General description

Hypomyelination of early myelinating structures (HEMS) is an X-linked recessive genetic disorder caused by pathogenic variants in exon 3B or intron 3 of the PLP1 gene, the same gene associated with Pelizaeus-Merzbacher disease (PMD). Unlike Pelizaeus-Merzbacher disease HEMS affects specific brain structures that are normally myelinated, leading to persistent abnormalities in myelination during early childhood.

In the first few months of life, affected infants typically develop normally without noticeable delays. However, as they grow, they begin to exhibit ataxia, spasticity, and nystagmus, which usually appears between six and twenty months of age. Motor development is delayed but continues gradually, and many patients eventually achieve independent walking, although some develop spastic paraplegia. Spasticity is more pronounced in the lower limbs, often accompanied by hyperactive deep tendon reflexes. Despite these motor impairments, cognitive development is relatively preserved. Additionally, some individuals experience autonomic symptoms such as urinary dysfunction.

A definitive diagnosis requires genetic analysis of the PLP1 gene. However, since the mutations causing this condition are often located in the intronic regions of the PLP1 gene, whole-exome sequencing may fail to detect these abnormalities. Therefore, this limitation should be taken into account during diagnosis.