Gene/phenotype/disorder under study
NKX6-2 (OMIM: #605955)
NKX6-2-related spastic ataxia 8 with hypomyelinating leukodystrophy (SPAX8) (OMIM: #617560; Orphanet: 527497)
Abstract
Hypomyelinating leukodystrophies are a heterogeneous group of genetic disorders characterised by impaired formation of the myelin sheath in the Central Nervous System (CNS). Bi-allelic variants in the NKX6-2 gene were identified to cause spastic ataxia 8 (SPAX8), autosomal recessive, with hypomyelinating leukodystrophy.
NKX6-2 gene encodes NK6 homeobox 2 protein, which is a transcription factor and member of the NKX homeobox family that control brain pattern formation and positional information during embryonic development. Expressed in the developing and adult human brain, NKX6-2 has a central role in oligodendrocyte maturation and CNS myelination.
Affected patients experience progressive motor dysfunction, ataxia, spasticity, developmental delay and hypomyelination on brain MRI imaging. In the severe form of the disease, there is a neonatal onset, where neurological features progress rapidly and include profound global psychomotor disability, failure to reach independent ambulation or speech, and complex medical needs. In the milder form of the disease, there is a childhood onset with predominantly motor deficits, in addition to slowly progressive complex spastic ataxia with pyramidal and cerebellar symptoms and loss of developmental milestones. Other features may also include nystagmus, hypotonia, scoliosis, dystonia, dysarthria, and cognitive impairment.
This study aims to evaluate genetic, clinical, biosample (plasma and serum) and neuroimaging data (brain MRI and spinal cord if available) in patients with NKX6-2-related leukodystrophy. In turn, this will accelerate our understanding of the genotype-phenotype correlations, aid understanding of the prevalence and biomarkers of the disease, as well as help inform future disease-modifying clinical trials.
Coordinating team
Kristina Zhelcheska – kristina.zhelcheska.20@ucl.ac.uk
Dr Viorica Chelban – v.chelban@ucl.ac.uk
Professor Henry Houlden – h.houlden@ucl.ac.uk
Institution
Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom
Specific requirements beyond clinical data and genotype data sharing:
1- Re-analysis of DNA samples: No
2- Resampling of patients: Yes
3- Linked to a translational/basic research project: Yes