Contribution of rare genetic variants to drug response in absence epilepsy.

OBJECTIVE: We investigated the possible significance of rare genetic variants to response to valproic acid (VPA) and ethosuximide (ETX) in patients with absence epilepsy. Our primary hypothesis was that rare CACNA1H variants are more frequent in ETX-non-responsive patients compared to ETX-responsive. Our secondary hypothesis was that rare variants in GABA-receptor genes are more frequent in VPA-non-responsive patients compared to VPA-responsive. METHODS: We recruited patients with absence epilepsy treated with both VPA and ETX, and performed whole exome sequencing in order to investigate the potential role of rare variants in CACNA1H, other voltage-gated calcium channel (VGCC) genes, or GABA-receptor genes in predicting response to ETX or VPA. RESULTS: Sixty-two patients were included; 12 were ETX-responsive, 14 VPA-responsive, and 36 did not have a clear positive response to either medication. We did not find significant enrichment inCACNA1H rare variants in ETX-responsive patients (odds ratio 3.43; 0.43-27.65; p = 0.20), nor was there enrichment for other VGCC genes. No significant enrichment of GABA-receptor gene rare variants was seen for VPA-non-responsive patients versus VPA-responsive. We found enrichment of rare GABA-receptor variants in our absence cohort compared to controls (odds ratio 3.82; 1.68-8.69). There was no difference in frequency of CACNA1H rs61734410 and CACNA1I rs3747178 polymorphisms between ETX-responsive and ETX-non-responsive groups; these polymorphisms have previously been reported to predict lack of response to ETX in absence epilepsy. SIGNIFICANCE: We conclude that if CACNA1H rare variants predict lack of response to ETX, a larger sample is necessary to test this with sufficient power. Increased GABA-receptor gene rare variant frequency in absence epilepsy patients who fail initial anti-seizure therapy suggests subtle GABA receptor dysfunction may contribute to the underlying pathophysiology.

Elevated Creatine Kinase in a 6-Year-Old Boy.

Paucisymptomatic or asymptomatic but persistently elevated serum creatine kinase is not an uncommon pediatric neurology referral question. The challenge is in promptly identifying etiologies with specific treatments, even if they are rare. The presenting features for a child or adolescent with juvenile-onset Pompe disease (JOPD) can be nonspecific and heterogeneous. Clinical manifestations can appear at any age after 2 years and before adulthood, with insidious onset of symptoms related to slowly progressive skeletal or respiratory muscle weakness. This reported case highlights the importance of screening for JOPD in children with "hyper-CK-emia." Dried blood spot measuring acid α-glucosidase enzyme activity is reliable, rapid, noninvasive, and inexpensive, allowing early diagnosis. Diagnosis of JOPD is important as enzyme replacement therapy with alglucosidase alpha, an intravenous recombinant α-glucosidase, is available, and early treatment improves muscle function, quality of life, and long-term survival.

Genetic and environmental factors in vascular dementia: an update of blood brain barrier dysfunction.

Vascular dementia (VaD) describes a combination of both cognitive and behavioural manifestations associated with variable brain lesions of vascular origin. While vascular risk factors have been implicated in VaD, the relationship is most evident when the factors are considered together and not individually. This review will examine the significance of the integrity of blood brain barrier (BBB) tight junction (TJ) proteins - occludin and claudins in the pathophysiology of VaD. Specifically, some of the genetic contributors to VaD, namely those responsible for the integrity of the BBB, will be reviewed in detail. Moreover, environmental factors will be considered in conjunction with these genes to examine how the interaction of environmental and genetic factors contributes to one's susceptibility to VaD.

A diagnostic approach to recurrent myalgia and rhabdomyolysis in children.

Episodic myalgia is a common complaint in children and young adults. While many cases remain idiopathic even after extensive investigation, myalgia can be the first symptom of an underlying serious neuromuscular condition, and can be associated with an increased risk of such serious complications as rhabdomyolysis and malignant hyperthermia. We review and highlight the metabolic myopathies and other increasingly recognised muscle disorders that may present to paediatricians with episodic myalgia or isolated episodes of rhabdomyolysis, and propose a diagnostic algorithm for investigation of these complaints.

Dark chocolate for children's blood pressure: randomised trial.

BACKGROUND: Higher adult blood pressure, even without hypertension, predicts cardiovascular outcomes, and is predicted by childhood blood pressure. Regular dark chocolate intake lowers blood pressure in adults, but effects in children are unknown. AIM: To examine the feasibility of school-based provision of dark chocolate and its short-term efficacy in reducing mean group blood pressure. METHODS: 194 children (aged 10-12 years) were randomised by class to intervention (7 g dark chocolate daily for 7 weeks, n=124) or control (n=70) groups; 98% and 93% provided baseline and follow-up measurements, respectively. RESULTS: Intervention and control students had similar systolic (mean difference 1.7 mm Hg, 95% CI -0.6 to 4.1) and diastolic (-1.2 mm Hg, 95% CI -3.6 to 1.3) blood pressure, anthropometry and well-being at outcome. CONCLUSION: Results show that providing dark chocolate is feasible and acceptable in the school setting. For a definitive trial, the authors recommend a larger sample, endovascular function measures, and consideration of higher antioxidant 'dose' by virtue of duration and/or content.

Spontaneous intracranial hypotension in childhood: a case report and review of the literature.

Spontaneous intracranial hypotension results from 1 or more spontaneous spinal cerebrospinal fluid leaks, and generally presents with severe and persisting orthostatic headache. Diagnosis can be difficult as spontaneous intracranial hypotension is very rare in childhood and has a wide spectrum of clinical features and neuroimaging findings. Lumbar autologous epidural blood patch can be helpful for confirmation of diagnosis and symptom relief. We report a 15-year-old female with spontaneous intracranial hypotension who experienced immediate resolution of her symptoms following lumbar autologous epidural blood patch on 2 occasions, and review the literature on this well-recognized but probably underdiagnosed headache syndrome in childhood.

What works for therapists conducting family meetings: treatment integrity in family-focused grief therapy during palliative care and bereavement.

The purpose of this study was to evaluate the treatment integrity of Family-Focused Grief Therapy (FFGT), a preventive intervention designed for families at high risk of poor functioning during palliative care and bereavement. From the 81 families participating in a randomized controlled trial (53 assigned to therapy), 28 were randomly selected for this study of treatment fidelity using the FFGT integrity measure. A total of 109 family sessions were appraised. This represented a review of 62% of treated families, 38% of total therapy sessions, and 87% of the 15 participating therapists. Weighted mean percentage occurrences of therapist behaviors permitted trends in therapy application to be observed. Inter-rater reliability using the FFGT integrity measure was satisfactory, with 88% overall agreement. Eighty-six percent of therapists adhered faithfully to core elements of the model. Therapist competence was evidenced by a strong therapeutic alliance (94%), affirmation of family strengths in over 90%, and focus on agreed themes in 76% of sessions. Therapists averaged 10 grief-related questions per session, 7 on communication-related issues during assessment, 7 on conflict late in therapy, and 4 on cohesiveness across the course of therapy. Consistent application of FFGT, with attention to its four key themes of family communication, cohesiveness, conflict resolution, and shared grief has been demonstrated. The model is generalizable when applied by family therapists.