Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies.

Idiopathic generalized epilepsy (IGE) is an inherited neurological disorder affecting about 0.4% of the world's population. Mutations in ten genes causing distinct forms of idiopathic epilepsy have been identified so far, but the genetic basis of many IGE subtypes is still unknown. Here we report a gene associated with the four most common IGE subtypes: childhood and juvenile absence epilepsy (CAE and JAE), juvenile myoclonic epilepsy (JME), and epilepsy with grand mal seizures on awakening (EGMA; ref. 8). We identified three different heterozygous mutations in the chloride-channel gene CLCN2 in three unrelated families with IGE. These mutations result in (i) a premature stop codon (M200fsX231), (ii) an atypical splicing (del74-117) and (iii) a single amino-acid substitution (G715E). All mutations produce functional alterations that provide distinct explanations for their pathogenic phenotypes. M200fsX231 and del74-117 cause a loss of function of ClC-2 channels and are expected to lower the transmembrane chloride gradient essential for GABAergic inhibition. G715E alters voltage-dependent gating, which may cause membrane depolarization and hyperexcitability.

The role of electronic assessment of adherence in the education and counseling of children taking growth hormone: progress and challenges.

There are numerous issues surrounding adherence in children taking recombinant human growth hormone (rh-GH). New technologies capable of accurately recording/monitoring may highlight some of these issues, and have value in optimizing adherence levels through education and counseling. The intention of this review is to guide healthcare professionals (HCPs). PubMed, Google Scholar and citations in published papers were used to substantiate the views expressed by the authors. Both perceptional and practical factors influence the adherence levels of children taking rh-GH. Understanding such factors may help to identify the characteristics of ideal rh-GH devices and their potential impact on adherence. New technologies, such as electronic monitors, may facilitate patient-provider discussions on adherence, and help identify barriers that are amenable to change. Monitoring adherence may also help differentiate nonadherence from biological low response to rh-GH therapy. However, the medical, psychological, social and ethical aspects of electronic assessment require further investigation.

Growth hormone and treatment outcomes: expert review of current clinical practice.

Although there are guidelines for treatment of short stature, open questions regarding optimal management of growth hormone therapy still exist. Experts attending six international meetings agree that successful therapy results in the patient attaining mid-parental height, and relies on correct diagnosis and early intervention. Experts advocate patient followup every 3-6 months, and that growth and adherence should be monitored at each visit. Growth response is variable, and an accepted definition of good/poor response is lacking. Combined with patient education and regular patient follow-up, a definition of treatment response could lead to improved treatment outcomes. Few experts use prediction models in clinical practice, but all agree that pharmacogenetics might improve prediction, enable early therapy modulation, and promote growth. Poor growth is often due to low adherence. Guidance on optimal management of growth hormone therapy is required, with focus on early diagnosis, dosing, treatment monitoring, adherence, and motivation.

Development of mental health dysfunction in childhood epilepsy.

A marked prevalence of mental health dysfunction in childhood epilepsy has been documented in the literature. While several individual risk factors have been identified, which are statistically associated with an impaired mental health outcome, there is a lack of knowledge on the pathways taken by these risk factors on disease development and treatment. The relevant literature of the last decade will be reviewed in this paper to provide evidence for the conceptual framework presented here. Thus, the emergence of mental health dysfunction in childhood epilepsy is analyzed under three levels. Pathogenetic causes: These involve both the underlying CNS pathology and the associated epilepsy disorder characterized by specific time of onset duration type and severity. Mediators and moderators connecting causes to outcomes: These comprise, firstly, the differentiation between the intervening role of anti-epileptic drugs and their positive psychotropic impact via suppression of seizure activity and transient cognitive impairments, as against their negative psychotropic side-effects; secondly, the psychological processes of adaptation which entail responding to three major demands (adherence to treatment requirements, exercising self-control and lifestyle modification to reduce seizure activity, and coping with the psychosocial stressors secondary to living with epilepsy); thirdly, the age-dependent level of neurocognitive and behavioral functioning; and, fourthly, contextual risks and protective factors within the family and social environment. Mental health outcome: This encompasses three major domains: risks for learning disability, for impairments of health-related quality of life, and for psychopathology. The proposed framework serves the development and validation of hypotheses and can be applied to testing procedures aimed at investigating the emergence of mental health dysfunction in childhood epilepsy. On the scientific level, it provides an appropriate tool to approach childhood epilepsy in general, whereas on the clinical level, it facilitates the assessment and management of individual patients.

Risk analyses for the cognitive phenotype in Turner's syndrome: evidence of familial influence as a decisive factor.

The interindividual varying cognitive performance in female patients with Turner's syndrome has usually been attributed to the interindividual varying mosaicism with a consecutive variable loss of X-chromosome DNA or to secondary risk factors such as estrogen deficiency owing to ovarian failure. The aim of our study was to determine the specific impact of X chromosome-related features and associated risk factors, on the one hand and familial influences, on the other hand on the interindividual variation in the cognitive phenotype. One hundred and one subjects with Turner's syndrome and 53 sisters as controls for familial influences were examined by comparing the cognitive information processing abilities (Kaufmann Assessment Battery for Children [K-ABC]). Subjects with Turner's syndrome performed at a significantly lower level than sisters on all subscales (eg, Mental Processing Composite: Turner's syndrome 86.4 [SD 15.0] versus sisters 99.3 [SD 10.6]; P < .001). For the neurocognitive phenotype in subjects with Turner's syndrome, a significant correlation was found only with the sisters' cognitive abilities (Mental Processing Composite: r = .38, P < .05). In contrast, neither the individual mosaic status nor the known associated risk factors predicted the neurocognitive phenotype in Turner's syndrome. These results are corroborated in the regression analyses in those subjects with Turner's syndrome with a sister (Simultaneous Processing(sister) for Simultaneous Processing(Turner's syndrome): beta = .346, P < .05, corrected R2 = .049; and Mental Processing Composite(sister) for Mental Processing Composite(Turner's syndrome): beta = .354, P < .05, corrected R2 = .033). The interindividual variation of intellectual abilities in Turner's syndrome seems to be primarily related to familial coinfluences and not to the interindividual varying loss of X-chromosome DNA in terms of hidden mosaicism or potential associated risk factors.

A review of biopsychosocial strategies to prevent and overcome early-recognized poor adherence in growth hormone therapy of children.

BACKGROUND: Adherence to growth hormone (GH) therapy among children is variable and remains a problem, possibly affecting growth outcomes and future health, and having economic consequences. OBJECTIVE: To provide a review of the issues related to poor adherence to GH therapy in children and describe integrative strategies that may improve adherence. RESULTS: Poor adherence may be caused by various factors, affecting both the children and their families. The key reasons for adherence difficulties are psychological/emotional problems, social/everyday problems and technical handling issues of the drug delivery device. Correspondingly a broad range of strategies to address adherence to GH therapy often revolve around counseling and education, not just for the patient but also for the family giving care. LIMITATIONS: This review is intended as a general survey of strategies which could help, in clinical practice, to overcome poor adherence to growth hormone therapy in children; it summarizes the representative literature but it does not aim to be a rigorous database literature search in every aspect. CONCLUSIONS: If poor adherence is recognized early on during treatment, appropriate steps may be taken to identify barriers that are amenable to change for encouraging the child to adhere to the treatment regimen. A preventative approach may also be considered; for example, doctors could address adherence issues early and train families of children treated with GH to recognize the resources as well as the barriers to adherence. The broad range of different causes for poor adherence demands a great variety of interventions, making it important to individualize optimal treatment behavior. Additionally, economic studies are required to quantify the cost of poor adherence to GH therapy and to show the financial benefits of good adherence.

Observations of nonadherence to recombinant human growth hormone therapy in clinical practice.

BACKGROUND: The effectiveness of all prescribed treatments is contingent on patient adherence. The reported levels of adherence to recombinant human growth hormone (r-hGH) therapy are highly variable, but it has been suggested that nonadherence might be as high as 36% to 49%. OBJECTIVES: This commentary discusses the factors that affect long-term adherence to injection treatment, of which r-hGH therapy is a particular challenge. It also explores potential strategies to improve adherence to injection treatments in clinical practice. METHODS: The opinion of the authors was validated and supported by published literature. A PubMed literature search was conducted in November 2006, identifying English-language articles containing key terms growth hormone, adherence, and compliance. RESULTS: This study found that factors associated with poor adherence to injection treatments include patients' lack of understanding of their disease, patient age, chronicity of the disease, complex treatment regimens, and insufficient information on the implications of nonadherence. Strengthening the patient-physician relationship by providing the patient with a clear understanding of his/her disease and the benefits of adherence, making improvements in injection devices, and eliminating subjective illness concepts, might increase adherence to SC injection treatments, thereby reducing increasing health care costs associated with nonadherence. CONCLUSIONS: Poor adherence to r-hGH therapy has a dual effect, in that it leads to reduced efficacy out-comes and increased health care costs. Implementing strategies to improve adherence with injection treatment might be of particular clinical benefit to patients undergoing r-hGH therapy.

Treatment of adductor spasticity with BTX-A in children with CP: a randomized, double-blind, placebo-controlled study.

Adductor spasticity in children with cerebral palsy (CP) impairs motor function and development. In a placebo-controlled, double-blind, randomized multicentre study, we evaluated the effects of botulinum toxin A(BTX-A) in 61 children (37 males, 24 females; mean age 6 years 1 month [SD 3y 1mo]) with CP (leg-dominated tetraparesis, n=39; tetraparesis, n=22; GMFCS level I, n=3; II, n=6; III, n=17; IV, n=29; V, n=6). Four weeks after treatment, a significant superiority of BTX-A was observed in the primary outcome measure (knee-knee distance 'fast catch', p=0.002), the Ashworth scale (p=0.001), and the Goal Attainment Scale (p=0.037).

Psychomotor development in children with early diagnosed giant interhemispheric cysts.

Systematic studies of cognitive development in individuals with congenital giant interhemispheric cysts (GIC) without neurosurgical intervention are rare. However, data from such studies are of great importance in deciding whether or not to perform cerebral shunting in otherwise asymptomatic patients. In this study, psychomotor function was examined in 13 children (three females, 10 males; mean age at follow-up: females 1 year 6 months, males 3 years 2 months; age range: females 13 months to 4.2 years, males 10 months to 10 years) all diagnosed with GIC during the neonatal period after indicative foetal ultrasound. Eight patients received neurosurgical treatment due to increased intracerebral pressure during the first year of life. Psychomotor development was evaluated using Griffith's Psychomotor Developmental Scales, the Sniders-Oomen Non-verbal Intelligence Scale for Young Children and the Kaufmann Assessment Battery for Children. The majority of patients showed normal intelligence, irrespective of the presence or absence of neurosurgical intervention. Evidence was found that the cognitive outcome might be related to an association of GIC with agenesis of the corpus callosum or additional congenital cerebral malformations, such as gyration anomalies. Main postoperative complications were chronic subdural effusions with spastic cerebral (hemi)-paresis; were present in three patients. In view of the risk of severe postoperative neurological complications and a comparable psychomotor development in patients without neurosurgical treatment, recommendations for early neurosurgical intervention in otherwise asymptomatic patients with a foetal or neonatal diagnosis of GIC should be viewed with caution.

Familial factors and hearing impairment modulate the neuromotor phenotype in Turner syndrome.

In Turner syndrome (TS), an X-chromosomal anomaly characterised by total or partial loss of the second X-chromosome, muscle hypotonia, and lower proficiency in fine and gross motor skills have been described. It is assumed that the neuromotor phenotype in TS is linked with X-chromosomal factors (individual mosaicism) and with the oestrogen deficiency due to streak gonads. From studies in normal populations, a further risk factor may be recurrent otitis media (OM), which occurs frequently in TS, often in combination with hearing impairment (HI). It is also likely that familial factors are involved. The aim of our study was to specify the respective impact of the interindividual varying status of mosaicism and of hypergonadotropic hypogonadism as well as of the risk factors recurrent OM and HI in comparison to familial coinfluences on the neuromotor proficiency (MOP) in TS. We used the Bruininks-Oseretsky Test of Motor Proficiency to examine 105 subjects with TS (mean age 9.4 years; SD 3.3 years) and 52 sisters (mean age 9.8 years; SD 3.7 years). Significant correlations were found for familial covariance regarding the relation between TS subjects and their sisters ( r=0.42, P<0.01) and HI and MOP ( r=-0.39, P<0.01) CONCLUSION: we conclude that the familial influences and risk factors such as recurrent otitis media in combination with hearing impairment serve primarily as important predictors of the individual neuromotor phenotype in Turner syndrome.