Mutations disrupting neuritogenesis genes confer risk for cerebral palsy.

In addition to commonly associated environmental factors, genomic factors may cause cerebral palsy. We performed whole-exome sequencing of 250 parent-offspring trios, and observed enrichment of damaging de novo mutations in cerebral palsy cases. Eight genes had multiple damaging de novo mutations; of these, two (TUBA1A and CTNNB1) met genome-wide significance. We identified two novel monogenic etiologies, FBXO31 and RHOB, and showed that the RHOB mutation enhances active-state Rho effector binding while the FBXO31 mutation diminishes cyclin D levels. Candidate cerebral palsy risk genes overlapped with neurodevelopmental disorder genes. Network analyses identified enrichment of Rho GTPase, extracellular matrix, focal adhesion and cytoskeleton pathways. Cerebral palsy risk genes in enriched pathways were shown to regulate neuromotor function in a Drosophila reverse genetics screen. We estimate that 14% of cases could be attributed to an excess of damaging de novo or recessive variants. These findings provide evidence for genetically mediated dysregulation of early neuronal connectivity in cerebral palsy.

Mutations in SNORD118 cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts.

Although ribosomes are ubiquitous and essential for life, recent data indicate that monogenic causes of ribosomal dysfunction can confer a remarkable degree of specificity in terms of human disease phenotype. Box C/D small nucleolar RNAs (snoRNAs) are evolutionarily conserved non-protein-coding RNAs involved in ribosome biogenesis. Here we show that biallelic mutations in the gene SNORD118, encoding the box C/D snoRNA U8, cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts (LCC), presenting at any age from early childhood to late adulthood. These mutations affect U8 expression, processing and protein binding and thus implicate U8 as essential in cerebral vascular homeostasis.

Splint: the efficacy of orthotic management in rest to prevent equinus in children with cerebral palsy, a randomised controlled trial.

BACKGROUND: Range of motion deficits of the lower extremity occur in about the half of the children with spastic cerebral palsy (CP). Over time, these impairments can cause joint deformities and deviations in the children's gait pattern, leading to limitations in moblity. Preventing a loss of range of motion is important in order to reduce secondary activity limitations and joint deformities. Sustained muscle stretch, imposed by orthotic management in rest, might be an effective method of preventing a decrease in range of motion. However, no controlled study has been performed. METHODS: A single blind randomised controlled trial will be performed in 66 children with spastic CP, divided over three groups with each 22 participants. Two groups will be treated for 1 year with orthoses to prevent a decrease in range of motion in the ankle (either with static or dynamic knee-ankle-foot-orthoses) and a third group will be included as a control group and will receive usual care (physical therapy, manual stretching). Measurements will be performed at baseline and at 3, 6, 9 and 12 months after treatment allocation. The primary outcome measure will be ankle dorsiflexion at full knee extension, measured with a custom designed hand held dynamometer. Secondary outcome measures will be i) ankle and knee flexion during gait and ii) gross motor function. Furthermore, to gain more insight in the working mechanism of the orthotic management in rest, morphological parameters like achilles tendon length, muscle belly length, muscle fascicle length, muscle physiological cross sectional area length and fascicle pennation angle will be measured in a subgroup of 18 participants using a 3D imaging technique. DISCUSSION: This randomised controlled trial will provide more insight into the efficacy of orthotic management in rest and the working mechanisms behind this treatment. The results of this study could lead to improved treatments. TRIAL REGISTRATION NUMBER: Nederlands Trial Register NTR2091.

Repair of strabismus and binocular fusion in children with cerebral palsy: gross motor function classification scale.

PURPOSE: Children with cerebral palsy (CP) tend to be either excluded from studies of strabismus repair or pooled with children who have other neurologic disorders. The authors limited this study to children with defined CP to determine the success or failure of restoring eye alignment and fusion. METHODS: An observational, cross-sectional, prospective study was conducted on a representative cohort of 50 children. CP severity ranged from Gross Motor Function Classification System (GMFCS) level 1 (least severe) to 5 (most severe). Mean age at entrance and surgery was 3.5 years, and mean follow-up was 4.1 years (minimum 1 year). RESULTS: The predominant form of strabismus was infantile-onset: esotropia in 54%, exotropia in 26%, and dyskinesia in 10%. Sixty-six percent of esotropic children and 61% of exotropic children achieved optimal (microtropic) alignment after an average of 2 and 1.8 surgical procedures, respectively. The likelihood of optimal alignment was similar in children with mild (GMFCS level 1-2) versus severe (GMFCS level 3-5) CP (P = 0.7; χ(2)). Irrespective of GMFCS severity, 46% of children gained binocular fusion/stereopsis, but the quality of fusion gained was greater in children with mild CP (P < 0.05). Earlier surgery was more likely to be successful (P < 0.05). CONCLUSIONS: Restoration of binocular alignment and a degree of fusion is a realistic goal in the majority of strabismic CP children. Repair may be achieved in children at both the mild and the severe ends of the GMFCS spectrum, without undue concern about treatment futility or excessive reoperation.