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. 2024 Jun;271(6):3546-3553.
doi: 10.1007/s00415-024-12319-y. Epub 2024 Mar 28.

Variants in mitochondrial disease genes are common causes of inherited peripheral neuropathies

Tomas Ferreira  1 , Kiran Polavarapu  2 , Catarina Olimpio  1   3 , Ida Paramonov  4 , Hanns Lochmüller  2   4   5   6   7 , Rita Horvath  8
Affiliations

Variants in mitochondrial disease genes are common causes of inherited peripheral neuropathies

Tomas Ferreira et al. J Neurol. 2024 Jun.

Abstract

Background: Peripheral neuropathies in mitochondrial disease are caused by mutations in nuclear genes encoding mitochondrial proteins, or in the mitochondrial genome. Whole exome or genome sequencing enable parallel testing of nuclear and mtDNA genes, and it has significantly advanced the genetic diagnosis of inherited diseases. Despite this, approximately 40% of all Charcot-Marie-Tooth (CMT) cases remain undiagnosed.

Methods: The genome-phenome analysis platform (GPAP) in RD-Connect was utilised to create a cohort of 2087 patients with at least one Human Phenotype Ontology (HPO) term suggestive of a peripheral neuropathy, from a total of 10,935 patients. These patients' genetic data were then analysed and searched for variants in known mitochondrial disease genes.

Results: A total of 1,379 rare variants were identified, 44 of which were included in this study as either reported pathogenic or likely causative in 42 patients from 36 families. The most common genes found to be likely causative for an autosomal dominant neuropathy were GDAP1 and GARS1. We also detected heterozygous likely pathogenic variants in DNA2, MFN2, DNM2, PDHA1, SDHA, and UCHL1. Biallelic variants in SACS, SPG7, GDAP1, C12orf65, UCHL1, NDUFS6, ETFDH and DARS2 and variants in the mitochondrial DNA (mtDNA)-encoded MT-ATP6 and MT-TK were also causative for mitochondrial CMT. Only 50% of these variants were already reported as solved in GPAP.

Conclusion: Variants in mitochondrial disease genes are frequent in patients with inherited peripheral neuropathies. Due to the clinical overlap between mitochondrial disease and CMT, agnostic exome or genome sequencing have better diagnostic yields than targeted gene panels.

Keywords: CMT; Genetic heterogeneity; Genome-phenome analysis platform (GPAP); Mitochondrial disease; Peripheral neuropathies; Rare variants.

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Conflict of interest statement

The authors have no financial or non-financial interest that are directly or indirectly related to the work submitted for publication.

Figures

Fig. 1
Fig. 1
Study algorithm – highlighting the steps taken in the study process
Fig. 2
Fig. 2
Prevalence of mitochondrial disease genes in the neuropathy cohort per inheritance pattern
See this image and copyright information in PMC

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