Progressive Spastic Ataxia Research Articles

Immune‐mediated spastic ataxia masquerading as clinically probable multisystem atrophy in an elderly woman

AbstractBackgroundAutoimmune neurological syndromes pose diagnostic challenges due to their resemblance to neurodegenerative conditions. Autoimmune spastic ataxia is a rare phenomenon. This case presents a 56‐y‐old woman with subacute‐onset spastic ataxia, highlighting the complexities in diagnosis and the role of autoimmunity in such cases.Case PresentationA woman in her fifties developed progressive spastic ataxia over a year and presented to our outpatient department for evaluation. The patient exhibited clinical signs including saccadic intrusions, gaze‐evoked nystagmus, mixed dysarthria, spasticity, exaggerated reflexes, and cerebellar dysfunction. Brain magnetic resonance imaging (MRI) displayed the “hot cross bun sign” and cerebral and cerebellar atrophy. Initial tests yielded minimal abnormalities, but a positive antinuclear antibody (ANA) emerged. The patient initially declined immunotherapy. Upon symptom progression, a repeat cerebrospinal fluid (CSF) analysis showed inflammatory changes and a whole‐body positron emission tomography (PET) scan indicated reduced uptake in the cerebellum and brainstem. Subsequent paraneoplastic antibody testing revealed an unspecified neuronal antibody targeting capillaries and arterioles. Treatment with steroids, plasmapheresis, and azathioprine led to sustained improvement, reducing spasticity, and enabling her to walk short distances.ConclusionsThis case emphasizes the diagnostic complexity of autoimmune neurological syndromes, particularly spastic ataxia. Autoimmune etiology should be considered even when neurodegenerative conditions seem likely. The presence of neuronal antibodies, inflammatory CSF, and response to immunotherapy underscores the role of autoimmunity in this case. Additionally, the “hot cross bun sign” may not always signify neurodegeneration, but can indicate immune‐mediated neural damage. Recognizing autoimmune involvement early offers therapeutic possibilities and highlights the need for a comprehensive diagnostic approach in such cases.

Novel loss of function mutation in TUBA1A gene compromises tubulin stability and proteostasis causing spastic paraplegia and ataxia.

Microtubules are dynamic cytoskeletal structures involved in several cellular functions, such as intracellular trafficking, cell division and motility. More than other cell types, neurons rely on the proper functioning of microtubules to conduct their activities and achieve complex morphologies. Pathogenic variants in genes encoding for α and β-tubulins, the structural subunits of microtubules, give rise to a wide class of neurological disorders collectively known as "tubulinopathies" and mainly involving a wide and overlapping range of brain malformations resulting from defective neuronal proliferation, migration, differentiation and axon guidance. Although tubulin mutations have been classically linked to neurodevelopmental defects, growing evidence demonstrates that perturbations of tubulin functions and activities may also drive neurodegeneration. In this study, we causally link the previously unreported missense mutation p.I384N in TUBA1A, one of the neuron-specific α-tubulin isotype I, to a neurodegenerative disorder characterized by progressive spastic paraplegia and ataxia. We demonstrate that, in contrast to the p.R402H substitution, which is one of the most recurrent TUBA1A pathogenic variants associated to lissencephaly, the present mutation impairs TUBA1A stability, reducing the abundance of TUBA1A available in the cell and preventing its incorporation into microtubules. We also show that the isoleucine at position 384 is an amino acid residue, which is critical for α-tubulin stability, since the introduction of the p.I384N substitution in three different tubulin paralogs reduces their protein level and assembly into microtubules, increasing their propensity to aggregation. Moreover, we demonstrate that the inhibition of the proteasome degradative systems increases the protein levels of TUBA1A mutant, promoting the formation of tubulin aggregates that, as their size increases, coalesce into inclusions that precipitate within the insoluble cellular fraction. Overall, our data describe a novel pathogenic effect of p.I384N mutation that differs from the previously described substitutions in TUBA1A, and expand both phenotypic and mutational spectrum related to this gene.

Stiff-Person syndrome: A rare neurological disorder

The Stiff-person syndrome (SPS) is an uncommon disorder characterized by progressive rigidity, muscle stiffness, and spasm involving the axial muscles, resulting in severe impairment of ambulation. We present the case of a 49-year-old gentleman with recent onset of progressive asymmetric spastic ataxia, subsequently diagnosed with SPS.

Spastic Paraplegia and Ataxia in a Welder.

A 51-year-old welder (nonsmoker) developed subacute lower paresthesias and progressive spastic paraplegia and ataxia. Symptoms appeared 10 days after the first zinc exposure in the yacht construction site (8-hour day/40 days in a confined space with face shield only). Examination revealed loss of vibratory sensation, spasticity, hyperreflexia, and sensory ataxia. Serum heavy metals (Cu 1 mg/L and Pb 4,22 μg/L), B-complex vitamins, and paraneoplastics on serum and CSF were unremarkable. The elevated zinc level (137 μg/dL) was found. Spinal MRI showed combined degeneration (Figure). Myelopathy in zinc smelter workers was reported in the 19th century1 and recently rediscovered in excessive zinc ingestion. Copper secondary deficiency is hypothesized even if the normal copper serum level is reported.2 Two months later, copper became low (0.8 mg/L), a time-dependent process might explain late copper deficiency in our case. Symptoms ameliorated 4 months later with normalization of serum zinc/copper levels.

A novel compound heterozygous SPG7 variant is associated with progressive spastic ataxia and persecutory delusions found in Chinese patients: two case reports

BackgroundHereditary spastic paraplegia 7 (SPG7) is one of the subtypes of autosomal-recessive hereditary spastic paraplegia, which is a clinically heterogeneous neurodegenerative disorder. SPG7 often displays a complicated phenotype, including optic atrophy, ophthalmoparesis, and impaired emotional communication. In the Chinese population, sporadic cases of SPG7 variant-associated spastic ataxia are rarely reported.Case presentationWe carefully analysed the clinical features, imaging and genetic tests of two sporadic patients with SPG7, both from the Hebei region of China. One patient presented with progressive bilateral lower limb weakness, spastic-ataxia and no cognitive impairment. Brain MRI revealed mild cerebellar atrophy. Genetic analysis revealed c.1150_1151insCTAC (p.G384Afs*13) frameshift variant and exon1-3 heterozygous deletion. The other patient presented with progressive bilateral lower limb weakness, ataxia, dysarthria and a mild psychosis associated with persecutory delusions, which drew almost no attention, in addition to mild cognitive impairments characterized by a decrease in verbal memory and executive function. Genetic analysis identified two heterozygous variants in the SPG7 gene: c.1150_1151insCTAC (p.G384Afs*13) and c.1496delC (p.Q500Sfs*13).ConclusionsThe c.1496delC (p.Q500Sfs*13) variant in exon 11 has not been reported before. The c.1150_1151insCTAC variant is speculated to be a hotspot variant in the Chinese population. Patients with SPG7 may have cognitive impairments and psychosis, displaying specific characteristics, which should be of concern.

Whole-exome sequencing confirms implication of VPS13D as a potential cause of progressive spastic ataxia

BackgroundVPS13D is a large ubiquitin-binding protein playing an essential role in mitophagy by regulating mitochondrial fission. Recently, VPS13D biallelic pathogenic variants have been reported in patients displaying variable neurological phenotypes, with an autosomic recessive inheritance.The objectives of the study were to determine the genetic etiology of a patient with early onset sporadic progressive spastic ataxia, and to investigate the pathogenicity of VPS13D variants through functional studies on patient’s skin fibroblasts.Case presentationWe report the case of a 51-year-old patient with spastic ataxia, with an acute onset of the disease at age 7. Walking difficulties slowly worsened over time, with the use of a wheelchair since age 26. We have used trio-based whole-exome sequencing (WES) to identify genes associated with spastic ataxia. The impact of the identified variants on mitochondrial function was assessed in patient’s fibroblasts by imaging mitochondrial network and measuring level of individual OXPHOS complex subunits. Compound heterozygous variants were identified in VPS13D: c.946C > T, p.Arg316* and c.12416C > T, p.(Ala4139Val). Primary fibroblasts obtained from this patient revealed an altered mitochondrial morphology, and a decrease in levels of proteins from complex I, III and IV.ConclusionsOur findings confirmed implication of VPS13D in spastic ataxia and provided further support for mitochondrial defects in patient’s skin fibroblasts with VPS13D variants. This report of long-term follow up showed a slowly progressive course of the spastic paraplegia with cerebellar features. Furthermore, the performed functional studies could be used as biomarker helping diagnosis of VPS13D-related neurological disorders when molecular results are uneasy to interpret.

A novel homozygous synonymous variant further expands the phenotypic spectrum of POLR3A‐related pathologies

Pathogenic biallelic variants in POL3RA have been associated with different disorders characterized by progressive neurological deterioration. These include the 4H leukodystrophy syndrome (hypomyelination, hypogonadotropic hypogonadism, and hypodontia) and adolescent-onset progressive spastic ataxia, as well as Wiedemann-Rautenstrauch syndrome (WRS), a recognizable neonatal progeroid syndrome. The phenotypic differences between these disorders are thought to occur mainly due to different functional effects of underlying POLR3A variants. Here we present the detailed clinical course of a 37-year-old woman in whom we identified a homozygous synonymous POLR3A variant c.3336G>A resulting in leaky splicing r.[3336ins192, =, 3243_3336del94]. She presented at birth with intrauterine growth retardation, lipodystrophy, muscular hypotonia, and several WRS-like facial features, albeit without sparse hair and prominent scalp veins. She had no signs of developmental delay or intellectual disability. Over the years, above characteristic facial features, she showed severe postnatal growth retardation, global lipodystrophy, joint contractures, thoracic hypoplasia, scoliosis, anodontia, spastic quadriplegia, bilateral hearing loss, aphonia, hypogonadotropic hypogonadism, and cerebellar peduncles hyperintensities in brain imaging. These manifestations partially overlap the clinical features of the previously reported POLR3A-associated disorders, mostly mimicking the WRS. Thus, our study expands the POLR3A-mediated phenotypic spectrum and suggests existence of a phenotypic continuum underlying biallelic POLR3A variants.

Two intronic cis-acting variants in both alleles of the POLR3A gene cause progressive spastic ataxia with hypodontia.

POLR3A encodes the largest subunit of the DNA-dependent RNA polymerase III. Pathogenic variants in this gene are associated with dysregulation of tRNA production and other non-coding RNAs. POLR3A-related disorders include variable phenotypes. The genotype-phenotype correlation is still unclear. Phenotypic analysis and exome sequencing were performed in four affected siblings diagnosed clinically with hereditary spastic ataxia, two healthy siblings and their unaffected mother. All four affected siblings (ages 46-55) had similar clinical features of early childhood-onset hypodontia and adolescent-onset progressive spastic ataxia. None had progeria, gonadal dysfunction or dysmorphism. All affected individuals had biallelic POLR3A pathogenic variants composed by two cis-acting intronic splicing-altering variants, c.1909 + 22G > A and c.3337-11 T > C. The two healthy siblings had wild-type alleles. The mother and another unaffected sibling were heterozygous for the allele containing both variants. This is the first report addressing the clinical consequence associated with homozygosity for a unique pathogenic intronic allele in the POLR3A gene. This allele was previously reported in compound heterozygous combinations in patients with Wiedemann-Rautenstrauch syndrome, a severe progeroid POLR3A-associated phenotype. We show that homozygosity for this allele is associated with spastic ataxia with hypodontia, and not with progeroid features. These findings contribute to the characterization of genotype-phenotype correlation in POLR3A-related disorders.

A novel SACS p.Pro4154GlnfsTer20 mutation in a family with autosomal recessive spastic ataxia of Charlevoix-Saguenay.

Loss-of-function mutations in the sacsin (SACS) gene lead to autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), impairing the function of sacsin. Genotype-phenotype correlations are still unclear for the different mutations reported in ARSACS. Here, we present a Turkish ARSACS family in whom the novel homozygous frameshift mutation in SACS c.12461delC (p.Pro4154GlnfsTer20) was detected by next-generation sequencing (NGS). The index patient was admitted with progressive spastic ataxia and dysarthria. Since no common mutation in autosomal recessive (AR) cerebellar ataxias, whole gene sequencing provide an advantage to detect novel mutations and may be more effective for clinical diagnosis.

Blended phenotype of adult-onset Alexander disease and spinocerebellar ataxia type 6.

Alexander disease is an autosomal dominant hereditary disease characterized by progressive spastic paraplegia, ataxia, and bulbar symptoms caused by mutations in the glial fibrillary acidic protein ( GFAP ) gene. Previous nation-wide surveillance revealed that the prevalence rate in Japan is estimated at 1 in 2.7 million people.1 Meanwhile, SCA6 is an autosomal dominant spinocerebellar ataxia characterized by adult-onset pure cerebellar ataxia. The prevalence of SCA6 is estimated to be 1 in 100,000 people in Japan.2 Here, we report an extremely rare case presenting with a blended phenotype of adult-onset Alexander disease and SCA6. The authors thank Shoko Watanabe, PhD, for technical assistance including mutational analysis.

A homozygous missense variant in the homeobox domain of the NKX6-2 results in progressive spastic ataxia type 8 associated with lower limb weakness and neurological manifestations.

Progressive spastic ataxia is a heterogeneous disorder characterized by cerebellar ataxia and limb spasticity associated with other severe neurological complications. Spastic ataxia is classified into pure and complex types, inherited in both an autosomal recessive and autosomal dominant manner. It is caused by pathogenic variants in at least eight different genes, including NKX6-2 (MIM 607063) located on chromosome 10q26.3. The present study aimed to identify the genetic variant(s) underlying progressive spastic ataxia and to establish the genotype-phenotype correlation. We collected a large consanguineous family having four affected individuals segregating progressive spastic ataxia in an autosomal recessive manner. To investigate the molecular cause of the disease, genomic DNA of three affected individuals underwent whole exome sequencing. All of the affected individuals showed progressive clinical features such as spastic ataxia, lower limb weakness and other mild neurological abnormalities. Whole exome sequencing data were analyzed using different filters. Filtering of rare and shared homozygous variants revealed a novel homozygous missense variant (c.545C>T; p.Ala182Val) in a highly conserved homeobox domain of the NKX6-2 protein. The findings of the present study add a novel variant to the NKX6-2 mutation spectrum and provide evidence that homozygous variants in the NKX6-2 cause progressive spastic ataxia associated with other abnormalities.

Cerebello-Cortical Alterations Linked to Cognitive and Social Problems in Patients With Spastic Paraplegia Type 7: A Preliminary Study.

Spastic paraplegia type 7 (SPG7), which represents one of the most common forms of autosomal recessive spastic paraplegia (MIM#607259), often manifests with a complicated phenotype, characterized by progressive spastic ataxia with evidence of cerebellar atrophy on brain MRI. Recent studies have documented the presence of peculiar dentate nucleus hyperintensities on T2-weighted images and frontal executive dysfunction in neuropsychological tests in SPG7 patients. Therefore, we decided to assess whether any particular MRI pattern might be specifically associated with SPG7 mutations and possibly correlated with patients' cognitive profiles. For this purpose, we evaluated six SPG7 patients, studying the cerebello-cortical network by MRI voxel-based morphometry and functional connectivity techniques, compared to 30 healthy control subjects. In parallel, we investigated the cognitive and social functioning of the SPG7 patients. Our results document specific cognitive alterations in language, verbal memory, and executive function in addition to an impairment of social task and emotional functions. The MRI scans showed a diffuse symmetric reduction in the cerebellar gray matter of the right lobule V, right Crus I, and bilateral lobule VI, together with a cerebral gray matter reduction in the lingual gyrus, precuneus, thalamus, and superior frontal gyrus. The evidence of an over-connectivity pattern between both the right and left cerebellar dentate nuclei and specific cerebral regions (the lateral occipital cortex, precuneus, left supramarginal gyrus, and left superior parietal lobule) confirms the presence of cerebello-cortical dysregulation in different networks involved in cognition and social functioning in SPG7 patients.

Exploring the molecular basis of hereditary spinocerebellar degeneration in a large Sudanese family

Spinocerebellar neurodegeneration (SCD) is phenotypically and genetically complex forming a heterogeneous spectrum of disorders with hereditary spastic paraplegias on one end and hereditary ataxias on the other. Genetics of SCD has been a target for extensive researches worldwide, yet little is known about SCD genetics in Sub-Saharan African population. We recruited a large consanguineous Sudanese family with five affected siblings. Extracted genomic DNA was screened for genetic variations using whole exome sequencing (WES). Analysis was done to identify the culprit variations using bioinformatics tools. Clinical results showed a complex phenotype of progressive spastic-ataxia, deafness and microcephaly. Analysis of WES data suggested two homozygous missense variants in two candidate genes (MYO15A and SEMA5D) that were not reported to be linked to similar disease before. The first variant in MYO15A gene (NM_016239.3: c.1634C>T) was reported to cause autosomal recessive hearing loss but was not reported in similar neurological disease. The second variant in SEMA4D gene (NM_006378.3:c.1588G>A) which involved in brain development but not reported to be associated with inherited neurological conditions before. Both variants were extremely rare and highly conserved. They were predicted to be highly pathogenic using bioinformatics tools. The scarcity of genetic data in the highly consanguineous Sudanese population makes whole exome sequencing a powerful and cost effective strategy to identify both known and new pathogenic variations and genes. Sanger sequencing and further functional studies are recommended to prove the association of MYO15A gene and SEMA4D gene with the complex clinical phenotype of deafness, spasticity and ataxia.

ANO10 mutational screening in recessive ataxia: genetic findings and refinement of the clinical phenotype.

Autosomal recessive cerebellar ataxia type 3 (ARCA3) is a rare inherited disorder caused by mutations in the ANO10 gene. The disease is characterized by slowly progressive spastic ataxia variably associated with motor neuron involvement, epilepsy, and cognitive decline. We performed mutational screening in 80 patients with sporadic or autosomal recessive adult-onset ataxia. We identified 11 ANO10 gene variants in 10 patients from 8 families (10%): 4 mutations were previously described and 7 were novel. Age at onset ranged between 27 and 53years. All patients presented ataxia, pyramidal signs and cerebellar atrophy at brain MRI. Additional signs were bradykinesia (7/10), mild vertical gaze paresis (5/10), pes cavus (4/10), and sphincteric disturbances (3/10). Six patients, with normal MMSE score, failed several neuropsychological tests rating executive functions. Three patients had giant somatosensory evoked potentials and epileptic spikes in EEG without clinical evidence of seizures. Our observational study indicates a high frequency of ARCA3 disease in sporadic patients with adult-onset cerebellar ataxia. We extended the ANO10 mutational spectrum with the identification of novel gene variants, and further defined the clinical, cognitive, and neurophysiological features in a new cohort of patients. These findings may contribute to the refinement of the complex ARCA3 phenotype and be valuable in clinical management and natural history studies.

Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome

BackgroundWiedemann-Rautenstrauch syndrome (WRS) is a form of segmental progeria presenting neonatally, characterised by growth retardation, sparse scalp hair, generalised lipodystrophy with characteristic local fatty tissue accumulations and unusual face. We...

Recessive mutations in VPS13D cause childhood onset movement disorders.

VPS13 protein family members VPS13A through VPS13C have been associated with various recessive movement disorders. We describe the first disease association of rare recessive VPS13D variants including frameshift, missense, and partial duplication mutations with a novel complex, hyperkinetic neurological disorder. The clinical features include developmental delay, a childhood onset movement disorder (chorea, dystonia, or tremor), and progressive spastic ataxia or paraparesis. Characteristic brain magnetic resonance imaging shows basal ganglia or diffuse white matter T2 hyperintensities as seen in Leigh syndrome and choreoacanthocytosis. Muscle biopsy in 1 case showed mitochondrial aggregates and lipidosis, suggesting mitochondrial dysfunction. These findings underline the importance of the VPS13 complex in neurological diseases and a possible role in mitochondrial function. Ann Neurol 2018;83:1089-1095.

Defective kinesin binding of TUBB2A causes progressive spastic ataxia syndrome resembling sacsinopathy.

Microtubules participate in fundamental cellular processes, including chromosomal segregation and cell division, migration and intracellular trafficking. Their proper function is required for correct central nervous system development and operative preservation, and mutations in genes coding tubulins, the constituting units of microtubules, underlie a family of neurodevelopmental and neurodegenerative diseases, collectively known as 'tubulinopathies', characterized by a wide range of neuronal defects resulting from defective proliferation, migration and function. Here, we causally link a previously unreported missense mutation in TUBB2A (c.1249G>A, p.D417N), encoding one of the neuron-specific β-tubulin isotype II, to a disorder characterized by progressive spastic paraplegia, peripheral sensory-motor polyneuropathy and ataxia. Asp417 is a highly conserved solvent-exposed residue at the site mediating binding of kinesin superfamily motors. Impaired binding to KIF1A, a neuron-specific kinesin required for transport of synaptic vesicle precursors of the disease-associated TUBB2A mutant, was predicted by structural analyses and confirmed experimentally in vitro. We show that overexpression of TUBB2AD417N disrupts the mitotic spindle bipolarity and morphology and affects the M phase entry and length. Differently from the TUBB2AN247K and TUBB2AA248V, two mutants previously identified to affect neurodevelopment, TUBB2AD417N retains the ability to assemble into microtubules. Consistent with the differential clinical and structural impact, TUBB2AA248V does not drastically affect TUBB2A binding to KIF1A, nor mitotic spindle bipolarity. Overall, our data demonstrate a pathogenic role of the p.D417N substitution that is different from previously reported TUBB2A mutations and expand the phenotypic spectrum associated with mutations in this gene.

Mutations in nkx6-2 cause progressive spastic-ataxia and hypomyelination

Background: The combination of progressive limb spasticity and cerebellar ataxia are frequently found in clinical practice and form a heterogeneous group of degenerative disorders that are classified as either pure spastic ataxia, or complex with additional neurological signs. Inheritance is either autosomal dominant or recessive. Hypomyelinating features on MRI are not uncommonly seen with spastic-ataxia but this is usually mild in adults, and severe and life-limiting in children.

DARS2 protects against neuroinflammation and apoptotic neuronal loss, but is dispensable for myelin producing cells.

Although mitochondria are ubiquitous, each mitochondrial disease has surprisingly distinctly different pattern of tissue and organ involvement. Congruently, mutations in genes encoding for different mitochondrial tRNA synthetases result in the development of a very flamboyant group of diseases. Mutations in some of these genes, including aspartyl-tRNA synthetase (DARS2), lead to the onset of a white matter disease-leukoencephalopathy with brainstem and spinal cord involvement, and lactate elevation (LBSL) characterized by progressive spastic ataxia and characteristic leukoencephalopathy signature with multiple long-tract involvements. Puzzled by the white matter disease phenotypes caused by DARS2 deficiency when numerous other mutations in the genes encoding proteins involved in mitochondrial translation have a detrimental effect predominantly on neurons, we generated transgenic mice in which DARS2 was specifically depleted in forebrain-hippocampal neurons or myelin-producing cells. Our results now provide the first evidence that loss of DARS2 in adult neurons leads to strong mitochondrial dysfunction and progressive loss of cells. In contrast, myelin-producing cells seem to be resistant to cell death induced by DARS2 depletion despite robust respiratory chain deficiency arguing that LBSL might originate from the primary neuronal and axonal defect. Remarkably, our results also suggest a role for early neuroinflammation in the disease progression, highlighting the possibility for therapeutic interventions of this process.

Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination

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.