Novel Clinical and Neurophysiological Insights in Neonatal-Onset 3-Methylglutaconic Aciduria Type VIII due to HTRA2...

Type VIII 3-methylglutaconic aciduria (MGCA8) is a neurodegenerative disorder which involves biallelic pathogenic variants of HTRA2. This gene encodes a mitochondrial serine protease responsible for apoptosis regulation and mitochondrial proteins' quality. Clinical manifestations include dysfunctional muscle tone, movement disorder, severe encephalopathy, epileptic seizures, dysautonomia, feeding difficulty, intermittent neutropenia, bradycardia, and recurrent apneas, often progressing into respiratory failure.

We describe a newborn presenting with abnormal muscle tone, progressive dystonic movements, recurrent apneas, feeding difficulties, and epileptic seizures. Biochemical analysis revealed a markedly elevated urinary 3-methylglutaconic acid, and genetic test identified biallelic pathogenic variant in HTRA2. Brain MRI revealed progressive brain atrophy, thalamic hypoplasia, and ventriculomegaly. EEG recordings found organizational abnormalities that turned into epileptic spasms. Despite intensive care, the patient suffered rapid neurological decline and died following a prolonged apnea episode. Thereafter the family had another infant diagnosed with the same biallelic pathogenic variant in HTRA2, that died a few days after birth due to respiratory failure.

MGCA8 is a lethal condition characterized by loss-of-function biallelic mutations in HTRA2, which lead to mitochondrial dysfunction and altered apoptosis regulation, especially in the brain. High levels of 3-methylglutaconic acid in urine are one important early diagnostic marker, when associated with a consistent clinical phenotype. Our report contributes to the limited existing case series and provides a detailed characterization of the EEG findings associated with this rare condition.