Expanding the phenotype of DYNC1H1-associated diseases with a rare variant resulting in spinal muscular atrophy with lower extremity predominance (SMA-LED) and upper motor neuron signs.

BACKGROUND: Spinal muscular atrophy with lower extremity predominance (SMA-LED) is an autosomal dominant disorder. Since SMA-LED affects lower motor neurons, the disease is characterized by weakness and atrophy of lower limb muscles. We present a familial case series of SMA-LED with upper motor neuron signs associated with a rare variant in DYNC1H1. CASE: The index case was referred to Pediatric Neurology at the age of two and half years, due to delayed mobility. The child was diagnosed with congenital vertical talus at birth, which was managed with serial bilateral casting and surgery. The delayed mobility was initially attributed to lower limb weakness secondary to prolonged periods of immobilization from casting of his lower limbs. He had a striking waddling gait and proximal muscle weakness on neurological assessment. He had lower motor neuron signs predominantly in his lower limbs that were in keeping with SMA-LED. Surprisingly, he also demonstrated a brisk crossed adductor response that was not in keeping with an isolated primary neuro-muscular disorder and suggested a mixed upper and lower motor neuron pathology. The inherited neuropathy gene panel revealed a heterozygous sequence change in the DYNC1H1 gene which was present in all affected family members. CONCLUSIONS: We present the first report of a familial case series of SMA-LED with upper motor neuron signs associated with an extremely rare variant in DYNC1H1: c.1808A > T (p.Glu603Val). As per the American College of Medical Genetics and Genomics (ACMG) guidelines for variant classification, we would recommend that this variant be reclassified as `Likely Pathogenic` due to matching 1 moderate (PM1-PM6) and ≥4 supporting (PP1-PP5) criteria in the reported case series.

Evolving Cognitive Dysfunction in Children with Neurologically Stable Opsoclonus-Myoclonus Syndrome.

Cognitive and acquired neurodevelopmental deficits have been reported in children with opsoclonus-myoclonus syndrome (OMS) and are known to be associated with more severe and relapsing disease course. However, there is a paucity of data regarding cognitive dysfunction in children with stable neurological disease. We report three children with OMS and evolving cognitive dysfunction in the context of a mild disease course. The children's ages at disease onset were between 17 and 35 months and they were followed up for 4-10 years. Neuroblastoma was identified in one child. OMS severity scores ranged between 8 and 12/15 at presentation. They underwent immunotherapy and all were in remission by 7 months (range 4-13 months), with treatment maintained for 1 year. One child remained relapse-free, while two others had one clinical relapse each and were immunotherapy-responsive again. In all cases, evolving cognitive dysfunction was reported despite being in remission and stable off treatment for a median of 20 months (range of 12-31 months; two OMS scores of 0/15 and one of 2/15). In children with OMS who have completed treatment and have made full or near full neurological recovery, concerns remain regarding long-term outcome in terms of future learning and cognitive development.

Trends in phenotype in the English paediatric neurofibromatosis type 2 cohort stratified by genetic severity.

Childhood onset neurofibromatosis type 2 can be severe and genotype dependent. We present a retrospective phenotypic analysis of all ascertained children in England 1.0). Focal cortical dysplasia occurred in 26% group 3 and 4% 2A. A total of 48% of group 3 underwent ≥1 major intervention (intracranial/spinal surgery/Bevacizumab/radiotherapy) compared to 35% of 2A; with 23% group 3 undergoing spinal surgery (schwannoma/ependymoma/meningioma resection) compared to 4% of 2A. Mean age starting Bevacizumab was 12.7 in group 3 and 14.9 years in 2A. In conclusion, group 3 phenotype manifests earlier with greater tumour load, poorer visual outcomes and more intervention.

Diagnosis of sporadic neurofibromatosis type 2 in the paediatric population.

OBJECTIVE: Onset of symptoms in severe sporadic neurofibromatosis type 2 (NF2) is typically within childhood; however, there is poor awareness of presenting features in young children, potentially resulting in delayed diagnosis and poorer outcome. We have reviewed presentation of sporadic paediatric NF2 to raise awareness of early features, highlighting those requiring further investigation. DESIGN: Patients diagnosed with NF2 at age ≤16 and seen between 2012 and 2015 were notified via the British Paediatric Neurology Surveillance Unit or identified through the English NF2 service. RESULTS: Epidemiological data estimate that 1 in 110 611 births are affected with childhood-onset NF2. Notes of 32 patients with sporadic NF2 were reviewed. Of those presenting under the age of 5, 89% (17/19) had ocular, 74% (14/19) dermatological and 58% (11/19) neurological signs; in 84% (16/19) features were multisystemic. Sixty-six per cent (21/32) had ≥1 atypical feature, including cerebellar hypoplasia in three cases (9%) and focal cortical dysplasia in five out of seven seizure-related presentations. Five cases presented with a sometimes transient or intermittent cranial nerve mononeuropathy. The mean delay to diagnosis was 3.16 years; in eight cases (25%) this exceeded 6 years. Most significant delay occurred in mononeuropathy, ophthalmological and/or seizure presentations, with a mean delay of 3, 4.5 and 6 years, respectively. Eighty-four per cent (27/32) of cases needed intervention in childhood. CONCLUSIONS: All non-vestibular schwannoma NF2 presentations in childhood had significant diagnostic delay. We emphasise the importance of detailed assessment of skin and eyes in unusual presentations and propose an aide to prompt timely referral to specialist services.

Altered functional brain connectivity in children and young people with opsoclonus-myoclonus syndrome.

AIM: Opsoclonus-myoclonus syndrome (OMS) is a rare, poorly understood condition that can result in long-term cognitive, behavioural, and motor sequelae. Several studies have investigated structural brain changes associated with this condition, but little is known about changes in function. This study aimed to investigate changes in brain functional connectivity in patients with OMS. METHOD: Seven patients with OMS and 10 age-matched comparison participants underwent 3T magnetic resonance imaging (MRI) to acquire resting-state functional MRI data (whole-brain echo-planar images; 2mm isotropic voxels; multiband factor ×2) for a cross-sectional study. A seed-based analysis identified brain regions in which signal changes over time correlated with the cerebellum. Model-free analysis was used to determine brain networks showing altered connectivity. RESULTS: In patients with OMS, the motor cortex showed significantly reduced connectivity, and the occipito-parietal region significantly increased connectivity with the cerebellum relative to the comparison group. A model-free analysis also showed extensive connectivity within a visual network, including the cerebellum and basal ganglia, not present in the comparison group. No other networks showed any differences between groups. INTERPRETATION: Patients with OMS showed reduced connectivity between the cerebellum and motor cortex, but increased connectivity with occipito-parietal regions. This pattern of change supports widespread brain involvement in OMS.

Cerebellar and cortical abnormalities in paediatric opsoclonus-myoclonus syndrome.

AIM: Paediatric opsoclonus-myoclonus syndrome (OMS) is a poorly understood condition with long-term cognitive, behavioural, and motor sequelae. Neuroimaging has indicated cerebellar atrophy in the chronic phase, but this alone may not explain the cognitive sequelae seen in many children with OMS. This study aimed to determine the extent of structural change throughout the brain that may underpin the range of clinical outcomes. METHOD: Nine participants with OMS (one male, eight females; mean age [SD] 14y, [6y 5mo], range 12-30y) and 10 comparison individuals (three males, seven females; mean age 12y 6mo, [4y 9mo], range 10-23y) underwent magnetic resonance imaging to acquire T1-weighted structural images, diffusion-weighted images, and magnetic resonance spectroscopy scans. Neuroblastoma had been present in four participants with OMS. Voxel-based morphometry was used to determine changes in grey matter volume, tract-based spatial statistics to analyze white matter integrity, and Freesurfer to analyze cortical thickness across visual and motor cortices. RESULTS: Whole-brain analysis indicated that cerebellar grey matter was significantly reduced in the patients with OMS, particularly in the vermis and flocculonodular lobe. A region-of-interest analysis indicated significantly lower cerebellar grey matter volume, particularly in patients with the greatest OMS scores. Diffusion-weighted images did not show effects at a whole brain level, but all major cerebellar tracts showed increased mean diffusivity when analysis was restricted to the cerebellum. Cortical thickness was reduced across the motor and visual areas in the OMS group, indicating involvement beyond the cerebellum. INTERPRETATION: Across individuals with OMS, there is considerable cerebellar atrophy, particularly in the vermis and flocculonodular lobes with atrophy severity associated with persistent symptomatology. Differences in cerebral cortical thickness indicate disease effects beyond the cerebellum.