Prognostic value of pathogenic variants in Lafora Disease: systematic review and meta-analysis of patient-level data
Abstract Background Lafora disease (LD) is a fatal form of progressive myoclonic epilepsy caused by biallelic pathogenic variants in EPM2A or NHLRC1. With a few exceptions, the influence of genetic factors on disease progression has yet to be confirmed. We present a systematic review and meta-analys...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-09-01
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| Series: | Orphanet Journal of Rare Diseases |
| Online Access: | https://doi.org/10.1186/s13023-023-02880-6 |
| _version_ | 1797451559090520064 |
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| author | Federica Pondrelli Raffaella Minardi Lorenzo Muccioli Corrado Zenesini Luca Vignatelli Laura Licchetta Barbara Mostacci Paolo Tinuper Craig W. Vander Kooi Matthew S. Gentry Francesca Bisulli |
| author_facet | Federica Pondrelli Raffaella Minardi Lorenzo Muccioli Corrado Zenesini Luca Vignatelli Laura Licchetta Barbara Mostacci Paolo Tinuper Craig W. Vander Kooi Matthew S. Gentry Francesca Bisulli |
| author_sort | Federica Pondrelli |
| collection | DOAJ |
| description | Abstract Background Lafora disease (LD) is a fatal form of progressive myoclonic epilepsy caused by biallelic pathogenic variants in EPM2A or NHLRC1. With a few exceptions, the influence of genetic factors on disease progression has yet to be confirmed. We present a systematic review and meta-analysis of the known pathogenic variants to identify genotype–phenotype correlations. Methods We collected all reported cases with genetically-confirmed LD containing data on disease history. Pathogenic variants were classified into missense (MS) and protein-truncating (PT). Three genotype classes were defined according to the combination of the variants: MS/MS, MS/PT, and PT/PT. Time-to-event analysis was performed to evaluate survival and loss of autonomy. Results 250 cases described in 70 articles were included. The mutated gene was NHLRC1 in 56% and EPM2A in 44% of cases. 114 pathogenic variants (67 EPM2A; 47 NHLRC1) were identified. The NHLRC1 genotype PT/PT was associated with shorter survival [HR 2.88; 95% CI 1.23–6.78] and a trend of higher probability of loss of autonomy [HR 2.03, 95% CI 0.75–5.56] at the multivariable Cox regression analysis. The population carrying the homozygous p.Asp146Asn variant of NHLRC1 genotype was confirmed to have a more favourable prognosis in terms of disease duration. Conclusions This study demonstrates the existence of prognostic genetic factors in LD, namely the genotype defined according to the functional impact of the pathogenic variants. Although the reasons why NHLRC1 genotype PT/PT is associated with a poorer prognosis have yet to be fully elucidated, it may be speculated that malin plays a pivotal role in LD pathogenesis. |
| first_indexed | 2024-03-09T14:55:26Z |
| format | Article |
| id | doaj.art-a141b74afcff49a9a4cd0c5090e3921e |
| institution | Directory Open Access Journal |
| issn | 1750-1172 |
| language | English |
| last_indexed | 2024-03-09T14:55:26Z |
| publishDate | 2023-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Orphanet Journal of Rare Diseases |
| spelling | doaj.art-a141b74afcff49a9a4cd0c5090e3921e2023-11-26T14:12:40ZengBMCOrphanet Journal of Rare Diseases1750-11722023-09-0118111010.1186/s13023-023-02880-6Prognostic value of pathogenic variants in Lafora Disease: systematic review and meta-analysis of patient-level dataFederica Pondrelli0Raffaella Minardi1Lorenzo Muccioli2Corrado Zenesini3Luca Vignatelli4Laura Licchetta5Barbara Mostacci6Paolo Tinuper7Craig W. Vander Kooi8Matthew S. Gentry9Francesca Bisulli10Department of Biomedical and Neuromotor Sciences, University of BolognaIRCCS Istituto delle Scienze Neurologiche di Bologna, Full Member of the European Reference Network for Rare and Complex Epilepsies (EpiCARE)Department of Biomedical and Neuromotor Sciences, University of BolognaIRCCS Istituto delle Scienze Neurologiche di Bologna, Full Member of the European Reference Network for Rare and Complex Epilepsies (EpiCARE)IRCCS Istituto delle Scienze Neurologiche di Bologna, Full Member of the European Reference Network for Rare and Complex Epilepsies (EpiCARE)IRCCS Istituto delle Scienze Neurologiche di Bologna, Full Member of the European Reference Network for Rare and Complex Epilepsies (EpiCARE)IRCCS Istituto delle Scienze Neurologiche di Bologna, Full Member of the European Reference Network for Rare and Complex Epilepsies (EpiCARE)Department of Biomedical and Neuromotor Sciences, University of BolognaDepartment of Biochemistry and Molecular Biology, University of FloridaDepartment of Biochemistry and Molecular Biology, University of FloridaDepartment of Biomedical and Neuromotor Sciences, University of BolognaAbstract Background Lafora disease (LD) is a fatal form of progressive myoclonic epilepsy caused by biallelic pathogenic variants in EPM2A or NHLRC1. With a few exceptions, the influence of genetic factors on disease progression has yet to be confirmed. We present a systematic review and meta-analysis of the known pathogenic variants to identify genotype–phenotype correlations. Methods We collected all reported cases with genetically-confirmed LD containing data on disease history. Pathogenic variants were classified into missense (MS) and protein-truncating (PT). Three genotype classes were defined according to the combination of the variants: MS/MS, MS/PT, and PT/PT. Time-to-event analysis was performed to evaluate survival and loss of autonomy. Results 250 cases described in 70 articles were included. The mutated gene was NHLRC1 in 56% and EPM2A in 44% of cases. 114 pathogenic variants (67 EPM2A; 47 NHLRC1) were identified. The NHLRC1 genotype PT/PT was associated with shorter survival [HR 2.88; 95% CI 1.23–6.78] and a trend of higher probability of loss of autonomy [HR 2.03, 95% CI 0.75–5.56] at the multivariable Cox regression analysis. The population carrying the homozygous p.Asp146Asn variant of NHLRC1 genotype was confirmed to have a more favourable prognosis in terms of disease duration. Conclusions This study demonstrates the existence of prognostic genetic factors in LD, namely the genotype defined according to the functional impact of the pathogenic variants. Although the reasons why NHLRC1 genotype PT/PT is associated with a poorer prognosis have yet to be fully elucidated, it may be speculated that malin plays a pivotal role in LD pathogenesis.https://doi.org/10.1186/s13023-023-02880-6 |
| spellingShingle | Federica Pondrelli Raffaella Minardi Lorenzo Muccioli Corrado Zenesini Luca Vignatelli Laura Licchetta Barbara Mostacci Paolo Tinuper Craig W. Vander Kooi Matthew S. Gentry Francesca Bisulli Prognostic value of pathogenic variants in Lafora Disease: systematic review and meta-analysis of patient-level data Orphanet Journal of Rare Diseases |
| title | Prognostic value of pathogenic variants in Lafora Disease: systematic review and meta-analysis of patient-level data |
| title_full | Prognostic value of pathogenic variants in Lafora Disease: systematic review and meta-analysis of patient-level data |
| title_fullStr | Prognostic value of pathogenic variants in Lafora Disease: systematic review and meta-analysis of patient-level data |
| title_full_unstemmed | Prognostic value of pathogenic variants in Lafora Disease: systematic review and meta-analysis of patient-level data |
| title_short | Prognostic value of pathogenic variants in Lafora Disease: systematic review and meta-analysis of patient-level data |
| title_sort | prognostic value of pathogenic variants in lafora disease systematic review and meta analysis of patient level data |
| url | https://doi.org/10.1186/s13023-023-02880-6 |
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