Neurology May 2012 Volume 78 Issue 22

Objective: To identify the gene responsible for 14q32-linked dominant spinal muscular atrophy with lower extremity predominance (SMA-LED, OMIM 158600).Methods: Target exon capture and next generation sequencing was used to analyze the 73 genes in the 14q32 linkage interval in 3 SMA-LED family members. Candidate gene sequencing in additional dominant SMA families used PCR and pooled target capture methods. Patient fibroblasts were biochemically analyzed.Results: Regional exome sequencing of all candidate genes in the 14q32 interval in the original SMA-LED family identified only one missense mutation that segregated with disease state-a mutation in the tail domain of DYNC1H1 (I584L). Sequencing of DYNC1H1 in 32 additional probands with lower extremity predominant SMA found 2 additional heterozygous tail domain mutations (K671E and Y970C), confirming that multiple different mutations in the same domain can cause a similar phenotype. Biochemical analysis of dynein purified from patient-derived fibroblasts demonstrated that the I584L mutation dominantly disrupted dynein complex stability and function.Conclusions: We demonstrate that mutations in the tail domain of the heavy chain of cytoplasmic dynein (DYNC1H1) cause spinal muscular atrophy and provide experimental evidence that a human DYNC1H1 mutation disrupts dynein complex assembly and function. DYNC1H1 mutations were recently found in a family with Charcot-Marie-Tooth disease (type 2O) and in a child with mental retardation. Both of these phenotypes show partial overlap with the spinal muscular atrophy patients described here, indicating that dynein dysfunction is associated with a range of phenotypes in humans involving neuronal development and maintenance.GLOSSARY: CMT: Charcot-Marie-ToothgDNA: genomic DNAindels: insertions/deletionsSDS-PAGE: sodium dodecyl sulfate polyacrylamide gel electrophoresisSMA: spinal muscular atrophySMA-LED: spinal muscular atrophy with lower extremity predominanceSNP: single nucleotide polymorphism.(C)2012 American Academy of Neurology

Objective: To design and perform a case-control study of multiple sclerosis (MS) in Crete, an island of 0.6 million people, that has experienced profound socioeconomic changes in recent decades.Methods: All MS cases occurring on Crete from 1980 to 2008 were ascertained. To search for putative risk factors, a structured questionnaire of 71 variables was employed, with patients with MS (n = 657) being compared to random controls (n = 593) matched for age, gender, and current place of residence.Results: MS incidence rose markedly on Crete over the past 3 decades. This increase was associated with a major shift in MS distribution among genders (1980: F/M = 0.9; 2008: F/M = 2.1), with females living in towns or having relocated at a young age from the countryside to urban centers being mainly affected. In rural Crete, MS showed lesser increases and gender preference. Of the major changes that accompanied urbanization, smoking among women with MS increased dramatically, while imported pasteurized cow milk virtually replaced fresh goat milk produced locally. Compared to controls, female patients with MS more often used contraceptives and were older at first childbirth. Besides smoking, alcohol drinking and vitamin intake was more common among female patients with MS. Also, the distribution of childhood diseases and chronic medical conditions differed significantly between patients with MS and controls.Conclusions: MS incidence rose markedly over 3 decades in a genetically stable population in tandem with a transition from rural to urban living, thus possibly implicating environmental factors introduced by urbanization.GLOSSARY: CI: confidence intervalMS: multiple sclerosisOR: odds ratio.(C)2012 American Academy of Neurology

Objective: To report that antibodies to synaptic proteins may occur in association with slow, progressive cognitive decline.Methods: A total of 24 patients with progressive cognitive dysfunction of unclear etiology were examined for onconeuronal and synaptic receptor antibodies. The effect of serum was examined in cultures of dissociated mouse hippocampal neurons.Results: Seven patients had immunoglobulin A (IgA), but no immunoglobulin G (IgG), antibodies against NMDA receptor (NMDAR). Anti-NMDAR IgA positive patients' serum, but not serum from control individuals, caused dramatic decrease of the levels of NMDAR and other synaptic proteins in neurons, along with prominent changes in NMDAR-mediated currents. These effects correlated with the titer of IgA NMDAR antibodies and were reversed after removing patients' serum from the culture media. When available, comprehensive clinical assessment and brain metabolic imaging showed neurologic improvement after immunotherapy.Conclusions: A subset of patients with slowly progressive cognitive impairment has an underlying synaptic autoimmunity that decreases the density of NMDAR and other synaptic proteins, and alters synaptic currents. This autoimmunity can be demonstrated examining patients' serum and CSF for NMDAR IgA antibodies, identifying possible candidates for immunotherapy.GLOSSARY: ACSF: artificial CSFAD: Alzheimer diseaseFDG: fluorodeoxyglucoseFTLD: frontotemporal lobe degenerationGABA: [gamma]-aminobutyric acidGM: gray matterIgA: immunoglobulin AIgG: immunoglobulin GLBD: Lewy body diseaseNMDAR: NMDA receptorNMDAR-AI: NMDAR antibody indexPE: plasma exchangesEPSC: spontaneously occurring excitatory postsynaptic currentVGLUT1: vesicular glutamate transporter-1VOI: volume of interestWM: white matter(C)2012 American Academy of Neurology

Objective: To evaluate the distribution of white matter (WM) disease in frontotemporal lobar degeneration (FTLD) and Alzheimer disease (AD) and to evaluate the relative usefulness of WM and gray matter (GM) for distinguishing these conditions in vivo.Methods: Patients were classified as having FTLD (n = 50) or AD (n = 42) using autopsy-validated CSF values of total-tau:[beta]-amyloid (t-tau:A[beta]1-42) ratios. Patients underwent WM diffusion tensor imaging (DTI) and volumetric MRI of GM. We employed tract-specific analyses of WM fractional anisotropy (FA) and whole-brain GM density analyses. Individual patient classification was performed using receiver operator characteristic (ROC) curves with FA, GM, and a combination of the 2 modalities.Results: Regional FA and GM were significantly reduced in FTLD and AD relative to healthy seniors. Direct comparisons revealed significantly reduced FA in the corpus callosum in FTLD relative to AD. GM analyses revealed reductions in anterior temporal cortex for FTLD relative to AD, and in posterior cingulate and precuneus for AD relative to FTLD. ROC curves revealed that a multimodal combination of WM and GM provide optimal classification (area under the curve = 0.938), with 87% sensitivity and 83% specificity.Conclusions: FTLD and AD have significant WM and GM defects. A combination of DTI and volumetric MRI modalities provides a quantitative method for distinguishing FTLD and AD in vivo.GLOSSARY: A[beta]1-42: [beta]-amyloidAD: Alzheimer diseaseCC: corpus callosumCST: corticospinal tractDTI: diffusion tensor imagingDWI: diffusion-weighted imageFA: fractional anisotropyFDR: false discovery rateFTLD: frontotemporal lobar degenerationGM: gray matterIFO: inferior fronto-occipitalILF: inferior longitudinal fasciculusMMSE: Mini-Mental State ExaminationMPRAGE: magnetization-prepared rapid gradient echoPBAC: Philadelphia Brief Assessment of CognitionROC: receiver operator characteristicSLF: superior longitudinal fasciculust-tau: total-tauTSA: tract-specific analysisUNC: uncinate fasciculusWM: white matter.(C)2012 American Academy of Neurology

Objective: To determine whether exposure to repetitive head impacts over a single season negatively affects cognitive performance in collegiate contact sport athletes.Methods: This is a prospective cohort study at 3 Division I National Collegiate Athletic Association athletic programs. Participants were 214 Division I college varsity football and ice hockey players who wore instrumented helmets that recorded the acceleration-time history of the head following impact, and 45 noncontact sport athletes. All athletes were assessed prior to and shortly after the season with a cognitive screening battery (ImPACT) and a subgroup of athletes also were assessed with 7 measures from a neuropsychological test battery.Results: Few cognitive differences were found between the athlete groups at the preseason or postseason assessments. However, a higher percentage of the contact sport athletes performed more poorly than predicted postseason on a measure of new learning (California Verbal Learning Test) compared to the noncontact athletes (24% vs 3.6%; p < 0.006). On 2 postseason cognitive measures (ImPACT Reaction Time and Trails 4/B), poorer performance was significantly associated with higher scores on several head impact exposure metrics.Conclusion: Repetitive head impacts over the course of a single season may negatively impact learning in some collegiate athletes. Further work is needed to assess whether such effects are short term or persistent.GLOSSARY: ANCOVA: analysis of covarianceANOVA: analysis of varianceBVMT-R: Brief Visual Memory Test-RevisedCG: center of gravityCVLT: California Verbal Learning TestD-KEFS: Delis-Kaplan Executive Function SystemHIE: head impact exposureHITsp: measure of head impact severityImPACT: Immediate Post-Concussion Assessment and Cognitive TestMTBI: mild traumatic brain injuryNCAA: National Collegiate Athletic AssociationPASAT: Paced Auditory Serial Addition TaskWRAT IV: Wide Range Achievement Test 4(C)2012 American Academy of Neurology

Objective: Limited information is available regarding the current state of neurocritical care education for neurology residents. The goal of our survey was to assess the need and current state of neurocritical care training for neurology residents.Methods: A survey instrument was developed and, with the support of the American Academy of Neurology, distributed to residency program directors of 132 accredited neurology programs in the United States in 2011.Results: A response rate of 74% (98 of 132) was achieved. A dedicated neuroscience intensive care unit (neuro-ICU) existed in 64%. Fifty-six percent of residency programs offer a dedicated rotation in the neuro-ICU, lasting 4 weeks on average. Where available, the neuro-ICU rotation was required in the vast majority (91%) of programs. Neurology residents' exposure to the fundamental principles of neurocritical care was obtained through a variety of mechanisms. Of program directors, 37% indicated that residents would be interested in performing away rotations in a neuro-ICU. From 2005 to 2010, the number of programs sending at least one resident into a neuro-ICU fellowship increased from 14% to 35%.Conclusions: Despite the expansion of neurocritical care, large proportions of US neurology residents have limited exposure to a neuro-ICU and neurointensivists. Formal training in the principles of neurocritical care may be highly variable. The results of this survey suggest a charge to address the variability of resident education and to develop standardized curricula in neurocritical care for neurology residents.GLOSSARY: AAN: American Academy of NeurologyGES: Graduate Education SubcommitteeICU: intensive care unitneuro-ICU: neuroscience intensive care unitUCNS: United Council for Neurologic Subspecialties(C)2012 American Academy of Neurology