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.

Incidence of acquired demyelinating syndromes of the CNS in Dutch children: a nationwide study.

Acquired demyelinating syndromes (ADS) can be a first presentation of multiple sclerosis (MS) in children. The incidence of these disorders in Europe is currently unknown. Children (<18 years old) living in the Netherlands who presented with ADS were included from January 1, 2007 to December 31, 2010 by the Dutch pediatric MS study group and the Dutch surveillance of rare pediatric disorders. Demographic and clinical data were collected. Eighty-six patients were identified over 4 years, resulting in an incidence of 0.66/1,00,000 per year. Most patients presented with polyfocal ADS without encephalopathy (30%), followed by polyfocal ADS with encephalopathy (24%), optic neuritis (ON, 22%), monofocal ADS (16%), transverse myelitis (3%), and neuromyelitis optica (3%). Patients with polyfocal ADS with encephalopathy were younger (median 3.9 years) than patients with ON (median 14.6 years, p < 0.001) or monofocal ADS (median 16.0 years, p < 0.001). Patients with polyfocal ADS without encephalopathy (median 9.2 years) were also younger than monofocal ADS patients (median 16.0 years, p < 0.001). There was a slight female preponderance in all groups except the ON group, and a relatively large number of ADS patients (29%) reported a non-European ancestry. Familial autoimmune diseases were reported in 23%, more often in patients with relapsing disease than monophasic disease (46 vs. 15%, p = 0.002) and occurring most often in the maternal family (84%, p < 0.001). During the study period, 23% of patients were subsequently diagnosed with MS. The annual incidence of ADS in the Netherlands is 0.66/1,00,000 children/year. A polyfocal disease onset of ADS was most common.

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

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.

Cerebral white matter abnormalities in 6p25 deletion syndrome.

Submicroscopic deletion of the terminal part of the short arm of chromosome 6, including 6p25, leads to developmental retardation, hearing impairment, ocular dysgenesis, and dysmorphic features. We diagnosed 3 patients referred because of white matter abnormalities of unknown origin. MR imaging showed multifocal areas of abnormal signal and enlarged perivascular spaces in the cerebral white matter that were stable during follow-up. Multifocal white matter abnormalities are most commonly seen in static, nonmetabolic encephalopathies, including chromosomal abnormalities.

GLUT-1 deficiency without epilepsy--an exceptional case.

The GLUT-1 deficiency is a metabolic disorder caused by a defect in glucose transport across the blood-brain barrier as a result of a defect in the glucose-transport protein. Patients present with epileptic seizures, delayed development, ataxia and hypotonia, and in many cases acquired microcephaly. In most patients, treatment with a ketogenic diet proved to be successful in controlling the epilepsy. We report a 9-year-old boy with retardation and ataxia, but without epilepsy, caused by GLUT-1 deficiency, proven biochemically and by DNA analysis. Treatment with a medium-chain triglyceride ketogenic diet had a beneficial effect.

Rhombencephalosynapsis: clinical findings and neuroimaging in 9 children.

Rhombencephalosynapsis is a rare congenital abnormality characterised by dorsal fusion of the cerebellar hemispheres, agenesis or hypogenesis of the vermis, fusion of dentate nuclei and superior cerebellar peduncles. We describe 9 children, aged 1.5 to 6 years, with rhombencephalosynapsis. Isolated rhombencephalosynapsis was found in 2 patients, hydrocephalus in 3 children and another 3 children had ventriculomegaly. Additional supratentorial abnormalities were documented in 5 patients. Clinical findings ranged from mild truncal ataxia and normal cognitive abilities to severe cerebral palsy and mental retardation. No correlation between clinical findings and magnetic resonance imaging could be established so far.