Chronic progressive external ophthalmoplegia (CPEO) is common in mitochondrial disorders and is frequently associated with multiple mtDNA deletions. The onset is typically in adulthood, and affected subjects can also present with general muscle weakness. The underlying genetic defects comprise autosomal-dominant or recessive mutations in several nuclear genes, most of which play a role in mtDNA replication. Next-generation sequencing led to the identification of compound-heterozygous RNASEH1mutations in two singleton subjects and a homozygous mutation in four siblings. RNASEH1, encoding ribonuclease H1 (RNase H1), is an endonuclease that is present in both the nucleus and mitochondria and digests the RNA component of RNA-DNA hybrids. Unlike mitochondria, the nucleus harbors a second ribonuclease (RNase H2). All affected individuals first presented with CPEO and exercise intolerance in their twenties, and these were followed by muscle weakness, dysphagia, and spino-cerebellar signs with impaired gait coordination, dysmetria, and dysarthria. Ragged-red and cytochrome c oxidase (COX)-negative fibers, together with impaired activity of various mitochondrial respiratory chain complexes, were observed in muscle biopsies of affected subjects. Western blot analysis showed the virtual absence of RNase H1 in total lysate from mutant fibroblasts. By an in vitro assay, we demonstrated that altered RNase H1 has a reduced capability to remove the RNA from RNA-DNA hybrids, confirming their pathogenic role. Given that an increasing amount of evidence indicates the presence of RNA primers during mtDNA replication, this result might also explain the accumulation of mtDNA deletions and underscores the importance of RNase H1 for mtDNA maintenance.
AJHG 2015
sabato 20 giugno 2015
Dose-dependent teratogenicity of valproate in mono- and polytherapy An observational study
Objective: To assess the risk of major congenital malformations (MCMs) in association with maternal use of valproic acid (VPA) in monotherapy or adjunctive therapy, and its relationship with dose.
Methods: The analysis was based on prospectively acquired data from EURAP, a registry enrolling women treated with antiepileptic drugs (AEDs) in early pregnancy, in which the primary outcome is presence of MCMs at 1 year after birth. Exposure was defined as type and dose of AEDs at time of conception. A comparison was made among 3 exposure types: (1) VPA monotherapy (n = 1,224); (2) VPA combined with lamotrigine (LTG) (n = 159); and (3) VPA combined with another AED but not LTG (n = 205).
Results: The frequency of MCMs at 1 year after birth was 10.0% for VPA monotherapy, 11.3% for exposures to VPA and LTG, and 11.7% for exposures to VPA + another (non-LTG) AED. Regardless of exposure group, the frequency of MCMs increased with dose of VPA, being highest at doses ≥1,500 mg/d (24.0% for monotherapy, 31.0% for VPA + LTG, and 19.2% for VPA + other AEDs), and was similar across treatment groups at the lowest VPA dose level of <700 mg/d (5.9% for monotherapy, 7.0% for VPA + LTG, and 5.4% for VPA + other AEDs).
Conclusions: The risk of MCMs associated with VPA exposure increases with increasing VPA dose, both in the presence and in the absence of one concomitant AED, and appears to be related primarily to the dose of VPA.
Neurology 2015
ADCY5 mutations are another cause of benign hereditary chorea
Objective: To determine the contribution of ADCY5 mutations in cases with genetically undefined benign hereditary chorea (BHC).
Methods: We studied 18 unrelated cases with BHC (7 familial, 11 sporadic) who were negative for NKX2-1mutations. The diagnosis of BHC was based on the presence of a childhood-onset movement disorder, predominantly characterized by chorea and no other major neurologic features. ADCY5 analysis was performed by whole-exome sequencing or Sanger sequencing. ADCY5 and NKX2-1 expression during brain development and in the adult human brain was assessed using microarray analysis of postmortem brain tissue.
Results: The c.1252C>T; p.R418W mutation was identified in 2 cases (1 familial, 1 sporadic). The familial case inherited the mutation from the affected father, who had a much milder presentation, likely due to low-grade somatic mosaicism. The mutation was de novo in the sporadic case. The clinical presentation of these cases featured nonparoxysmal generalized chorea, as well as dystonia in the most severely affected, but no facial myokymia. We observed significant progression of symptoms in ADCY5 mutation carriers, in contrast to BHC secondary to NKX2-1mutations. The difference in the clinical course is mirrored by the brain expression data, showing increasing ADCY5expression in the striatum during brain development, whereas NKX2-1 shows an opposite trend.
Conclusions: Our study identifies mutations in ADCY5, the gene previously linked to familial dyskinesia with facial myokymia, as a cause of familial and sporadic BHC. ADCY5 genetic analysis should be performed in cases with a benign choreiform movement disorder even in the absence of facial myokymia.
Neurology 2015
Patients optimizing epilepsy management via an online community The POEM Study
Objective: The study objective was to test whether engaging in an online patient community improves self-management and self-efficacy in veterans with epilepsy.
Methods: The study primary outcomes were validated questionnaires for self-management (Epilepsy Self-Management Scale [ESMS]) and self-efficacy (Epilepsy Self-Efficacy Scale [ESES]). Results were based on within-subject comparisons of pre- and postintervention survey responses of veterans with epilepsy engaging with the PatientsLikeMe platform for a period of at least 6 weeks. Analyses were based on both completer and intention-to-treat scenarios.
Results: Of 249 eligible participants enrolled, 92 individuals completed both surveys. Over 6 weeks, completers improved their epilepsy self-management (ESMS total score from 139.7 to 142.7, p = 0.02) and epilepsy self-efficacy (ESES total score from 244.2 to 254.4, p = 0.02) scores, with greatest impact on an information management subscale (ESMS–information management total score from 20.3 to 22.4, p < 0.001). Results were similar in intention-to-treat analyses. Median number of logins, postings to forums, leaving profile comments, and sending private messages were more common in completers than noncompleters.
Conclusions: An internet-based psychosocial intervention was feasible to implement in the US veteran population and increased epilepsy self-management and self-efficacy scores. The greatest improvement was noted for information management behaviors. Patients with chronic conditions are increasingly encouraged to self-manage their condition, and digital communities have potential advantages, such as convenience, scalability to large populations, and building a community support network.
Classification of evidence: This study provides Class IV evidence that for patients with epilepsy, engaging in an online patient community improves self-management and self-efficacy.
- Neurology 2015
International consensus diagnostic criteria for neuromyelitis optica spectrum disorders
Neuromyelitis optica (NMO) is an inflammatory CNS syndrome distinct from multiple sclerosis (MS) that is associated with serum aquaporin-4 immunoglobulin G antibodies (AQP4-IgG). Prior NMO diagnostic criteria required optic nerve and spinal cord involvement but more restricted or more extensive CNS involvement may occur. The International Panel for NMO Diagnosis (IPND) was convened to develop revised diagnostic criteria using systematic literature reviews and electronic surveys to facilitate consensus. The new nomenclature defines the unifying term NMO spectrum disorders (NMOSD), which is stratified further by serologic testing (NMOSD with or without AQP4-IgG). The core clinical characteristics required for patients with NMOSD with AQP4-IgG include clinical syndromes or MRI findings related to optic nerve, spinal cord, area postrema, other brainstem, diencephalic, or cerebral presentations. More stringent clinical criteria, with additional neuroimaging findings, are required for diagnosis of NMOSD without AQP4-IgG or when serologic testing is unavailable. The IPND also proposed validation strategies and achieved consensus on pediatric NMOSD diagnosis and the concepts of monophasic NMOSD and opticospinal MS.
Neurology 2015
Neurology 2015
Status epilepticus of inflammatory etiology A cohort study
Objective: Inflammation-related epilepsy is increasingly recognized; however, studies on status epilepticus (SE) are very infrequent. We therefore aimed to determine the frequency of inflammatory etiologies in adult SE, and to assess related demographic features and outcomes.
Methods: This was a retrospective analysis of a prospective registry of adult patients with SE treated in our center, from January 2008 to June 2014, excluding postanoxic causes. We classified SE episodes into 3 etiologic categories: infectious, autoimmune, and noninflammatory. Demographic and clinical variables were analyzed regarding their relationship to etiologies and functional outcome.
Results: Among the 570 SE consecutive episodes, 33 (6%) were inflammatory (2.5% autoimmune; 3.3% infectious), without any change in frequency over the study period. Inflammatory SE episodes involved younger patients (mean age 53 vs 61 years, p = 0.015) and were more often refractory to initial antiepileptic treatment (58% vs 38%, odds ratio = 2.19, 95% confidence interval = 1.07–4.47, p = 0.041), despite similar clinical outcome. Subgroup analysis showed that, compared with infectious SE episodes, autoimmune SE involved younger adults (mean age 44 vs 60 years, p = 0.017) and was associated with lower morbidity (return to baseline conditions in 71% vs 32%, odds ratio = 5.41, 95% confidence interval = 1.19–24.52, p = 0.043) without any difference in mortality.
Conclusions: Despite increasing awareness, inflammatory SE etiologies were relatively rare; their occurrence in younger individuals and higher refractoriness to treatment did not have any effect on outcome. Autoimmune SE episodes also occurred in younger patients, but tended to have better outcomes in survivors than infectious SE.
- Neurology 2015
Sudden cardiac arrest in people with epilepsy in the community Circumstances and risk factors
Objective: To ascertain whether characteristics of ventricular tachycardia/fibrillation (VT/VF) differed between people with epilepsy and those without and which individuals with epilepsy were at highest risk.
Methods: We ascertained 18 people with active epilepsy identified in a community-based registry of sudden cardiac arrest (SCA) with ECG-confirmed VT/VF (cases). We compared them with 470 individuals with VT/VF without epilepsy (VT/VF controls) and 54 individuals with epilepsy without VT/VF (epilepsy controls). Data on comorbidity, epilepsy severity, and medication use were collected and entered into (conditional) logistic regression models to identify determinants of VT/VF in epilepsy.
Results: In most cases, there was an obvious (10/18) or presumed cardiovascular cause (5/18) in view of preexisting heart disease. In 2 of the 3 remaining events, near–sudden unexpected death in epilepsy (SUDEP) was established after successful resuscitation. Cases had a higher prevalence of congenital/inherited heart disease (17% vs 1%, p = 0.002), and experienced VT/VF at younger age (57 vs 64 years, p = 0.023) than VT/VF controls. VT/VF in cases occurred more frequently at/near home (89% vs 58%, p = 0.009), and was less frequently witnessed (72% vs 89%, p= 0.048) than in VT/VF controls. Cases more frequently had clinically relevant heart disease (50% vs 15%, p = 0.005) and intellectual disability (28% vs 1%, p < 0.001) than epilepsy controls.
Conclusion: Cardiovascular disease rather than epilepsy characteristics is the main determinant of VT/VF in people with epilepsy in the community. SCA and SUDEP are partially overlapping disease entities.
Neurology 2015
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