Phenotypic intrafamilial variability of 5q-associated spinal muscular atrophy: A systematic multicentre sibling study

Benedikt Becker¹, Isabell Cordts¹, Jutta Becker², Rene Günther³, Matthias Baumann⁴, Günther Bernert⁵, Astrid Eisenkölbl⁶, Barbara Fiedler⁷, Marina Flotats-Bastardas⁸, Martin Fleger⁹, Tim Hagenacker¹⁰, Andreas Hahn¹¹, Elke Hobbiebrunken¹², Andrea Bevot¹³, Jörg Jahnel¹⁴, Jessika Johannsen¹⁵, Christoph Kamm¹⁶, Jan Christoph Koch¹⁷, Cornelia Köhler¹⁸, Heike Kölbel¹⁹, Wolfgang Müller-Felber²⁰, Christoph Neuwirth²¹, Barbara Plecko²², Christian Stadler²³, Martin Smitka²⁴, Arpad Von Moers²⁵, Regina Trollmann²⁶, Markus Weiler²⁷, Andreas Ziegler²⁸, Susanne Goldbach²⁹, Kristina Probst-Schendzielorz²⁹, Hanns Lochmüller^{30

31}, Ulrike Schara-Schmidt¹⁹, Maggie C Walter³², Janbernd Kirschner³¹, Brunhilde Wirth², Astrid Pechmann³¹, Marcus Deschauer¹; with SMArtCARE study group

Affiliations

¹ Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, School of Medicine and Health, Munich, Germany.
² Institute of Human Genetics, Center for Molecular Medicine, and Center for Rare Diseases and Institute for Genetics, University Hospital of Cologne, University of Cologne, Cologne, Germany.
³ Department of Neurology, University Hospital Carl Gustav Carus, Technical University of Dresden, Dresden, Germany.
⁴ Department of Pediatrics I, Division of Pediatric Neurology, Medical University of Innsbruck, Innsbruck, Austria.
⁵ Department of Pediatrics, Clinic Favoriten, Vienna, Austria.
⁶ Department of Paediatrics and Adolescent Medicine, Johannes Kepler University Linz, Kepler University Hospital, Linz, Austria.
⁷ Department of Neuropediatrics, University Children's Hospital, Münster, Germany.
⁸ Department of General Pediatrics and Neonatology, Division of Neuropediatrics, Saarland University, Homburg Saar, Germany.
⁹ Department of Pediatrics, Bregenz Regional Hospital, Bregenz, Austria.
¹⁰ Department of Neurology, and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Medicine Essen, Essen, Germany.
¹¹ Department of Child Neurology, Justus-Liebig University, Giessen, Germany.
¹² Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, University Medical Center Göttingen, Georg August University, Göttingen, Germany.
¹³ Department of Paediatric Neurology, University Children's Hospital, Tübingen, Germany.
¹⁴ Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, LKH Klagenfurt, Medical University of Graz, Graz, Austria.
¹⁵ Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁶ Department of Neurology, University of Rostock, Rostock, Germany.
¹⁷ Department of Neurology, University Medical Center Göttingen, Göttingen, Germany.
¹⁸ Ruhr University Bochum, St Josef-Hospital, Department for Neuropediatrics, University Medical Center for Pediatrics and Adolescent Medicine, Bochum, Germany.
¹⁹ Department of Neuropediatrics and Neuromuscular Centre for Children and Adolescents, Center for Translational Neuro- and Behavioral Sciences, University of Duisburg-Essen, Essen, Germany.
²⁰ Department of Neuropediatrics, UMC, LMU Munich, Munich, Germany.
²¹ Neuromuscular Diseases Unit / ALS Clinic, Cantonal Hospital St Gallen, St. Gallen, Switzerland.
²² Department of Pediatrics and Adolescent Medicine, Division of General Pediatrics, Medical University of Graz, Graz, Austria.
²³ Department of Neurology, Klinikum Klagenfurt am Wörthersee, Klagenfurt am Wörthersee, Austria.
²⁴ Department of Neuropediatrics, UMC Carl Gustav Carus, Technical University of Dresden, Dresden, Germany.
²⁵ Department of Pediatrics and Neuropediatrics, DRK Klinikum Westend, Berlin, Germany.
²⁶ Department of Pediatrics, Division of Pediatric Neurology, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany.
²⁷ Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany.
²⁸ Department of Neuropediatrics and Metabolic Medicine, University Hospital Heidelberg, Heidelberg, Germany.
²⁹ Deutsche Gesellschaft für Muskelkranke, Freiburg, Germany.
³⁰ Children's Hospital of Eastern Ontario Research Institute, Division of Neurology, Department of Medicine, The Ottawa Hospital and Brain and Mind Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
³¹ Department of Neuropediatrics and Muscle Disorders, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
³² Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University of Munich, Munich, Germany.

PMID: 40938628
DOI: 10.1177/22143602251370577

Free article

Phenotypic intrafamilial variability of 5q-associated spinal muscular atrophy: A systematic multicentre sibling study

Benedikt Becker et al. J Neuromuscul Dis. 2025.

Free article

. 2025 Sep 12:22143602251370577.

doi: 10.1177/22143602251370577. Online ahead of print.

Authors

Affiliations

¹ Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, School of Medicine and Health, Munich, Germany.
² Institute of Human Genetics, Center for Molecular Medicine, and Center for Rare Diseases and Institute for Genetics, University Hospital of Cologne, University of Cologne, Cologne, Germany.
³ Department of Neurology, University Hospital Carl Gustav Carus, Technical University of Dresden, Dresden, Germany.
⁴ Department of Pediatrics I, Division of Pediatric Neurology, Medical University of Innsbruck, Innsbruck, Austria.
⁵ Department of Pediatrics, Clinic Favoriten, Vienna, Austria.
⁶ Department of Paediatrics and Adolescent Medicine, Johannes Kepler University Linz, Kepler University Hospital, Linz, Austria.
⁷ Department of Neuropediatrics, University Children's Hospital, Münster, Germany.
⁸ Department of General Pediatrics and Neonatology, Division of Neuropediatrics, Saarland University, Homburg Saar, Germany.
⁹ Department of Pediatrics, Bregenz Regional Hospital, Bregenz, Austria.
¹⁰ Department of Neurology, and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Medicine Essen, Essen, Germany.
¹¹ Department of Child Neurology, Justus-Liebig University, Giessen, Germany.
¹² Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, University Medical Center Göttingen, Georg August University, Göttingen, Germany.
¹³ Department of Paediatric Neurology, University Children's Hospital, Tübingen, Germany.
¹⁴ Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, LKH Klagenfurt, Medical University of Graz, Graz, Austria.
¹⁵ Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁶ Department of Neurology, University of Rostock, Rostock, Germany.
¹⁷ Department of Neurology, University Medical Center Göttingen, Göttingen, Germany.
¹⁸ Ruhr University Bochum, St Josef-Hospital, Department for Neuropediatrics, University Medical Center for Pediatrics and Adolescent Medicine, Bochum, Germany.
¹⁹ Department of Neuropediatrics and Neuromuscular Centre for Children and Adolescents, Center for Translational Neuro- and Behavioral Sciences, University of Duisburg-Essen, Essen, Germany.
²⁰ Department of Neuropediatrics, UMC, LMU Munich, Munich, Germany.
²¹ Neuromuscular Diseases Unit / ALS Clinic, Cantonal Hospital St Gallen, St. Gallen, Switzerland.
²² Department of Pediatrics and Adolescent Medicine, Division of General Pediatrics, Medical University of Graz, Graz, Austria.
²³ Department of Neurology, Klinikum Klagenfurt am Wörthersee, Klagenfurt am Wörthersee, Austria.
²⁴ Department of Neuropediatrics, UMC Carl Gustav Carus, Technical University of Dresden, Dresden, Germany.
²⁵ Department of Pediatrics and Neuropediatrics, DRK Klinikum Westend, Berlin, Germany.
²⁶ Department of Pediatrics, Division of Pediatric Neurology, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany.
²⁷ Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany.
²⁸ Department of Neuropediatrics and Metabolic Medicine, University Hospital Heidelberg, Heidelberg, Germany.
²⁹ Deutsche Gesellschaft für Muskelkranke, Freiburg, Germany.
³⁰ Children's Hospital of Eastern Ontario Research Institute, Division of Neurology, Department of Medicine, The Ottawa Hospital and Brain and Mind Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
³¹ Department of Neuropediatrics and Muscle Disorders, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
³² Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University of Munich, Munich, Germany.

PMID: 40938628
DOI: 10.1177/22143602251370577

Abstract

Background and objectivesThe severity of the phenotype of spinal muscular atrophy (SMA) is highly variable, yet little is known about the phenotypic variation among siblings. We systematically investigated the phenotypic variability of therapy-naïve 5q-SMA siblings leveraging a large multicentre cohort from the SMArtCARE registry.ResultsClinical information was available from 132 siblings of 65 families. There were 24 (18.2%) type 1, 38 (28.7%) type 2, 54 (40.9%) type 3 patients, and 16 (12.1%) presymptomatic individuals. In 17 families (32.1%), there was discordance in the type of SMA among symptomatic siblings. We found no influence of gender on discordance in SMA type among siblings (p = 0.528). The median age at disease onset within all sibships varied by 6 months (interquartile range (IQR) = 1-30). There was no correlation in age of onset among siblings (r = 0.405; p = 0.052). Among siblings who lost ambulation, the median interval between the start of wheelchair use was 12 months, but the maximal interval was 18 years. In one pair of siblings, one sibling lost the ability to walk at the age of 13, whereas the other sibling was still ambulatory at the age of 54. In 6 sibling pairs (9.5%), only one of both siblings had a history of scoliosis surgery. Analysing SMN2 copy numbers, in one sibling pair (1.8%) 1 SMN2 gene copy was detected, while 10 (17.5%) had 2 copies, 23 (40.4%) had 3 copies, and 17 (29.8%) had 4 copies. Concordance in SMN2 copy numbers across siblings was observed in 90% of families. With increasing SMN2 copy number, the median differences in age of onset among siblings increased without reaching statistical significance.ConclusionThis study reports considerable phenotypic variability in therapy-naïve SMA sibships that cannot solely be explained by differences in SMN2 copy numbers.

Keywords: SMA; SMN2; Spinal muscular atrophy; age of onset; intrafamilial variability; siblings.

PubMed Disclaimer

LinkOut - more resources

Full Text Sources
- Atypon
- IOS Press

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Phenotypic intrafamilial variability of 5q-associated spinal muscular atrophy: A systematic multicentre sibling study

Affiliations

Phenotypic intrafamilial variability of 5q-associated spinal muscular atrophy: A systematic multicentre sibling study

Authors

Affiliations

Abstract

LinkOut - more resources

Full Text Sources