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Corticomotoneuronal dysfunction in ALS patients with different SOD1 mutations.
Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience.
Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
2006 (English)In: Clinical Neurophysiology, ISSN 1388-2457, Vol. 117, no 8, 1850-1861 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: To examine corticomotoneuronal function in amyotrophic lateral sclerosis (ALS) patients carrying superoxide dismutase 1 (SOD1) mutations using peristimulus time histograms (PSTH). METHODS: Six I113T, 3 A4V, one G41D and one G114A patient were studied along with 21 healthy control subjects. Analyses included comparison with previously reported data from 8 D90A homozygous and 12 sporadic ALS (SALS) patients examined by the authors using identical methodology. RESULTS: Cortical threshold was significantly reduced in A4V patients (41.3%) compared to I113T (58%), SALS (57%) and D90A (71%) patients, as well as healthy controls (49.7%). Estimated excitatory postsynaptic potentials (EPSPs) were significantly larger in A4V patients (4.39 mV) compared to healthy controls (2.95 mV), I113T (2.71 mV) and SALS (2.39 mV) patients. Clinical features and PSTH parameters in I113T were similar to SALS, however, PSTH primary peaks (PP) were significantly more dispersed, 9.5 ms compared to 4ms in SALS. PSTHs from single G41D and G114A patients were unremarkable, apart from large EPSP amplitudes in the G114A patient. CONCLUSIONS: ALS patients with A4V and I113T SOD1 mutations have distinctive corticomotoneuronal changes that are different from those in D90A homozygous and SALS patients. SIGNIFICANCE: PSTH studies should be considered for future in vivo studies of SOD1 pathophysiology in ALS.

Place, publisher, year, edition, pages
2006. Vol. 117, no 8, 1850-1861 p.
Keyword [en]
Adult, Aged, Aged; 80 and over, Amyotrophic Lateral Sclerosis/*genetics/*physiopathology, Brain/*physiopathology, Evoked Potentials; Motor/*physiology, Female, History; 17th Century, Humans, Male, Motor Neurons/pathology/physiology, Mutation, Superoxide Dismutase/*genetics
URN: urn:nbn:se:umu:diva-7128DOI: 10.1016/j.clinph.2006.04.004PubMedID: 16793335OAI: diva2:146799
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2009-11-27Bibliographically approved
In thesis
1. Amyotrophic lateral sclerosis (ALS) associated with superoxide dismutase 1 (SOD1) mutations in British Columbia, Canada: clinical, neurophysiological and neuropathological features
Open this publication in new window or tab >>Amyotrophic lateral sclerosis (ALS) associated with superoxide dismutase 1 (SOD1) mutations in British Columbia, Canada: clinical, neurophysiological and neuropathological features
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by loss of motor neurons and their supporting cells in the brain, brainstem and spinal cord, resulting in muscle paresis and paralysis including the bulbar (speech, chewing, swallowing) and respiratory muscles. The average age at onset is 55 years, and death due to respiratory failure occurs 2-5 years after symptom onset in ~ 85% of cases. Five to 10% of ALS is familial, and about 20% of familial cases are associated with mutations in the superoxide dismutase 1 (SOD1) gene. To date, 118 SOD1 mutations have been reported worldwide (www All are dominantly inherited, except for the D90A mutation, which is typically recessively inherited. D90A homozygous ALS is associated with long (~14 years) survival, and some atypical symptoms and signs. The reason for this is not known. In contrast, most other SOD1 mutations are associated with average survival, while some are associated with aggressive disease having lower motor neuron predominance and survival less than 12 months. The A4V mutation, which is the most frequently occurring SOD1 mutation in the United States, is an example of the latter. Understanding the pathogenic mechanisms of SOD1 mutants causing widely different disease forms like D90A and A4V is of paramount importance. Overwhelming scientific evidence indicates that mutations in the SOD1 gene are cytotoxic by a “gain of noxious” function, which although not fully understood results in protein aggregation and loss of cell function.

This thesis explores different ALS-SOD1 gene mutations in British Columbia (BC), Canada. Two hundred and fifty-three ALS patients were screened for SOD1 mutations, and 12 (4.7%) unrelated patients were found to carry one of 5 different SOD1 mutations: A4V (n=2); G72C (n=1); D76Y (n=1); D90A (n=2); and 113T (n=6). Incomplete penetrance was observed in 3/12 families. Bulbar onset disease was not observed in the SOD1 mutation carriers in this study, but gender distribution was similar to previously reported studies. Age at symptom onset for all patients enrolled, with or without SOD1 mutations, was older than reported in previous studies. On average, patients with SOD1 mutations experience a longer diagnostic delay (22.6 months) compared to patients without mutations (12 months). Two SOD1 patients were originally misdiagnosed including the G72C patient who’s presenting features resembled a proximal myopathy. Neuropathological examination of this patient failed to reveal upper motor neuron disease. The I113T mutation was associated with variable age of onset and survival time, and was found in 2 apparently sporadic cases. The D76Y mutation was also found in an apparently sporadic case. I113T and D76Y are likely influenced by other genetic or environmental factors in some individuals. Two patients were homozygous for the D90A mutation, with clinical features comparable to patients originally described in Scandinavia. Clinical and electrophysiological motor neuron abnormalities were observed in heterozygous relatives of one D90A homozygous patient. The A4V patients were similar to those described in previous studies, although one had significant upper motor neuron disease both clinically and neuropathologically.

Clinical neurophysiology is essential in the diagnosis of ALS, and helpful in monitoring disease progression. A number of transcranial magnetic stimulation (TMS) studies may detect early dysfunction of upper motor neurons when imaging techniques lack sensitivity. Peristimulus time histograms (PSTHs), which assess corticospinal function via recording of voluntarily activated single motor units during low intensity TMS of the motor cortex, were used to study 19 ALS patients having 5 different SOD1 mutations (including 8 of the 12 patients identified with SOD1 mutations from BC). Results were compared with idiopathic ALS cases, patients with multiple sclerosis (MS), and healthy controls. Significant differences were found in corticospinal pathophysiology between ALS patients with SOD1 mutations, idiopathic ALS, and MS patients. In addition, different SOD1 mutants were associated with significantly different neurophysiologic abnormalities. D90A homozygous patients show preserved if not exaggerated cortical inhibition and slow central conduction, which may reflect the more benign disease course associated with this mutant. In contrast, A4V patients show cortical hyper-excitability and only slightly delayed central conduction. I113T patients display a spectrum of abnormalities. This suggests mutant specific SOD1 pathology(s) of the corticospinal pathways in ALS.

Place, publisher, year, edition, pages
Umeå: Farmakologi och klinisk neurovetenskap, 2005. 54 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 995
ALS, SOD1, complete penetrance, incomplete penetrance, mis-diagnosis, upper motor neuron, clinical neurophysiology, transcranial magnetic stimulation, peristimulus time histogram, corticospinal pathway, cortical inhibition, cortical hyper-excitability
urn:nbn:se:umu:diva-638 (URN)91-7305-981-1 (ISBN)
Public defence
2005-12-05, Sal B, plan 9, Tandläkarhögskolan, By 1D, NUS, Umeå, 09:00 (English)
Available from: 2005-11-17 Created: 2005-11-17 Last updated: 2009-11-27Bibliographically approved

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