Works In Progress AbstractsThese works in progress abstracts were presented at theAmerican Neurological Associations 127th Annual Meetingin New York, October 1316, 2002.
1. A Role for Neuregulin-1 in Muscle SpindleDifferentiationNeil A. Shneider, Simon Hippenmeyer, Carmen Birchmeier,Thomas Jessell, Silvia Arber, and Steve Burden;Basel, Switzerland, Berlin, Germany, and New York, NY
Muscle spindles are specialized, stretch-sensitive mechanorecep-tors in skeletal muscle that are innervated by both motor andsensory axons. Differentiation of muscle spindles depends on in-nervation by group IA proprioceptive afferents, which presum-ably supply an inductive signal to the nascent muscle spindle.Using a genetic approach in the mouse, we have identifiedneuregulin-1 (Nrg-1), a ligand for ErbB receptor complexes, as acrucial factor in the initiation of muscle spindle differentiation.In the absence of neuronal Nrg-1 expression, the peripheral end-ings of IA afferent axons contact primary myotubes normally butsubsequently fail to elaborate typical, spiral endings around nas-cent muscle spindles. These IA afferent neurons, deleted ofNrg-1, also fail to induce expression of a set of genetic markers ofearly spindle differentiation in primary myotubes. In contrast, thedevelopment and morphology of central projections of group IAafferents does not appear to be affected. Together, these findingsdemonstrate that Nrg-1 supplied by proprioceptive sensory neu-rons is essential for the initiation of muscle spindle differentiation.In addition, we provide genetic evidence that Nrg1 isoforms con-taining an immunoglobulin (Ig)like domain are sufficient to in-duce early muscle spindle differentiation in vivo, consistent withan isoform-specific function for Ig-Nrg1 in the afferent-dependentinduction of muscle spindles.
2. A New Recessive Syndrome of Cerebellar Ataxiawith Saccadic Intrusions and Sensorimotor Neuropathy(CASI) Maps to Chr1p36Barbara E. Swartz, Sheng Li, R. John Leigh,Eugene Dulaney, Irina N. Bespalova, and Margit Burmeister;Cleveland, OH, Ann Arbor, MI, and Burlington, VT
We have reported a family of Slovenian descent, with at least 5of 14 siblings (1 woman) affected by progressive ataxia, macro-saccadic oscillations that intrude on fixation, and sensorimotorneuropathy. Neither parent and none of more than 50 offspringare affected, indicating probable autosomal recessive inheritance.Median age of onset is 36 years with slow progression. SCA1-3,6-8, Friedreichs ataxia, and EPM1 were excluded by commer-cial tests whereas linkage to known recessive ataxias (19p13.3;21q) was excluded. A genome scan with 374 tetrameric micro-satellite markers was performed by Marshfield/WI Center forMedical Genetics for the mother and five affected and four un-affected individuals. Markers on 1p36 could not be excludedand underwent additional testing (ABIs 5cM genome scanpanel, U of Mi sequencing core). Several markers were com-pletely informative, showing linkage with a maximal LOD score(at 0cM) of 3.03. The region is flanked by markers D1S468 andD1S507, which span approximately 30cM or approximately 13megabases. Within this interval, more than 20 additional mark-ers were tested for homozygosity. The five affected are homozy-gous in an area of 1 to 3Mbp near the KIF1B gene, which codes
for kinesin. Mutations in KIF1B cause dominant CharcotMarieTooth (CMT) disease type 2A and may be a candidategene for this disorder. Mutation testing is in progress. CMT2Ais a dominant sensory neuropathy with some overlapping symp-toms, but CASI shows specific findings: limb and gait ataxia,horizontal macrosaccadic oscillations with increased saccadicspeed, pyramidal tract signs, and myoclonus. CASI is recessive,whereas CMT2A is dominant. It is possible that mutations inthe same gene lead to both CMT2A and CASI, but that hy-pothesis remains to be proved. Because the biology of saccadiceye movements is well documented, the mechanisms wherebythe kinesin protein affects neuronal function is especially acces-sible to study.
1. A Gene Mutated in Juvenile Myoclonic EpilepsyEncodes a Protein with EF-handT. Suzuki, A. V. Delgado-Escueta, M. E. Alonso, R. Morita,M. T. Medina, S. Ganesh, D. Bai, T. Sugimoto,J. N. Bailey, A. Ochoa, J. A. Prado, A. Rasmussen,J. R. Peek, S. Cordova, F. Rubio-Donnadieu, X. Inoue,M. Osawa, S. Kaneko, H. Oguni, and K. Yamakawa;Saitama, Tokyo, Shizuoka, and Aomori, Japan,Los Angeles, CA, Mexico City, Mexico,Tegucigalpa, Honduras, and Delhi, India
Among idiopathic generalized epilepsies, juvenile myoclonic epi-lepsy (JME) is the most common, accounting for 12 to 30% of allepilepsies. We previously mapped convulsive and electroencepha-logram traits of JME to a 7cM region (EJM1) of chromosome6p12-11. More recently, recombinations of 21 new families fromMexico narrowed EJM1 further between D6S1960 and 255gt/1180e22 where we found myoclonin/EFHC1. Mutational anal-ysis in the 21 JME families showed mutations segregating in 21epilepsy or electroencephalogram polyspike wave affected mem-bers of six unrelated families. Those include three heterozygous(Phe229Leu in Families 3 and 4; Asp210Asn in Family 5;Asp253Tyr in Family 6) and one doubly heterozygous missensemutation (Pro77Thr and Arg221His in Families 1 and 2). Thesemutations were not observed in 232 unrelated healthy controls(102 Mexicans, 96 Japanese, and 34 whites). The only knownfunctional domain is the EF-hand motif, suggesting a role in sens-ing, binding, and modulating neuronal calcium. Mutations inmyoclonin/EFHC1 could be influenced by sleep deprivation andalcohol and affect calcium binding and intracellular calcium con-centrations and shift voltage to the depolarizing potentials of ep-ilepsy. Production of transgenic EFHC1 mouse models is neces-sary to prove that EFHC1 is indeed a gene for JME.
2. Bilateral Frontoparietal Polymicrogyria: AnAutosomal Recessive Syndrome of CorticalMalformation with Distinct Clinical andRadiological FeaturesBernard Chang, Xianhua Piao, and Christopher A. Walsh;Boston, MA
Polymicrogyria is a common malformation of cortical develop-ment characterized by an excessive number of small gyri and ab-normal cortical lamination. Multiple familial syndromes ofregion-specific bilateral symmetric polymicrogyria have been re-ported. We previously have described two families with bilateralfrontoparietal polymicrogyria (BFPP), an autosomal recessive syn-drome that we mapped to a locus on chromosome 16q12-21.Here, we extend our observations to include 18 patients from 10chromosome 16linked kindreds, allowing us to define the clin-
AMERICAN NEUROLOGICAL ASSOCIATION 127TH ANNUAL MEETINGOCTOBER 1316, 2002NEW YORK, NY
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ical and radiological features of BFPP in detail. The syndrome ischaracterized by cognitive and motor delay of at least moderateseverity, seizures, dysconjugate gaze, and bilateral pyramidal andcerebellar signs. Magnetic resonance imaging demonstrates sym-metric polymicrogyria affecting the frontoparietal regions most se-verely, as well as ventriculomegaly, bilateral white matter signalchange, and hypoplasia of the brainstem and cerebellar vermis.We have refined our genetic mapping and describe two apparentfounder mutations, one of which is present in two families withBFPP and associated microcephaly. Because 11 of our patientsinitially were classified as having other malformations, the syn-drome of BFPP appears to be more common than previously rec-ognized and may be frequently misdiagnosed.
3. Sodium Channel MyastheniaAkira Tsujino, Chantal Maertens, Kinji Ohno,Xin-Ming Shen, C. Michael Harper, Stephen Cannon,and Andrew G. Engel; Rochester, MN, Boston, MA,and Dallas, TX
A 20-year-old woman had abrupt attacks of respiratory and bul-bar paralysis since birth lasting 3 to 30 minutes recurring one tothree times per month, ptosis, limited ocular ductions, andmarked fatigable weakness and was mentally retarded. Nervestimulation at 2Hz elicited no decremental response. Ten- or50Hz stimulation for 1 minute reduced the evoked muscle ac-tion potential by approximately 85%, and 2Hz stimulation nowelicited a significant decrement. Intercostal muscle studies at30C showed no abnormality of the resting membrane potential,evoked quantal release, synaptic potentials and currents, orAChR channel kinetics, but the muscle fibers were electricallyinexcitable. Pursuing this clue, we sequenced SCN4A encodingthe skeletal muscle sodium channel (NaV1.4) and detected twomutations involving conserved residues, not present in 400 nor-mal alleles: S246L in the S4/S5 cytoplasmic linker in domain Iand V1442E in the S3/S4 extracellular linker in domain IV.Asymptomatic mother and sister carry S246L; the fathers DNAwas unavailable. The genetically engineered V1442E-Na channelexpressed in HEK cells shows marked enhancement of fast in-activation close to the resting potential and enhanced use-dependent inactivation on high-frequency stimulation; S246L islikely a benign mutation. The V1442E sodium channel muta-tion defines a novel disease mechanism and a novel phenotypewith myasthenic features.
4. Apolipoprotein E Genotype Is a Risk Factor forDiabetic NeuropathyR. S. Bedlack, D. Kelling, D. Edelman, J. W. Gibbs III,W. Strittmatter, and J. Morgenlander; Concord, NC,and Durham, NC
We tested the hypothesis that apolipoprotein E (APOE) genotypepredicts diabetic neuropathy using a cross-sectional study of dia-betic patients in a primary care clinic. APOE genotype was ob-tained from cheek cells and characterized as high-risk (E4/E4 orE3/E4) or normal. Neuropathy was measured by the NeuropathyImpairment Score in the Lower Limbs (NISLL). A stepwise re-gression model was created using APOE genotype, age, diabetesduration, glycemic control, and triglycerides to predict NISLL.Covariates related to outcome with p value less than 0.05 wereadded. Approximately 19% of 187 patients had high-risk geno-type, and 74% had 1 point or higher on NISLL. Our best modelincluded age, duration of diabetes, and APOE status and pre-dicted NISLL with p value of 0.0083. Each component of thismodel predicted NISLL at p value less than 0.05 after adjustmentfor the other two components. Age was predictive at p value of
0.0001, with 2 points of NISLL for every 10 years of age. Dura-tion of diabetes was predictive at p value of 0.0044, with 2 pointsof NISLL for every 10 years of diabetes. APOE status was predic-tive at p value of 0.03, with high-risk patients having 3.12 morepoints than normal risk patients. High-risk APOE genotype pre-dicts diabetic neuropathy. Markers such as this may help directresource-intensive interventions that prevent neuropathy or itscomplications.
5. Autoantibody Reactivity to Myelin/OligodendrocyteGlycoprotein Correlates with Progressive Forms ofMultiple SclerosisClaude P. Genain, Antje Fuhrmann, Til Menge,Hans-Christian von Budingen, Stacey Bae, Amy Swerdlin,Alan Evangelista, Carolyn Woo, Daniel Pelletier,Emmanuelle Waubant, Douglas Goodin, Mariko Kita,Scott Zamvil, Bruce Cree, Donald Goodkin,and Stephen Hauser; San Francisco, CA, and Seattle, WA
The significance of humoral immunity against myelin/oligoden-drocyte glycoprotein (MOG) is unclear, because antiMOG an-tibodies are found in both multiple sclerosis (MS) and controlsubjects. We used specific ELISA systems to measure serum an-tibody reactivity against MOG (recombinant extracellular do-main) and native myelin basic protein (MBP) in 18 controls, 27patients with relapsing remitting (RR) MS, 17 patients with sec-ondary progressive (SP) MS, and 32 patients with primary pro-gressive (PP) MS, diagnosed according to Poser criteria, Age-matched controls were included. Consistent with previousstudies of Western blotting, antibodies to MOG were found in38% of controls and 33% of RRMS patients. However, theseautoantibodies were detected at considerably higher frequenciesin patients with SPMS (76%) and PPMS (89%). All SPMS andPPMS patients had EDSS values above 3.0 at the time of sam-pling. Compared with MOG, the incidence of antibodiesagainst MBP was lower across all MS groups (23%, 25%, and19%, respectively). Detailed analyses of epitope recognition ofMOG are in progress. The heightened occurrence of antiMOGautoantibodies in SPMS and PPMS may reflect specific mecha-nisms of disease in these chronic forms. We also propose thatantiMOG antibody titers might serve as paraclinical markers ofprogression and brain atrophy in MS.
6. The Frequency of Frontotemporal Lobar Dementiain an Amyotrophic Lateral Sclerosis Population: IsNeuropsychological Testing or NeuroimagingMore Sensitive?Catherine Lomen-Hoerth, Jennifer Murphy, Roland Henry,Marni Hillinger, Cynthia Chin, Joel Kramer,and Dallas Forshew; San Francisco, CA
We evaluated 23 consecutive amyotrophic lateral sclerosis (ALS;probable or definite by World Federation of Neurology criteria)patients without known dementia presenting to the ALS Centerat UCSF who consented to neuroimaging and neuropsycholog-ical testing. A battery of neuropsychological tests was adminis-tered to each patient. Patients also had anatomical and perfusionmagnetic resonance imaging (MRI) scans with whole-brain cov-erage and a subset had MR spectroscopy studies focusing on the
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frontal and temporal lobes. Quantitative measurement of brainatrophy was made with normalized values for head size and age.
Of the 23 patients, 13 had neuroimaging abnormalities.Seven patients had both frontal and temporal atrophy, four hadfrontal atrophy, and one had temporal atrophy. One additionalpatient had no atrophy on MRI but had abnormal perfusion ofhis frontal lobes. Nine patients had abnormalities on neuropsy-chological testing typical of FTLD (frontotemporal dementia,primary progressive aphasia, or semantic dementia), and all thesepatients had abnormal imaging.
Among 23 consecutive patients with ALS, we found cognitiveabnormalities in 40% and radiological abnormalities in 57%.Longitudinal follow-up is in progress to determine if any of thenormal subjects or subjects with radiological abnormalities de-velop cognitive abnormalities over time. Thus, FTLD is themost common dementia found in ALS and is an underrecog-nized feature.
7. Pretranslational Events Involving the MyHC GenesMay Contribute to the Selective Myosin Depletion inAcute Quadriplegic MyopathyTahseen Mozaffar, Fadia Haddad, Lily Qin, Ming Zeng,and Kenneth M. Baldwin; Irvine, CA
Acute quadriplegic myopathy (AQM) is characterized by flaccidquadriparesis, electrical inexcitability of muscle membranes, andmuscle atrophy with selective myosin heavy chain (MyHC) de-pletion, especially in fast-twitch muscles. Use of glucocorticoidsin the setting of pharmacological neuromuscular blockade(functional denervation) may precipitate this disease in hu-mans. We studied mRNA expression of MyHC and actin genesand various MyHC isoforms in plantaris muscle in a rat modelof AQM at 1 week, after unilateral denervation followed byhigh-do...