3‐Methylglutaconic aciduria type VIII in an Indian neonate

Abstract Neonatal encephalopathy manifests with altered sensorium, tone abnormalities, and often with abnormal movements and seizures. The causes are heterogeneous and many. We report a late preterm neonate who presented with depressed sensorium, cranial nerve abnormalities, mixed hypertonia and hypotonia, and respiratory failure. Neuroimaging and electrophysiological studies were normal. She had neutropenia and elevated lactates in blood. Her dried blood spot analysis by tandem MS/MS showed normal acylcarnitine and amino acid profile. Plasma and cerebro spinal fluid (CSF) amino acid quantification were inconclusive, CSF folate was normal. Urine organic acid analysis showed elevated lactate. Semi‐quantitative analysis of urine showed borderline elevation of 3‐methylglutaconic acid. Diagnosis of 3‐methylglutaconic aciduria (3MGA) type VIII was suggested by whole‐exome sequencing, which revealed a homozygous, likely pathogenic, missense mutation in Exon 2 of HTRA2 gene (chr2.74757898A>C). Her parents were found to be carriers of the same mutation. This underscores the importance of genetic studies in the evaluation of neonatal neuro‐metabolic disorders. We report the first case of 3MGA type VIII from our region with a review of already reported 11 cases.