Neurology July 2012 Volume 79 Issue 5

Objective: To identify rare variants contributing to multiple sclerosis (MS) susceptibility in a family we have previously reported with up to 15 individuals affected across 4 generations.Methods: We performed exome sequencing in a subset of affected individuals to identify novel variants contributing to MS risk within this unique family. The candidate variant was genotyped in a validation cohort of 2,104 MS trio families.Results: Four family members with MS were sequenced and 21,583 variants were found to be shared among these individuals. Refining the variants to those with 1) a predicted loss of function and 2) present within regions of modest haplotype sharing identified 1 novel mutation (rs55762744) in the tyrosine kinase 2 (TYK2) gene. A different polymorphism within this gene has been shown to be protective in genome-wide association studies. In contrast, the TYK2 variant identified here is a novel, missense mutation and was found to be present in 10/14 (72%) cases and 28/60 (47%) of the unaffected family members. Genotyping additional 2,104 trio families showed the variant to be transmitted preferentially from heterozygous parents (transmitted 16: not transmitted 5; [chi]2 = 5.76, p = 0.016).Conclusions: Rs55762744 is a rare variant of modest effect on MS risk affecting a subset of patients (0.8%). Within this pedigree, rs55762744 is common and appears to be a modifier of modest risk effect. Exome sequencing is a quick and cost-effective method and we show here the utility of sequencing a few cases from a single, unique family to identify a novel variant. The sequencing of additional family members or other families may help identify other variants important in MS.GLOSSARY: bp: base pairGERP: genomic evolutionary rate profilingMS: multiple sclerosisSNP: single nucleotide polymorphism.(C)2012 American Academy of Neurology

Objectives: To measure intensive care unit (ICU) admission, intubation, decompressive craniotomy, and outcomes at discharge in a large population-based study of children with ischemic and hemorrhagic stroke.Methods: In a retrospective study of all children enrolled in a Northern Californian integrated health care plan (1993-2003), we identified cases of symptomatic childhood stroke (age >28 days through 19 years) from inpatient and outpatient electronic diagnoses and radiology reports, and confirmed them through chart review. Data regarding stroke evaluation, management, and outcomes at discharge were abstracted. Intensive care unit (ICU) admission, intubation, and decompressive neurosurgery rates were measured, and multivariate logistic regression was used to identify predictors of critical care usage and outcomes at discharge.Results: Of 256 cases (132 hemorrhagic and 124 ischemic), 61% were admitted to the ICU, 32% were intubated, and 11% were treated with a decompressive neurosurgery. Rates were particularly high among children with hemorrhagic stroke (73% admitted to the ICU, 42% intubated, and 19% received a decompressive neurosurgery). Altered mental status at presentation was the most robust predictor for all 3 measures of critical care utilization. Neurologic deficits at discharge were documented in 57%, and were less common after hemorrhagic than ischemic stroke: 48% vs 66% (odds ratio 0.5, 95% confidence interval 0.3-0.8). Case fatality was 4% overall, 7% among children admitted to the ICU, and was similar between ischemic and hemorrhagic stroke.Conclusions: ICU admission is frequent after childhood stroke and appears to be justified by high rates of intubation and surgical decompression.GLOSSARY: CI: confidence intervalICU: intensive care unitKPMCP: Kaiser Permanente Medical Care ProgramKPSS: Kaiser Pediatric Stroke StudyOR: odds ratio(C)2012 American Academy of Neurology

Objective: To present a new family with tyrosine hydroxylase deficiency (THD) that presented with a new phenotype of predominant, levodopa-responsive myoclonus with dystonia due to compound heterozygosity of one previously reported mutation in the promoter region and a novel nonsynonymous mutation in the other allele, thus expanding the clinical and genetic spectrum of this disorder.Methods: We performed detailed clinical examination of the family and electrophysiology to characterize the myoclonus. We performed analysis of the TH gene and in silico prediction of the possible effect of nonsynonymous substitutions on protein structure.Results: Electrophysiology suggested that the myoclonus was of subcortical origin. Genetic analysis of the TH gene revealed compound heterozygosity of a point mutation in the promoter region (c.1-71 C>T) and a novel nonsynonymous substitution in exon 12 (c.1282G>A, p.Gly428Arg). The latter is a novel variant, predicted to have a deleterious effect on the TH protein function and is the first pathogenic TH mutation in patients of African ancestry.Conclusion: We presented a THD family with predominant myoclonus-dystonia and a new genotype. It is important to consider THD in the differential diagnosis of myoclonus-dystonia, because early treatment with levodopa is crucial for these patients.GLOSSARY: CRE: cyclic adenosine monophosphate response element5-HIAA: 5-hydroxyindoleacetic acidHVA: homovanillic acidM-D: myoclonus-dystoniaTHD: tyrosine hydroxylase deficiency(C)2012 American Academy of Neurology

Objective: To characterize the molecular basis of a novel fast-channel congenital myasthenic syndrome.Methods: We used the candidate gene approach to identify the pathogenic mutation in the acetylcholine receptor (AChR) [Latin Small Letter Open E] subunit, genetically engineered the mutant AChR into HEK cells, and evaluated the level of expression and kinetic properties of the mutant receptor.Results: An 8-year-old boy born to consanguineous parents had severe myasthenic symptoms since birth. He is wheelchair bound and pyridostigmine therapy enables him to take only a few steps. Three similarly affected siblings died in infancy. He carries a homozygous p.W55R mutation at the [alpha]/[Latin Small Letter Open E] subunit interface of the AChR agonist binding site. The mutant protein expresses well in HEK cells. Patch-clamp analysis of the mutant receptor expressed in HEK cells reveals 30-fold reduced apparent agonist affinity, 75-fold reduced apparent gating efficiency, and strikingly attenuated channel opening probability (Popen) over a range agonist concentrations.Conclusion: Introduction of a cationic Arg into the anionic environment of [alpha]/[Latin Small Letter Open E] AChR binding site hinders stabilization of cationic ACh by aromatic residues and accounts for the markedly perturbed kinetic properties of the receptor. The very low Popen explains the poor response to pyridostigmine and the high fatality of the disease.GLOSSARY: AChR: acetylcholine receptorCMS: congenital myasthenic syndromeEP: endplateHEK: human embryonic kidney fibroblastPopen: channel open probability(C)2012 American Academy of Neurology

Objective: To describe the clinical features of syncope-like epileptic seizures (SLES) and their frequency in Panayiotopoulos syndrome (PS).Methods: This was a 6-year prospective study of all children aged 1-15 years referred for an EEG. PS was defined by the occurrence of at least one autonomic seizure (AS) in a neurodevelopmentally normal child and at least one EEG with focal spikes. SLES were defined as self-terminating events of sudden loss of postural tone and unresponsiveness, occurring either concurrently with other ictal autonomic symptoms and signs that characterize PS (AS + SLES) or on their own (pure SLES).Results: PS was diagnosed in 33 of 394 consecutive children with at least one afebrile seizure (8.4%). SLES occurred at least once in 17 of 33 children (51.5%); 12 presented SLES in all their AS, and 5 had also AS without SLES. Overall, 53 of 74 AS manifested with SLES (71.6%); 25 were AS + SLES and 28 were pure SLES. The latter occurred in 7 children suddenly and without premonition or obvious triggers while standing, sitting, lying down, or asleep, did not resolve in the horizontal position, and were not associated with stiffening or any involuntary movements, even when longer than a few minutes. Concurrent autonomic symptoms during AS + SLES included emesis, incontinence, mydriasis, miosis, and cardiorespiratory abnormalities.Conclusions: SLES is a common ictal manifestation of PS and should be considered in the differential diagnosis of suspected syncope, particularly when clinical signs are atypical for neurocardiogenic syncope and the EEG shows focal spikes.GLOSSARY: AS: autonomic seizurePS: Panayiotopoulos syndromeSLES: syncope-like epileptic seizure(C)2012 American Academy of Neurology

Objective: We aimed to study endothelial function with biochemical and ultrasonographic markers and its relation with endothelial progenitor cells (EPCs) in patients with migraine.Methods: We performed a case-control study including 47 patients with episodic migraine (International Headache Society 2004 criteria) and 23 control subjects. We analyzed flow-mediated dilation (FMD) in the dominant brachial artery, calcitonin gene-related peptide (CGRP), and vascular endothelial growth factor (VEGF) levels by ELISA, nitric oxide stable metabolites (NOx) by high-performance liquid chromatography, and EPCs in peripheral blood samples, obtained during interictal periods (n = 47) and migraine attacks (n = 19). Frequency, severity, duration of attacks, and time of evolution of migraine were also recorded.Results: Patients with migraine showed lower numbers of EPCs than control subjects (9.4 +/- 5.0 vs 17.9 +/- 6.0 colony forming unit-endothelial cells [CFU-ECs]; p < 0.0001) and higher levels of CGRP (164.2 +/- 139.1 vs 37.1 +/- 38.5 pg/mL), VEGF (473.4 +/- 398.7 vs 72.6 +/- 56.6 pg/mL), and NOx (1225.2 +/- 466.1 vs 671.9 +/- 358.6 [mu]M) (all p < 0.05). During attacks, higher levels for CGRP (298.2 +/- 100.3 pg/mL) and NOx (1,656.8 +/- 259.5 [mu]M) and lower numbers of EPC (7.2 +/- 3.2 CFU-ECs) were observed (all p < 0.05). No changes were found for FMD in interictal periods or during headache. In relation to clinical parameters, EPCs decreased with the time of evolution of migraine (r = -0.592; p < 0.0001).Conclusions: Patients with migraine show reduced numbers of EPCs and increased levels of CGRP, NOx, and VEGF than control subjects. Furthermore, EPC counts decrease as migraine progresses in time. These findings suggest altered endothelial function in patients with migraine.GLOSSARY: CFU-EC: colony forming unit-endothelial cellCGRP: calcitonin gene-related peptideEPC: endothelial progenitor cellFMD: flow-mediated dilationMA: migraine with auraMWA: migraine without auraNO: nitric oxideNOx: nitric oxide stable metabolitesVEGF: vascular endothelial growth factor(C)2012 American Academy of Neurology