Aicardi-Goutieres syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where data were available), or a post-natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non-syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow-up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic lupus erythematosus were seen frequently enough to be confirmed as real associations with the Aicardi-Goutieres syndrome phenotype. We observed a robust relationship between mutations in all seven genes with increased type I interferon activity in cerebrospinal fluid and serum, and the increased expression of interferon-stimulated gene transcripts in peripheral blood. We recorded a positive correlation between the level of cerebrospinal fluid interferon activity assayed within one year of disease presentation and the degree of subsequent disability. Interferon-stimulated gene transcripts remained high in most patients, indicating an ongoing disease process. On the basis of substantial morbidity and mortality, our data highlight the urgent need to define coherent treatment strategies for the phenotypes associated with mutations in the Aicardi-Goutieres syndrome-related genes. Our findings also make it clear that a window of therapeutic opportunity exists relevant to the majority of affected patients and indicate that the assessment of type I interferon activity might serve as a useful biomarker in future clinical trials.

/pdf/characterization-of-human-disease-phenotypes-associated-with-2vwbld8vaz.pdf

Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1.

Purpose: Optimizing home and community participation of children with physical disabilities is an important outcome of rehabilitation. Method: A review of literature identified research and theory on participation of children with physical disabilities. The authors’ incorporated current knowledge to conceptualize the experience of optimal participation, formulate principles of participation-based physical and occupational therapy, and develop a five-step process for intervention. A case report was completed to illustrate application to practice. Results: Optimal participation involves the dynamic interaction of determinants (attributes of the child, family, and environment) and dimensions (physical, social, and self engagement) of participation. Real-life experiences enable children to learn new activities and develop skills that optimize their participation and self-determination. Interventions are: goal-oriented, family-centered, collaborative, strengths-based, ecological, and self-determined. A disting...

Participation-based therapy for children with physical disabilities

Aim
The aim of this study was to develop a valid classification system to describe eating and drinking ability in people with cerebral palsy (CP), and to test its reliability.

Method
The Eating and Drinking Ability Classification System (EDACS) was developed in four stages in consultation with individuals with CP, parents, and health professionals: Stage 1, drafting informed by literature and clinical experience; Stage 2, modification by nominal groups; Stage 3, refinement in an international Delphi survey; and Stage 4, testing of agreement and reliability between classifications made by speech and language therapists (SaLTs), and between SaLTs and parents.

Results
Seven nominal groups involved 56 participants; 95 people participated in two rounds of the Delphi survey. Using the version of EDACS produced from this process, SaLTs in pairs classified 100 children. The rate of absolute agreement was 78% (kappa=0.72; intraclass correlation coefficient [ICC]=0.93; 95% confidence interval [CI] 0.90–0.95). Any disagreement was only by one level, with one exception. SaLTs and parents classified 48 children. The rate of absolute agreement was 58% (kappa=0.45, ICC=0.86; 95% CI 0.76–0.92). Parents either agreed with SaLTs or rated their children as more able by one level.

Interpretation
The EDACS provides a valid and reliable system for classifying eating and drinking performance of people with CP, for use in both clinical and research contexts.

https://eprints.ncl.ac.uk/file_store/production/203566/C0A38E4D-6974-42B4-9B9E-AA07430831B0.pdf

Development and reliability of a system to classify the eating and drinking ability of people with cerebral palsy

Cerebral palsy-the most common physical disability of childhood-is a clinical diagnosis encompassing a heterogeneous group of neurodevelopmental disorders that cause impairments of movement and posture that persist throughout life. Despite being commonly attributed to a range of environmental factors, particularly birth asphyxia, the specific cause of cerebral palsy remains unknown in most individuals. A growing body of evidence suggests that cerebral palsy is probably caused by multiple genetic factors, similar to other neurodevelopmental disorders such as autism and intellectual disability. Recent advances in next-generation sequencing technologies have made possible rapid and cost-effective sequencing of the entire human genome. Novel cerebral palsy genes will probably be identified as more researchers and clinicians use this approach to study individuals with undiagnosed neurological disorders. As our knowledge of the underlying pathophysiological mechanisms of cerebral palsy increases, so will the possibility of developing genomically guided therapeutic interventions.

Genetic insights into the causes and classification of the cerebral palsies

Cerebral palsy (CP) is a disorder characterized by abnormal tone, posture and movement and clinically classified based on the predominant motor syndrome-spastic hemiplegia, spastic diplegia, spastic quadriplegia, and extrapyramidal or dyskinetic. The incidence of CP is 2-3 per 1,000 live births. Prematurity and low birthweight are important risk factors for CP; however, multiple other factors have been associated with an increased risk for CP, including maternal infections, and multiple gestation. In most cases of CP the initial injury to the brain occurs during early fetal brain development; intracerebral hemorrhage and periventricular leukomalacia are the main pathologic findings found in preterm infants who develop CP. The diagnosis of CP is primarily based on clinical findings. Early diagnosis is possible based on a combination of clinical history, use of standardized neuromotor assessment and findings on magnetic resonance imaging (MRI); however, in most clinical settings CP is more reliably recognized by 2 years of age. MRI scan is indicated to delineate the extent of brain lesions and to identify congenital brain malformations. Genetic tests and tests for inborn errors of metabolism are indicated based on clinical findings to identify specific disorders. Because CP is associated with multiple associated and secondary medical conditions, its management requires a multidisciplinary team approach. Most children with CP grow up to be productive adults.

Cerebral palsy in children: a clinical overview

Individuals with cerebral palsy (CP) have sensorimotor and developmental issues that affect their daily lives by restricting their mobility, manipulation of objects, and/or communication.1 Within the framework of the World Health Organization’s International Classification of Functioning, Disability and Health (ICF),2,3 the Gross Motor Function Classification System (GMFCS)4 and the Manual Ability Classification System (MACS) for children with CP5 make it possible to classify mobility and handling objects respectively, at the ICF activity/participation level.6 However, no analogous classification of functional communication has been available for use in CP practice and research. The lack of a communication classification tool that is quick, reliable, valid, and easy to use limits the comparison of descriptive CP epidemiology studies as well as the interpretation and generalizability of CP treatment studies.

Communication disorders can be described from several perspectives: body structure and function level, activity level, and participation level, as well as environmental and personal levels.2,3,7–13 Estimates of communication disorders in CP have varied from 31%14 to 88%.15 This wide range is partly a result of the lack of a consensus definition of communication disorders within CP research and practice. A recent study from a Norwegian CP registry reported that 51% of children with CP had speech problems as classified by ratings of ‘slightly indistinct’, ‘obviously indistinct’, ‘severely indistinct’, or ‘no speech’, including 19% who had ‘no speech’.16 This population-based estimate reporting indistinct or no speech may underestimate CP communication disorders as it may not capture other types of communication problems resulting from hearing or language impairments. However, reporting speech, language, and hearing difficulties simply suggests the range of associated impairments in CP, not the more pertinent daily-life issues of how well a child with CP communicates with family, friends, acquaintances, and strangers.13

The purpose of this study was to create and validate a communication function classification system (CFCS) for children with CP, for use by a wide variety of individuals interested in CP. This required a shift from the traditional focus on body structure and function (i.e. assessing components of speech, language, and hearing problems), to a focus on activity/participation, specifically the way in which to classify a person’s communication capacity within real-life situations.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1469-8749.2011.03996.x

Brenda Johnson

Papers

Developing and validating the Communication Function Classification System for individuals with cerebral palsy

Communication Function Classification System