Gene/phenotype/disorder under study
Gene DARS2 (OMIM *610956) / Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation (LBSL) / Axonal Charcot-Marie-Tooth disease type 2LL
Abstract
DARS2-related disease is caused by biallelic variants in DARS2, which encodes the mitochondrial isoform of aspartyl-tRNA synthetase, an enzyme that catalyzes the aminoacylation of aspartate to its cognate mt-tRNA and is essential for mitochondrial protein synthesis.
Most cases of DARS2-related disease hitherto reported are compound heterozygotes, while the occurrence of homozygous variants is rare and often associated with earlier disease onset or more severe phenotypes. The most common pathogenic variant is a splice variant in intron 2 (c.228-20_21delTTinsC) leading to exon 3 skipping.
The phenotypic spectrum is broad, ranging from childhood-onset leukoencephalopathy with brainstem and spinal cord involvement to perinatal manifestations, including epileptic encephalopathy, microcephaly, and spastic quadriplegia. Milder phenotypes include isolated cerebellar ataxia or late-onset spastic paraplegia. Additionally, axonal Charcot-Marie-Tooth disease without leukoencephalopathy has been described. Brain MRI usually shows white matter abnormalities involving the spinal cord, brainstem, and cerebellum, often with elevated lactate, although imaging patterns may vary depending on disease severity.
We aim to conduct a comprehensive pheno-genotypic analysis and define the natural history of DARS2-related disease in a large international cohort.
Coordinating clinician
Dr Francesca Magrinelli – f.magrinelli@ucl.ac.uk
Institution
Department of Clinical and Movement Neurosciences, 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: Yes (not mandatory)
2- Resampling of patients: Yes (not mandatory)
3- Linked to a translational/basic research project: No