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


ABSTRACT: 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.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.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.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.

SUBMITTER: Scoto M 

PROVIDER: S-EPMC4336105 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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

Scoto Mariacristina M   Rossor Alexander M AM   Harms Matthew B MB   Cirak Sebahattin S   Calissano Mattia M   Robb Stephanie S   Manzur Adnan Y AY   Martínez Arroyo Amaia A   Rodriguez Sanz Aida A   Mansour Sahar S   Fallon Penny P   Hadjikoumi Irene I   Klein Andrea A   Yang Michele M   De Visser Marianne M   Overweg-Plandsoen W C G Truus WC   Baas Frank F   Taylor J Paul JP   Benatar Michael M   Connolly Anne M AM   Al-Lozi Muhammad T MT   Nixon John J   de Goede Christian G E L CG   Foley A Reghan AR   Mcwilliam Catherine C   Pitt Matthew M   Sewry Caroline C   Phadke Rahul R   Hafezparast Majid M   Chong W K Kling WK   Mercuri Eugenio E   Baloh Robert H RH   Reilly Mary M MM   Muntoni Francesco F  

Neurology 20150121 7


<h4>Objective</h4>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.<h4>Methods</h4>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.<h4>Results</h4>We report a co  ...[more]

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