malonyl-CoA decarboxylase deficiency.

Conclusions: This case underscores the role of next generation sequencing technologies in the diagnostic evaluation of children presenting with unexplained hypoglycemic episodes, especially with regard to ultra-rare inherited IEMs, and when the initial biochemical metabolic evaluation fails to reach a timely diagnosis.