Multilevel evidence of MECP2-associated mitochondrial dysfunction and its therapeutic implications
We present a male patient carrying a pathogenic MECP2 p. Arg179Trp variant with predominant negative psychiatric features and multilevel evidence of mitochondrial dysfunction who responded to the cariprazine treatment. He had delayed speech development and later experienced severe social anxiety, le...
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| Format: | Article |
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Frontiers Media S.A.
2024-01-01
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| Series: | Frontiers in Psychiatry |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fpsyt.2023.1301272/full |
| _version_ | 1797365542888144896 |
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| author | Peter Balicza Peter Balicza Andras Gezsi Mariann Fedor Judit C. Sagi Aniko Gal Noemi Agnes Varga Maria Judit Molnar Maria Judit Molnar |
| author_facet | Peter Balicza Peter Balicza Andras Gezsi Mariann Fedor Judit C. Sagi Aniko Gal Noemi Agnes Varga Maria Judit Molnar Maria Judit Molnar |
| author_sort | Peter Balicza |
| collection | DOAJ |
| description | We present a male patient carrying a pathogenic MECP2 p. Arg179Trp variant with predominant negative psychiatric features and multilevel evidence of mitochondrial dysfunction who responded to the cariprazine treatment. He had delayed speech development and later experienced severe social anxiety, learning disabilities, cognitive slowing, and predominant negative psychiatric symptoms associated with rigidity. Clinical examinations showed multisystemic involvement. Together with elevated ergometric lactate levels, the clinical picture suggested mitochondrial disease, which was also supported by muscle histopathology. Exploratory transcriptome analysis also revealed the involvement of metabolic and oxidative phosphorylation pathways. Whole-exome sequencing identified a pathogenic MECP2 variant, which can explain both the dopamine imbalance and mitochondrial dysfunction in this patient. Mitochondrial dysfunction was previously suggested in classical Rett syndrome, and we detected related phenotype evidence on multiple consistent levels for the first time in a MECP2 variant carrier male. This study further supports the importance of the MECP2 gene in the mitochondrial pathways, which can open the gate for more personalized therapeutic interventions. Good cariprazine response highlights the role of dopamine dysfunction in the complex psychiatric symptoms of Rett syndrome. This can help identify the optimal treatment strategy from a transdiagnostic perspective instead of a classical diagnostic category. |
| first_indexed | 2024-03-08T16:51:28Z |
| format | Article |
| id | doaj.art-dbee1aee261740828aabf8ee2e9df22f |
| institution | Directory Open Access Journal |
| issn | 1664-0640 |
| language | English |
| last_indexed | 2024-03-08T16:51:28Z |
| publishDate | 2024-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Psychiatry |
| spelling | doaj.art-dbee1aee261740828aabf8ee2e9df22f2024-01-05T04:36:30ZengFrontiers Media S.A.Frontiers in Psychiatry1664-06402024-01-011410.3389/fpsyt.2023.13012721301272Multilevel evidence of MECP2-associated mitochondrial dysfunction and its therapeutic implicationsPeter Balicza0Peter Balicza1Andras Gezsi2Mariann Fedor3Judit C. Sagi4Aniko Gal5Noemi Agnes Varga6Maria Judit Molnar7Maria Judit Molnar8Institute of Genomic Medicine and Rare Disorders, Semmelweis University, Budapest, HungaryEotvos Lorand Research Network, Multiomic Neurodegeneration Research Group, Budapest, HungaryDepartment of Measurement and Information Systems, Budapest University of Technology and Economics, Budapest, HungaryInstitute of Genomic Medicine and Rare Disorders, Semmelweis University, Budapest, HungaryInstitute of Genomic Medicine and Rare Disorders, Semmelweis University, Budapest, HungaryInstitute of Genomic Medicine and Rare Disorders, Semmelweis University, Budapest, HungaryInstitute of Genomic Medicine and Rare Disorders, Semmelweis University, Budapest, HungaryInstitute of Genomic Medicine and Rare Disorders, Semmelweis University, Budapest, HungaryEotvos Lorand Research Network, Multiomic Neurodegeneration Research Group, Budapest, HungaryWe present a male patient carrying a pathogenic MECP2 p. Arg179Trp variant with predominant negative psychiatric features and multilevel evidence of mitochondrial dysfunction who responded to the cariprazine treatment. He had delayed speech development and later experienced severe social anxiety, learning disabilities, cognitive slowing, and predominant negative psychiatric symptoms associated with rigidity. Clinical examinations showed multisystemic involvement. Together with elevated ergometric lactate levels, the clinical picture suggested mitochondrial disease, which was also supported by muscle histopathology. Exploratory transcriptome analysis also revealed the involvement of metabolic and oxidative phosphorylation pathways. Whole-exome sequencing identified a pathogenic MECP2 variant, which can explain both the dopamine imbalance and mitochondrial dysfunction in this patient. Mitochondrial dysfunction was previously suggested in classical Rett syndrome, and we detected related phenotype evidence on multiple consistent levels for the first time in a MECP2 variant carrier male. This study further supports the importance of the MECP2 gene in the mitochondrial pathways, which can open the gate for more personalized therapeutic interventions. Good cariprazine response highlights the role of dopamine dysfunction in the complex psychiatric symptoms of Rett syndrome. This can help identify the optimal treatment strategy from a transdiagnostic perspective instead of a classical diagnostic category.https://www.frontiersin.org/articles/10.3389/fpsyt.2023.1301272/fullMECP2 mutationRett syndromelearning disabilityanxietynegative symptomscariprazine |
| spellingShingle | Peter Balicza Peter Balicza Andras Gezsi Mariann Fedor Judit C. Sagi Aniko Gal Noemi Agnes Varga Maria Judit Molnar Maria Judit Molnar Multilevel evidence of MECP2-associated mitochondrial dysfunction and its therapeutic implications Frontiers in Psychiatry MECP2 mutation Rett syndrome learning disability anxiety negative symptoms cariprazine |
| title | Multilevel evidence of MECP2-associated mitochondrial dysfunction and its therapeutic implications |
| title_full | Multilevel evidence of MECP2-associated mitochondrial dysfunction and its therapeutic implications |
| title_fullStr | Multilevel evidence of MECP2-associated mitochondrial dysfunction and its therapeutic implications |
| title_full_unstemmed | Multilevel evidence of MECP2-associated mitochondrial dysfunction and its therapeutic implications |
| title_short | Multilevel evidence of MECP2-associated mitochondrial dysfunction and its therapeutic implications |
| title_sort | multilevel evidence of mecp2 associated mitochondrial dysfunction and its therapeutic implications |
| topic | MECP2 mutation Rett syndrome learning disability anxiety negative symptoms cariprazine |
| url | https://www.frontiersin.org/articles/10.3389/fpsyt.2023.1301272/full |
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