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TRPV4 mutation causing dominantly inherited scapuloperoneal spinal muscle atrophy
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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
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