Infantile Neuroaxonal Dystrophy: Diagnosis and Possible Treatments

Abstract

Infantile Neuroaxonal Dystrophy (INAD) is a rare neurodegenerative disease that often cuts short the life span of a child to 10 years. With a typical onset at 6 months of age, INAD is characterized by regression of acquired motor skills, delayed motor coordination and eventual loss of voluntary muscle control. Biallelic mutations in the PLA2G6 gene have been identified as the most frequent cause of INAD. We highlight the salient features of INAD molecular pathology and the progress made in molecular diagnostics. We reiterate that enhanced molecular diagnostic methodologies such as targeted gene panel testing, exome sequencing, and whole genome sequencing can help ascertain a molecular diagnosis. We describe how the defective catalytic activity of the PLA2G6 gene could be potentially overcome by enzyme replacement or gene correction, giving examples and challenges specific to INAD. This is expected to encourage steps toward developing and testing emerging therapies that might alleviate INAD progression and help realize objectives of patient formed organizations such as the INADcure Foundation.

Keywords: CRISPR/Cas9; enzyme replacement therapy; exome sequencing; infantile neuroaxonal dystrophy; rare disease; vector gene therapy.

FIGURE 1

Infantile neuroaxonal dystrophy (INAD) is a neurodegenerative disorder related to mutations in the PLA2G6 gene. Various mutations of PLA2G6 lead to dysfunctional A2 phospholipase that leads to mitochondrial and axonal membrane defects. These defects cause neuronal damage visualized as axonal swellings and accumulation of pre-synaptic spheroids. Enzyme replacement to restore functions, gene replacement or editing to correct the defective PLA2G6 are proposed therapeutic strategies.