A number sign (#) is used with this entry because of evidence that autosomal recessive spastic ataxia-8 with hypomyelinating leukodystrophy (SPAX8) is caused by homozygous or compound heterozygous mutation in the NKX6-2 gene (605955) on chromosome 8q21.

Spastic ataxia-8 with hypomyelinating leukodystrophy (SPAX8) is an autosomal recessive progressive neurodegenerative disorder characterized by onset of primarily motor dysfunction within the first year of life. Affected individuals initially have hypotonia and later develop ataxia, spasticity, and a pyramidal syndrome with weakness and loss of ambulation. Other features may include dystonia, dysarthria, and abnormal eye movements. Brain imaging shows cerebellar atrophy and hypomyelinating leukodystrophy. One family with cognitive impairment has also been reported (summary by Chelban et al., 2017).

For a discussion of genetic heterogeneity of spastic ataxia, see SPAX1 (108600).

Chelban et al. (2017) reported 7 patients from 3 unrelated consanguineous families with SPAX8. The patients presented within the first year of life with a progressive neurodegenerative disorder with primarily motor features, including spasticity, ataxia, and abnormal eye movements such as nystagmus, hypometric saccades, and impaired up-gaze. Initial features included hypotonia, which developed into a pyramidal syndrome with weakness and hyperreflexia mainly involving the lower limbs, as well as truncal and limb ataxia, dysarthria, and head titubation. Several patients had cervical and/or limb dystonia. Four patients in the first 2 families were adults ranging in age from 23 to 44 years. One never achieved walking and was wheelchair-bound early in life, and another became wheelchair-bound later in life. Another member of the first family was wheelchair-bound at age 8. Five patients from the first 2 families had normal cognitive development and function, whereas 2 sibs in a consanguineous Saudi Arabian family also had severe global psychomotor delay with cognitive impairment. Brain imaging showed cerebellar atrophy and hypomyelinating leukodystrophy in all patients tested. None had sensory deficits, and nerve conduction velocities performed in 1 family were normal.

Dorboz et al. (2017) reported 5 patients, including 2 sib pairs, from 3 unrelated families with SPAX8. Four patients were alive at ages 2 to 8 years; the fifth patient died at age 16.5 months due to respiratory failure. Four of the patients presented with nystagmus between 1 and 3 months of age, and 1 patient presented with gross motor delay at 6 months of age. Development was normal in the newborn period in 2 patients, until 3 months of age in 2 patients, and until 6 months of age in 1 patient. All of the patients developed spasticity between 6 and 9 months of age, 4 developed hypotonia between 3 and 6 months of age, and 3 developed severe dystonia between 8 and 12 months of age. Four patients had optic nerve pallor, and 3 patients required a gastrostomy for poor feeding. At last examination, the 4 living patients had severely impaired motor and cognitive development. Only 1 patient acquired speech and could say single words. Brain MRIs demonstrated structurally normal, hypomyelinated brains in all of the patients. Brain MRIs showed abnormal signal in the thalamus in 4 patients, atrophy of the cerebellar vermis in 2 patients, and diffuse atrophy of the cerebellum in 1 patient.

The transmission pattern of SPAX8 in the families reported by Chelban et al. (2017) was consistent with autosomal recessive inheritance.

In 7 patients from 3 unrelated families with SPAX8, Chelban et al. (2017) identified homozygous mutations in the NKX6-2 gene (K41X, 605955.0001 and L163V, 605955.0002). The mutations, which were found by exome sequencing, segregated with the disorder in the families. Cells from a patient with the nonsense mutation showed absence of the truncated protein, consistent with a complete loss of function; functional studies and studies of patient cells with the missense mutation were not performed. Using in silico analysis, gene-regulatory networks, and coexpression data in humans, Chelban et al. (2017) concluded that NKX6-2 is involved in the genesis and development of oligodendrocytes.

Dorboz et al. (2017) identified biallelic mutations in the NKX6-2 gene in 5 patients, including 2 sib pairs, from 3 unrelated families with SPAX8. The patients from families 1 and 2 had homozygous mutations (605955.0003 and 605955.0004) and the sibs from family 3 had compound heterozygous mutations (605955.0005 and 605955.0006). The mutations were identified by whole-exome sequencing. Functional studies in patient cells were not performed.

Southwood et al. (2004) found that Nkx6-2-null mice had deficits in motor coordination and nerve conduction in the central nervous system. These abnormalities were associated with myelination defects at paranodal junctions, particularly in the optic nerve, and aberrant expression of downstream genes involved in cytoskeletal and cell adhesion functions. The findings suggested a role for Nkx6-2 in the regulation of axon-glial interactions at myelin paranodes.