Hypomyelinating leukodystrophy associated with a deleterious mutation in the ATRN gene.

Hypomyelinating leukodystrophies are a group of neurodevelopmental disorders that affect proper formation of the myelin sheath in the central nervous system. They are characterized by developmental delay, hypotonia, spasticity, and variable intellectual disability. We used whole exome analysis to study the molecular basis of hypomyelinating leukodystrophy in two sibs from a consanguineous family. A homozygous mutation, c.3068+5G>A, was identified in the ATRN gene, with the consequent insertion of an intronic sequence into the patients' cDNA and a predicted premature termination of the ATRN polypeptide. ATRN encodes Attractin, which was previously shown to play a critical role in central myelination. Several spontaneous ATRN rodent mutants exhibited impaired myelination which was attributed to oxidative stress and accelerated apoptosis. ATRN can now be added to the growing list of genes associated with hypomyelinating leukodystrophy. The disease seems to be confined to the CNS; however, given the young age of our patients, longer follow-up may be required.