Expanding the Clinical Spectrum of LONP1-Related Mitochondrial Cytopathy
Open accessAbstract
Pathogenic variants in the LONP1 gene have been associated with CODAS syndrome (Cerebral, Ocular, Dental, Auricular, and Skeletal Anomalies Syndrome). A recent report identified the first newborn case with LONP1-related mitochondrial cytopathy due to a compound heterozygous pathogenic variant in LONP1 without features of CODAS. The proband had manifested with severe congenital lactic acidosis and profound multiple respiratory chain complex activity deficiencies associated with the quantitative loss of mtDNA copy number in muscle. A subsequent report identified two siblings with regression during infancy, profound hypotonia and muscle weakness, severe intellectual disability, progressive cerebellar atrophy, where muscle biopsy showed an electron dense mitochondrial inclusions without ragged-red fibers and normal electron transport chain enzyme activities. Here we report an additional case of autosomal recessive mitochondrial cytopathy due to a homozygous missense variant in LONP1 that was identified on whole exome sequencing (c.810G>A; p.D463N). The proband, a 20-year-old male born to consanguineous parents, presented with global developmental delay, emotional outbursts, speech and swallowing difficulties, hypotonia, and ataxia since childhood. Muscle biopsy showed massive granular bodies, increased oxidative stress and autophagic block and reduced mitochondrial state 3 respiration. We have identified another case of LONP1-related mitochondrial cytopathy further confirming a neurological phenotype without CODAS features.
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In human skeletal muscle, reduction of LonP1 activity results in electron-dense intra-mitochondrial accumulations, mitochondrial dysfunction, oxidative stress, and muscle weakness.
“In human skeletal muscle, the reduction of LonP1 activity results in electron-dense intra-mitochondrial accumulations, mitochondrial dysfunction, oxidative stress, and muscle weakness [162–164].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [163]
The matrix mitochondrial protease LonP1 is necessary for maintenance of mitochondrial matrix proteostasis.
“The matrix mitochondrial protease LonP1 is necessary for the maintenance of mitochondrial matrix proteostasis.”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [163]
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- Authors
- Hannah-Shmouni, F., MacNeil, L., Brady, L., Nilsson, M. I., & Tarnopolsky, M.
- Affiliations
- University of Toronto (CA)
- McMaster University (CA)
- Corresponding author
- Tarnopolsky, Mark
- Venue
- Frontiers in Neurology
- Publisher
- Frontiers Media SA
- Published
- 2019-10-04
- Volume
- 10
- Pages
- 981-981
- ISSN
- 1664-2295 (ISSN-L)
- PMC
- PMC6787162
- OpenAlex
- W2970189619
- Cited by
- 19
- References
- 27
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 5 · 2021: 3 · 2020: 4
- FWCI
- 0.99
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Neurology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- LONP1, mitochondrial disease, compound heterozygosity, homozygous missense mutation, autosomal recessive inheritance, congenital lactic acidosis, oxidative stress, mitochondrial respiration, developmental delay, ataxia, hypotonia, neurological phenotype
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