Session Information
Date: Monday, September 23, 2019
Session Title: Genetics
Session Time: 1:45pm-3:15pm
Location: Les Muses Terrace, Level 3
Objective: To determine cause of disease in an adult patient with an undiagnosed chronic neurodegenerative disease.
Background: POLG2 is a nuclear gene responsible for mtDNA replication. Its impaired function results in mitochondrial DNA (mtDNA) depletion. There was only one described case of homozygous POLG2 mutation (Chr17 (Hg19): 62492543G>A POLG2) so far, resulting in mitochondrial depletion syndrome and fatal hepatic failure at 3 months of age [1]. Other described cases in POLG2 were in heterozygous state and manifested with broad clinical spectrum of movement disorders including parkinsonism, ataxia and tremor [2].
Method: 39 year old female presenting with optic atrophy and severe visual impairment, mixed polyneuropathy, spinal and cerebellar ataxia and generalized chorea found with severe mtDNA depletion.
Results: Whole-exome sequencing identified a homozygous missense variant located at (Hg19) Chr17: 062474101-C>A (p.Asp433Tyr) in POLG2. The POLG2 variant was in heterozygous state in both parents and two sisters of the patient (who were all healthy). The POLG2 variant was absent from gnomAD database and was predicted as pathogenic by MutationTaster, FATHMM, FATHMM-MKL, MetaSVM, MetalR,MutationAssessor, SIFT, Provean. The mtDNA/nDNA ratio in white blood cells from patient was reduced to approx. 44% of the mean value for control samples.
Conclusion: This is the first case of homozygous mutation in POLG2 gene in adult patient with mtDNA depletion.
References: 1. Varma H, Faust PL, Iglesias AD, Lagana SM, Wou K, Hirano M, et al. Whole exome sequencing identifies a homozygous POLG2 missense variant in an infant with fulminant hepatic failure and mitochondrial DNA depletion. Eur J Med Genet. 2016;59(10):540–5. pmid:2759214 2. Van Maldergem L, Besse A, De Paepe B, et al. POLG2 deficiency causes adult-onset syndromic sensory neuropathy, ataxia and parkinsonism. Ann Clin Transl Neurol. 2016;4(1):4-14.
To cite this abstract in AMA style:
P. Dosekova, V. Habalova, M. Skirkova, V. Han, A. Mosejova, Z. Gdovinova, M. Skorvanek, R. Ploski. Whole Exome Sequencing Identifies a Homozygous POLG2 Missense Variant in an adult patient presenting with movement disorders and Mitochondrial DNA Depletion [abstract]. Mov Disord. 2019; 34 (suppl 2). https://www.mdsabstracts.org/abstract/whole-exome-sequencing-identifies-a-homozygous-polg2-missense-variant-in-an-adult-patient-presenting-with-movement-disorders-and-mitochondrial-dna-depletion/. Accessed June 14, 2025.« Back to 2019 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/whole-exome-sequencing-identifies-a-homozygous-polg2-missense-variant-in-an-adult-patient-presenting-with-movement-disorders-and-mitochondrial-dna-depletion/