Hypomyelinating leukodystrophy – NKX6–2 gene variant as a cause

Abstract Hypomyelinating leukodystrophies are heterogeneous genetic diseases with a wide phenotypic spectrum. Diagnosis and classification are often impaired by unspecific clinical and imaging features. A 16-year-old boy from Syria is described with spastic ataxia 8 (SPAX8, MIM: 617,560 ) caused by a novel homozygous nonsense variant (c.475C>T, p.Gln159*) in the NKX6–2 gene (NM_177,400.2). At the age of 2 weeks, nystagmus was the first symptom of the disease. Developmental milestones such as head control and sitting upright were not achieved. Feeding problems and failure to thrive occurred. Magnetic resonance imaging revealed hypomyelinating leukodystrophy. A trio-based whole exome sequencing analysis revealed a novel homozygous nonsense variant leading to an early stop (c.475C>T, p.Gln159*) at the homeobox domain of the NKX6–2 gene (NM_177,400.2). Other family members were most likely also affected but died without confirmed diagnosis at 15 and 17 years of age. The diagnostic work-up for hypomyelinating leukodystrophies consists of clinical suspicion, clinical examination, neuroimaging, biochemical and extensive genetic testing (e.g., panel or whole-exome sequencing).