ENG showed acute and chronic motor neuron damage and 129th Annual Meeting sensitive axonal neuropathy, confirmed by muscle and nerve biopsies. Brain MRI revealed cerebellar atrophy. MEP, EEG, Monday, October 4, 2004 and fundoscopy were normal. ␤-HEXB activity was unde- tectable in leukocytes. Molecular genetic studies are in Abstracts: Poster Sessions progress. ␤-HEXB deficiency should be considered in differ- ential diagnosis of juvenile MND, also for prognostic rea- sons: indeed, studies with animal models indicate substrate deprivation as a potential treatment for ␤-HEXB deficiency. FUNCTIONAL GENETICS WALKING TOUR 1. Transgenic Mouse Model for the Human GLUT1- 3. Effect of Tau and ApoE Genotypes on Age at Deficiency Syndrome Onset and Age at Death in Progressive Supranuclear Charles Heilig, Vasilis Koliatsos, Jehuda Sepkuty, Palsy Kathleen Heilig, Shenglin Chen, Minghui Xiang, Yasuhiko Baba, Yoshio Tsuboi, Keith A. Josephs, Donald Price, James Fox, Martin Pomper, David Borchelt, Natalie Cookson, Zbigniew K. Wszolek, and and Alena Savonenko; Baltimore, MD Dennis W. Dickson; Jacksonville, FL; Fukuoka, Japan; and The human GLUT1-deficiency syndrome (GLUT1DS) is Rochester, MN characterized by mutations that decrease GLUT1 expression OBJECTIVE: To assess the effect of tau and ApoE geno- or produce dysfunctional GLUT1 protein, resulting in re- types on age at onset (AAO) and age at death (AAD) of duced glucose transport across the blood-brain barrier. Af- pathologically confirmed progressive supranuclear palsy fected individuals appear normal at birth, but have hypogly- (PSP). METHODS: Fifty-two pathologically proven PSP corrachia, and eventually exhibit developmental delay, cases that lacked any other prominent neurodegenerative dis- acquired microcephaly, recurrent seizures, abnormal coordi- order were taken from the PSP Brain Bank and enrolled. nation ,and hindlimb spasticity. We produced GLUT1- Tau and ApoE genotypes were examined using DNA iso- deficient transgenic mice with an antisense-GLUT1 trans- lated from frozen brain tissue. The distribution and severity gene that is widely expressed, reducing GLUT1 in of Alzheimer type neurofibrillary degeneration was also esti- developing brain, heart, and kidney. Transgenics appeared mated with Braak NFT staging. Clinical information was normal at birth. At 3 weeks of age, many exhibited ataxia gathered from available clinical records. The relationship of and developmental delay, followed by seizures, hindlimb tau and ApoE genotypes to AAO and AAD was assessed us- spasticity, and adult brain weights 45% below normal. They ing the Mann-Whitney U-test. RESULTS: PSP cases with had grossly impaired function on the rotorod test, front-limb H1/H1 and e4 genotypes (n ϭ 8) exhibited significantly ear- and hind-limb grasp tests, open-field motor activity, and gait lier AAO (59.5 Ϯ 4.6 years) and AAD (67.0 Ϯ 5.0 years) testing. CSF glucose concentrations and CSF/blood glucose ϭ 18 than those without H1/H1 and e4 genotypes (n 7) (AAO ratios were reduced 71% and 68%, respectively. FDG PET 67.0 Ϯ 5.4, AAD 77.1 Ϯ 10.1 years, p Ͻ 0.03, respec- revealed markedly reduced glucose uptake in several brain tively), or those with H1/H1 but no e4 genotypes (n ϭ 37) areas, including the neocortex and cerebellum. Affected (AAO 64.9 Ϯ 7.6, p Ͻ 0.05, AAD 72.8 Ϯ 7.1 years, p Ͻ transgenics had frequent seizure activity at baseline, which 0.02). There were no differences in Braak NFT stages or increased substantially with 6 hr of fasting. Conclusion: We disease duration associated with each genotype. CONCLU- produced GLUT1-deficient mice with a phenotype mimick- SIONS: A genetic phenotype of tau H1/H1 and ApoE e4 ing GLUT1DS. They should be useful for determination of genotypes influences the prognosis in PSP (earlier symptom- the mechanisms and potential treatments for the abnormal atic disease onset and shorter survival). Y.B. is a recipient of phenotype and seizures. Robert and Clarice Smith Fellowship award. 2. GM2 Gangliosidosis Manifesting as Familial Motor 4. Neuroprotective Effect of Insulin-Like Growth Neuron Disease Factor-I against Glutamate- and Axotomy-Induced Gabriella Silvestri, Anna Modoni, Enzo Ricci, Motor Neuron Death Mauro Lo Monaco, Fiorella Piemonte, Pietro A. Tonali, Yasuo Iwasaki, Osamu Igarasshi, Yasumitsu Ichikawa, Alessandro Salviati, and Mario Sabatelli; Rome, Italy and Joe Aoyagi, and Ken Ikeda; Tokyo, Japan Verona, Italy Insulin-like growth factor-I (IGF-I) is a potent survival factor GM2 gangliosidosis (Sandhoff disease) is a lisosomal disorder for motor neurons that is being investigated as a possible due to ␤-hexosaminidase subunit (␤-HEXB) deficiency. Its therapeutic agent for amyotrophic lateral sclerosis (ALS).To most frequent clinical manifestation is indistinguishable from examine the possible neuroprotective effect of IGF-I in vitro Tay Sachs’disease. Other clinical forms include juvenile-onset and in vivo, the following experiments were conducted. In spinocerebellar ataxia and, rarely, motor neuron diseases vitro, we analyzed the pharmacological utility of IGF-I in a (MNDs). We report a ␤-HEXB deficiency manifesting as an postnatal orgatypic culture model of motor neuron degener- autosomal recessive MND. A 62-year-old sister and a 49- ation induced by glutamate. Cultivation span was 2 weeks. year-old brother came to our observation because of progres- Treatment with glutamate resulted in a significant reduction sive limb weakness, dysarthria, and dysphagia. Their parents of motor neuron numbers.Cotreatment with glutamate and originated from a small village. Other two out of six germans IGF-I revealed a protective effect against motor neuron were affected, with onset of symptoms between 30 and 40. death. In vivo, we examined the ability of IGF-I on axoto- Both patients showed proximal muscles wasting and weak- mized spinal motor neuron death in the rat spinal cord. After ness, predominantly at lower limbs, and areflexia; the sister the postnatal unilateral section of sciatic nerve, there was ap- had lost deambulation. The brother was able to walk and proximately a 50% survival of motor neurons in the fourth showed, as a striking feature, diffuse fasciculations. EMG/ lumbar segment. In comparison with vehicle, intraperitoneal S12 © 2004 American Neurological Association Published by Wiley-Liss, Inc., through Wiley Subscription Services injection of IGF-I for 14 days rescued spinal motor neurons. diagnosis, and genetic counseling for this severe form of ep- There was no significant relationship between rescue of mo- ilepsy. tor neuron numbers and doses of IGF-I, whether in vitro or in vivo. These in vitro and in vivo studies show that IGF-I may play an important role in the neuroprotective effect of 7. Withdrawn motor neurons, providing a rational treatment for motor neuron diseases, such as motor neuropathies and ALS. CLINICAL TRIALS 8. Rasagiline Provides Significant Symptom Benefit as 5. Autosomal Recessive Forms of Charcot-Marie-Tooth Initial Monotherapy and as Adjunct Therapy in Early Disease: Histological Phenotypes and Genotypes and Moderate-to-Advanced Parkinson’s Disease Jean-Michel Vallat, Djamel Grid, Corinne Magdelaine, Phyllis M. Salzman, Eli Eyal, Todd J. Kunkel, and Franck Sturtz, and Meriem Tazir; Limoges, France; Evry, Neil T. Malone; North Wales, PA; Netanya, Israel; and France; and Algiers, Algeria Kansas City, MO In some countries with a high prevalence of consanguineous Rasagiline (N-propargyl-1[R]-aminoindan) mesylate is a po- marriages, autosomal recessive inheritance is likely to account tent, selective, second-generation, irreversible MAO-B inhib- for more than 50% of all forms of Charcot-Marie-Tooth itor. Two multicenter, randomized, double-blind, placebo- Disease (CMT). As with the dominant forms, it is usual to controlled, 6-month trials, conducted by the PSG, analyzed differentiate the demyelinating forms (recessive CMT 1: AR- the effects of once-daily rasagiline 1 mg on Parkinson’s dis- CMT 1 or CMT 4) from the axonal forms (recessive CMT ease (PD) symptoms. The Unified Parkinson’s Disease Rat- 2: AR-CMT 2). Genetic analysis of large families with reces- ing Scale (UPDRS) was the primary efficacy measure in the sive transmission has proved to be an efficient means of dis- TEMPO study (N ϭ 404), which evaluated rasagiline mono- covering novel CMT genotypes (genes: GDAP1, MTMR2, therapy in early PD patients (mean age: 60.8 Ϯ 10.8 years; MTMR13, KIAA1985, NDGR1, periaxin, and lamin). Clin- disease duration: 1.0 Ϯ 1.24 years), and was a secondary ical and especially histological phenotypes often lead to a sus- efficacy measure in PRESTO (N ϭ 472), which evaluated picion that a specific gene is implicated. We have studied 10 rasagiline ϩ levodopa/carbidopa (LD/CD) vs. placebo ϩ nerve biopsies from patients belonging to different consan- LD/CD in moderate-to-advanced patients (mean age: guineous Algerian families. So, we will outline the character- 63.3 Ϯ 9.5 years, PD duration: 9.3 Ϯ 5.3 years). In istic lesions that may suggest the need to look for mutations TEMPO and PRESTO, rasagiline was superior to placebo in genes such as GDAP1, MTMR2, KIAA1985, and peri- for total UPDRS (p Ͻ 0.0001 and p ϭ 0.0084, respectively) axin for AR-CMT1 and in genes such as lamin for AR- and motor subscale (p Ͻ 0.0001 and p ϭ 0.0011, respec- CMT2. In two cases, the electron microscopic lesions were tively). Symptom score analyses were conducted post hoc, very unusual. At the present time, there is therefore an indi- without correcting for multiple comparisons. In TEMPO cation for nerve biopsy to orient diagnostic research in mo- and PRESTO, rasagiline reduced tremor (p ϭ 0.002 and lecular biology, which is very time-consuming and can be p ϭ 0.0021, respectively) and reduced bradykinesia (p Ͻ performed only in highly specialized laboratories. 0.0001 and p ϭ 0.0493, respectively) vs. placebo. Rasagiline patients experienced less rigidity in PRESTO (p ϭ 0.0239) vs. LD/CD ϩ placebo. These findings demonstrate signifi- 6.