loss of myelinated fibers and axonal degeneration but not onion-bulb formations in Schwann cells. We have identified a new genetic variant in the GADP1 gene (Arg226del), which represents a founder effect. Clinical, epidemiological, electrophysiological and pathological evidence supports a pathogenic role. GADP1 genetic analysis in mild hereditary or sporadic axonal polyneuropathies is warranted. doi:10.1016/j.nmd.2011.06.917 P3.24 A deletion in ARHGEF10 is highly associated with early onset inherited polyneuropathy in Leonberger and St. Bernard dogs G.D. Shelton a , K. Ekenstedt b , C. Dro ¨ gemu ¨ ller c , K.M. Minor b , D. Becker d , T. Leeb c , N. Patterson b , J. Mickelson e a University of California, San Diego, Department of Pathology, La Jolla, CA, United States; b University of Minnesota, College of Veterinary Medicine, St. Paul, MN, United States; c University of Berne, Institute of Genetics, Berne, United States; d University of Berne, Institute of Genetics, Berne, Switzerland; e University of Minnesota, Department of Veterinary and Biomedical Sciences, St. Paul, MN, United States Polyneuropathy in large breed dogs is a relatively common clinical problem for which the genetic basis is generally unknown. A spontane- ous, distal and symmetrical polyneuropathy with onset between 1 and 9 years of age has been identified in Leonberger dogs (LPN) and char- acterized clinically, electrophysiologically, histologically and morphomet- rically. There were striking similarities between LPN and the Charcot- Marie-Tooth group of human inherited sensory and motor polyneurop- athies, which have many known genetic mutations. A genome-wide case- control association study for LPN was performed with 53 cases and 42 controls on high-density 170 K canine SNP arrays and revealed a signif- icantly associated region on CFA 16 (Praw = 2.36 Â 10-10, Pge- nome = 9.99 Â 10-5). A clear association of an approximately 1 Mb CFA16 haplotype with cases (it P = 1.71 Â 10-8) was observed, particu- larly with those cases that were affected more severely and at a younger age (P = 2.55 Â 10-11). A positional candidate gene, ARHGEF10, which has previously been associated with peripheral nerve abnormali- ties in humans, was sequenced, revealing a deletion that results in a frame shift and premature stop codon. Of all Leonbergers with young onset LPN (before 4 years), 48.5% (32 of 66) have two copies of this deletion, and, of all young onset Leonbergers that are nerve biopsy posi- tive for LPN, 59.4% (19 of 32) have two copies of this deletion. Impor- tantly, nearly all dogs carrying two copies of the deletion (32 of 34 or 94.1%) are affected with LPN by the age of 4 years. The Leonberger breed was generated from crossing several breeds, including the St. Ber- nard. The identical ARHGEF10 mutation was identified in DNA extracted from archived frozen muscle biopsy specimens from St. Ber- nard dogs affected with early onset polyneuropathy (n = 3) suggesting the mutation may have been passed through the St. Bernard to the Leonberger. doi:10.1016/j.nmd.2011.06.918 P3.25 Charcot-Marie-Tooth type 1E associated with Dandy-Walker malformation in monozygotic twins: Case report A.L. Massano , A. Geraldo, A. Matos, L. Negra ˜o Hospital Universidade de Coimbra, Neurologia, Coimbra, Portugal The Charcot-Marie-Tooth disease (CMT) comprises a clinically and genetically heterogeneous group of hereditary neuropathies, whose diag- nosis and classification becomes increasingly more complex. CMT 1E is <5% of the forms of CMT1 and was classically defined by the association of demyelinating polyneuropathy and deafness caused by point mutations in the PMP22 gene. The Dandy-Walker malformation (DWM) is a rare cerebellar developmental anomaly (incidence: <1 per 35.000) consisting of a triad: (1) partial or complete agenesis of cerebellar vermis, (2) cystic dilatation of the fourth ventricle, (3) floor elevation of the posterior fossa. We describe the clinical cases of monozygotic twin sisters, age 18, daugh- ters of healthy unrelated parents with no family history of neurological disease. Psychomotor development was normal until they were five years old. After this age, they began to have difficulty in running, gait instability and frequent falls which had been progressive. At 13 years of age their neurological examination showed: a distal flaccid tetraparesis G4/ 5 in upper and G3/ 5 in lower limbs, atrophy of leg muscles and ”pes cavus”, a steppage gait, generalized areflexia, and hypoesthesia in sock and glove for all types of sensibility. Electrophysiological study showed a demyelin- ating sensory- motor polyneuropathy. The brain MRI revealed a moder- ate ventriculomegaly, accompanied by thinning of corpus callosum and cerebellar vermis atrophy. The study of molecular genetics has identified the point mutation c.320G> T (p.Gly107Val) in heterozygosity in the PMP22 gene. The motor and sensory deficits have remained stable and there is no evidence or complaints of hearing loss. We present these case report due to the association of the two rare diseases in these monozygotic twin sisters. doi:10.1016/j.nmd.2011.06.919 P3.26 Analysis of the Giant axonal neuropathy fibroblasts proteome R. Van Coster a , S. Mussche a , B. De Paepe a , J. Smet a , W. Lissens b , V. Rasic c , B. Devreese d a University Hospital, Department of Pediatrics, Ghent, Belgium; b Univer- sity Hospital, Center for Medical Genetics, Brussels, Belgium; c University of Belgrade, Clinic for Child Neurology and Psychiatry, Belgrade, Belgium; d Ghent University, Laboratory for Protein Biochemistry and Biomolecular Engineering, Ghent, Belgium Giant axonal neuropathy (GAN) is a hereditary disease characterized by severe loss of mental and motor functions. This disease is morpholog- ically characterized by aggregation of intermediate filaments, a part of the cytoskeleton. Underlying mutations are found in the GAN gene encoding the protein gigaxonin which is involved in clearance of misfolded or dam- aged proteins by means of the ubiquitin–proteasome system, but the underlying mechanism still remains elusive. The aim of our study was to test the hypothesis of accumulation of microtubule associated with skeletal proteins in cultured skin fibroblasts and provide additional proteomics based insight into the cellular impact of gigaxonin mutations. We used the quantitative iTRAQ 8-plex labeling method in combination with LC-MALDI to compare the proteome of four control fibroblasts with that of four GAN patients. A total of 845 proteins were identified and 66 pro- teins were differentially expressed in GAN fibroblasts. No upregulation of gigaxonin binding proteins could be demonstrated in fibroblasts. Differen- tially expressed proteins were mainly associated with the intracellular cyto- skeleton, neurogenic cell function, protein trafficking and protein translation and regulation. Although the results require further analysis, they cast new light onto the changes caused by gigaxonin dysfunction and can be of great help to other GAN researchers. Also they put forward cultured skin fibroblasts as an attractive in vitro set up to study GAN and other disorders. doi:10.1016/j.nmd.2011.06.920 Abstracts / Neuromuscular Disorders 21 (2011) 639–751 689