Novel mutations expand the clinical spectrum of DYNC1H1-associated spinal muscular atrophy

OBJECTIVE: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 n...

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Published in:	Neurology Vol. 84; no. 7; pp. 668 - 679
Main Authors:	Scoto, Mariacristina, Rossor, Alexander M, Harms, Matthew B, Cirak, Sebahattin, Calissano, Mattia, Robb, Stephanie, Manzur, Adnan Y, Martínez Arroyo, Amaia, Rodriguez Sanz, Aida, Mansour, Sahar, Fallon, Penny, Hadjikoumi, Irene, Klein, Andrea, Yang, Michele, De Visser, Marianne, Overweg-Plandsoen, W.C.G (Truus), Baas, Frank, Taylor, J Paul, Benatar, Michael, Connolly, Anne M, Al-Lozi, Muhammad T, Nixon, John, de Goede, Christian G.E.L, Foley, A Reghan, Mcwilliam, Catherine, Pitt, Matthew, Sewry, Caroline, Phadke, Rahul, Hafezparast, Majid, Chong, W.K “Kling, Mercuri, Eugenio, Baloh, Robert H, Reilly, Mary M, Muntoni, Francesco
Format:	Journal Article
Language:	English
Published:	United States American Academy of Neurology 17-02-2015 Lippincott Williams & Wilkins
Subjects:	Adolescent Adult Aged, 80 and over Brain - pathology Child Child, Preschool Cohort Studies Cytoplasmic Dyneins - genetics Family Humans Infant Leg - pathology Leg - physiopathology Middle Aged Muscular Atrophy, Spinal - genetics Muscular Atrophy, Spinal - pathology Muscular Atrophy, Spinal - physiopathology Mutation Phenotype Young Adult
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Summary:	OBJECTIVE: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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. These authors contributed equally to this work.
ISSN:	0028-3878 1526-632X
DOI:	10.1212/WNL.0000000000001269