Case Report: Rare Homozygous RNASEH1 Mutations Associated With Adult-Onset Mitochondrial Encephalomyopathy and Multiple Mitochondrial DNA Deletions
Mitochondrial DNA (mtDNA) maintenance disorders embrace a broad range of clinical syndromes distinguished by the evidence of mtDNA depletion and/or deletions in affected tissues. Among the nuclear genes associated with mtDNA maintenance disorders, RNASEH1 mutations produce a homogeneous phenotype, w...
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| Format: | Article |
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Frontiers Media S.A.
2022-05-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2022.906667/full |
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| author | Arianna Manini Leonardo Caporali Megi Meneri Megi Meneri Simona Zanotti Daniela Piga Ignazio Giuseppe Arena Stefania Corti Stefania Corti Antonio Toscano Giacomo Pietro Comi Giacomo Pietro Comi Olimpia Musumeci Valerio Carelli Valerio Carelli Dario Ronchi Dario Ronchi |
| author_facet | Arianna Manini Leonardo Caporali Megi Meneri Megi Meneri Simona Zanotti Daniela Piga Ignazio Giuseppe Arena Stefania Corti Stefania Corti Antonio Toscano Giacomo Pietro Comi Giacomo Pietro Comi Olimpia Musumeci Valerio Carelli Valerio Carelli Dario Ronchi Dario Ronchi |
| author_sort | Arianna Manini |
| collection | DOAJ |
| description | Mitochondrial DNA (mtDNA) maintenance disorders embrace a broad range of clinical syndromes distinguished by the evidence of mtDNA depletion and/or deletions in affected tissues. Among the nuclear genes associated with mtDNA maintenance disorders, RNASEH1 mutations produce a homogeneous phenotype, with progressive external ophthalmoplegia (PEO), ptosis, limb weakness, cerebellar ataxia, and dysphagia. The encoded enzyme, ribonuclease H1, is involved in mtDNA replication, whose impairment leads to an increase in replication intermediates resulting from mtDNA replication slowdown. Here, we describe two unrelated Italian probands (Patient 1 and Patient 2) affected by chronic PEO, ptosis, and muscle weakness. Cerebellar features and severe dysphagia requiring enteral feeding were observed in one patient. In both cases, muscle biopsy revealed diffuse mitochondrial abnormalities and multiple mtDNA deletions. A targeted next-generation sequencing analysis revealed the homozygous RNASEH1 mutations c.129-3C>G and c.424G>A in patients 1 and 2, respectively. The c.129-3C>G substitution has never been described as disease-related and resulted in the loss of exon 2 in Patient 1 muscle RNASEH1 transcript. Overall, we recommend implementing the use of high-throughput sequencing approaches in the clinical setting to reach genetic diagnosis in case of suspected presentations with impaired mtDNA homeostasis. |
| first_indexed | 2024-12-12T06:06:11Z |
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| id | doaj.art-dea81be6a7b2422d9517c6157fe6e829 |
| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-12-12T06:06:11Z |
| publishDate | 2022-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-dea81be6a7b2422d9517c6157fe6e8292022-12-22T00:35:16ZengFrontiers Media S.A.Frontiers in Genetics1664-80212022-05-011310.3389/fgene.2022.906667906667Case Report: Rare Homozygous RNASEH1 Mutations Associated With Adult-Onset Mitochondrial Encephalomyopathy and Multiple Mitochondrial DNA DeletionsArianna Manini0Leonardo Caporali1Megi Meneri2Megi Meneri3Simona Zanotti4Daniela Piga5Ignazio Giuseppe Arena6Stefania Corti7Stefania Corti8Antonio Toscano9Giacomo Pietro Comi10Giacomo Pietro Comi11Olimpia Musumeci12Valerio Carelli13Valerio Carelli14Dario Ronchi15Dario Ronchi16Dino Ferrari Center, Department of Pathophysiology and Transplantation, University of Milan, Milan, ItalyIstituto delle Scienze Neurologiche di Bologna, Programma di Neurogenetica, Bologna, ItalyDino Ferrari Center, Department of Pathophysiology and Transplantation, University of Milan, Milan, ItalyFoundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurology Unit, Department of Neuroscience, Milan, ItalyFoundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neuromuscular and Rare Diseases Unit, Department of Neuroscience, Milan, ItalyFoundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurology Unit, Department of Neuroscience, Milan, ItalyUnit of Neurology and Neuromuscular disorders, Department of Clinical and Experimental Medicine, University of Messina, Messina, ItalyDino Ferrari Center, Department of Pathophysiology and Transplantation, University of Milan, Milan, ItalyFoundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurology Unit, Department of Neuroscience, Milan, ItalyUnit of Neurology and Neuromuscular disorders, Department of Clinical and Experimental Medicine, University of Messina, Messina, ItalyDino Ferrari Center, Department of Pathophysiology and Transplantation, University of Milan, Milan, ItalyFoundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neuromuscular and Rare Diseases Unit, Department of Neuroscience, Milan, ItalyUnit of Neurology and Neuromuscular disorders, Department of Clinical and Experimental Medicine, University of Messina, Messina, ItalyIstituto delle Scienze Neurologiche di Bologna, Programma di Neurogenetica, Bologna, ItalyDipartimento di Scienze Biomediche e Neuromotorie (DIBINEM), University of Bologna, Bologna, ItalyDino Ferrari Center, Department of Pathophysiology and Transplantation, University of Milan, Milan, ItalyFoundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurology Unit, Department of Neuroscience, Milan, ItalyMitochondrial DNA (mtDNA) maintenance disorders embrace a broad range of clinical syndromes distinguished by the evidence of mtDNA depletion and/or deletions in affected tissues. Among the nuclear genes associated with mtDNA maintenance disorders, RNASEH1 mutations produce a homogeneous phenotype, with progressive external ophthalmoplegia (PEO), ptosis, limb weakness, cerebellar ataxia, and dysphagia. The encoded enzyme, ribonuclease H1, is involved in mtDNA replication, whose impairment leads to an increase in replication intermediates resulting from mtDNA replication slowdown. Here, we describe two unrelated Italian probands (Patient 1 and Patient 2) affected by chronic PEO, ptosis, and muscle weakness. Cerebellar features and severe dysphagia requiring enteral feeding were observed in one patient. In both cases, muscle biopsy revealed diffuse mitochondrial abnormalities and multiple mtDNA deletions. A targeted next-generation sequencing analysis revealed the homozygous RNASEH1 mutations c.129-3C>G and c.424G>A in patients 1 and 2, respectively. The c.129-3C>G substitution has never been described as disease-related and resulted in the loss of exon 2 in Patient 1 muscle RNASEH1 transcript. Overall, we recommend implementing the use of high-throughput sequencing approaches in the clinical setting to reach genetic diagnosis in case of suspected presentations with impaired mtDNA homeostasis.https://www.frontiersin.org/articles/10.3389/fgene.2022.906667/fullRNASEH1ribonuclease H1mitochondrial DNAmtDNA maintenance disordersmyopathyCPEO |
| spellingShingle | Arianna Manini Leonardo Caporali Megi Meneri Megi Meneri Simona Zanotti Daniela Piga Ignazio Giuseppe Arena Stefania Corti Stefania Corti Antonio Toscano Giacomo Pietro Comi Giacomo Pietro Comi Olimpia Musumeci Valerio Carelli Valerio Carelli Dario Ronchi Dario Ronchi Case Report: Rare Homozygous RNASEH1 Mutations Associated With Adult-Onset Mitochondrial Encephalomyopathy and Multiple Mitochondrial DNA Deletions Frontiers in Genetics RNASEH1 ribonuclease H1 mitochondrial DNA mtDNA maintenance disorders myopathy CPEO |
| title | Case Report: Rare Homozygous RNASEH1 Mutations Associated With Adult-Onset Mitochondrial Encephalomyopathy and Multiple Mitochondrial DNA Deletions |
| title_full | Case Report: Rare Homozygous RNASEH1 Mutations Associated With Adult-Onset Mitochondrial Encephalomyopathy and Multiple Mitochondrial DNA Deletions |
| title_fullStr | Case Report: Rare Homozygous RNASEH1 Mutations Associated With Adult-Onset Mitochondrial Encephalomyopathy and Multiple Mitochondrial DNA Deletions |
| title_full_unstemmed | Case Report: Rare Homozygous RNASEH1 Mutations Associated With Adult-Onset Mitochondrial Encephalomyopathy and Multiple Mitochondrial DNA Deletions |
| title_short | Case Report: Rare Homozygous RNASEH1 Mutations Associated With Adult-Onset Mitochondrial Encephalomyopathy and Multiple Mitochondrial DNA Deletions |
| title_sort | case report rare homozygous rnaseh1 mutations associated with adult onset mitochondrial encephalomyopathy and multiple mitochondrial dna deletions |
| topic | RNASEH1 ribonuclease H1 mitochondrial DNA mtDNA maintenance disorders myopathy CPEO |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2022.906667/full |
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