Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination

Abstract

Progressive limb spasticity and cerebellar ataxia are frequently found together in clinical practice and form a heterogeneous group of degenerative disorders that are classified either as pure spastic ataxia or as complex spastic ataxia with additional neurological signs. Inheritance is either autosomal dominant or autosomal recessive. Hypomyelinating features on MRI are sometimes seen with spastic ataxia, but this is usually mild in adults and severe and life limiting in children. We report seven individuals with an early-onset spastic-ataxia phenotype. The individuals come from three families of different ethnic backgrounds. Affected members of two families had childhood onset disease with very slow progression. They are still alive in their 30s and 40s and show predominant ataxia and cerebellar atrophy features on imaging. Affected members of the third family had a similar but earlier-onset presentation associated with brain hypomyelination. Using a combination of homozygozity mapping and exome sequencing, we mapped this phenotype to deleterious nonsense or homeobox domain missense mutations in NKX6-2. NKX6-2 encodes a transcriptional repressor with early high general and late focused CNS expression. Deficiency of its mouse ortholog results in widespread hypomyelination in the brain and optic nerve, as well as in poor motor coordination in a pattern consistent with the observed human phenotype. In-silico analysis of human brain expression and network data provides evidence that NKX6-2 is involved in oligodendrocyte maturation and might act within the same pathways of genes already associated with central hypomyelination. Our results support a non-redundant developmental role of NKX6-2 in humans and imply that NKX6-2 mutations should be considered in the differential diagnosis of spastic ataxia and hypomyelination.

Expanding the clinical and genetic spectra of NKX6‐2‐related disorder

“…All variants identified by the present study were found in patients of Middle East origin. Two of them were observed more than once (Figure ), and these 2 variants have previously been reported from Saudi Arab patients . This fact, along with our haplotyping data for carriers of the c.196delC variant (Figure S1A), supports the hypothesis of founder variants to contribute to NKX6‐2 ‐related disease .…”

“…The clinical findings were rather uniform in our cohort of patients (Table ). Regarding age at onset and severity, our patients and most of those reported previously are highly similar . A notable exception are 2 families that carry the c.121A>T (p.(Lys41*)) variant.…”

“…Many genetic HLDs still remain undiagnosed, but the advances in NGS have strongly reduced the number of unsolved/unsolvable cases . NKX6‐2 is one of the most recent additions to the growing list of potential HLD genes . Our study involves 6 novel families and the largest cohort of patients reported to date; it thereby represents final proof for a causal connection between biallelic NKX6‐2 variants and HLD.…”

“…Biallelic variants in NKX6‐2 (OMIM *605955; OMIM #617560) are one of the most recently identified causes of HLD. Three studies almost simultaneously reported a total of 15 pertinent patients from 7 families in 2017 . Although overall clinical and imaging data were consistent with HLD, 1 of the 2 larger studies characterized the disease as very severe, while the other emphasized a comparatively mild phenotype in 2 of 3 families presented .…”

“…Three studies almost simultaneously reported a total of 15 pertinent patients from 7 families in 2017 . Although overall clinical and imaging data were consistent with HLD, 1 of the 2 larger studies characterized the disease as very severe, while the other emphasized a comparatively mild phenotype in 2 of 3 families presented . As both studies were submitted, reviewed and published in parallel in different journals, a discussion of these apparent discrepancies is currently lacking.…”