Risk of hospital-treated injury in children with cerebral palsy: a population-based cohort study.

AIM: To study whether cerebral palsy (CP) increases the risk of hospital-treated injuries in children up to 13 years of age. METHODS: A Finnish population-based cohort (n=328 903) of children born during 2001 to 2006 was followed up for hospital-treated injuries until the end of 2014 via linkage of nation-wide registers. The rate of first injury was compared in children with and without CP. The effect of CP type, gender, severe comorbidities (intellectual disability, epilepsy, hearing or visual impairment), and the type of injury was evaluated. RESULTS: Children with CP had an increased risk of injury compared with children without CP (unadjusted HR: 1.2, 95% CI: 1.0 - 1.4, p=0.40). Girls with CP (n = 191) had a higher risk of injury compared with girls without CP (29% vs 22%, HR: 1.4, 95% CI: 1.1 to 1.8, p = 0.01). Any comorbidity increased the risk of injury (HR: 1.5, 95% CI: 1.1 to 2.2, p = 0.015) among children with CP. Children with CP had a higher risk of traumatic brain injury (HR: 1.7, 95% CI 1.2 to 2.4, p = 0.002) than children without CP. CONCLUSION: Girls with CP had the highest risk of hospital-treated injury. Children with CP are particularly prone to traumatic brain injuries.

Two middle-aged women with the Finnish variant of muscle-eye-brain disease (MEB).

Muscle-eye-brain disease (MEB) is a recessively inherited rare disease. Sixteen different gene mutations are known, with the most common mutations in the POMGNT1 gene. The disease is now called congenital muscular dystrophy-dystroglycanopathy type A3 (MDDGA3). It manifests itself as muscular dystrophy with eye and brain anomalies and intellectual disability. Previous clinical reports describe young patients. We have been able to follow two patients for almost 40 years. Their clinical picture has remained quite stable since adolescence, appearing as severe intellectual and motor disability, extremely limited communication skills, visual impairment, epilepsy, joint contractures, repeated bowel obstructions, teeth abrasion due to bruxism, an irregular sleep pattern and as a previously unreported feature hypothermic periods manifesting as excessive sleepiness.

Heterozygous loss of function of IQSEC2/Iqsec2 leads to increased activated Arf6 and severe neurocognitive seizure phenotype in females.

Clinical presentations of mutations in the IQSEC2 gene on the X-chromosome initially implicated to cause non-syndromic intellectual disability (ID) in males have expanded to include early onset seizures in males as well as in females. The molecular pathogenesis is not well understood, nor the mechanisms driving disease expression in heterozygous females. Using a CRISPR/Cas9-edited Iqsec2 KO mouse model, we confirm the loss of Iqsec2 mRNA expression and lack of Iqsec2 protein within the brain of both founder and progeny mice. Both male (52%) and female (46%) Iqsec2 KO mice present with frequent and recurrent seizures. Focusing on Iqsec2 KO heterozygous female mice, we demonstrate increased hyperactivity, altered anxiety and fear responses, decreased social interactions, delayed learning capacity and decreased memory retention/novel recognition, recapitulating psychiatric issues, autistic-like features, and cognitive deficits present in female patients with loss-of-function IQSEC2 variants. Despite Iqsec2 normally acting to activate Arf6 substrate, we demonstrate that mice modelling the loss of Iqsec2 function present with increased levels of activated Arf6. We contend that loss of Iqsec2 function leads to altered regulation of activated Arf6-mediated responses to synaptic signalling and immature synaptic networks. We highlight the importance of IQSEC2 function for females by reporting a novel nonsense variant c.566C > A, p.(S189*) in an elderly female patient with profound intellectual disability, generalised seizures, and behavioural disturbances. Our human and mouse data reaffirm IQSEC2 as another disease gene with an unexpected X-chromosome heterozygous female phenotype. Our Iqsec2 mouse model recapitulates the phenotypes observed in human patients despite the differences in the IQSEC2/Iqsec2 gene X-chromosome inactivation between the species.

A 69-year-old woman with Coffin-Siris syndrome.

Coffin-Siris syndrome (CSS) is a rare intellectual disability syndrome classically characterized by aplasia or hypoplasia of the distal phalanx or nail of the fifth and other digits, distinctive facial features, hirsutism/hypertrichosis, and sparce scalp hair. It is genetically heterogeneous but most often caused by a pathogenic variant in the ARID1B gene. Previous clinical reports of CSS patients are mainly based on young or middle-aged individuals. Here, we report a 69-year-old woman with CSS phenotype and a pathogenic ARID1B loss-of-function variant c.5259_5260dup. She has severe intellectual disability but otherwise she is in relatively good health both physically and mentally. There is no evident history of chronic illness or progressive disability. CSS appears to be compatible with long survival and most likely it is underdiagnosed in geriatric patients with intellectual disability.