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Next generation sequencing identifies a novel ATP7A mutation in two brothers with distal hereditary motor neuropathy and autonomic dysfunction
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Abstracts / Neuromuscular Disorders 25 (2015) S184–S316
trafficking in DYNC1H1-associated motor neuron disease and suggest a potential therapeutic target for treatment of motor neuron disease. http://dx.doi.org/10.1016/j.nmd.2015.06.142
G.P.128 Occurrence of CHCHD10 mutations in Finnish patients with motor neuron disorder S. Penttilä *,1, M. Jokela 2, A. Saukkonen 3, J. Toivanen 3, B. Udd 1 1 University of Tampere, Neuromuscular Research Unit, Tampere, Finland; 2 Turku University Hospital and University of Turku, Division of Clinical Neurosciences, Turku, Finland; 3 Central Hospital of Northern Karelia, Department of Neurology, Joensuu, Finland Spinal muscular atrophy Jokela type (SMAJ, OMIM #615048) is a relatively benign form of motor neuron disease that has been described in 55 patients in 17 Finnish families. The disease is caused by a dominant mutation c.197G>T p.G66V in CHCHD10. All reported families with SMAJ share an identical disease-associated haplotype, proving a founder effect in the Finnish population. Other mutations in CHCHD10 have been reported to cause FTDALS with mitochondrial myopathy and isolated mitochondrial myopathy. Some mutations have been associated with FTD-ALS but their pathogenicity has remained uncertain. Because of this large clinical variability in CHCHD10 mutations, we wanted to know if the Finnish founder mutation p.G66V also might cause other phenotypes besides SMAJ. Other aims of the study were to find out if there are other mutations of CHCHD10 in Finnish patients and if CHCHD10 mutations are frequent among patients with distinct neurogenic disorders. Exon 2 of CHCHD10 that harbors all reported mutations was sequenced in 293 patients. In 103 patients the whole coding region of the gene was sequenced. Of the patients included in the study, 193 patients had a phenotype compatible with SMAJ, 24 patients had a non-specific neurogenic disorder, 12 patients had mitochondrial myopathy, and 64 patients had diagnosis of ALS. The founder mutation was found in 16 patients. All of them were suspected to have SMAJ, which suggests the phenotype caused by p.G66V is not highly variable. No mutations were found in other patient groups. One other mutation besides p.G66V was found: two siblings were found to carry the mutation c.100C>T p.P34S that has been previously reported to be associated with FTD-ALS. However, the mutation did not segregate correctly, suggesting it may not be pathogenic. Our results suggest that the CHCHD10 mutation p.G66V is a common mutation in Finland with a prevalence around 2/100,000, and that the clinical outcome is very restricted to the SMAJ phenotype.
identified once previously in a patient with CMT2C. This patient displayed moderate exertional dyspnoea and diaphragmatic involvement as well as sensory deficits, neither of which was apparent in our patients. Our data underline the substantial phenotypic variation in TRPV4-associated neuronopathies, even when caused by a single mutation. http://dx.doi.org/10.1016/j.nmd.2015.06.144
G.P.130 Atypical presentation of SMARD1 R. Kulshrestha *, N. Kiely, T. Willis Robert Jones and Agnes Hunt Orthopaedic Hospital NHS Trust, Oswestry, UK Immunoglobulin-helicase-µ-binding protein 2 (IGHMBP2) mutations usually lead to spinal muscular atrophy with respiratory distress type 1 (SMARD1); most infants die before 1 year of age. Individuals with axonal neuropathy with this mutation have been described with slowly progressive weakness, wasting, sensory loss, axonal neuropathy typical of CMT (Charcot– Marie–Tooth disease) type 2 but no significant respiratory compromise. We present two cases of IGHMBP2 mutation without respiratory involvement but with variable neurophysiology. The first patient, a 10 year old boy, presented at 6 months with late onset bilateral equinovarus deformities of feet. He had minimal movement at ankle and knee joints. He achieved walking with support at two years. He had progressive proximal weakness and distal muscle wasting of both upper and lower limbs, leading to wheelchair dependence at 8 years. He had developed scoliosis. Respiratory status is satisfactory at 10 years. Neurophysiology is consistent with demyelinating neuropathy with nerve conduction velocity of 23m/s. There are two heterozygous variants in IGHMBP2 gene c.1156>C in exon 8 and c.2747G>A in exon 14. The second variant has not been reported. The second patient, a 35 year old lady, had early presentation of feet deformities, requiring surgery at 18 months. She managed walking until 15 years. She is unable to stand but can kneel. Her respiratory status is satisfactory. Neurophysiology is suggestive of denervation and no evidence of demyelinating or axonal neuropathy. She has two heterozygous pathogenic variants in IGHMBP2 gene c.1478C>T and c.2368C>T. These cases highlight that mutations in IGHMBP2 should be considered in the molecular genetic workup of patients with demyelinating hereditary sensorimotor neuropathies and distal spinal muscular atrophy even in the absence of respiratory symptoms. http://dx.doi.org/10.1016/j.nmd.2015.06.145
http://dx.doi.org/10.1016/j.nmd.2015.06.143
G.P.129 TRPV4 mutation causing dominantly inherited scapuloperoneal spinal muscle atrophy P. Sanaker *,1, L. Bindoff 2 1 Haukeland University Hospital, Department of Neurology, Bergen, Norway; 2 University of Bergen, Department of Clinical Medicine, Bergen, Norway Mutations in the calcium permeable cation channel TRPV4 are known to cause a variety of clinical manifestations, usually divided into four different (but, in some cases, overlapping) clinical entities: congenital distal spinal muscular atrophy; Charcot–Marie–Tooth disease type 2C (CMT2C) – comprising axonal sensorimotor neuropathy with diaphragmatic and vocal cord paresis; scapuloperoneal spinal muscular atrophy (SPSMA); and a range of skeletal dysplasias. We investigated a father and daughter with early onset hypotonia, slowly progressive scapuloperoneal weakness and no sensory complaints or findings. The phenotype was in keeping with previous descriptions of SPSMA. Additional features included skeletal anomalies (congenital talus verticalis), absence of muscles (sternomastoids), vocal cord palsy and mild bulbar weakness causing slight dysphagia. Both harboured a heterozygote mutation in TRPV4; c.947G>A (R316H), which has been
G.P.131 Next generation sequencing identifies a novel ATP7A mutation in two brothers with distal hereditary motor neuropathy and autonomic dysfunction C. Scotton 1, E. Italyankina 1, M. Storbeck 2, K. Vezyroglou 2, R. Heller 2, M. Neri 1, F. Di Raimo 1, A. Mauro 1, V. Tugnoli 3, V. Timmerman 4, B. Wirth 2, D. De Grandis 5, F. Gualandi 1, A. Ferlini *,1 1 Università Ferrara, UOL Medical Genetics, Ferrara, Italy; 2 University Hospital of Cologne, Institute of Human Genetics, Cologne, Germany; 3 University of Ferrara, Department of Neuroscience and Rehabilitation, Ferrara, Italy; 4 University of Antwerpen, VIB – Department of Molecular Genetics Peripher, Antwerpen, Belgium; 5 UILDM- Verona, Verona, Italy Distal hereditary motor neuropathies (dHMNs), also known as distal SMAs, are genetically heterogeneous diseases characterized by lower motor neuron distal weakness. Two brothers were evaluated in our Neurogenetic Clinic, presenting with a distal axonal motor neuropathy and a focal autonomic dysfunction, whose main manifestation was retrograde ejaculation. One also suffered from enhanced gastro-intestinal motility and bradycardia. First symptoms arose around 27 years of age and presentation was with cramps, progressive difficulties in feet dorsiflexion, lower limbs distal muscle weakness and distal muscle atrophy. EMG and muscular biopsy showed neurogenic
Abstracts / Neuromuscular Disorders 25 (2015) S184–S316 patterns. Within the European Neuromics Project we have studied the two patients by next generation sequencing (NGS) using an in-house-designed lower motor neuron diseases gene panel. The panel includes 21 ALS-, 13 SMA-, 16 HMN- and 14 CMT-associated genes. This analysis allowed us to identify a hemizygous missense mutation (p.A991D) in exon 15 of the X-linked ATP7A gene, present in both affected brothers. The unaffected mother was heterozygous for the mutation. Mutations in the ATP7A gene have been classically identified in the severe infantile neurodegenerative Menkes disease and in its milder variant, Occipital Horn Syndrome (OHC). ATP7A missense mutations were also identified in two families with X-linked dHMN (SMAX3). One of the reported variant (p.A994I) is within the same a-helix-TH domain of the novel mutation identified in our family, only 3 residues apart. In previously described SMAX3 affected subjects, a pure axonal distal motor neuropathy was present, but without symptoms of dysautonomia. Thus, the phenotype we describe in our family is novel since it includes autonomic dysfunction, expanding the ATP7A clinical spectrum. The utilized NGS clinical genes panel for lower motor neuron diseases is therefore a powerful tool for HMN diagnosis and new phenotype discovery. http://dx.doi.org/10.1016/j.nmd.2015.06.146
G.P.132 Mutations in ASAH1 may cause spinal muscular atrophy A. Behin *,1, I. Nelson 2, G. Bonne 2, N. Romero 3, R. Froissart 4 1 APHP, GH, Pitie-Salpetriere, Institute of Myology, Reference Center for Neuromuscular Disorders, 75013, France; 2 UMRS 974 UPMC – INSERM – FRE 3617 CNRS – AIM, GH Pitie-Salpetriere, Paris, France; 3 APHP, Labotatoire de Pathologie Risler, GH Pitie-Salpetriere, Paris, France; 4 Centre de biologie et pathologie Est – Maladies héréditaires et du métabolisme – CHU de Lyon, Bron, France Mutations in ASAH1, a gene encoding for acid ceramidase, a major enzyme of lipid metabolism, have been reported to cause Farber lipogranulomatosis and severe, early-onset forms of spinal muscular atrophy with progressive myoclonic epilepsy. We describe here a case of a classical form of spinal muscular atrophy with neither epilepsy nor systemic abnormalities. A 19-year-old female patient was referred to our center for a five-year history of slowly progressive, proximal weakness and postural tremor. On clinical examination, symmetrical weakness was found in iliopsoas (MRC 3+/5), gluteus maximus (MRC 3−/5), deltoid (MRS 4/5) and biceps brachialis (MRC 3+/5) muscles. Achillean contractures were also present. CKs and nerve conduction velocities were normal, electromyography showed neurogenic traces. Muscle MRI of the lower limbs displayed no major fatty degeneration but an atrophy of proximal, especially gluteal muscle. Search for SMN1 mutations was performed twice, showing no abnormality. Muscle biopsy was performed at that point, confirming a typical neurogenic pattern. Whole exome sequencing was thus proposed, and revealed two mutations: a paternally inherited c.77C>G (p.P26R) substitution in exon 1 and a c.125+1G>A mutation in intron 2 present in the patient’s mother. Mutations were confirmed in the French reference laboratory for Farber disease. ASAH1 mutations can account for a spinal muscular atrophy (SMA) phenotype presenting like classical type III-IV forms linked to SMN1 mutations. In patients with no SMN1 deletions, search for mutations in ASAH1 should thus be considered. http://dx.doi.org/10.1016/j.nmd.2015.06.147
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within the 3 to 5 years after diagnosis by respiratory failure. About 10% of ALS cases are familial (fALS), and although 20 candidate genes have been associated with fALS, the pathogenic mechanisms underlying this disease still remain largely unknown. Recently, mutations in the UBIQUILIN-2 (UBQLN2) gene, which encodes for the Ubiquitin-like protein Ubiquilin-2, have been identified in dominantly inherited forms of ALS and ALS/dementia linked to chromosome X. UBQLN2 is involved in the degradation of the ubiquitinated proteins, and functional studies showed that these UBQLN2 mutations induce abnormal protein aggregation and neurodegeneration in cells expressing mutant Ubiquilin-2. Interestingly, UBQLN2 pathology was described in the spinal cord of ALS cases and in the brain of ALS/dementia cases, with or without UBQLN2 mutations, suggesting a common pathogenic process linked to UBQLN2 positive inclusions in familial and sporadic ALS cases. In this study, we generated the first successful mouse model of UBQLN2-linked ALS, which – unlike previous transgenic mouse models – recapitulates most clinical and histopathological features of the human disease. Using an AAV10 vector capable of transducing most central nervous system (CNS) cells after intracerebroventricular (ICV) injection, we induced mutant UBQLN2 overexpression in wild-type mice. This model will be helpful for a better understanding not only of the pathogenic mechanisms of UBQLN2-linked ALS, but also of familial or sporadic ALS, leading to potential identification of new therapeutic targets. http://dx.doi.org/10.1016/j.nmd.2015.06.148
G.P.134 High intensity training in patients with spinal and bulbar muscular atrophy K. Heje *, G. Andersen, J. Vissing Rigshospitalet, University Hospital, Copenhagen, Denmark Spinal and bulbar muscular dystrophy (SBMA) is caused by a mutation of the androgen receptor gene on the X chromosome, causing progressive loss of muscle strength. Moderate intensity exercise, 2 hrs weekly, has been shown to be safe, but causes fatigue in patients. We speculated that shorter duration, but higher intensity training could be better tolerated. Patients with SBMA were randomized to either 8 weeks of supervised, high intensity training followed by 8 weeks of optional training (n = 5; age: 25–63; gender: male; BMI: 22–26) or 8 weeks of non-supervised high intensity training (n = 2; age: 49–60; gender: male; BMI: 28–32). Healthy controls (n = 4; age: 28–64; gender: male; BMI: 22–24) were matched by gender, BMI and physical activity level to each participant in the supervised patient group. Training consisted of 2 × 5 minutes with 30, 20 and 10 seconds of work with increasing intensity on a bicycle ergometer. All patients completed training, but one healthy control dropped out. Maximal oxygen capacity was measured before and after training by an incremental test. Plasma creatine kinase levels were monitored throughout the training period. Patients in the supervised group were offered to keep training without supervision for another 8 weeks after the supervised training. This is an ongoing study. Preliminary data show a still non-significant increase in VO2max in the supervised group (6.5%), but less so in the non-supervised group (2.5%) and healthy controls (0.4%). Plasma creatine kinase levels did not change with training. Four out of five patients kept training in the optional training period. They all stuck to the high intensity training 3 times a week. The preliminary data suggest that high intensity training is safe in SBMA, is very well tolerated and appears to improve fitness. http://dx.doi.org/10.1016/j.nmd.2015.06.149
G.P.133 Modeling and pathophysiological analysis of the ubiquilin-2-linked amyotrophic lateral sclerosis (ALS) with AAV vectors C. Bos *, M. Biferi, M. Cohen-Tannoudji, M. Roda, M. Barkats Research Center for Myology, Paris, France Amyotrophic Lateral Sclerosis (ALS) is devastating neurodegenerative disease characterized by a progressive loss of motor neurons (MNs) in motor cortex, brainstem and spinal cord which leads to progressive paralysis and death
G.P.135 Effects of a program based on home exercise on muscle force and functional independence in patients with amyotrophic lateral sclerosis: A 2-year follow-up study M. Piemonte 1, C. Ramirez 1, M. Voos *,1, T. Oliveira 1, C. Miranda 1, H. Silva 2, D. Callegaro 2
Abstracts / Neuromuscular Disorders 25 (2015) S184–S316
trafficking in DYNC1H1-associated motor neuron disease and suggest a potential therapeutic target for treatment of motor neuron disease. http://dx.doi.org/10.1016/j.nmd.2015.06.142
G.P.128 Occurrence of CHCHD10 mutations in Finnish patients with motor neuron disorder S. Penttilä *,1, M. Jokela 2, A. Saukkonen 3, J. Toivanen 3, B. Udd 1 1 University of Tampere, Neuromuscular Research Unit, Tampere, Finland; 2 Turku University Hospital and University of Turku, Division of Clinical Neurosciences, Turku, Finland; 3 Central Hospital of Northern Karelia, Department of Neurology, Joensuu, Finland Spinal muscular atrophy Jokela type (SMAJ, OMIM #615048) is a relatively benign form of motor neuron disease that has been described in 55 patients in 17 Finnish families. The disease is caused by a dominant mutation c.197G>T p.G66V in CHCHD10. All reported families with SMAJ share an identical disease-associated haplotype, proving a founder effect in the Finnish population. Other mutations in CHCHD10 have been reported to cause FTDALS with mitochondrial myopathy and isolated mitochondrial myopathy. Some mutations have been associated with FTD-ALS but their pathogenicity has remained uncertain. Because of this large clinical variability in CHCHD10 mutations, we wanted to know if the Finnish founder mutation p.G66V also might cause other phenotypes besides SMAJ. Other aims of the study were to find out if there are other mutations of CHCHD10 in Finnish patients and if CHCHD10 mutations are frequent among patients with distinct neurogenic disorders. Exon 2 of CHCHD10 that harbors all reported mutations was sequenced in 293 patients. In 103 patients the whole coding region of the gene was sequenced. Of the patients included in the study, 193 patients had a phenotype compatible with SMAJ, 24 patients had a non-specific neurogenic disorder, 12 patients had mitochondrial myopathy, and 64 patients had diagnosis of ALS. The founder mutation was found in 16 patients. All of them were suspected to have SMAJ, which suggests the phenotype caused by p.G66V is not highly variable. No mutations were found in other patient groups. One other mutation besides p.G66V was found: two siblings were found to carry the mutation c.100C>T p.P34S that has been previously reported to be associated with FTD-ALS. However, the mutation did not segregate correctly, suggesting it may not be pathogenic. Our results suggest that the CHCHD10 mutation p.G66V is a common mutation in Finland with a prevalence around 2/100,000, and that the clinical outcome is very restricted to the SMAJ phenotype.
identified once previously in a patient with CMT2C. This patient displayed moderate exertional dyspnoea and diaphragmatic involvement as well as sensory deficits, neither of which was apparent in our patients. Our data underline the substantial phenotypic variation in TRPV4-associated neuronopathies, even when caused by a single mutation. http://dx.doi.org/10.1016/j.nmd.2015.06.144
G.P.130 Atypical presentation of SMARD1 R. Kulshrestha *, N. Kiely, T. Willis Robert Jones and Agnes Hunt Orthopaedic Hospital NHS Trust, Oswestry, UK Immunoglobulin-helicase-µ-binding protein 2 (IGHMBP2) mutations usually lead to spinal muscular atrophy with respiratory distress type 1 (SMARD1); most infants die before 1 year of age. Individuals with axonal neuropathy with this mutation have been described with slowly progressive weakness, wasting, sensory loss, axonal neuropathy typical of CMT (Charcot– Marie–Tooth disease) type 2 but no significant respiratory compromise. We present two cases of IGHMBP2 mutation without respiratory involvement but with variable neurophysiology. The first patient, a 10 year old boy, presented at 6 months with late onset bilateral equinovarus deformities of feet. He had minimal movement at ankle and knee joints. He achieved walking with support at two years. He had progressive proximal weakness and distal muscle wasting of both upper and lower limbs, leading to wheelchair dependence at 8 years. He had developed scoliosis. Respiratory status is satisfactory at 10 years. Neurophysiology is consistent with demyelinating neuropathy with nerve conduction velocity of 23m/s. There are two heterozygous variants in IGHMBP2 gene c.1156>C in exon 8 and c.2747G>A in exon 14. The second variant has not been reported. The second patient, a 35 year old lady, had early presentation of feet deformities, requiring surgery at 18 months. She managed walking until 15 years. She is unable to stand but can kneel. Her respiratory status is satisfactory. Neurophysiology is suggestive of denervation and no evidence of demyelinating or axonal neuropathy. She has two heterozygous pathogenic variants in IGHMBP2 gene c.1478C>T and c.2368C>T. These cases highlight that mutations in IGHMBP2 should be considered in the molecular genetic workup of patients with demyelinating hereditary sensorimotor neuropathies and distal spinal muscular atrophy even in the absence of respiratory symptoms. http://dx.doi.org/10.1016/j.nmd.2015.06.145
http://dx.doi.org/10.1016/j.nmd.2015.06.143
G.P.129 TRPV4 mutation causing dominantly inherited scapuloperoneal spinal muscle atrophy P. Sanaker *,1, L. Bindoff 2 1 Haukeland University Hospital, Department of Neurology, Bergen, Norway; 2 University of Bergen, Department of Clinical Medicine, Bergen, Norway Mutations in the calcium permeable cation channel TRPV4 are known to cause a variety of clinical manifestations, usually divided into four different (but, in some cases, overlapping) clinical entities: congenital distal spinal muscular atrophy; Charcot–Marie–Tooth disease type 2C (CMT2C) – comprising axonal sensorimotor neuropathy with diaphragmatic and vocal cord paresis; scapuloperoneal spinal muscular atrophy (SPSMA); and a range of skeletal dysplasias. We investigated a father and daughter with early onset hypotonia, slowly progressive scapuloperoneal weakness and no sensory complaints or findings. The phenotype was in keeping with previous descriptions of SPSMA. Additional features included skeletal anomalies (congenital talus verticalis), absence of muscles (sternomastoids), vocal cord palsy and mild bulbar weakness causing slight dysphagia. Both harboured a heterozygote mutation in TRPV4; c.947G>A (R316H), which has been
G.P.131 Next generation sequencing identifies a novel ATP7A mutation in two brothers with distal hereditary motor neuropathy and autonomic dysfunction C. Scotton 1, E. Italyankina 1, M. Storbeck 2, K. Vezyroglou 2, R. Heller 2, M. Neri 1, F. Di Raimo 1, A. Mauro 1, V. Tugnoli 3, V. Timmerman 4, B. Wirth 2, D. De Grandis 5, F. Gualandi 1, A. Ferlini *,1 1 Università Ferrara, UOL Medical Genetics, Ferrara, Italy; 2 University Hospital of Cologne, Institute of Human Genetics, Cologne, Germany; 3 University of Ferrara, Department of Neuroscience and Rehabilitation, Ferrara, Italy; 4 University of Antwerpen, VIB – Department of Molecular Genetics Peripher, Antwerpen, Belgium; 5 UILDM- Verona, Verona, Italy Distal hereditary motor neuropathies (dHMNs), also known as distal SMAs, are genetically heterogeneous diseases characterized by lower motor neuron distal weakness. Two brothers were evaluated in our Neurogenetic Clinic, presenting with a distal axonal motor neuropathy and a focal autonomic dysfunction, whose main manifestation was retrograde ejaculation. One also suffered from enhanced gastro-intestinal motility and bradycardia. First symptoms arose around 27 years of age and presentation was with cramps, progressive difficulties in feet dorsiflexion, lower limbs distal muscle weakness and distal muscle atrophy. EMG and muscular biopsy showed neurogenic
Abstracts / Neuromuscular Disorders 25 (2015) S184–S316 patterns. Within the European Neuromics Project we have studied the two patients by next generation sequencing (NGS) using an in-house-designed lower motor neuron diseases gene panel. The panel includes 21 ALS-, 13 SMA-, 16 HMN- and 14 CMT-associated genes. This analysis allowed us to identify a hemizygous missense mutation (p.A991D) in exon 15 of the X-linked ATP7A gene, present in both affected brothers. The unaffected mother was heterozygous for the mutation. Mutations in the ATP7A gene have been classically identified in the severe infantile neurodegenerative Menkes disease and in its milder variant, Occipital Horn Syndrome (OHC). ATP7A missense mutations were also identified in two families with X-linked dHMN (SMAX3). One of the reported variant (p.A994I) is within the same a-helix-TH domain of the novel mutation identified in our family, only 3 residues apart. In previously described SMAX3 affected subjects, a pure axonal distal motor neuropathy was present, but without symptoms of dysautonomia. Thus, the phenotype we describe in our family is novel since it includes autonomic dysfunction, expanding the ATP7A clinical spectrum. The utilized NGS clinical genes panel for lower motor neuron diseases is therefore a powerful tool for HMN diagnosis and new phenotype discovery. http://dx.doi.org/10.1016/j.nmd.2015.06.146
G.P.132 Mutations in ASAH1 may cause spinal muscular atrophy A. Behin *,1, I. Nelson 2, G. Bonne 2, N. Romero 3, R. Froissart 4 1 APHP, GH, Pitie-Salpetriere, Institute of Myology, Reference Center for Neuromuscular Disorders, 75013, France; 2 UMRS 974 UPMC – INSERM – FRE 3617 CNRS – AIM, GH Pitie-Salpetriere, Paris, France; 3 APHP, Labotatoire de Pathologie Risler, GH Pitie-Salpetriere, Paris, France; 4 Centre de biologie et pathologie Est – Maladies héréditaires et du métabolisme – CHU de Lyon, Bron, France Mutations in ASAH1, a gene encoding for acid ceramidase, a major enzyme of lipid metabolism, have been reported to cause Farber lipogranulomatosis and severe, early-onset forms of spinal muscular atrophy with progressive myoclonic epilepsy. We describe here a case of a classical form of spinal muscular atrophy with neither epilepsy nor systemic abnormalities. A 19-year-old female patient was referred to our center for a five-year history of slowly progressive, proximal weakness and postural tremor. On clinical examination, symmetrical weakness was found in iliopsoas (MRC 3+/5), gluteus maximus (MRC 3−/5), deltoid (MRS 4/5) and biceps brachialis (MRC 3+/5) muscles. Achillean contractures were also present. CKs and nerve conduction velocities were normal, electromyography showed neurogenic traces. Muscle MRI of the lower limbs displayed no major fatty degeneration but an atrophy of proximal, especially gluteal muscle. Search for SMN1 mutations was performed twice, showing no abnormality. Muscle biopsy was performed at that point, confirming a typical neurogenic pattern. Whole exome sequencing was thus proposed, and revealed two mutations: a paternally inherited c.77C>G (p.P26R) substitution in exon 1 and a c.125+1G>A mutation in intron 2 present in the patient’s mother. Mutations were confirmed in the French reference laboratory for Farber disease. ASAH1 mutations can account for a spinal muscular atrophy (SMA) phenotype presenting like classical type III-IV forms linked to SMN1 mutations. In patients with no SMN1 deletions, search for mutations in ASAH1 should thus be considered. http://dx.doi.org/10.1016/j.nmd.2015.06.147
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within the 3 to 5 years after diagnosis by respiratory failure. About 10% of ALS cases are familial (fALS), and although 20 candidate genes have been associated with fALS, the pathogenic mechanisms underlying this disease still remain largely unknown. Recently, mutations in the UBIQUILIN-2 (UBQLN2) gene, which encodes for the Ubiquitin-like protein Ubiquilin-2, have been identified in dominantly inherited forms of ALS and ALS/dementia linked to chromosome X. UBQLN2 is involved in the degradation of the ubiquitinated proteins, and functional studies showed that these UBQLN2 mutations induce abnormal protein aggregation and neurodegeneration in cells expressing mutant Ubiquilin-2. Interestingly, UBQLN2 pathology was described in the spinal cord of ALS cases and in the brain of ALS/dementia cases, with or without UBQLN2 mutations, suggesting a common pathogenic process linked to UBQLN2 positive inclusions in familial and sporadic ALS cases. In this study, we generated the first successful mouse model of UBQLN2-linked ALS, which – unlike previous transgenic mouse models – recapitulates most clinical and histopathological features of the human disease. Using an AAV10 vector capable of transducing most central nervous system (CNS) cells after intracerebroventricular (ICV) injection, we induced mutant UBQLN2 overexpression in wild-type mice. This model will be helpful for a better understanding not only of the pathogenic mechanisms of UBQLN2-linked ALS, but also of familial or sporadic ALS, leading to potential identification of new therapeutic targets. http://dx.doi.org/10.1016/j.nmd.2015.06.148
G.P.134 High intensity training in patients with spinal and bulbar muscular atrophy K. Heje *, G. Andersen, J. Vissing Rigshospitalet, University Hospital, Copenhagen, Denmark Spinal and bulbar muscular dystrophy (SBMA) is caused by a mutation of the androgen receptor gene on the X chromosome, causing progressive loss of muscle strength. Moderate intensity exercise, 2 hrs weekly, has been shown to be safe, but causes fatigue in patients. We speculated that shorter duration, but higher intensity training could be better tolerated. Patients with SBMA were randomized to either 8 weeks of supervised, high intensity training followed by 8 weeks of optional training (n = 5; age: 25–63; gender: male; BMI: 22–26) or 8 weeks of non-supervised high intensity training (n = 2; age: 49–60; gender: male; BMI: 28–32). Healthy controls (n = 4; age: 28–64; gender: male; BMI: 22–24) were matched by gender, BMI and physical activity level to each participant in the supervised patient group. Training consisted of 2 × 5 minutes with 30, 20 and 10 seconds of work with increasing intensity on a bicycle ergometer. All patients completed training, but one healthy control dropped out. Maximal oxygen capacity was measured before and after training by an incremental test. Plasma creatine kinase levels were monitored throughout the training period. Patients in the supervised group were offered to keep training without supervision for another 8 weeks after the supervised training. This is an ongoing study. Preliminary data show a still non-significant increase in VO2max in the supervised group (6.5%), but less so in the non-supervised group (2.5%) and healthy controls (0.4%). Plasma creatine kinase levels did not change with training. Four out of five patients kept training in the optional training period. They all stuck to the high intensity training 3 times a week. The preliminary data suggest that high intensity training is safe in SBMA, is very well tolerated and appears to improve fitness. http://dx.doi.org/10.1016/j.nmd.2015.06.149
G.P.133 Modeling and pathophysiological analysis of the ubiquilin-2-linked amyotrophic lateral sclerosis (ALS) with AAV vectors C. Bos *, M. Biferi, M. Cohen-Tannoudji, M. Roda, M. Barkats Research Center for Myology, Paris, France Amyotrophic Lateral Sclerosis (ALS) is devastating neurodegenerative disease characterized by a progressive loss of motor neurons (MNs) in motor cortex, brainstem and spinal cord which leads to progressive paralysis and death
G.P.135 Effects of a program based on home exercise on muscle force and functional independence in patients with amyotrophic lateral sclerosis: A 2-year follow-up study M. Piemonte 1, C. Ramirez 1, M. Voos *,1, T. Oliveira 1, C. Miranda 1, H. Silva 2, D. Callegaro 2