Session Time: 1:45pm-3:15pm
Location: Hall 3FG
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.
To cite this abstract in AMA style:V. Chelban, N. Kaya, M. Alsagob, S. Efthymiou, J. Vandrovcova, D. Lynch, K. Kloth, A. Chirita-Emandi, F. Alkuraya, N. Wood, H. Houlden. A new distinct spastic ataxia with hypomyelination: Clinical, neuroimaging and molecular expression of NKX6-2 mutations [abstract]. Mov Disord. 2018; 33 (suppl 2). https://www.mdsabstracts.org/abstract/a-new-distinct-spastic-ataxia-with-hypomyelination-clinical-neuroimaging-and-molecular-expression-of-nkx6-2-mutations/. Accessed December 5, 2023.
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