Comparison of two clinical motor scales in individuals with giant axonal neuropathy (GAN)

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previously described and this result confirmed a diagnosis of X-linked CMT in this family. http://dx.doi.org/10.1016/j.nmd.2015.06.350

G.P.327 Dynamic pedobarography assessment in children and adolescent with Charcot–Marie–Tooth disease A. Mattiello-Sverzut *,1, A. Nascimento-Elias 2, C. Baptista 2, P. Calori 2, B. Garcia 2, C. Sartor 3, I. Sacco 3, W. Marques Jr. 2 1 Medical School of Ribeirão Preto – University of São Paulo, Biomechanics, Medicine and Rehabilitation of Locomotor Apparatus, 14049-900, Brazil; 2 Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil; 3 Facultyof Medicine, University of São Paulo, São Paulo, Brazil Charcot–Marie–Tooth (CMT) disease is a heterogeneous group of hereditary motor and sensory neuropathies that are either demyelinating or axonal. Peripheral nerve loss causes progressive weakness and deformity of the hands and feet. The aim of this study was to characterise the feet changes of CMT children and adolescents. Eleven patients and seven controls were evaluated (ages 8–16 years) and 22 CMT and 14 control feet were analysed. Assessment of foot strength-hand-held dynamometry (inversors, eversors, plantar flexors, dorsiflexors), foot alignment (Foot Postural Index-FPI) and dynamic pedobarography were performed. The volunteers walked on a flat surface with a constant velocity. The variables contact areas, maximum force, peak pressure and maximum mean pressure were acquired using de PedarX System Novel and analysed using a mask with four areas (heel, mid foot, medial and lateral forefoot) and the total foot area. The FPI of CMT feet indicated 42% cavus, 38% flat and 20% normal. Analysing the type of foot and the ages, we observed higher frequency of cavus foot with the increase in ages. The foot strength was lesser in CMT patients than in controls. The results of PedarX in total foot of CMT and control were respectively: contact areas (cm2) 76.6 ± 19.9 and 90.7 ± 19.9; maximum force (N) 483.1 ± 195.4 and 436.3 ± 153.9; peak pressure (kPa) 375.9 ± 105.2 and 298.9 ± 90.3; maximum mean pressure (kPa) 115.2 ± 24.1 and 113.1 ± 28.9. These variables were not significantly different. The values of peak pressure obtained in mid foot (CMT 164.6 ± 96.1; Control 110.8 ± 44.3) and lateral forefoot (CMT 289.7 ± 191.1; Control 128.1 ± 51.4) showed significant difference between CMT and controls, indicating a tendency towards cavus foot in these patients. New patients are being added to the sample. The better characterisation of CMT feet could contribute to therapeutic interventions preventing and/or reducing the deformities as well as prescription of some devices. http://dx.doi.org/10.1016/j.nmd.2015.06.351

G.P.328 Stabilometric findings in children and adolescent with Charcot–Marie– Tooth disease A. Mattiello-Sverzut *,1, C. Baptista 2, P. Calori 2, B. Garcia 2, W. Marques Jr. 2 1 Medical School of Ribeirão Preto – University of São Paulo, Biomechanics, Medicine and Rehabilitation of Locomotor Apparatus, 14049-900, Brazil; 2 Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil Failure in postural control of children and adolescents with Charcot–Marie– Tooth neuropathy (CMT) is a common clinical finding with multifactorial causes and qualitative evaluation. This study aimed to explore some stabilometric parameters and data of clinical evaluation in children and adolescents with CMT. Seven volunteers with different subtypes of CMT (age 6 to 18; 4 male and 6 female) were enrolled and submitted to anthropometric measures and standardized clinical evaluation (lower limb passive range of movement; dynamometry for muscle strength test, postural foot index – PFI). Two trials of 30 s of quiet standing was recorded by a Bertec force platform (FP 4060-08) and the mean values were considered for analysis. Velocity of the center of pressure

(Vcp) displacement, frequency (F) and confidence ellipse area were studied in 4 conditions: opened (OE), closed eyes (CE), opened eyes and foam surface (OEF), closed eyes and foam surface (CEF). Statistical software was used to obtain descriptive analysis. Conditions without visual or somatosensory feedback presented tendency to higher Vcp, lower F and increased area. Data of clinical evaluation as range of lower limb movement and PFI suggested weak correlation to stabilometric parameters. Isometric muscle strength of inversors, plantar flexors, dorsiflexors, hip and knee extensors correlated to Vcp (r > −0.7), mainly in condition EC. These findings are coherent with the assumption that velocity-related measures are good indicators of postural instability in peripheral neuropathies. Monitoring these stabilometric parameters can be helpful to track strategies used by children with CMT to manage quiet standing. http://dx.doi.org/10.1016/j.nmd.2015.06.352

G.P.329 Giant axonal neuropathy – clinical trial preparedness and evaluation of markers of disease severity D. Bharucha-Goebel *,1, D. Ezzo 2, M. Jain 3, M. Waite 3, C. Nichols 3, T. Lehky 3, P. Mohassel 3, S. Donkervoort 3, M. Leach 4, J. Dastgir 5, J. Marra 5, W. Zein 3, C. Bönnemann 2 1 National Institutes of Health & Children’s National Medical Center, NINDS/Neurogenetics Branch, Bethesda, USA; 2 National Institutes of Health, NINDS/Neurogenetics Branch, Bethesda, USA; 3 National Institutes of Health, Bethesda, USA; 4 National Institutes of Health & Children’s National Medical Center, Bethesda, USA; 5 Columbia University Medical Center, New York, USA Giant axonal neuropathy (GAN) is a rare childhood onset progressive autosomal recessive disorder affecting the central and peripheral nervous system due to a loss of function of gigaxonin, a cytoskeletal regulatory protein. The clinical phenotype includes progressive sensorimotor neuropathy, optic neuropathy, nystagmus, dysarthria, dysphagia, seizures, and death often due to respiratory failure by the 2nd to 3rd decade of life. There is a paucity of established outcome measures correlating to disease severity and progression. Such measures are crucial to characterize the natural history and for developing efficacy endpoints to prepare for clinical trials. Twelve genetically confirmed GAN patients were evaluated at the National Institutes of Health. Our aim was to identify targeted quantitative physiologic, functional, and strength related outcome measures that correlate with disease severity (defined by Neuropathy Impairment Score – NIS). We utilized the motor function measure (MFM32), muscle strength (myometry), motor nerve amplitude (on nerve conduction study), and assessment of ophthalmologic pathology using ocular coherence tomography to evaluate the retinal nerve fiber layer. We found a significant correlation between: NIS and MFM32, MFM32 and lower extremity myometry, MFM32 and the median motor amplitude, and MFM32 and RNFL thickness. There was no significant correlation between upper extremity myometry and MFM32, likely indicative of the relative sparing of proximal upper extremity function in early to moderate stages of disease in these patients. This study identifies quantitative measures of muscle strength, muscle function, electrophysiological, and ophthalmologic function that correlate with clinical severity in GAN. These may serve as feasible and clinically meaningful motor endpoints to be used in the active AAV9 mediated intrathecal GAN gene transfer therapy trial taking place at the NIH and for other future studies in GAN. http://dx.doi.org/10.1016/j.nmd.2015.06.353

G.P.330 Comparison of two clinical motor scales in individuals with giant axonal neuropathy (GAN) M. Waite 1, D. Bharucha-Goebel 2, T. Moulton 1, C. Zampieri 1, C. Nichols 1, K. Alter 1, G. Averion 2, S. Donkervoort 2, M. Leach 2, J. Dastgir 2, P. Mohassel 2, M. Jain *,1, C. Bönnemann 2

Abstracts / Neuromuscular Disorders 25 (2015) S184–S316 1

National Institutes of Health, Rehabilitation Medicine Department, Bethesda, USA; 2 National Institutes of Health, NINDS, Bethesda, USA Giant axonal neuropathy (GAN) is a rare autosomal recessive neurodegenerative disease that affects the peripheral and the central nervous system. Clinical symptoms include neuropathy, ataxia, dysphagia, dysarthria, and distal and later proximal muscle weakness. There are currently no approved treatments for GAN. It is important to identify appropriate assessment tools to measure function in preparation for future interventional trials, such as gene transfer. The only recent natural history study to include functional measures in subjects with GAN uses the Gross Motor Function Measure (GMFM). The goal of this study is to compare the GMFM to the Motor Function Measure (MFM) in people with GAN. The GMFM was developed and validated in people with cerebral palsy; the MFM was developed and validated in people with progressive neuromuscular diseases. Our study included seven subjects (5 females) with a mean age of 8.8 years. All subjects completed the GMFM and MFM 32 except one young child who was assessed using the MFM 20 (version of the MFM 32 validated in individuals 2–6 years of age). Spearman’s rho correlations were used to compare the tests in three ways: (1) The D2 (axial and proximal motor function) domain of the MFM with the combined domains A and B (lying, rolling, and sitting) of the GMFM. (2) The D1 (standing and transfers) of the MFM and the combined domains D and E (standing, walking, running, and jumping) of the GMFM. (3) Total percentages for both the GMFM and the MFM. There was a strong correlation between the MFM (D2) and the GMFM (A + B) domains, rs = 1.0, p < .05, MFM (D1) and GMFM (D + E) domains rs = .964, p < .05, and between the total percentages for both the GMFM and the MFM, rs = 1.0, p < .05. We conclude that one test alone may be used to capture gross motor function in subjects with GAN. Given that the MFM is validated in subjects with progressive neuromuscular diseases, we recommend using the MFM for this population. http://dx.doi.org/10.1016/j.nmd.2015.06.354

G.P.331 A novel 9 amino acid in-frame deletion in the NTRK1 tyrosine kinase domain in a patient with congenital insensitivity to pain with anhidrosis (CIPA) N. Forrester 1, S. Burton-Jones 1, T. Antoniadi 1, A. Norman 2, A. Majumdar 3, K. Vijayakumar *,3 1 Bristol Genetics Laboratory, Pathology Sciences, Southmead Hospital, North Bris, Bristol, UK; 2 University Hospital NHS Foundation Trust, Clinical Genetics, Bristol, UK; 3 University Hospital NHS Foundation Trust, Paediatric Neurology, Bristol, UK The neurotrophic tyrosine kinase, receptor type 1 (NTRK1) gene encodes a membrane-bound nerve growth factor receptor involved in the development of the central and peripheral nervous systems. Through the kinase activity of this protein, pathways are activated that support the proliferation, differentiation and survival of sensory neurons from the dorsal root ganglia. Pathogenic sequence variants in NTRK1 have been associated with autosomal recessive congenital insensitivity to pain with anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV (HSAN-IV). Other clinical features of this condition include recurrent episodic fever, absence of reaction to noxious stimuli, self-mutilating behaviour and mental retardation. We present the case of a male infant with clinical features in-keeping with CIPA who exhibited irritability, restlessness and repetitive episodes of ‘unexplained’ hypothermia from early infancy. In addition to temperature instability, he also had marked hyperlacrimation suggestive of possible autonomic dysfunction. He had happy demeanour, deep eye socket, and behavioural stereotypes such as repetitive flapping of hands, grinding of his teeth and repetitive sucking and biting tendencies from birth. These tendencies subsequently lead to recurrent paronychia, resulting in osteomyelitis of fingers and also loss of tongue tissue from repetitive biting. He is making slow and steady developmental progress. We identified a novel 26 nucleotide deletion, c.2086_2112del, in the tyrosine kinase domain of NTRK1 using a targeted 56-gene panel assay and Next

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Generation Sequencing. This in-frame deletion is predicted to result in the production of an altered protein with a 9 amino acid deletion in its tyrosine kinase domain. This deletion was in compound heterozygosity with a previously reported pathogenic nonsense mutation p.(Gln770*). To our knowledge this represents the largest known CIPA-associated NTRK1 deletion. http://dx.doi.org/10.1016/j.nmd.2015.06.355

G.P.332 Charcot–Marie–Tooth type 4B1 (MTMR2 gene): Confounding clinical presentation and report of 5 original mutations R. Guimarães-Costa *,1, P. Latour 2, X. Ferrer 3, G. Solé 3, I. Husson 4, A. Lacour 5, O. Dubourg 1, S. Leonard-Louis 1, T. Stojkovic 1 1 Referral Center of Neuromuscular Diseases Paris-Est, Myology Institut, Pitié-Salpêtrière Hospital, Paris, France; 2 Center of Biology and Pathology, Laboratory of Molecular Neurogenetics, Hospices Civils, Lyon, France; 3 Department of Neurology, University Hospital of Bordeaux, Bordeaux, France; 4 Department of Neuropediatrics, Robert Dendré Hospital, Paris, France; 5 Department of Neurology, University Hospital of Lille, Lille, France Charcot–Marie–Tooth 4B1 (CMT4B1) is a rare demyelinating recessive CMT characterized by severe motor weakness, facial and bulbar palsy. We report on 6 patients belonging to 3 families in which classical clinical presentation was associated with distinctive features. Moreover 5 original MTMR2 mutations were identified. All patients, except one, presented delayed milestones. Severe distal weakness and cranial nerve involvement were present in all patients. Proximal motor weakness was either mild or moderate. The first family included 3 brothers, aged 24, 22 and 16 years, who were still ambulant. In this family, brain and cervical spine imagery were conducted initially to the diagnosis of Arnold–Chiari syndrome. However, reduced nerve conduction velocities pointed toward a demyelinating sensorimotor neuropathy. Moreover, these patients present important increase sweat in distal limbs, with no other dysautonomic features. The second family, comprising 2 sisters, presented severe motor deficit and were wheelchair bounded since the age of 6. They were firstly diagnosed for type 1 Usher syndrome (homozygous MYO7A mutation) in a context of congenital deafness and retinitis pigmentosa. However, contractures, demyelinating neuropathy and cranial nerve involvement raised suspicion of concomitant CMT4B1. The third family comprised a male aged 32 years old, wheelchair bounded since the age of 11 and presenting recurrent intestinal subocclusion in the context of mesenteric malformation. In these 3 families, we identified mutations in the MTMR2 gene, either in homozygous status (Gln344*) or compound heterozygous status for the first and third families (Arg459*/Thr537Ile and Trp206*/Trp583*). Our diagnosis of CMT4B1 was based upon the classical clinical features although accurate diagnosis was difficult due to coexisting disorders. Furthermore, patients presenting two stop mutations were associated with a more disabling phenotype compared to those compounded by stop and Thr537Ile mutations. http://dx.doi.org/10.1016/j.nmd.2015.06.356

G.P.333 Normative aerobic exercise values in CMT A. Wallace *,1, L. Dewar 1, A. Sterr 2, M. Hanna 1, M. Trenell 3, A. Pietrusz 1, M. Dudziec 1, P. Hennis 4, R. Stokes 5, M. Reilly 1, G. Ramdharry 1 1 MRC Centre for Neuromuscular Diseases, London, UK; 2 University of Surrey, Guilford, UK; 3 Newcastle University, Newcastle, UK; 4 University College London, London, UK; 5 City University, London, UK The objective of this study was to measure the cardiopulmonary response during maximal cycling exercise in a cohort of patients with Charcot–Marie– Tooth disease (CMT). Eleven CMT patients underwent cardiopulmonary exercise testing (CPET) in accordance with American Thoracic Society/ American College of Chest Physicians guidelines. In brief, patients performed a symptom-limited, incremental ramp protocol to volitional exhaustion using a