Expanding the phenotypic spectrum of BCS1L‐related mitochondrial disease
Abstract Objective To delineate the full phenotypic spectrum of BCS1L‐related disease, provide better understanding of the genotype–phenotype correlations and identify reliable prognostic disease markers. Methods We performed a retrospective multinational cohort study of previously unpublished patie...
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2021
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oai:doaj.org-article:7ea99688d16d4beba2c9f25ff13dc2762021-11-22T11:11:52ZExpanding the phenotypic spectrum of BCS1L‐related mitochondrial disease2328-950310.1002/acn3.51470https://doaj.org/article/7ea99688d16d4beba2c9f25ff13dc2762021-11-01T00:00:00Zhttps://doi.org/10.1002/acn3.51470https://doaj.org/toc/2328-9503Abstract Objective To delineate the full phenotypic spectrum of BCS1L‐related disease, provide better understanding of the genotype–phenotype correlations and identify reliable prognostic disease markers. Methods We performed a retrospective multinational cohort study of previously unpublished patients followed in 15 centres from 10 countries. Patients with confirmed biallelic pathogenic BCS1L variants were considered eligible. Clinical, laboratory, neuroimaging and genetic data were analysed. Patients were stratified into different groups based on the age of disease onset, whether homozygous or compound heterozygous for the c.232A>G (p.Ser78Gly) variant, and those with other pathogenic BCS1L variants. Results Thirty‐three patients were included. We found that growth failure, lactic acidosis, tubulopathy, hepatopathy and early death were more frequent in those with disease onset within the first month of life. In those with onset after 1 month, neurological features including movement disorders and seizures were more frequent. Novel phenotypes, particularly involving movement disorder, were identified in this group. The presence of the c.232A>G (p.Ser78Gly) variant was associated with significantly worse survival and exclusively found in those with disease onset within the first month of life, whilst other pathogenic BCS1L variants were more frequent in those with later symptom onset. Interpretation The phenotypic spectrum of BCS1L‐related disease comprises a continuum of clinical features rather than a set of separate syndromic clinical identities. Age of onset defines BCS1L‐related disease clinically and early presentation is associated with poor prognosis. Genotype correlates with phenotype in the presence of the c.232A>G (p.Ser78Gly) variant.Omar HikmatPirjo IsohanniNandaki KeshavanMatteo P. FerlaElisa FassoneMary‐Alice AbbottMarcello BellusciNiklas DarinDavid DimmockDaniele GhezziHenry HouldenFederica InvernizziNazreen B. Kamarus JamanManju A. KurianEva MoravaKarin NaessJuan Darío Ortigoza‐EscobarSumit ParikhAlessandra PennisiGiulia BarciaKarin B. TylleskärDamien BrackmanSaskia B. WortmannJenny C. TaylorLaurence A. BindoffVineta FellmanShamima RahmanWileyarticleNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571Neurology. Diseases of the nervous systemRC346-429ENAnnals of Clinical and Translational Neurology, Vol 8, Iss 11, Pp 2155-2165 (2021) |
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| collection |
DOAJ |
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Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Neurology. Diseases of the nervous system RC346-429 |
| spellingShingle |
Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Neurology. Diseases of the nervous system RC346-429 Omar Hikmat Pirjo Isohanni Nandaki Keshavan Matteo P. Ferla Elisa Fassone Mary‐Alice Abbott Marcello Bellusci Niklas Darin David Dimmock Daniele Ghezzi Henry Houlden Federica Invernizzi Nazreen B. Kamarus Jaman Manju A. Kurian Eva Morava Karin Naess Juan Darío Ortigoza‐Escobar Sumit Parikh Alessandra Pennisi Giulia Barcia Karin B. Tylleskär Damien Brackman Saskia B. Wortmann Jenny C. Taylor Laurence A. Bindoff Vineta Fellman Shamima Rahman Expanding the phenotypic spectrum of BCS1L‐related mitochondrial disease |
| description |
Abstract Objective To delineate the full phenotypic spectrum of BCS1L‐related disease, provide better understanding of the genotype–phenotype correlations and identify reliable prognostic disease markers. Methods We performed a retrospective multinational cohort study of previously unpublished patients followed in 15 centres from 10 countries. Patients with confirmed biallelic pathogenic BCS1L variants were considered eligible. Clinical, laboratory, neuroimaging and genetic data were analysed. Patients were stratified into different groups based on the age of disease onset, whether homozygous or compound heterozygous for the c.232A>G (p.Ser78Gly) variant, and those with other pathogenic BCS1L variants. Results Thirty‐three patients were included. We found that growth failure, lactic acidosis, tubulopathy, hepatopathy and early death were more frequent in those with disease onset within the first month of life. In those with onset after 1 month, neurological features including movement disorders and seizures were more frequent. Novel phenotypes, particularly involving movement disorder, were identified in this group. The presence of the c.232A>G (p.Ser78Gly) variant was associated with significantly worse survival and exclusively found in those with disease onset within the first month of life, whilst other pathogenic BCS1L variants were more frequent in those with later symptom onset. Interpretation The phenotypic spectrum of BCS1L‐related disease comprises a continuum of clinical features rather than a set of separate syndromic clinical identities. Age of onset defines BCS1L‐related disease clinically and early presentation is associated with poor prognosis. Genotype correlates with phenotype in the presence of the c.232A>G (p.Ser78Gly) variant. |
| format |
article |
| author |
Omar Hikmat Pirjo Isohanni Nandaki Keshavan Matteo P. Ferla Elisa Fassone Mary‐Alice Abbott Marcello Bellusci Niklas Darin David Dimmock Daniele Ghezzi Henry Houlden Federica Invernizzi Nazreen B. Kamarus Jaman Manju A. Kurian Eva Morava Karin Naess Juan Darío Ortigoza‐Escobar Sumit Parikh Alessandra Pennisi Giulia Barcia Karin B. Tylleskär Damien Brackman Saskia B. Wortmann Jenny C. Taylor Laurence A. Bindoff Vineta Fellman Shamima Rahman |
| author_facet |
Omar Hikmat Pirjo Isohanni Nandaki Keshavan Matteo P. Ferla Elisa Fassone Mary‐Alice Abbott Marcello Bellusci Niklas Darin David Dimmock Daniele Ghezzi Henry Houlden Federica Invernizzi Nazreen B. Kamarus Jaman Manju A. Kurian Eva Morava Karin Naess Juan Darío Ortigoza‐Escobar Sumit Parikh Alessandra Pennisi Giulia Barcia Karin B. Tylleskär Damien Brackman Saskia B. Wortmann Jenny C. Taylor Laurence A. Bindoff Vineta Fellman Shamima Rahman |
| author_sort |
Omar Hikmat |
| title |
Expanding the phenotypic spectrum of BCS1L‐related mitochondrial disease |
| title_short |
Expanding the phenotypic spectrum of BCS1L‐related mitochondrial disease |
| title_full |
Expanding the phenotypic spectrum of BCS1L‐related mitochondrial disease |
| title_fullStr |
Expanding the phenotypic spectrum of BCS1L‐related mitochondrial disease |
| title_full_unstemmed |
Expanding the phenotypic spectrum of BCS1L‐related mitochondrial disease |
| title_sort |
expanding the phenotypic spectrum of bcs1l‐related mitochondrial disease |
| publisher |
Wiley |
| publishDate |
2021 |
| url |
https://doaj.org/article/7ea99688d16d4beba2c9f25ff13dc276 |
| work_keys_str_mv |
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