- Email: [email protected]
Deletion of the P2 promoter of the GJB1 gene confirms X-linked Charcot–Marie–Tooth disease in a large family
Abstracts / Neuromuscular Disorders 25 (2015) S184–S316 homozygous state or in combination with another nonsense mutation on the other allele. One Hungarian family had a novel missense TMD mutation in TTN Mex6 in combination with a frameshift mutation on the other allele. In addition one Spanish family had a previously reported Iberian TMD mutation in combination with a frameshift mutation and another Spanish family had a novel missense mutation in TTN A-band in combination with a nonsense mutation and a novel titinopathy phenotype. Family members with only one TTN mutation were healthy. According to our previous results the frameshift and nonsense mutations located upstream of the last exons of TTN cause degradation of mRNA through nonsense-mediated decay and mainly the other mutated TTN allele is expressed. http://dx.doi.org/10.1016/j.nmd.2015.06.347
HMSN G.P.324 Neuropathological findings from a human post mortem case of distal hereditary motor neuropathy (dHMN) due to p.Ser135Phe HSPB1 mutation and transgenic mice with mutant or wild-type HSP27 overexpression R. Phadke *,1, A. Rossor 2, V. Benoy 3, B. Kalmar 2, R. King 4, L. Greensmith 2, L. Bosch 3, M. Reilly 2, H. Houlden 2 1 National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, WC1N 3BG, UK; 2 UCL Institute of Neurology, London, UK; 3 Vesalius Research Centre, Leuven, Belgium; 4 Royal Free Hospital NHS Trust, London, UK dHMNs are a heterogeneous disease group sharing the common feature of a length-dependent motor axonal neuropathy (LDMAN). We report the neuropathology from the first post mortem (PM) case of a 78 year old gentleman with dHMN; proband of a large dHMN family carrying HSPB1 p.Ser135Phe mutation previously published, along with pathological phenotyping of HSP27 transgenic mice with the same mutation. In the patient, symptoms started at 9 years manifested by distal length dependent weakness starting in the feet, gradually progressing to involve the upper limbs. Eventually he was wheel-chair bound. Neurophysiology was consistent with LDMAN. Death was due to terminal respiratory failure. Neuropathology showed patchy severe axonal loss, brisk regeneration, sparse degeneration and fibrosis throughout the proximo-distal peripheral nervous system (PNS) in motorsensory nerves. Numerous ubiquitin/p62/neurofilament + large axonal swellings and variably EMA+ fibro-cellular concentric onion bulb-like structures (EMA-OB) were seen throughout the PNS. Anterior horn cells (AHC) in the spinal cord were significantly depleted at all levels compared with an age-matched unaffected control (AMUC). Neurogenic atrophy affected the limb muscles and the diaphragm. Analysis of one PM case each of CMT1, MND and AMUC showed rare axonal swellings. EMA-OBs were absent. In all animal groups proximo-distal, sensory-motor nerves, spinal cords and muscles from decalcified whole limbs serially sectioned proximo-distally appeared normal. The human post mortem findings support a chronic slowly progressive LDMAN, with sub-clinical sensory involvement and secondary AHC loss. The frequent axonal swellings complement the findings in HSPB1-dHMN animal models, suggesting impaired axonal transport. EMA-OBs appear to be a unique feature of the human disease. Further pathological phenotyping of more severely symptomatic/ageing transgenic mice may shed light on the lack of morphological alterations at 6 months. http://dx.doi.org/10.1016/j.nmd.2015.06.348
G.P.325 Gait variability during prolonged walking in children and adolescents with Charcot–Marie–Tooth disease
,1
S283 1
1
2
R. Kennedy * , K. Carroll , M. Ryan , J. McGinley 1 The Royal Children’s Hospital, Neurology, Parkville, Australia; University of Melbourne, Physiotherapy, Parkville, Australia
2
The
Problems with walking, balance and endurance are known activity limitations in children and adolescents (children) with Charcot–Marie–Tooth disease (CMT). The distance walked in a six minute walk test (6MWT) is indicative of walking endurance and is commonly reduced in adolescents with CMT. Step to step (S-S) variability is associated with instability in gait. Increased variability has been associated with gait and balance disorders in other paediatric populations. The aim of this prospective observational study was to investigate if children with CMT increase S-S variability over time during the 6MWT, a prolonged walking activity. Children with a confirmed diagnosis of CMT completed the 6MWT according to a standardised protocol along a 20 metre indoor course. An electronic walkway placed within the course was traversed on every second lap. S-S variability was measured as the standard deviation of step length, base of support (BOS) width and stride time. Walk trials for the first and last minutes were extracted for comparison. Thirty children aged 4–17 years (mean 11.6 ± SD 3.8) walked on average 557 ± 73 metres in six minutes (range 372–665 m). An average of two walking trials/ minute were recorded over the walkway; therefore the first and last two trials for each child were compared with paired t-tests or Wilcoxan signed-ranks tests. There was an increase in S-S variability of BOS width between the first (2.44 cm 95%CI 2.03, 2.85) and last minute (2.97 cm 95%CI 2.59, 3.35), p = 0.018. No other measures showed significant difference. An increase in BOS variability during a prolonged walking activity was found in children with CMT. Increasing the BOS during a dynamic activity such as walking may be a strategy to prevent over balancing and falling. This study provides insight into gait problems in children and adolescents with CMT. Further investigation of associations between gait variability and falls is required. http://dx.doi.org/10.1016/j.nmd.2015.06.349
G.P.326 Deletion of the P2 promoter of the GJB1 gene confirms X-linked Charcot–Marie–Tooth disease in a large family R. Kulshrestha *,1, T. Antoniadi 2, S. Burton-Jones 2, M. Rogers 3, N. Kiely 1, T. Willis 1 1 Robert Jones and Agnes Hunt Orthopaedic Hospital NHS Trust, Oswestry, UK; 2 Bristol Genetics Laboratory, Southmead Hospital, North Bristol NHS Trust, Bristol, UK; 3 Medical Genetics, Cardiff and Vale UHW, Cardiff, UK X-linked Charcot–Marie–Tooth disease (CMT1X) is the second most common cause of CMT, and is usually caused by mutations in the gap junction protein beta 1 (GJB1) gene which codes for connexin 32 (CX32). CX32 has three tissue-specific promoters, P1 which is specific for liver and pancreas, P1a which is specific for liver, oocytes and embryonic stem cells, and P2 which is nerve-specific. Over 300 mutations have been described in GJB1, spread throughout the gene. We describe 7 patients of a single family with X-linked inheritance. Neurophysiology was consistent with axonal neuropathy in two females and two males and demyelinating neuropathy in one female. Females had planovalgus feet and valgus ankles unlike the usual phenotype of CMT and they also reported problematic hand spasms and ‘locking’ with little weakness. No mutations were found in the GJB1 coding region. MLPA analysis of the Xq13.1 region showed abnormal dosage of a single probe, indicating a heterozygous deletion within or including the exon 1B (non-coding) of the GJB1, and corresponding to the P2 promoter. The specific break point junctions were determined by PCR and subsequent sequence analysis. The deleted region extends from nucleotide c.-5413 (5769 bases upstream of the ATG start codon) to nucleotide c.-49 (405 bases upstream of the ATG). Additionally, a 32 base pair sequence is inserted between these break points; this matches the sequence of 32 nucleotides at positions c.*218_*249 in the 3′UTR downstream of the GJB1 gene. The deleted fragment (c.-5413_-49) included all of the P2 promoter, and it was subsequently found in all the affected family members tested. To the best of our knowledge deletion of P2 promoter alone has not been
S284
Abstracts / Neuromuscular Disorders 25 (2015) S184–S316
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
HMSN G.P.324 Neuropathological findings from a human post mortem case of distal hereditary motor neuropathy (dHMN) due to p.Ser135Phe HSPB1 mutation and transgenic mice with mutant or wild-type HSP27 overexpression R. Phadke *,1, A. Rossor 2, V. Benoy 3, B. Kalmar 2, R. King 4, L. Greensmith 2, L. Bosch 3, M. Reilly 2, H. Houlden 2 1 National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, WC1N 3BG, UK; 2 UCL Institute of Neurology, London, UK; 3 Vesalius Research Centre, Leuven, Belgium; 4 Royal Free Hospital NHS Trust, London, UK dHMNs are a heterogeneous disease group sharing the common feature of a length-dependent motor axonal neuropathy (LDMAN). We report the neuropathology from the first post mortem (PM) case of a 78 year old gentleman with dHMN; proband of a large dHMN family carrying HSPB1 p.Ser135Phe mutation previously published, along with pathological phenotyping of HSP27 transgenic mice with the same mutation. In the patient, symptoms started at 9 years manifested by distal length dependent weakness starting in the feet, gradually progressing to involve the upper limbs. Eventually he was wheel-chair bound. Neurophysiology was consistent with LDMAN. Death was due to terminal respiratory failure. Neuropathology showed patchy severe axonal loss, brisk regeneration, sparse degeneration and fibrosis throughout the proximo-distal peripheral nervous system (PNS) in motorsensory nerves. Numerous ubiquitin/p62/neurofilament + large axonal swellings and variably EMA+ fibro-cellular concentric onion bulb-like structures (EMA-OB) were seen throughout the PNS. Anterior horn cells (AHC) in the spinal cord were significantly depleted at all levels compared with an age-matched unaffected control (AMUC). Neurogenic atrophy affected the limb muscles and the diaphragm. Analysis of one PM case each of CMT1, MND and AMUC showed rare axonal swellings. EMA-OBs were absent. In all animal groups proximo-distal, sensory-motor nerves, spinal cords and muscles from decalcified whole limbs serially sectioned proximo-distally appeared normal. The human post mortem findings support a chronic slowly progressive LDMAN, with sub-clinical sensory involvement and secondary AHC loss. The frequent axonal swellings complement the findings in HSPB1-dHMN animal models, suggesting impaired axonal transport. EMA-OBs appear to be a unique feature of the human disease. Further pathological phenotyping of more severely symptomatic/ageing transgenic mice may shed light on the lack of morphological alterations at 6 months. http://dx.doi.org/10.1016/j.nmd.2015.06.348
G.P.325 Gait variability during prolonged walking in children and adolescents with Charcot–Marie–Tooth disease
,1
S283 1
1
2
R. Kennedy * , K. Carroll , M. Ryan , J. McGinley 1 The Royal Children’s Hospital, Neurology, Parkville, Australia; University of Melbourne, Physiotherapy, Parkville, Australia
2
The
Problems with walking, balance and endurance are known activity limitations in children and adolescents (children) with Charcot–Marie–Tooth disease (CMT). The distance walked in a six minute walk test (6MWT) is indicative of walking endurance and is commonly reduced in adolescents with CMT. Step to step (S-S) variability is associated with instability in gait. Increased variability has been associated with gait and balance disorders in other paediatric populations. The aim of this prospective observational study was to investigate if children with CMT increase S-S variability over time during the 6MWT, a prolonged walking activity. Children with a confirmed diagnosis of CMT completed the 6MWT according to a standardised protocol along a 20 metre indoor course. An electronic walkway placed within the course was traversed on every second lap. S-S variability was measured as the standard deviation of step length, base of support (BOS) width and stride time. Walk trials for the first and last minutes were extracted for comparison. Thirty children aged 4–17 years (mean 11.6 ± SD 3.8) walked on average 557 ± 73 metres in six minutes (range 372–665 m). An average of two walking trials/ minute were recorded over the walkway; therefore the first and last two trials for each child were compared with paired t-tests or Wilcoxan signed-ranks tests. There was an increase in S-S variability of BOS width between the first (2.44 cm 95%CI 2.03, 2.85) and last minute (2.97 cm 95%CI 2.59, 3.35), p = 0.018. No other measures showed significant difference. An increase in BOS variability during a prolonged walking activity was found in children with CMT. Increasing the BOS during a dynamic activity such as walking may be a strategy to prevent over balancing and falling. This study provides insight into gait problems in children and adolescents with CMT. Further investigation of associations between gait variability and falls is required. http://dx.doi.org/10.1016/j.nmd.2015.06.349
G.P.326 Deletion of the P2 promoter of the GJB1 gene confirms X-linked Charcot–Marie–Tooth disease in a large family R. Kulshrestha *,1, T. Antoniadi 2, S. Burton-Jones 2, M. Rogers 3, N. Kiely 1, T. Willis 1 1 Robert Jones and Agnes Hunt Orthopaedic Hospital NHS Trust, Oswestry, UK; 2 Bristol Genetics Laboratory, Southmead Hospital, North Bristol NHS Trust, Bristol, UK; 3 Medical Genetics, Cardiff and Vale UHW, Cardiff, UK X-linked Charcot–Marie–Tooth disease (CMT1X) is the second most common cause of CMT, and is usually caused by mutations in the gap junction protein beta 1 (GJB1) gene which codes for connexin 32 (CX32). CX32 has three tissue-specific promoters, P1 which is specific for liver and pancreas, P1a which is specific for liver, oocytes and embryonic stem cells, and P2 which is nerve-specific. Over 300 mutations have been described in GJB1, spread throughout the gene. We describe 7 patients of a single family with X-linked inheritance. Neurophysiology was consistent with axonal neuropathy in two females and two males and demyelinating neuropathy in one female. Females had planovalgus feet and valgus ankles unlike the usual phenotype of CMT and they also reported problematic hand spasms and ‘locking’ with little weakness. No mutations were found in the GJB1 coding region. MLPA analysis of the Xq13.1 region showed abnormal dosage of a single probe, indicating a heterozygous deletion within or including the exon 1B (non-coding) of the GJB1, and corresponding to the P2 promoter. The specific break point junctions were determined by PCR and subsequent sequence analysis. The deleted region extends from nucleotide c.-5413 (5769 bases upstream of the ATG start codon) to nucleotide c.-49 (405 bases upstream of the ATG). Additionally, a 32 base pair sequence is inserted between these break points; this matches the sequence of 32 nucleotides at positions c.*218_*249 in the 3′UTR downstream of the GJB1 gene. The deleted fragment (c.-5413_-49) included all of the P2 promoter, and it was subsequently found in all the affected family members tested. To the best of our knowledge deletion of P2 promoter alone has not been
S284
Abstracts / Neuromuscular Disorders 25 (2015) S184–S316
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