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Novel mutations expand the clinical spectrum of DYNC1H1-associated spinal muscular atrophy
journal contribution
posted on 2023-06-09, 00:00 authored by Mariacristina Scoto, Alexander M Rossor, Matthew B Harms, Sebahattin Cirak, Mattia Calissano, Stephanie Robb, Adnan Y Manzur, Amaia Martínez Arroyo, Aida Rodriguez Sanz, Sahar Mansour, Penny Fallon, Irene Hadjikoumi, Andrea Klein, Michele Yang, Marianne De Visser, W C G Truus Overweg-Plandsoen, Frank Baas, J Paul Taylor, Michael Benatar, Anne M Connolly, Muhammad T Al-Lozi, John Nixon, Christian G E L de Goede, A Reghan Foley, Catherine Mcwilliam, Matthew Pitt, Caroline Sewry, Rahul Phadke, Majid HafezparastMajid Hafezparast, W K Kling Chong, Eugenio Mercuri, Robert H Baloh, Mary M Reilly, Francesco MuntoniOBJECTIVE To expand the clinical phenotype of autosomal dominant congenital spinal muscular atrophy with lower extremity predominance (SMA-LED) due to mutations in the dynein, cytoplasmic 1, heavy chain 1 (DYNC1H1) gene. METHODS Patients with a phenotype suggestive of a motor, non-length-dependent neuronopathy predominantly affecting the lower limbs were identified at participating neuromuscular centers and referred for targeted sequencing of DYNC1H1. RESULTS We report a cohort of 30 cases of SMA-LED from 16 families, carrying mutations in the tail and motor domains of DYNC1H1, including 10 novel mutations. These patients are characterized by congenital or childhood-onset lower limb wasting and weakness frequently associated with cognitive impairment. The clinical severity is variable, ranging from generalized arthrogryposis and inability to ambulate to exclusive and mild lower limb weakness. In many individuals with cognitive impairment (9/30 had cognitive impairment) who underwent brain MRI, there was an underlying structural malformation resulting in polymicrogyric appearance. The lower limb muscle MRI shows a distinctive pattern suggestive of denervation characterized by sparing and relative hypertrophy of the adductor longus and semitendinosus muscles at the thigh level, and diffuse involvement with relative sparing of the anterior-medial muscles at the calf level. Proximal muscle histopathology did not always show classic neurogenic features. CONCLUSION Our report expands the clinical spectrum of DYNC1H1-related SMA-LED to include generalized arthrogryposis. In addition, we report that the neurogenic peripheral pathology and the CNS neuronal migration defects are often associated, reinforcing the importance of DYNC1H1 in both central and peripheral neuronal functions.
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Publication status
- Published
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- Published version
Journal
NeurologyISSN
1526-632XPublisher
American Academy of Neurology (AAN)External DOI
Issue
7Volume
84Page range
668-679Department affiliated with
- Neuroscience Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2016-01-15First Open Access (FOA) Date
2016-02-17First Compliant Deposit (FCD) Date
2016-01-15Usage metrics
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