Objective: Progressive leukoencephalopathy with primary ovarian failure (LKENP; OMIM # 615889) is a novel ovario-leukodystophy caused by compound heterozygote mutations in the AARS2 gene of the nuclear-encoded mitochondrial alanyl-tRNA synthetase (mtAlaRS).

Background: We report two Korean siblings with overall clinical, genetic and imaging features compatible LKENP.

Methods: The proband (III:1, Figure 1) is a female who presented with secondary amenorrhea due to ovarian failure at age 33. At age 35, she developed depression, cognitive deterioration, and behavioral problems with signs of frontal dysfunction. Neurologic examination revealed right hand postural tremor, stooped posture and gait disturbance, but otherwise no motor disability. Laboratory results ruled out other conventional leukodystrophies, such as, X-ADL, or MLD. The first clinical manifestation of patient 2 (III:2, Figure 1) was progressive cognitive decline with frontal dysfunction. Physical examination revealed no abnormalities. He could walk without support. ECG and cardiac ultrasound were normal.

Results: After obtaining informed consent, genomic DNA was extracted from blood samples of the patients and their father. Whole-exome sequencing (WES) of patient 1 (III:1) revealed two pathologic AARS2 mutations: nonsense c.C963A (p.Y321*) and missense c.T452C (p.M151T). We confirmed with Sanger sequencing of the genes identified by WES in patient 1 and patient 2 (Figure 2). No mutations in EIF2B1–5 genes had been found.

Conclusions: In this study, the authors describe two new Korean patients with similar phenotype as previously described in eight patients of European cohort with the same mutation by Dallabona and colleagues. Laboratory examinations ruled out classic leukodystrophies. There is no mutations in EIF2B1–5 gene. This is the second report of LKENP, and the first, to our knowledge, Asian case report of the progressive leukoencephalopathy with primary ovarian failure due to mutations in AARS2 gene.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/two-new-cases-of-a-novel-ovario-leukodystrophy-related-to-aars2-mutation-from-korea/