DARS2 mutations in mitochondrial leucoencephalopathy and multiple sclerosis.

Area of Science:

• Neurogenetics
• Mitochondrial diseases
• Leukodystrophies

Background:

• Leucoencephalopathy with brain stem and spinal cord involvement and high brain lactate (LBSL) is a rare neurological disorder characterized by specific MRI and spectroscopic findings.
• Clinical manifestations include progressive ataxia, spasticity, and dorsal column dysfunction, with onset typically in childhood or adolescence.
• Mutations in the DARS2 gene, encoding mitochondrial aspartyl-tRNA synthetase, have been identified as the cause of LBSL, presenting overlap with multiple sclerosis (MS).

Purpose of the Study:

• To investigate the molecular basis of LBSL in Finnish patients by analyzing DARS2 gene mutations.
• To determine the prevalence of specific DARS2 mutations in a cohort of Finnish multiple sclerosis (MS) patients.

Main Methods:

• Clinical assessment of eight LBSL patients.
• DARS2 gene sequencing and haplotype analysis.
• Carrier frequency determination for identified DARS2 mutations in the Finnish population.

Main Results:

• All eight LBSL patients were compound heterozygotes for DARS2 mutations, with common mutations R76SfsX5 and M134_K165del identified.
• Axonal neuropathy was observed in five of the eight LBSL patients.
• Carrier frequencies for R76SfsX5 and M134_K165del were 1:95 and 1:380, respectively; no enrichment of these mutations was found in 321 MS patients.

Conclusions:

• Homozygosity for DARS2 mutations may be lethal or result in a different phenotype, as all LBSL patients were compound heterozygotes.
• Clinical presentation of LBSL can be variable despite identical mutations, with axonal neuropathy being a significant feature.
• DARS2 mutations are confirmed as a cause of childhood-to-adolescence onset leucoencephalopathy but are not associated with MS in the studied population.