DARS2 – Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Lactate Elevation

Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a rare autosomal recessive leukodystrophy caused by biallelic variants in DARS2, encoding the mitochondrial aspartyl-tRNA synthetase. Clinical hallmarks include slowly progressive spasticity, cerebellar ataxia, dorsal column dysfunction, and characteristic MRI findings involving cerebral white matter and long tracts in the brainstem and spinal cord.

Inheritance is autosomal recessive, with most patients harboring compound heterozygous mutations in DARS2. Over 60 unrelated probands with biallelic DARS2 variants have been reported (PMID:24566671), with segregation documented in multiple consanguineous and non-consanguineous families involving at least 8 additional affected relatives (PMID:30352563).

The variant spectrum includes missense, splice site, frameshift, and deep-intronic mutations clustered at intron 2, notably c.492+2T>C. A recurrent missense allele, c.850G>A (p.Glu284Lys), has been described in adult-onset LBSL (PMID:23644316). Most patients possess one “leaky” intron 2 splice defect paired with a second coding or splice variant, leading to residual protein.

Phenotypic onset ranges from antenatal and infantile forms to adult presentations. Intra-familial variability is common, with siblings exhibiting discordant severity despite identical genotypes (PMID:30352563). Brain lactate elevation correlates inversely with age at onset, influencing prognosis (PMID:23644316).

Functional studies demonstrate that LBSL missense mutations impair mtAspRS localization, dimerization, and enzymatic activity in patient cells (PMID:23216004). Yeast msd1Δ models and patient fibroblasts show defective oxidative growth, reduced mitochondrial translation, and aberrant mitochondrial dynamics, which can be rescued by wild-type DARS2 but not by pathogenic alleles (PMID:35820270).

Collectively, genetic and experimental data fulfil ClinGen criteria for a definitive gene–disease relationship. DARS2 haploinsufficiency drives impaired mitochondrial protein synthesis, leading to white matter degeneration. Recognition of variant types and MRI hallmarks enables accurate molecular diagnosis and informs potential splice-modulating therapies.

Key Take-home: Biallelic DARS2 mutations cause autosomal recessive LBSL; integration of clinical, imaging, and genetic data supports definitive diagnosis and guides future therapeutic strategies.

References

• Neurology India • 2013 • Adult-onset leukoencephalopathy with brain stem and spinal cord involvement in Chinese Han population: a case report and literature review. PMID:23644316
• BMC Neurology • 2018 • Intra-familial phenotypic heterogeneity in a Sudanese family with DARS2-related leukoencephalopathy, brainstem and spinal cord involvement and lactate elevation: a case report. PMID:30352563
• Brain: a journal of neurology • 2014 • Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation: clinical and genetic characterization and target for therapy. PMID:24566671
• The Biochemical journal • 2013 • Pathogenic mutations causing LBSL affect mitochondrial aspartyl-tRNA synthetase in diverse ways. PMID:23216004
• Molecular genetics and metabolism • 2022 • Functional analysis of missense DARS2 variants in siblings with leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation. PMID:35820270

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