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G.P.1.11 Mitofusin gene mutations (MFN 2) cause a severe CMT2A with diaphragm paresis involvement
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Abstracts / Neuromuscular Disorders 18 (2008) 724–833
G.P.1.11 Mitofusin gene mutations (MFN 2) cause a severe CMT2A with diaphragm paresis involvement J. Colomer 1; A. Nascimento 1; F. Palau 2; A. Abeledo 2; C. Llarena 2; H. Galvez 1; C. Ortez 1; M. Pons 3 1 Hospital Sant Joan de De´u, Unitat de Patologia Neuromuscular. S. Neurologia, Esplugues de Llobregat, Barcelona, Spain; 2 Instituto de Biomedicina de Valencia, Unitat de Genetica y medicina molecular, Valencia, Spain; 3 Hospital Sant Joan de De´u, Pediatria, Esplugues de Llobregat, Barcelona, Spain Introduction: Mutations in mitofusin 2 (MFN2) gene, which encodes a GTPase mitochondrial outer membrane protein, cause mainly two phenotypes of disease: Charcot-Marie- Tooth 2A (CMT2A), and hereditary motor and sensory neuropathy type VI (HMSN VI).We hereby present two patients affected by CMT2A with confirmed mutations in MTN2 gene severely disabled and affected both by a diaphragmatic palsy. Patients and method: Two girls, currently 17 and 19 yeas old, respectively patient I and patient II, presented a similar clinical picture. Patient I was adopted. Patient II had related parents and her father presented slight decreased motor conduction velocity. Patient I started to walk at 17 and patient II at 16 months old. At 3 years old, both patients presented difficulties in walking with feet deformities and distal lower limbs atrophies. Illness progressed involving hands and proximal muscles, developing a severe scoliosis and leading to wheelchair bound before 12 years old. Assistance in all activities of daily living was required needing continuous support by BIPAP as a consequence of bilateral diaphragmatic palsy. Electrophysiological studies confirmed a peripheral axonal motor and sensory neuropathy with bilateral phrenic nerve involvement. Genetic studies: They confirmed respectively a heterocygous mutation p.V7051 (c.2113G>A) and p. P251L (c.572C>t) in MFN2 gene. Discussion: We have reported two cases of a very serious early onset CMT 2A with bilateral phrenic nerve palsy without vocal cord paresis involvement. Up to our knowledge the phrenic nerve palsy involvement associated to MFN gene mutation has not been previously reported. In order to prevent life threatening complications, phrenic nerve involvement should be ruled out in any patient affected by a serious axonal motor and sensory neuropathy. doi:10.1016/j.nmd.2008.06.037
G.P.1.12 Hereditary Motor Sensory Neuropathy Type 1A (HMSN1A) with superadded inflammatory polyneuropathy in two children A. Desurkar 1; J.P. Lin 1; W. Jan 2; S. Al-Sarraj 3; H. Jungbluth 1; E. Wraige 1 1 Evelina Children’s Hospital Guy’s & St Thomas’ NHS Foundation Trust, Department of Paediatric Neurology, London, UK; 2 Evelina Children’s Hospital Guy’s & St Thomas’ NHS Foundation Trust, Department of Paediatric Neuroradiology, London, UK; 3 King’s College Hospital, Department of Clinical Neuropathology, London, UK HMSN1A is the commonest inherited polyneuropathy and usually only slowly progressive; accelerated worsening of symptoms in a proportion of cases may be due to an additional immune polyneuropathy that may respond to anti-inflammatory treatment. We present two children with HMSN1A with acute deterioration and features consistent with an added inflammatory polyneuropathy. Case 1, a 3.5-year-old girl developed increasing weakness 48 h following a febrile illness; 3 months before she had an episode of dysarthria, wide-based gait and exacerbated weakness following febrile illness from which she completely recovered. CSF was acellular with raised protein and magnetic resonance imaging (MRI) showed cerebellar edema and enhancement of dorsal and ventral roots suggesting cerebellitis and inflammatory or demyelinating neuritis. Nerve conduction studies were consistent with demyelinating polyneuropathy and sural nerve biopsy demonstrated occasional macrophages but was otherwise in keeping with HMSN1A, subsequently confirmed genetically.
Because of likely inflammatory polyneuropathy complicating HMSN1A she had monthly immunoglobulin infusions for a year with some benefit. Case 2, a 9-year-old girl with a family history suggestive of HMSN1A and subsequently confirmed PMP22 duplication, presented with acute severe limb pains, weakness and autonomic disturbances. CSF studies demonstrating albumino-cytological dissociation and spine MRI showing enhancement of the dorsal roots were consistent with an inflammatory neuropathy; nerve conduction studies were consistent with a hereditary demyelinating polyneuropathy and features of a superadded inflammatory process. Mycoplasma pneumoniae IgM was elevated indicating acute infection. She made a good recovery with immunoglobulin treatment. HMSN1A complicated by inflammatory neuropathy has been reported in adults but the precise underlying mechanism remains uncertain. The diagnosis of acquired demyelination superimposed on an inherited neuropathy is difficult by both electrophysiology and nerve biopsy but of clinical importance as some cases may respond to immunomodulatory treatment. doi:10.1016/j.nmd.2008.06.038
G.P.1.13 A new locus for distal hereditary motor neuronopathy maps to chromosome 16p E. Brusse 1; D. Majoor-Krakauer 2; B.M. De Graaf 2; G.H. Visser 3; A.J.W. Boon 1; B.A. Oostra 2; A.M. Bertoli-Avella 2 1 Erasmus Medical Center, Neurology, Rotterdam, The Netherlands; 2 Erasmus Medical Center, Clinical Genetics, Rotterdam, The Netherlands; 3 Erasmus Medical Center, Clinical Neurophysiology, Rotterdam, The Netherlands Distal hereditary motor neuronopathy (dHMN) is a clinically and genetic heterogeneous disorder, defined by progressive muscle wasting and weakness without clinical, electrophysiological or morphological sensory involvement, due to anterior horn cell degeneration. We describe the spectrum of neurological and electrophysiological features of an extended Dutch family with autosomal dominant HMN. This family shows a distinct phenotype with mild to moderate, often asymmetrical muscle weakness and atrophy, localized predominantly in the upper or the lower limbs, with variable involvement of the pyramidal tracts. Onset was before the age of 20 years, with a variable course, ranging from asymptomatic pes cavus to quite invalidating muscle weakness. Electrophysiological evaluation, including an electrophysiological muscle scan (EMS), showed sign of motor neuron degeneration. After excluding the genes known to be associated with HMN, we performed a genome-wide linkage analysis, applying a new high-throughput SNP array technology. A new locus for HMN was identified on chromosome 16p (mLOD = 3.28), spanning 6Mb. The SIMPLE gene, associated with a variant of hereditary motor and sensory neuropathy (HMSN 1C) was excluded, leaving 48 candidate genes in this region. In this family, the locus on 16p shows a remarkably variable phenotype, overlapping with related hereditary motor neuron disorders, HMSN and spastic paraplegias. The application of EMS was shown to be useful in detecting signs of chronic motor neuron involvement even in clinically asymptomatic carriers of the disease allele. The clinical heterogeneity and incomplete penetrance suggest a complex of factors determining the development of this genetic disorder. doi:10.1016/j.nmd.2008.06.039
G.P.1.14 A novel form of severe childhood autosomal recessive sensory neuropathy associated with optic atrophy and deafness maps to chromosome 8 q24.22term M. Srour 1; M.I. Shevell 2; B. Brais 1 1 University of Montreal, Laboratoire de neuroge´ne´tique de la motricite´, Montreal, Canada; 2 McGill University, Neurology, Montreal, Canada
Abstracts / Neuromuscular Disorders 18 (2008) 724–833
G.P.1.11 Mitofusin gene mutations (MFN 2) cause a severe CMT2A with diaphragm paresis involvement J. Colomer 1; A. Nascimento 1; F. Palau 2; A. Abeledo 2; C. Llarena 2; H. Galvez 1; C. Ortez 1; M. Pons 3 1 Hospital Sant Joan de De´u, Unitat de Patologia Neuromuscular. S. Neurologia, Esplugues de Llobregat, Barcelona, Spain; 2 Instituto de Biomedicina de Valencia, Unitat de Genetica y medicina molecular, Valencia, Spain; 3 Hospital Sant Joan de De´u, Pediatria, Esplugues de Llobregat, Barcelona, Spain Introduction: Mutations in mitofusin 2 (MFN2) gene, which encodes a GTPase mitochondrial outer membrane protein, cause mainly two phenotypes of disease: Charcot-Marie- Tooth 2A (CMT2A), and hereditary motor and sensory neuropathy type VI (HMSN VI).We hereby present two patients affected by CMT2A with confirmed mutations in MTN2 gene severely disabled and affected both by a diaphragmatic palsy. Patients and method: Two girls, currently 17 and 19 yeas old, respectively patient I and patient II, presented a similar clinical picture. Patient I was adopted. Patient II had related parents and her father presented slight decreased motor conduction velocity. Patient I started to walk at 17 and patient II at 16 months old. At 3 years old, both patients presented difficulties in walking with feet deformities and distal lower limbs atrophies. Illness progressed involving hands and proximal muscles, developing a severe scoliosis and leading to wheelchair bound before 12 years old. Assistance in all activities of daily living was required needing continuous support by BIPAP as a consequence of bilateral diaphragmatic palsy. Electrophysiological studies confirmed a peripheral axonal motor and sensory neuropathy with bilateral phrenic nerve involvement. Genetic studies: They confirmed respectively a heterocygous mutation p.V7051 (c.2113G>A) and p. P251L (c.572C>t) in MFN2 gene. Discussion: We have reported two cases of a very serious early onset CMT 2A with bilateral phrenic nerve palsy without vocal cord paresis involvement. Up to our knowledge the phrenic nerve palsy involvement associated to MFN gene mutation has not been previously reported. In order to prevent life threatening complications, phrenic nerve involvement should be ruled out in any patient affected by a serious axonal motor and sensory neuropathy. doi:10.1016/j.nmd.2008.06.037
G.P.1.12 Hereditary Motor Sensory Neuropathy Type 1A (HMSN1A) with superadded inflammatory polyneuropathy in two children A. Desurkar 1; J.P. Lin 1; W. Jan 2; S. Al-Sarraj 3; H. Jungbluth 1; E. Wraige 1 1 Evelina Children’s Hospital Guy’s & St Thomas’ NHS Foundation Trust, Department of Paediatric Neurology, London, UK; 2 Evelina Children’s Hospital Guy’s & St Thomas’ NHS Foundation Trust, Department of Paediatric Neuroradiology, London, UK; 3 King’s College Hospital, Department of Clinical Neuropathology, London, UK HMSN1A is the commonest inherited polyneuropathy and usually only slowly progressive; accelerated worsening of symptoms in a proportion of cases may be due to an additional immune polyneuropathy that may respond to anti-inflammatory treatment. We present two children with HMSN1A with acute deterioration and features consistent with an added inflammatory polyneuropathy. Case 1, a 3.5-year-old girl developed increasing weakness 48 h following a febrile illness; 3 months before she had an episode of dysarthria, wide-based gait and exacerbated weakness following febrile illness from which she completely recovered. CSF was acellular with raised protein and magnetic resonance imaging (MRI) showed cerebellar edema and enhancement of dorsal and ventral roots suggesting cerebellitis and inflammatory or demyelinating neuritis. Nerve conduction studies were consistent with demyelinating polyneuropathy and sural nerve biopsy demonstrated occasional macrophages but was otherwise in keeping with HMSN1A, subsequently confirmed genetically.
Because of likely inflammatory polyneuropathy complicating HMSN1A she had monthly immunoglobulin infusions for a year with some benefit. Case 2, a 9-year-old girl with a family history suggestive of HMSN1A and subsequently confirmed PMP22 duplication, presented with acute severe limb pains, weakness and autonomic disturbances. CSF studies demonstrating albumino-cytological dissociation and spine MRI showing enhancement of the dorsal roots were consistent with an inflammatory neuropathy; nerve conduction studies were consistent with a hereditary demyelinating polyneuropathy and features of a superadded inflammatory process. Mycoplasma pneumoniae IgM was elevated indicating acute infection. She made a good recovery with immunoglobulin treatment. HMSN1A complicated by inflammatory neuropathy has been reported in adults but the precise underlying mechanism remains uncertain. The diagnosis of acquired demyelination superimposed on an inherited neuropathy is difficult by both electrophysiology and nerve biopsy but of clinical importance as some cases may respond to immunomodulatory treatment. doi:10.1016/j.nmd.2008.06.038
G.P.1.13 A new locus for distal hereditary motor neuronopathy maps to chromosome 16p E. Brusse 1; D. Majoor-Krakauer 2; B.M. De Graaf 2; G.H. Visser 3; A.J.W. Boon 1; B.A. Oostra 2; A.M. Bertoli-Avella 2 1 Erasmus Medical Center, Neurology, Rotterdam, The Netherlands; 2 Erasmus Medical Center, Clinical Genetics, Rotterdam, The Netherlands; 3 Erasmus Medical Center, Clinical Neurophysiology, Rotterdam, The Netherlands Distal hereditary motor neuronopathy (dHMN) is a clinically and genetic heterogeneous disorder, defined by progressive muscle wasting and weakness without clinical, electrophysiological or morphological sensory involvement, due to anterior horn cell degeneration. We describe the spectrum of neurological and electrophysiological features of an extended Dutch family with autosomal dominant HMN. This family shows a distinct phenotype with mild to moderate, often asymmetrical muscle weakness and atrophy, localized predominantly in the upper or the lower limbs, with variable involvement of the pyramidal tracts. Onset was before the age of 20 years, with a variable course, ranging from asymptomatic pes cavus to quite invalidating muscle weakness. Electrophysiological evaluation, including an electrophysiological muscle scan (EMS), showed sign of motor neuron degeneration. After excluding the genes known to be associated with HMN, we performed a genome-wide linkage analysis, applying a new high-throughput SNP array technology. A new locus for HMN was identified on chromosome 16p (mLOD = 3.28), spanning 6Mb. The SIMPLE gene, associated with a variant of hereditary motor and sensory neuropathy (HMSN 1C) was excluded, leaving 48 candidate genes in this region. In this family, the locus on 16p shows a remarkably variable phenotype, overlapping with related hereditary motor neuron disorders, HMSN and spastic paraplegias. The application of EMS was shown to be useful in detecting signs of chronic motor neuron involvement even in clinically asymptomatic carriers of the disease allele. The clinical heterogeneity and incomplete penetrance suggest a complex of factors determining the development of this genetic disorder. doi:10.1016/j.nmd.2008.06.039
G.P.1.14 A novel form of severe childhood autosomal recessive sensory neuropathy associated with optic atrophy and deafness maps to chromosome 8 q24.22term M. Srour 1; M.I. Shevell 2; B. Brais 1 1 University of Montreal, Laboratoire de neuroge´ne´tique de la motricite´, Montreal, Canada; 2 McGill University, Neurology, Montreal, Canada