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 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

Prednisone 10 days on/10 days off in patients with Duchenne muscular dystrophy.

Contains fulltext : 81898.pdf (publisher's version ) (Closed access)Corticosteroids are effective in improving motor function in Duchenne muscular dystrophy (DMD) patients within 6 months-2 years of treatment initiation, but there is as yet no consensus on which treatment scheme is the best. We retrospectively analyzed data of 35 DMD patients who were treated with prednisone 0.75 mg/kg per day intermittently 10 days on/10 days off. Prednisone was started during the ambulant phase at age 3.5-9.7 years (median 6.5 years). The median period of treatment was 27 months (range 3-123 months). The median age at which ambulation was lost was 10.8 years (mean 10.9 years; 95% confidence interval 10.0-11.8 years). Nine patients (26%) had excessive weight gain. Eight boys (21%) had a bone fracture, which was when four of these eight children lost the ability to walk. Treatment was stopped in two obese patients, two hyperactive boys and one patient following a fracture. Our data suggest that prednisone 10 on/10 off has relatively few side effects and extends the ambulant phase by 1 year compared to historical controls