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The effect of orthosis and foot surgery in a cohort of Charcot-Marie-Tooth disease children
Abstracts 2017 / Neuromuscular Disorders 27 (2017) S96–S249 differences in molecular and metabolic responses. The aim of our research is to define the mechanistic basis for this disease, in order to help identify specific targets for selection of best drugs for future therapeutic clinical use. http://dx.doi.org/10.1016/j.nmd.2017.06.195
P.166 A knock-in mouse model with nonsense dysferlin mutation J. Shin 1, S. Park 1, J. Park 2, D. Kim 1 1 Pusan National University Yangsan Hospital, Yangsan, Korea; 2 Kyungpook National University, Daegu, Korea Mutations in the dysferlin gene cause limb-girdle muscular dystrophy 2B or Miyoshi distal myopathy with autosomal recessive inheritance pattern. A few mouse models harboring truncating mutations have been in use for the research of the dysferlinopathy. We found nonsense mutations are most common among Korean patients with dysferlinopathy; more than half of the patients have at least one nonsense allele, which could be mitigated by readthrough strategy. Thus we generated a knock-in mouse with p.Q832* mutation, most frequently found among our dysferlinopathy cases. Mice with homozygous p.Q832* mutation, named dqx, performed poorer on Rotarod and treadmill test than wild type C57BL6 mice and moved less on activity monitoring. On eccentric contraction ex vivo, extensor digitorum longus muscle from dqx tended to break easily on the first few contractions. All these abnormality could successfully be alleviated when the mice were administered with gentamicin for 3 weeks. These results support that readthrough strategy may also be applicable to nonsense dysferlinopathy patients. http://dx.doi.org/10.1016/j.nmd.2017.06.196
CHARCOT-MARIE-TOOTH DISEASE AND DISTAL MYOPATHIES
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P.168 Falls in children and adolescents with Charcot-Marie-Tooth disease and typically developing children: a six month prospective study K. Carroll 1, J. McGinley 2, K. Paterson 2, M. Ryan 1, R. Kennedy 1 1 The Royal Children’s Hospital, Parkville, Australia; 2 The University of Melbourne, Parkville, Australia Children and adolescents with Charcot-Marie-Tooth disease (CMT) report frequent falls. Falls are a natural part of growth and development in childhood; but what is typical? There are no longitudinal studies of falls in children with CMT or typically developing children (TD). A prospective study evaluated falls over 6 months in 30 children with CMT and 30 age- and gender-matched TD children (mean age 11.5 years (3.8); 21 males). A daily diary recorded fall frequency and a questionnaire detailed the “worst” fall each day including location, time of day, surface type, mechanism and injuries. Diaries were returned by 25 CMT and 27TD children. Children with CMT recorded 2819 falls (range 0–1915) and TD children 31 falls (range 0–6). One child with CMT was an extreme outlier recording 1915 falls. Over 6 months 3 CMT and 19 TD children were classified as “non-fallers” (0 falls); 11 CMT and 2 TD children as “fallers” (1–2 falls); and 10 CMT and 6 TD children as “recurrent fallers” (>2 falls). All children 6 years or younger recorded falls whether with CMT or TD. Details of 216 CMT and 26 TD falls were collected by questionnaire. Approximately 40% of falls occurred at home. Afternoon and evening were the most common times that falls occurred (CMT 69%, TD 65%). More falls were recorded outdoors (flat surface, uneven terrain, playground; CMT 50%, TD 46%) than indoors (flat surface; CMT 35%, TD 34%) or on steps (CMT 13%, TD 20%). Tripping was the most frequent mechanism of falling (CMT 52%; TD 73%), with legs giving way (CMT 23%, TD 4%), overbalancing (CMT 12%, TD 8%) and rolling ankles (CMT 6%, TD 0%) also reported mechanisms of falls. Injury rate was higher in children with CMT (34%,TD 12%) with cuts/grazes most common. Children with CMT also reported bruising, ankle injuries and superficial head injuries. Falls are a major issue for children and adolescents with CMT. Further research is needed to understand what interventions may be effective in reducing falls in CMT. http://dx.doi.org/10.1016/j.nmd.2017.06.198
P.167 Severe form of recessive Charcot-Marie-Tooth disease with a novel mutation in myotubularin related protein 2 A. Bayram 1, K. Stumpfe 2, H. Wang 2, M. Pergande 2, H. Per 1, S. Çırak 2 1 Erciyes University, Kayseri, Turkey; 2 Cologne University, Cologne, Germany Charcot-Marie-Tooth type 4 (CMT4) is a severe form of recessive neuropathy with genetic heterogeneity. To date 11 different genes are detected of this rare autosomal recessive disorder. One form of this disease is caused by a mutation of the myotubularin-related 2 (MTMR2) gene. It is characterized by severe early childhood-onset demyelinating sensorimotor polyneuropathy, deformation of extremities and speech impairment up to vocal cord paresis. In the following we report the clinical course and electrophysiological findings of three pediatric sibling cases with a novel mutation in MTMR2. All of our patients first noticed quick fatigue after the first three years of life. As the disease progressed, they all developed muscle atrophy, facial weakness, pes cavus deformity and global developmental delay at the end of the first decade. Their deep tendon reflexes were absent. Sensory nerve action potentials and nerve conduction velocity were undetectable in all of them. Compound muscle action potential and motor conduction velocity were not recordable in two patients and were severely decreased in one patient. One of the patients was even confined to wheelchair. Molecular analysis with whole exome sequencing (WES) of the MTMR2 gene revealed a novel homozygous mutation in all siblings: c.1490insC; p.F498Ifs*2. In conclusion, the heterogeneous genetic spectrum of CMT4B1 has been expanded by a new mutation described before. Further studies are needed to improve the understanding of the pathomechanism behind the loss of myelin in the peripheral nervous system in order to establish new treatments. http://dx.doi.org/10.1016/j.nmd.2017.06.197
P.169 Aerobic anti-gravity exercise in patients with Charcot-Marie-Tooth disease. Types: a pilot study K. Knak, L. Andersen, J. Vissing Rigshospitalet, Copenhagen, Denmark Charcot-Marie-Tooth (CMT) disease is a hereditary neuropathy associated with impaired walking capacity. Some patients are too weak in the lower extremity muscles to walk at gravity with sufficient intensity or duration to gain benefit. The objective was to investigate the effect of aerobic anti-gravity exercise in weak patients with CMT 1A and X. Five adult patients performed moderate-intensity aerobic anti-gravity exercise 3/week for 10 weeks. There was a significant positive difference in Berg balance scale and postural stability test between test occasions, and walking distance in 6-Minute walk test trended to increase. The study indicates that anti-gravity treadmill training of weak patients with CMT should be pursued in larger CMT cohorts. http://dx.doi.org/10.1016/j.nmd.2017.06.199
P.170 The effect of orthosis and foot surgery in a cohort of Charcot-Marie-Tooth disease children E. Milev 1, T. Bhandari 1, M. Laura 2, M. Reilly 2, F. Muntoni 1 1 Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health and Great Ormond Street Hospital, London, UK; 2 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and UCLH NHS Foundation Trust, London, UK
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Abstracts 2017 / Neuromuscular Disorders 27 (2017) S96–S249
Charcot-Marie-Tooth disease (CMT) is the most common inherited neuromuscular disease. It is clinically characterised by distal weakness and sensory loss in the upper and lower limbs, and frequent foot deformities. Management of this condition includes use of orthoses and/or corrective surgery. Nevertheless, there have been limited studies looking at the effect of those interventions. As part of an ongoing International natural history study we analysed the six-minute walking test (6MWT) performed as part of a validated scale to assess impairment in children with CMT (CPTPaediatric score (CMTPeds)). We also assessed the impact of both orthoses (by comparing outcome of 6MWT with and without them) and surgical intervention to correct foot deformities in children with CMT. A total of 103 patients with confirmed diagnosis of CMT have been recruited since 2010. Four (4) patients had surgery and eight (8) patients performed the 6MWT with and without orthoses. The mean 6MWT score for preoperative patients was 315 meters (50- 477m) and 212m (0– 448m) for patients who have done the test postoperatively where the minimal time allowed before the first postoperative assessment was 5 months (average of 9 months for all 4 patients). Furthermore, only two of the children had more than one postoperative assessment but in both the 6MWT showed decline (mean = 171,5m) over the 2-year follow up measurement. When the 6MWT was reviewed with patients who used orthoses the results revealed an improvement in the covered distance when wearing assistive devices (mean = 430m, 305 – 599m) compared to the results of when the test was done without orthoses (mean = 384m, 258 – 515m). Data collected to date suggested that surgery intervention did not improve walking distance in this limited CMT patient population. However more studies are needed to support these findings due to the small sample size. Conversely, the usage of orthoses did prove to sustain gait and muscle capacity. http://dx.doi.org/10.1016/j.nmd.2017.06.200
P.171 CNTNAP1: Extending the phenotype of congenital hypomyelinating neuropathy in 6 further patients K. Low 1, K. Stals 2, R. Caswell 2, J. Clayton-Smith 3, A. Donaldson 1, N. Foulds 4, M. Splitt 5, A. Norman 1, K. Urankar 6, K. Vijayakumar 1, D. Study 7, S. Ellard 2, A. Majumdar 1, S. Smithson 1 1 University Hospital Bristol, Bristol, UK; 2 Exeter Clinical Genetics Laboratory, Exeter, UK; 3 Manchester Centre for Genomic Medicine, Manchester, UK; 4 Wessex Clinical Genetics Service, Southampton, UK; 5 Institute of Genetic Medicine, Newcastle, UK; 6 University of Bristol, Bristol, UK; 7 Sanger Institute, Cambridge, UK CNTNAP1 (OMIM # 602346) encodes rat contactin-associated protein (CASPR) and was first implicated in human disease in 2014.1 CASPR2, forms part of a high molecular mass complex in the paranodal junction and interacts with contactin. Normal paranodal junctions do not form if CASPR is absent and this occurs in conjunction with disruption of the paranodal loops. Using a whole exome sequencing (WES) approach in 31 non-syndromic arthrogryposis multiplex congenital families, Laquerriere et al identified four unrelated familes with homozygous frameshift mutations in CNTNAP1. Death occurred within the first 40 days of life in all four cases. CNTNAP1 has since been described in association with a severe congenital hypomyelinating neuropathy (CHN) in a further 5 patients in the literature. We describe the clinical findings in 6 further patients extending the phenotype beyond that of neonatal lethality. We report neuropathological findings on muscle and nerve biopsy of 3 of the patients. Further molecular genetic analysis is ongoing and the results will be reported. Our findings demonstrate that CNTNAP1 causes a reproducible specific phenotype of polyhydramnios with associated premature birth, severe central hypotonia from birth with severe demyelinating peripheral neuropathy, cranial nerve involvement including orobulbar dysfunction, vocal cord palsy, severe respiratory distress from birth with associated requirement for tracheostomy and profound intellectual disability. Onion bulb fibres were noted on neuropathological specimens concurring with previous reports, although not specific to CNTNAP1. Brain MRI demonstrated a varying combination of
central hypomyelination, delayed myelination and loss of white matter bulk. This specific clinical pattern has not been previously reported in association with any of the other genes associated with CHN and should guide clinical management and genetic counselling. http://dx.doi.org/10.1016/j.nmd.2017.06.201
P.172 Homozygous p.R707W MFN2 mutation is associated with neuropathy, lipomatosis, peripheral lipoatrophy and metabolic alterations M. Masingue 1, C. Vatier 2, I. Jéru 2, P. Latour 3, C. Jardel 4, P. Laforêt 1, B. Eymard 1, C. Vigouroux 2, T. Stojkovic 1 1 Institut de Myologie, Paris, France; 2 Hôpital Saint Antoine, Paris, France; 3 CHU de Lyon HCL – GH Est, Lyon, France; 4 Hôpital Universitaire Pitié Salpêtrière, Paris, France Mutations in mitofusin 2 (MFN2), a nuclear encoded mitochondrial GTPase, classically induce autosomal-dominant axonal Charcot-Marie-Tooth (CMT2A) neuropathy, and more rarely recessive demyelinating or axonal forms. A homozygous p.R707W MFN2 mutation was reported in two families with lipomatosis and neuropathy. We studied, in three patients carrying the p.R707W homozygous MFN2 mutations, the characteristics of the peripheral neuropathy and the adipose tissue and metabolic alterations. The first patient, a woman of 52 years old, presented with pes cavus as a child, multiple lipomas affecting cranial, cervicothoracic and abdominal regions since the age of 25, absent ankle reflexes and quadriceps muscle weakness. Lipoatrophy was observed in lower limbs with decreased fat mass (19% of total body mass). Electroneuromyography (ENMG) showed an axonal sensory-motor neuropathy. She also displayed hypertriglyceridemia (2.7 mmol/l), insulin resistant diabetes and liver steatosis. A second 71-yearold patient complained of walking disorder and pes cavus since childhood. She progressively developed distal contractures and muscle weakness of upper and lower limbs, loss of sensitivity in the feet, and exercise intolerance. Lipoatrophy was present in the four limbs, with shoulder and neck lipomas. ENMG revealed anaxonal polyneuropathy. She had hypertriglyceridemia (3.7 mmol/l). A third 55-year-old patient presented with progressive fourlimbs lipoatrophy, lipomatosis and abolished reflexes since she was a child. Ankle contractures appeared at 45, walking disorder at 55. Clinical examination showed pes cavus, distal weakness, and proprioceptive disturbance. A sensorimotor demyelinating neuropathy was found on the ENMG. She had hypertriglyceridemia (8.9 mmol/l) and diabetes since age 24. Unlike MT-TK gene mutations (MERRF: myoclonic epilepsy with ragged red fibers), the MFN2 p.R707W homozygous mutation associates not only lipomatosis and CMT but also lipoatrophy and metabolic alterations, and this work emphasize the fact that the MFN2 gene should be screened in cases presenting as such. http://dx.doi.org/10.1016/j.nmd.2017.06.202
P.173 Clinical characteristics of spectrum of GNE gene mutations in Reunion-Island cohort. I. Grigorashvili-Coin 1, M. Campech 1, F. Darcel 1, M. Jacquemont 1, M. Kranh 2, M. Cerino 2, A. Choumert 1 1 CHU de La Réunion, Saint-Pierre, France; 2 Aix Marseille Univ, Inserm, GMGF, Marseille, France GNE myopathy is a rare autosomal recessive myopathy characterized by distal muscle weakness and atrophy. The mutations in the gene GNE encode a defective UDP-N-acetyl-glucosamine 2-epimerase/N-acetyl-mannosamine kinase, a key bifunctional enzyme in sialic acid biosynthesis. This condition is thought to be ubiquitous, even if actually most of the descriptions proceed from
P.166 A knock-in mouse model with nonsense dysferlin mutation J. Shin 1, S. Park 1, J. Park 2, D. Kim 1 1 Pusan National University Yangsan Hospital, Yangsan, Korea; 2 Kyungpook National University, Daegu, Korea Mutations in the dysferlin gene cause limb-girdle muscular dystrophy 2B or Miyoshi distal myopathy with autosomal recessive inheritance pattern. A few mouse models harboring truncating mutations have been in use for the research of the dysferlinopathy. We found nonsense mutations are most common among Korean patients with dysferlinopathy; more than half of the patients have at least one nonsense allele, which could be mitigated by readthrough strategy. Thus we generated a knock-in mouse with p.Q832* mutation, most frequently found among our dysferlinopathy cases. Mice with homozygous p.Q832* mutation, named dqx, performed poorer on Rotarod and treadmill test than wild type C57BL6 mice and moved less on activity monitoring. On eccentric contraction ex vivo, extensor digitorum longus muscle from dqx tended to break easily on the first few contractions. All these abnormality could successfully be alleviated when the mice were administered with gentamicin for 3 weeks. These results support that readthrough strategy may also be applicable to nonsense dysferlinopathy patients. http://dx.doi.org/10.1016/j.nmd.2017.06.196
CHARCOT-MARIE-TOOTH DISEASE AND DISTAL MYOPATHIES
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P.168 Falls in children and adolescents with Charcot-Marie-Tooth disease and typically developing children: a six month prospective study K. Carroll 1, J. McGinley 2, K. Paterson 2, M. Ryan 1, R. Kennedy 1 1 The Royal Children’s Hospital, Parkville, Australia; 2 The University of Melbourne, Parkville, Australia Children and adolescents with Charcot-Marie-Tooth disease (CMT) report frequent falls. Falls are a natural part of growth and development in childhood; but what is typical? There are no longitudinal studies of falls in children with CMT or typically developing children (TD). A prospective study evaluated falls over 6 months in 30 children with CMT and 30 age- and gender-matched TD children (mean age 11.5 years (3.8); 21 males). A daily diary recorded fall frequency and a questionnaire detailed the “worst” fall each day including location, time of day, surface type, mechanism and injuries. Diaries were returned by 25 CMT and 27TD children. Children with CMT recorded 2819 falls (range 0–1915) and TD children 31 falls (range 0–6). One child with CMT was an extreme outlier recording 1915 falls. Over 6 months 3 CMT and 19 TD children were classified as “non-fallers” (0 falls); 11 CMT and 2 TD children as “fallers” (1–2 falls); and 10 CMT and 6 TD children as “recurrent fallers” (>2 falls). All children 6 years or younger recorded falls whether with CMT or TD. Details of 216 CMT and 26 TD falls were collected by questionnaire. Approximately 40% of falls occurred at home. Afternoon and evening were the most common times that falls occurred (CMT 69%, TD 65%). More falls were recorded outdoors (flat surface, uneven terrain, playground; CMT 50%, TD 46%) than indoors (flat surface; CMT 35%, TD 34%) or on steps (CMT 13%, TD 20%). Tripping was the most frequent mechanism of falling (CMT 52%; TD 73%), with legs giving way (CMT 23%, TD 4%), overbalancing (CMT 12%, TD 8%) and rolling ankles (CMT 6%, TD 0%) also reported mechanisms of falls. Injury rate was higher in children with CMT (34%,TD 12%) with cuts/grazes most common. Children with CMT also reported bruising, ankle injuries and superficial head injuries. Falls are a major issue for children and adolescents with CMT. Further research is needed to understand what interventions may be effective in reducing falls in CMT. http://dx.doi.org/10.1016/j.nmd.2017.06.198
P.167 Severe form of recessive Charcot-Marie-Tooth disease with a novel mutation in myotubularin related protein 2 A. Bayram 1, K. Stumpfe 2, H. Wang 2, M. Pergande 2, H. Per 1, S. Çırak 2 1 Erciyes University, Kayseri, Turkey; 2 Cologne University, Cologne, Germany Charcot-Marie-Tooth type 4 (CMT4) is a severe form of recessive neuropathy with genetic heterogeneity. To date 11 different genes are detected of this rare autosomal recessive disorder. One form of this disease is caused by a mutation of the myotubularin-related 2 (MTMR2) gene. It is characterized by severe early childhood-onset demyelinating sensorimotor polyneuropathy, deformation of extremities and speech impairment up to vocal cord paresis. In the following we report the clinical course and electrophysiological findings of three pediatric sibling cases with a novel mutation in MTMR2. All of our patients first noticed quick fatigue after the first three years of life. As the disease progressed, they all developed muscle atrophy, facial weakness, pes cavus deformity and global developmental delay at the end of the first decade. Their deep tendon reflexes were absent. Sensory nerve action potentials and nerve conduction velocity were undetectable in all of them. Compound muscle action potential and motor conduction velocity were not recordable in two patients and were severely decreased in one patient. One of the patients was even confined to wheelchair. Molecular analysis with whole exome sequencing (WES) of the MTMR2 gene revealed a novel homozygous mutation in all siblings: c.1490insC; p.F498Ifs*2. In conclusion, the heterogeneous genetic spectrum of CMT4B1 has been expanded by a new mutation described before. Further studies are needed to improve the understanding of the pathomechanism behind the loss of myelin in the peripheral nervous system in order to establish new treatments. http://dx.doi.org/10.1016/j.nmd.2017.06.197
P.169 Aerobic anti-gravity exercise in patients with Charcot-Marie-Tooth disease. Types: a pilot study K. Knak, L. Andersen, J. Vissing Rigshospitalet, Copenhagen, Denmark Charcot-Marie-Tooth (CMT) disease is a hereditary neuropathy associated with impaired walking capacity. Some patients are too weak in the lower extremity muscles to walk at gravity with sufficient intensity or duration to gain benefit. The objective was to investigate the effect of aerobic anti-gravity exercise in weak patients with CMT 1A and X. Five adult patients performed moderate-intensity aerobic anti-gravity exercise 3/week for 10 weeks. There was a significant positive difference in Berg balance scale and postural stability test between test occasions, and walking distance in 6-Minute walk test trended to increase. The study indicates that anti-gravity treadmill training of weak patients with CMT should be pursued in larger CMT cohorts. http://dx.doi.org/10.1016/j.nmd.2017.06.199
P.170 The effect of orthosis and foot surgery in a cohort of Charcot-Marie-Tooth disease children E. Milev 1, T. Bhandari 1, M. Laura 2, M. Reilly 2, F. Muntoni 1 1 Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health and Great Ormond Street Hospital, London, UK; 2 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and UCLH NHS Foundation Trust, London, UK
S148
Abstracts 2017 / Neuromuscular Disorders 27 (2017) S96–S249
Charcot-Marie-Tooth disease (CMT) is the most common inherited neuromuscular disease. It is clinically characterised by distal weakness and sensory loss in the upper and lower limbs, and frequent foot deformities. Management of this condition includes use of orthoses and/or corrective surgery. Nevertheless, there have been limited studies looking at the effect of those interventions. As part of an ongoing International natural history study we analysed the six-minute walking test (6MWT) performed as part of a validated scale to assess impairment in children with CMT (CPTPaediatric score (CMTPeds)). We also assessed the impact of both orthoses (by comparing outcome of 6MWT with and without them) and surgical intervention to correct foot deformities in children with CMT. A total of 103 patients with confirmed diagnosis of CMT have been recruited since 2010. Four (4) patients had surgery and eight (8) patients performed the 6MWT with and without orthoses. The mean 6MWT score for preoperative patients was 315 meters (50- 477m) and 212m (0– 448m) for patients who have done the test postoperatively where the minimal time allowed before the first postoperative assessment was 5 months (average of 9 months for all 4 patients). Furthermore, only two of the children had more than one postoperative assessment but in both the 6MWT showed decline (mean = 171,5m) over the 2-year follow up measurement. When the 6MWT was reviewed with patients who used orthoses the results revealed an improvement in the covered distance when wearing assistive devices (mean = 430m, 305 – 599m) compared to the results of when the test was done without orthoses (mean = 384m, 258 – 515m). Data collected to date suggested that surgery intervention did not improve walking distance in this limited CMT patient population. However more studies are needed to support these findings due to the small sample size. Conversely, the usage of orthoses did prove to sustain gait and muscle capacity. http://dx.doi.org/10.1016/j.nmd.2017.06.200
P.171 CNTNAP1: Extending the phenotype of congenital hypomyelinating neuropathy in 6 further patients K. Low 1, K. Stals 2, R. Caswell 2, J. Clayton-Smith 3, A. Donaldson 1, N. Foulds 4, M. Splitt 5, A. Norman 1, K. Urankar 6, K. Vijayakumar 1, D. Study 7, S. Ellard 2, A. Majumdar 1, S. Smithson 1 1 University Hospital Bristol, Bristol, UK; 2 Exeter Clinical Genetics Laboratory, Exeter, UK; 3 Manchester Centre for Genomic Medicine, Manchester, UK; 4 Wessex Clinical Genetics Service, Southampton, UK; 5 Institute of Genetic Medicine, Newcastle, UK; 6 University of Bristol, Bristol, UK; 7 Sanger Institute, Cambridge, UK CNTNAP1 (OMIM # 602346) encodes rat contactin-associated protein (CASPR) and was first implicated in human disease in 2014.1 CASPR2, forms part of a high molecular mass complex in the paranodal junction and interacts with contactin. Normal paranodal junctions do not form if CASPR is absent and this occurs in conjunction with disruption of the paranodal loops. Using a whole exome sequencing (WES) approach in 31 non-syndromic arthrogryposis multiplex congenital families, Laquerriere et al identified four unrelated familes with homozygous frameshift mutations in CNTNAP1. Death occurred within the first 40 days of life in all four cases. CNTNAP1 has since been described in association with a severe congenital hypomyelinating neuropathy (CHN) in a further 5 patients in the literature. We describe the clinical findings in 6 further patients extending the phenotype beyond that of neonatal lethality. We report neuropathological findings on muscle and nerve biopsy of 3 of the patients. Further molecular genetic analysis is ongoing and the results will be reported. Our findings demonstrate that CNTNAP1 causes a reproducible specific phenotype of polyhydramnios with associated premature birth, severe central hypotonia from birth with severe demyelinating peripheral neuropathy, cranial nerve involvement including orobulbar dysfunction, vocal cord palsy, severe respiratory distress from birth with associated requirement for tracheostomy and profound intellectual disability. Onion bulb fibres were noted on neuropathological specimens concurring with previous reports, although not specific to CNTNAP1. Brain MRI demonstrated a varying combination of
central hypomyelination, delayed myelination and loss of white matter bulk. This specific clinical pattern has not been previously reported in association with any of the other genes associated with CHN and should guide clinical management and genetic counselling. http://dx.doi.org/10.1016/j.nmd.2017.06.201
P.172 Homozygous p.R707W MFN2 mutation is associated with neuropathy, lipomatosis, peripheral lipoatrophy and metabolic alterations M. Masingue 1, C. Vatier 2, I. Jéru 2, P. Latour 3, C. Jardel 4, P. Laforêt 1, B. Eymard 1, C. Vigouroux 2, T. Stojkovic 1 1 Institut de Myologie, Paris, France; 2 Hôpital Saint Antoine, Paris, France; 3 CHU de Lyon HCL – GH Est, Lyon, France; 4 Hôpital Universitaire Pitié Salpêtrière, Paris, France Mutations in mitofusin 2 (MFN2), a nuclear encoded mitochondrial GTPase, classically induce autosomal-dominant axonal Charcot-Marie-Tooth (CMT2A) neuropathy, and more rarely recessive demyelinating or axonal forms. A homozygous p.R707W MFN2 mutation was reported in two families with lipomatosis and neuropathy. We studied, in three patients carrying the p.R707W homozygous MFN2 mutations, the characteristics of the peripheral neuropathy and the adipose tissue and metabolic alterations. The first patient, a woman of 52 years old, presented with pes cavus as a child, multiple lipomas affecting cranial, cervicothoracic and abdominal regions since the age of 25, absent ankle reflexes and quadriceps muscle weakness. Lipoatrophy was observed in lower limbs with decreased fat mass (19% of total body mass). Electroneuromyography (ENMG) showed an axonal sensory-motor neuropathy. She also displayed hypertriglyceridemia (2.7 mmol/l), insulin resistant diabetes and liver steatosis. A second 71-yearold patient complained of walking disorder and pes cavus since childhood. She progressively developed distal contractures and muscle weakness of upper and lower limbs, loss of sensitivity in the feet, and exercise intolerance. Lipoatrophy was present in the four limbs, with shoulder and neck lipomas. ENMG revealed anaxonal polyneuropathy. She had hypertriglyceridemia (3.7 mmol/l). A third 55-year-old patient presented with progressive fourlimbs lipoatrophy, lipomatosis and abolished reflexes since she was a child. Ankle contractures appeared at 45, walking disorder at 55. Clinical examination showed pes cavus, distal weakness, and proprioceptive disturbance. A sensorimotor demyelinating neuropathy was found on the ENMG. She had hypertriglyceridemia (8.9 mmol/l) and diabetes since age 24. Unlike MT-TK gene mutations (MERRF: myoclonic epilepsy with ragged red fibers), the MFN2 p.R707W homozygous mutation associates not only lipomatosis and CMT but also lipoatrophy and metabolic alterations, and this work emphasize the fact that the MFN2 gene should be screened in cases presenting as such. http://dx.doi.org/10.1016/j.nmd.2017.06.202
P.173 Clinical characteristics of spectrum of GNE gene mutations in Reunion-Island cohort. I. Grigorashvili-Coin 1, M. Campech 1, F. Darcel 1, M. Jacquemont 1, M. Kranh 2, M. Cerino 2, A. Choumert 1 1 CHU de La Réunion, Saint-Pierre, France; 2 Aix Marseille Univ, Inserm, GMGF, Marseille, France GNE myopathy is a rare autosomal recessive myopathy characterized by distal muscle weakness and atrophy. The mutations in the gene GNE encode a defective UDP-N-acetyl-glucosamine 2-epimerase/N-acetyl-mannosamine kinase, a key bifunctional enzyme in sialic acid biosynthesis. This condition is thought to be ubiquitous, even if actually most of the descriptions proceed from