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124. Evidence for respiratory chain abnormalities in the peripheral nerves of patients with MELAS
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Abstracts / Journal of Clinical Neuroscience 16 (2009) 462–481
122. Voltage-gated Potassium Channel Autoimmunity Mimicking Creutzfeldt-Jakob Disease K Meng Tan a, Michael D. Geschwind b, Vanda A. Lennon a, Sean J. Pittock a a b
Mayo Clinic College of Medicine, United States University of California, San Francisco, United States
Manifestations of voltage-gated potassium channel (VGKC) autoimmunity may mimic Creutzfeldt-Jakob disease (CJD), especially in cases of subacute cognitive impairment and myoclonus. We describe 15 patients provisionally diagnosed with (CJD), prior to serological detection of (VGKC) autoantibodies, and favorable therapeutic responses in 12 of 13 cases. In service serological evaluation for paraneoplastic autoantibodies, 2001-2007, the Mayo Clinic Neuroimmunology Laboratory identified 15 patients with a provisional diagnosis of CJD and high-titer VGKC autoantibodies. Clinical information was obtained by reviewing medical records. Seven patients were women, median age at onset was 70 years (range, 58–84). Median follow-up was 11 months (range, 1–78). Median VGKC autoantibody titer by RIA was 1.53 nmol/L (range 0.16-51.9). Symptom onset was subacute (median 5 months; range, 0-13). All had cognitive impairment, 12 myoclonus, 12 seizures, 10 behavioral disturbance, 7 dysomnia, 6 tremor/parkinsonism, 6 dysautonomia, 5 ataxia, 5 hallucinations, 7 hyponatraemia, and 2 hyperphagia. Brain MRI was abnormal in 9 of 13; one had widespread cortical restricted diffusion. EEG revealed diffuse slowing in 9 of 13. CSF 14-3-3 protein or neuron-specific enolase were elevated in 6 of 8 patients. Active neoplasia was confirmed or suspected in 8 patients. Of 13 patients receiving immunomodulatory therapy (corticosteroids, plasmapheresis, IVIG), 12 showed improvement (5 marked, 6 moderate, 1 mild). Seven had relapses requiring ongoing immunotherapy. VGKC autoantibody testing is justified in the evaluation of suspected CJD. Positive serology may obviate brain biopsy. Patients with VGKC autoimmunity generally have a beneficial response to antibody-depleting therapy. doi:10.1016/j.jocn.2008.07.021
123. The clinical spectrum of X-Linked charcot-marie tooth disease in childhood Eppie M. Yiu a, Nimeshan Geevasinga b, Garth A. Nicholson c, Robert A. Ouvrier b, Monique M. Ryan a a
Royal Children’s Hospital Melbourne The Children’s Hospital at Westmead c Concord Hospital Sydney b
Objectives: X-linked Charcot-Marie-Tooth disease (CMTX), the second most common form of CMT, is most commonly caused by mutations in GJB1, (designated CMTX1). CMTX is rarely recognised in childhood, and the clinical features in this age group are not well described. We reviewed clinical, neurophysiologic and pathological findings on a cohort of paediatric patients with CMTX. Methods: A retrospective review of patients with CMTX treated at the Children’s Hospital at Westmead Sydney, and The Royal Children’s Hospital Melbourne. The diagnosis of CMTX was based on an identifiable GJB1 mutation (CMTX1), or a consistent pedigree and/or neurophysiological features in children without a GJB1 mutation (non-CMTX1). Results: Seventeen patients (14 male and three female) were identified. Five males and two females had CMTX1, and nine males
and one female non-CMTX1. Age of onset was six months to 13 years, mean 6.3 years. At least one patient was symptomatic from early infancy. Clinical features included pes cavus, gait abnormalities, length dependent wasting and weakness, and distal areflexia. Less common features included sensorineural hearing loss, tremor, pathologic fractures and transient central nervous system disturbances. Intermediate median motor nerve conduction velocities in children above age two years (male and female) were seen (ranging from 30–54 m/sec), with lower amplitude motor responses in the lower extremities. Temporal dispersion was present in two patients. Conclusions: The clinical phenotype of CMTX is broader than previously reported, with some cases presenting early in life and with symptoms being apparent in some carrier females, even in childhood. doi:10.1016/j.jocn.2008.07.022
124. Evidence for respiratory chain abnormalities in the peripheral nerves of patients with MELAS Karl Ng a, Susanne Winter b, Carolyn Sue c, David Burke d a Royal North Shore Hospital and Institute of Clinical Neurosciences, Royal Prince Alfred Hospital and University of Sydney b Royal North Shore Hospital c Royal North Shore Hospital and University of Sydney d Institute of Clinical Neurosciences, Royal Prince Alfred Hospital and University of Sydney
Background: Disorders arising from primary mitochondrial genetic defects are known to be associated with peripheral neuropathy. The mechanisms underlying this are poorly understood, and may be secondary to disordered oxidative phosphorylation and reduced energy-dependent maintenance of ionic gradients necessary for impulse propagation and neuronal cell integrity. Methods: Fifteen patients with mitochondrial disorders (MELAS 6, CPEO 5, MERRF 1, Pearson’s 1, undetermined 2) either confirmed by genetic characterisation or suspected on muscle biopsy were evaluated clinically and electrophysiologically. Axonal excitability was assessed in median motor nerves at the wrist and compared with 50 normal controls. Results: As a group, there was no significant difference in excitability parameters. However, the MELAS subgroup (4 genetically confirmed) showed significant changes in 5 threshold electrotonus parameters that could result from membrane depolarisation (TEd peak and at 10–20ms, TEh at 10–20, 20–40, 90–100ms; p = 0.020.03). In support of this interpretation, there were trends for appropriate changes in the relative refractory period, refractoriness and superexcitability. These trends were not significant, possibly because of the small sample size. Half the MELAS patients in the subgroup had diabetes or impaired glucose tolerance, and one had an axonal neuropathy on standard nerve conduction. None of the 15 had abnormal autonomic studies (RR interval with deep breathing, standing and Valsalva; SSR). Conclusion: Even with these small numbers, the suggestive evidence for axonal depolarisation in patients with MELAS accords with the a priori hypothesis of respiratory chain abnormalities. The manifestations appear to be subclinical in most patients. doi:10.1016/j.jocn.2008.07.024
125. Conduction failure and fatigue in diabetic neuropathy Arun V. Krishnan, Cindy S. Lin, Matthew C. Kiernan Prince of Wales Medical Research Institute
Abstracts / Journal of Clinical Neuroscience 16 (2009) 462–481
122. Voltage-gated Potassium Channel Autoimmunity Mimicking Creutzfeldt-Jakob Disease K Meng Tan a, Michael D. Geschwind b, Vanda A. Lennon a, Sean J. Pittock a a b
Mayo Clinic College of Medicine, United States University of California, San Francisco, United States
Manifestations of voltage-gated potassium channel (VGKC) autoimmunity may mimic Creutzfeldt-Jakob disease (CJD), especially in cases of subacute cognitive impairment and myoclonus. We describe 15 patients provisionally diagnosed with (CJD), prior to serological detection of (VGKC) autoantibodies, and favorable therapeutic responses in 12 of 13 cases. In service serological evaluation for paraneoplastic autoantibodies, 2001-2007, the Mayo Clinic Neuroimmunology Laboratory identified 15 patients with a provisional diagnosis of CJD and high-titer VGKC autoantibodies. Clinical information was obtained by reviewing medical records. Seven patients were women, median age at onset was 70 years (range, 58–84). Median follow-up was 11 months (range, 1–78). Median VGKC autoantibody titer by RIA was 1.53 nmol/L (range 0.16-51.9). Symptom onset was subacute (median 5 months; range, 0-13). All had cognitive impairment, 12 myoclonus, 12 seizures, 10 behavioral disturbance, 7 dysomnia, 6 tremor/parkinsonism, 6 dysautonomia, 5 ataxia, 5 hallucinations, 7 hyponatraemia, and 2 hyperphagia. Brain MRI was abnormal in 9 of 13; one had widespread cortical restricted diffusion. EEG revealed diffuse slowing in 9 of 13. CSF 14-3-3 protein or neuron-specific enolase were elevated in 6 of 8 patients. Active neoplasia was confirmed or suspected in 8 patients. Of 13 patients receiving immunomodulatory therapy (corticosteroids, plasmapheresis, IVIG), 12 showed improvement (5 marked, 6 moderate, 1 mild). Seven had relapses requiring ongoing immunotherapy. VGKC autoantibody testing is justified in the evaluation of suspected CJD. Positive serology may obviate brain biopsy. Patients with VGKC autoimmunity generally have a beneficial response to antibody-depleting therapy. doi:10.1016/j.jocn.2008.07.021
123. The clinical spectrum of X-Linked charcot-marie tooth disease in childhood Eppie M. Yiu a, Nimeshan Geevasinga b, Garth A. Nicholson c, Robert A. Ouvrier b, Monique M. Ryan a a
Royal Children’s Hospital Melbourne The Children’s Hospital at Westmead c Concord Hospital Sydney b
Objectives: X-linked Charcot-Marie-Tooth disease (CMTX), the second most common form of CMT, is most commonly caused by mutations in GJB1, (designated CMTX1). CMTX is rarely recognised in childhood, and the clinical features in this age group are not well described. We reviewed clinical, neurophysiologic and pathological findings on a cohort of paediatric patients with CMTX. Methods: A retrospective review of patients with CMTX treated at the Children’s Hospital at Westmead Sydney, and The Royal Children’s Hospital Melbourne. The diagnosis of CMTX was based on an identifiable GJB1 mutation (CMTX1), or a consistent pedigree and/or neurophysiological features in children without a GJB1 mutation (non-CMTX1). Results: Seventeen patients (14 male and three female) were identified. Five males and two females had CMTX1, and nine males
and one female non-CMTX1. Age of onset was six months to 13 years, mean 6.3 years. At least one patient was symptomatic from early infancy. Clinical features included pes cavus, gait abnormalities, length dependent wasting and weakness, and distal areflexia. Less common features included sensorineural hearing loss, tremor, pathologic fractures and transient central nervous system disturbances. Intermediate median motor nerve conduction velocities in children above age two years (male and female) were seen (ranging from 30–54 m/sec), with lower amplitude motor responses in the lower extremities. Temporal dispersion was present in two patients. Conclusions: The clinical phenotype of CMTX is broader than previously reported, with some cases presenting early in life and with symptoms being apparent in some carrier females, even in childhood. doi:10.1016/j.jocn.2008.07.022
124. Evidence for respiratory chain abnormalities in the peripheral nerves of patients with MELAS Karl Ng a, Susanne Winter b, Carolyn Sue c, David Burke d a Royal North Shore Hospital and Institute of Clinical Neurosciences, Royal Prince Alfred Hospital and University of Sydney b Royal North Shore Hospital c Royal North Shore Hospital and University of Sydney d Institute of Clinical Neurosciences, Royal Prince Alfred Hospital and University of Sydney
Background: Disorders arising from primary mitochondrial genetic defects are known to be associated with peripheral neuropathy. The mechanisms underlying this are poorly understood, and may be secondary to disordered oxidative phosphorylation and reduced energy-dependent maintenance of ionic gradients necessary for impulse propagation and neuronal cell integrity. Methods: Fifteen patients with mitochondrial disorders (MELAS 6, CPEO 5, MERRF 1, Pearson’s 1, undetermined 2) either confirmed by genetic characterisation or suspected on muscle biopsy were evaluated clinically and electrophysiologically. Axonal excitability was assessed in median motor nerves at the wrist and compared with 50 normal controls. Results: As a group, there was no significant difference in excitability parameters. However, the MELAS subgroup (4 genetically confirmed) showed significant changes in 5 threshold electrotonus parameters that could result from membrane depolarisation (TEd peak and at 10–20ms, TEh at 10–20, 20–40, 90–100ms; p = 0.020.03). In support of this interpretation, there were trends for appropriate changes in the relative refractory period, refractoriness and superexcitability. These trends were not significant, possibly because of the small sample size. Half the MELAS patients in the subgroup had diabetes or impaired glucose tolerance, and one had an axonal neuropathy on standard nerve conduction. None of the 15 had abnormal autonomic studies (RR interval with deep breathing, standing and Valsalva; SSR). Conclusion: Even with these small numbers, the suggestive evidence for axonal depolarisation in patients with MELAS accords with the a priori hypothesis of respiratory chain abnormalities. The manifestations appear to be subclinical in most patients. doi:10.1016/j.jocn.2008.07.024
125. Conduction failure and fatigue in diabetic neuropathy Arun V. Krishnan, Cindy S. Lin, Matthew C. Kiernan Prince of Wales Medical Research Institute