Fetal Akinesia/Hypokinesia and Arthrogryposis of Neuromuscular Origin: Etiologic Groups, Genetics, and Phenotypic Spectrum
ABSTRACT Objective To provide a comprehensive clinical and genetic characterization of individuals with arthrogryposis multiplex congenita (AMC), focusing on the distribution of genetic etiologies across the neuromuscular spectrum and comparing myogenic and neurogenic subtypes. Methods A total of 10...
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2025-08-01
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| Series: | Annals of Clinical and Translational Neurology |
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| Online Access: | https://doi.org/10.1002/acn3.70088 |
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| author | Florencia Pérez‐Vidarte Berta Estévez‐Arias Leslie Matalonga Delia Yubero Anna Codina Carlos Ortez Julita Medina Lidia DeSena DeCabo Laura Carrera‐García Jesica Expósito‐Escudero Cristina Jou Eduardo F. Tizzano Andres Nascimento Daniel Natera‐de Benito |
| author_facet | Florencia Pérez‐Vidarte Berta Estévez‐Arias Leslie Matalonga Delia Yubero Anna Codina Carlos Ortez Julita Medina Lidia DeSena DeCabo Laura Carrera‐García Jesica Expósito‐Escudero Cristina Jou Eduardo F. Tizzano Andres Nascimento Daniel Natera‐de Benito |
| author_sort | Florencia Pérez‐Vidarte |
| collection | DOAJ |
| description | ABSTRACT Objective To provide a comprehensive clinical and genetic characterization of individuals with arthrogryposis multiplex congenita (AMC), focusing on the distribution of genetic etiologies across the neuromuscular spectrum and comparing myogenic and neurogenic subtypes. Methods A total of 105 individuals with AMC were clinically and genetically evaluated in a single‐center study. Participants were stratified based on the primary site of involvement, and further classification was performed for neuromuscular cases into neurogenic and myogenic subtypes. Genetic diagnoses were made through using a range of next‐generation sequencing techniques, including exome sequencing (42 individuals), gene panel testing (40 individuals), genome sequencing (24 individuals), and targeted‐gene testing in selected cases. In most individuals who underwent genome sequencing, this was preceded by exome or gene panel testing. Results Of the 105 individuals, 4 were classified as Amyoplasia and 1 as FARAD. Among the remaining 100 cases, 81 (81%) presented with neuromuscular AMC, with defects involving motor neurons/peripheral nerves (52%, 42/81), neuromuscular junctions (7%, 6/81), and skeletal muscle (41%, 33/81). A genetic diagnosis was achieved in 55% (55/100) of the entire cohort and in 58% (47/81) of individuals with neuromuscular AMC. The most frequently implicated genes were TTN (16%, 9/55), CHRNG (10.9%, 6/55), PIEZO2 (9.1%, 5/55), ZC4H2 (9.1%, 5/55), DYNC1H1 (7.2%, 4/55), MYH3 (5.4%, 3/55), and RYR1 (5.4%, 3/55). Diagnostic yield varied significantly between subgroups, with 84.6% (33/39) of myogenic AMC cases genetically resolved, compared to 33.3% (14/42) of neurogenic cases. TTN was the most common gene in myogenic AMC, while ZC4H2 and DYNC1H1 were predominant in neurogenic AMC. Interpretation This study provides a detailed phenotypic and genetic characterization of neuromuscular AMC, highlighting the most frequently affected genes and their associated phenotypes. The findings underscore the challenges in diagnosing a significant proportion of cases, especially within the neurogenic subgroup, and emphasize the importance of integrating detailed phenotypic data with genetic analysis to enhance diagnosis, prognosis, and management of family expectations. |
| format | Article |
| id | doaj-art-653dec4d770f4c41933a66eb0c984818 |
| institution | Kabale University |
| issn | 2328-9503 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Annals of Clinical and Translational Neurology |
| spelling | doaj-art-653dec4d770f4c41933a66eb0c9848182025-08-20T03:41:57ZengWileyAnnals of Clinical and Translational Neurology2328-95032025-08-011281528154710.1002/acn3.70088Fetal Akinesia/Hypokinesia and Arthrogryposis of Neuromuscular Origin: Etiologic Groups, Genetics, and Phenotypic SpectrumFlorencia Pérez‐Vidarte0Berta Estévez‐Arias1Leslie Matalonga2Delia Yubero3Anna Codina4Carlos Ortez5Julita Medina6Lidia DeSena DeCabo7Laura Carrera‐García8Jesica Expósito‐Escudero9Cristina Jou10Eduardo F. Tizzano11Andres Nascimento12Daniel Natera‐de Benito13Neuromuscular Unit, Department of Neurology Hospital Sant Joan de Déu Barcelona SpainNeuromuscular Unit, Department of Neurology Hospital Sant Joan de Déu Barcelona SpainCentro Nacional de Análisis Genómico (CNAG) Barcelona SpainCenter for Biomedical Research Network on Rare Diseases (CIBERER), ISCIII SpainApplied Research in Neuromuscular Diseases Institut de Recerca Sant Joan de Déu Barcelona SpainNeuromuscular Unit, Department of Neurology Hospital Sant Joan de Déu Barcelona SpainApplied Research in Neuromuscular Diseases Institut de Recerca Sant Joan de Déu Barcelona SpainDepartment of Pediatric Orthopaedic Surgery Hospital Sant Joan de Deu Barcelona SpainNeuromuscular Unit, Department of Neurology Hospital Sant Joan de Déu Barcelona SpainNeuromuscular Unit, Department of Neurology Hospital Sant Joan de Déu Barcelona SpainCenter for Biomedical Research Network on Rare Diseases (CIBERER), ISCIII SpainApplied Research in Neuromuscular Diseases Institut de Recerca Sant Joan de Déu Barcelona SpainNeuromuscular Unit, Department of Neurology Hospital Sant Joan de Déu Barcelona SpainNeuromuscular Unit, Department of Neurology Hospital Sant Joan de Déu Barcelona SpainABSTRACT Objective To provide a comprehensive clinical and genetic characterization of individuals with arthrogryposis multiplex congenita (AMC), focusing on the distribution of genetic etiologies across the neuromuscular spectrum and comparing myogenic and neurogenic subtypes. Methods A total of 105 individuals with AMC were clinically and genetically evaluated in a single‐center study. Participants were stratified based on the primary site of involvement, and further classification was performed for neuromuscular cases into neurogenic and myogenic subtypes. Genetic diagnoses were made through using a range of next‐generation sequencing techniques, including exome sequencing (42 individuals), gene panel testing (40 individuals), genome sequencing (24 individuals), and targeted‐gene testing in selected cases. In most individuals who underwent genome sequencing, this was preceded by exome or gene panel testing. Results Of the 105 individuals, 4 were classified as Amyoplasia and 1 as FARAD. Among the remaining 100 cases, 81 (81%) presented with neuromuscular AMC, with defects involving motor neurons/peripheral nerves (52%, 42/81), neuromuscular junctions (7%, 6/81), and skeletal muscle (41%, 33/81). A genetic diagnosis was achieved in 55% (55/100) of the entire cohort and in 58% (47/81) of individuals with neuromuscular AMC. The most frequently implicated genes were TTN (16%, 9/55), CHRNG (10.9%, 6/55), PIEZO2 (9.1%, 5/55), ZC4H2 (9.1%, 5/55), DYNC1H1 (7.2%, 4/55), MYH3 (5.4%, 3/55), and RYR1 (5.4%, 3/55). Diagnostic yield varied significantly between subgroups, with 84.6% (33/39) of myogenic AMC cases genetically resolved, compared to 33.3% (14/42) of neurogenic cases. TTN was the most common gene in myogenic AMC, while ZC4H2 and DYNC1H1 were predominant in neurogenic AMC. Interpretation This study provides a detailed phenotypic and genetic characterization of neuromuscular AMC, highlighting the most frequently affected genes and their associated phenotypes. The findings underscore the challenges in diagnosing a significant proportion of cases, especially within the neurogenic subgroup, and emphasize the importance of integrating detailed phenotypic data with genetic analysis to enhance diagnosis, prognosis, and management of family expectations.https://doi.org/10.1002/acn3.70088AmyoplasiaCHRNGDYNC1H1myopathyneuropathyPIEZO2 |
| spellingShingle | Florencia Pérez‐Vidarte Berta Estévez‐Arias Leslie Matalonga Delia Yubero Anna Codina Carlos Ortez Julita Medina Lidia DeSena DeCabo Laura Carrera‐García Jesica Expósito‐Escudero Cristina Jou Eduardo F. Tizzano Andres Nascimento Daniel Natera‐de Benito Fetal Akinesia/Hypokinesia and Arthrogryposis of Neuromuscular Origin: Etiologic Groups, Genetics, and Phenotypic Spectrum Annals of Clinical and Translational Neurology Amyoplasia CHRNG DYNC1H1 myopathy neuropathy PIEZO2 |
| title | Fetal Akinesia/Hypokinesia and Arthrogryposis of Neuromuscular Origin: Etiologic Groups, Genetics, and Phenotypic Spectrum |
| title_full | Fetal Akinesia/Hypokinesia and Arthrogryposis of Neuromuscular Origin: Etiologic Groups, Genetics, and Phenotypic Spectrum |
| title_fullStr | Fetal Akinesia/Hypokinesia and Arthrogryposis of Neuromuscular Origin: Etiologic Groups, Genetics, and Phenotypic Spectrum |
| title_full_unstemmed | Fetal Akinesia/Hypokinesia and Arthrogryposis of Neuromuscular Origin: Etiologic Groups, Genetics, and Phenotypic Spectrum |
| title_short | Fetal Akinesia/Hypokinesia and Arthrogryposis of Neuromuscular Origin: Etiologic Groups, Genetics, and Phenotypic Spectrum |
| title_sort | fetal akinesia hypokinesia and arthrogryposis of neuromuscular origin etiologic groups genetics and phenotypic spectrum |
| topic | Amyoplasia CHRNG DYNC1H1 myopathy neuropathy PIEZO2 |
| url | https://doi.org/10.1002/acn3.70088 |
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