Congenital muscular dystrophies display a wide phenotypic and genetic heterogeneity. The combination of clinical, biochemical, and molecular genetic findings must be considered to obtain the precise diagnosis and provide appropriate genetic counselling. Here we report five individuals from four families presenting with variable clinical features including muscular dystrophy with a reduction in dystroglycan glycosylation, short stature, intellectual disability, and cataracts, overlapping both the dystroglycanopathies and Marinesco-Sjögren syndrome. Whole-exome sequencing revealed homozygous missense and compound heterozygous mutations in INPP5K in the affected members of each family. INPP5K encodes the inositol polyphosphate-5-phosphatase K, also known as SKIP (skeletal muscle and kidney enriched inositol phosphatase), which is highly expressed in the brain and muscle. INPP5K localizes to both the endoplasmic reticulum and to actin ruffles in the cytoplasm. It has been shown to regulate myoblast differentiation and has also been implicated in protein processing through its interaction with the ER chaperone HSPA5/BiP. We show that morpholino-mediated inpp5k loss of function in the zebrafish results in shortened body axis, microphthalmia with disorganized lens, microcephaly, reduced touch-evoked motility, and highly disorganized myofibers. Altogether these data demonstrate that mutations in INPP5K cause a congenital muscular dystrophy syndrome with short stature, cataracts, and intellectual disability.

Objective: To determine effects of implementing a practice period of modified constraint-induced movement therapy in a virtual environment on upper limb function in children with spastic hemiparetic cerebral palsy. Methods: In a single-blinded, randomised, controlled trial, 32 participants (18 female, 14 male) received 18 hours training in 3 different groups (virtual reality, modified constraint-induced movement therapy, and a combination group). The fourth group was a control group. Training sessions occurred every other day, 3 times per week for 4-week. Each session lasted for 1.5 hours. Assessment sessions were conducted before, after, and 3-month after treatment period using pediatric motor activity log and the speed and dexterity subtest of the bruininks-oseretsky test of motor proficiency. Data analysis was conducted by ANOVA with repeated measures using SPSS 16.0 with alpha levels set at P < 0.05. Results: Significantly higher gains were observed in the combination therapy group for the amount of limb use (mean change, 2.72), quality of movement (mean change, 2.79), and speed and dexterity (mean change, 1.74) at post-test. These gains were maintained at the 3-month follow-up assessment. Conclusions: Modified constraint-induced movement therapy in a virtual environment could be a promising rehabilitation procedure to enhance the benefits of both virtual reality and constraint-induced therapy techniques.

Modified CIMT is effective in improving upper limb function in children with spastic hemiplegic cerebral palsy. In addition, more improved performance in home group places the practice in natural context as the preferred method for treatment of these children.

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Biallelic mutations of the alsin Rho guanine nucleotide exchange factor (ALS2) gene cause a group of overlapping autosomal recessive neurodegenerative disorders including infantile-onset ascending hereditary spastic paralysis (IAHSP), juvenile primary lateral sclerosis (JPLS), and juvenile amyotrophic lateral sclerosis (JALS/ALS2), caused by retrograde degeneration of the upper motor neurons of the pyramidal tracts. Here, we describe 11 individuals with IAHSP, aged 2-48 years, with IAHSP from three unrelated consanguineous Iranian families carrying the homozygous c.1640+1G>A founder mutation in ALS2. Three affected siblings from one family exhibit generalized dystonia which has not been previously described in families with IAHSP and has only been reported in three unrelated consanguineous families with JALS/ALS2. We report the oldest individuals with IAHSP to date and provide evidence that these patients survive well into their late 40s with preserved cognition and normal eye movements. Our study delineates the phenotypic spectrum of IAHSP and ALS2-related disorders and provides valuable insights into the natural disease course.