Objective: To identify the phenotypic, neuroimaging and genotype-phenotype expression of NKX6-2 mutations.

Background: Despite advances in genetic testing a large number of hyopomyelinating disorders remain a genetic mystery. We identified a new distinct phenotype of spastic-ataxia with hyopomyelination negative for previously known hyopomyelinating genes.

Methods: We used a combination of homozygozity mapping, exome sequencing, immunobloting, clinical and neuroimaging for novel gene discovery. Using gene expression and network analysis with Weighed Genes Co-expression we placed the new gene within a regulatory pathway.

Results: We mapped this phenotype to deleterious bi-allellic mutations in NKX6-2 in 14 cases of different ethnic backgrounds providing evidence for a high NKX6-2 mutation burden in hypomyelinating leukodystrophy disease spectrum. We show that the phenotypic and neuroimaging expression in NKX6-2 is mutation-specific and that phenotypes with epilepsy in the absence of overt hypomyelination, as well as diffuse hypomyelination without seizures can occur. Our data suggests that the phenotypic consequences of NKX6-2 mutations is classified in three main subgroups: severe global psychomotor delay with widespread hypomyelination, spastic-ataxia with hypomyelination and spastic-ataxia with seizures.In-silico analysis of human brain expression and network data shows that NKX6-2 is involved in oligodendrocyte maturation and may act within the same pathways of genes already associated with central hypomyelination.

Conclusions: Combining genetic, phenotypic and functional data this study contributes with the discovery of novel NKX6-2 pathogenic mutations and provides new insights into NKX6-2 related disease. Therefore, our case series suggests that NKX6-2 mutations should be considered in patients with autosomal recessive, very early onset of nystagmus, cerebellar ataxia with spasticity particularly when associated with typical neuroimaging signs of hypomyelination.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-new-distinct-spastic-ataxia-with-hypomyelination-clinical-neuroimaging-and-molecular-expression-of-nkx6-2-mutations/