umu.sePublications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Amyotrophic lateral sclerosis (ALS) associated with superoxide dismutase 1 (SOD1) mutations in British Columbia, Canada: clinical, neurophysiological and neuropathological features
Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience.
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 alsod.org). 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.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 995
Keyword [en]
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
Identifiers
URN: urn:nbn:se:umu:diva-638ISBN: 91-7305-981-1 (print)OAI: oai:DiVA.org:umu-638DiVA: diva2:144091
Public defence
2005-12-05, Sal B, plan 9, Tandläkarhögskolan, By 1D, NUS, Umeå, 09:00 (English)
Opponent
Available from: 2005-11-17 Created: 2005-11-17 Last updated: 2009-11-27Bibliographically approved
List of papers
1. SOD1 gene mutations in ALS patients from British Columbia, Canada: Clinical features, pathology and ethical issues in management
Open this publication in new window or tab >>SOD1 gene mutations in ALS patients from British Columbia, Canada: Clinical features, pathology and ethical issues in management
Show others...
Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-4834 (URN)
Available from: 2005-11-17 Created: 2005-11-17 Last updated: 2010-01-13Bibliographically approved
2. Clinicopathological phenotype of ALS with a novel G72C SOD1 gene mutation mimicking a myopathy.
Open this publication in new window or tab >>Clinicopathological phenotype of ALS with a novel G72C SOD1 gene mutation mimicking a myopathy.
Show others...
2006 (English)In: Muscle and Nerve, ISSN 0148-639X, Vol. 33, no 5, 701-706 p.Article in journal (Refereed) Published
Abstract [en]

A 71-year-old woman with a family history of amyotrophic lateral sclerosis (ALS) was investigated for symmetrical, proximal limb and abdominal muscle weakness. Initial examination showed mild proximal muscle weakness in the arms and legs, slightly elevated serum creatine kinase (CK) level, and normal electromyographic (EMG) findings. A myopathy was the presumed diagnosis. Over the next year, weakness became severe and tendon reflexes became unelicitable; no upper motor signs were present. EMG then showed acute and chronic denervation and a muscle biopsy showed target fibers and grouped atrophy. DNA analysis revealed a G72C CuZn-superoxide dismutase (SOD1) mutation. Fasciculations were absent throughout the disease. The patient died 53 months after symptom onset and autopsy revealed loss of lower motor neurons (LMN) and SOD1-positive inclusions. This case expands the phenotypic spectrum of ALS associated with SOD1 mutations to include presenting features that mimic a myopathy.

Keyword
Aged, Amyotrophic Lateral Sclerosis/complications/*genetics/pathology, Blotting; Western/methods, Creatine/blood, Cysteine/*genetics, DNA Mutational Analysis/methods, Family Health, Female, Glycine/*genetics, Humans, Immunohistochemistry/methods, Muscular Diseases/etiology/*genetics/pathology, Mutation, Myosins/metabolism, NAD/metabolism, Phenotype, Superoxide Dismutase/*genetics/metabolism, Ubiquitin/metabolism
Identifiers
urn:nbn:se:umu:diva-15416 (URN)10.1002/mus.20495 (DOI)16435343 (PubMedID)
Available from: 2008-01-10 Created: 2008-01-10 Last updated: 2009-11-27Bibliographically approved
3. Motor system abnormalities in heterozygous relatives of a D90A homozygous CuZn-SOD ALS patient of Finnish extraction.
Open this publication in new window or tab >>Motor system abnormalities in heterozygous relatives of a D90A homozygous CuZn-SOD ALS patient of Finnish extraction.
Show others...
1999 (English)In: Journal of Neurological Sciences, ISSN 1302-1664, Vol. 169, no 1-2, 49-55 p.Article in journal (Refereed) Published
Abstract [en]

Presently, 64 mutations in the gene encoding the enzyme CuZn-superoxide dismutase have been found in a small fraction of amyotrophic lateral sclerosis patients worldwide. All but one of these mutations show autosomal dominant inheritance. In Scandinavia, the D90A mutation is inherited as an autosomal recessive trait and patients have an easily recognizable characteristic phenotype with little variation among patients, even amongst different families. Importantly, all D90A heterozygous relatives of Scandinavian D90A homozygous patients have been reported as clinically unaffected. We have investigated a Canadian family of Finnish extraction in which the D90A homozygous proband developed ALS with the characteristic phenotype. Remarkably, two D90A heterozygous relatives show slight symptoms and signs of motor system involvement, suggesting that the final phenotype of an individual with a CuZn-superoxide dismutase mutation is shaped by the combination of the particular CuZn-SOD mutation, other polymorphic modifying genes elsewhere in the genome, stochastics and possible environmental factors.

Identifiers
urn:nbn:se:umu:diva-4836 (URN)10.1016/S0022-510X(99)00215-4 (DOI)10540007 (PubMedID)
Available from: 2005-11-17 Created: 2005-11-17Bibliographically approved
4. Preserved slow conducting corticomotoneuronal projections in ALS patients with autosomal recessive D90A CuZn-SOD mutation.
Open this publication in new window or tab >>Preserved slow conducting corticomotoneuronal projections in ALS patients with autosomal recessive D90A CuZn-SOD mutation.
2000 (English)In: Brain, ISSN 0006-8950, Vol. 123, no 7, 1505-1515 p.Article in journal (Refereed) Published
Abstract [en]

Recently, a subgroup of the amyotrophic lateral sclerosis (ALS) syndrome associated with mutations in the gene encoding the free radical scavenging enzyme CuZn-superoxide dismutase (CuZn-SOD, SOD1) has been identified. Some 67 different mutations have been reported worldwide to date, comprising about one-fifth of familial ALS cases in the populations studied. The autosomal recessively inherited D90A CuZn-SOD mutation has been associated with a very slowly progressive, clinically distinct phenotype, and is neurophysiologically characterized by very slow central motor conduction. It is not known which physiological and/or biochemical mechanisms are responsible for the different clinical course. To delineate ALS associated with this particular CuZn-SOD mutation from ALS without mutations, we performed a detailed neurophysiological study of the corticomotoneuronal function using peristimulus time histograms (PSTHs) in eight ALS patients homozygous for the D90A CuZn-SOD mutation. The results were compared with those obtained in 12 non-hereditary ALS patients and 11 healthy subjects. PSTHs were constructed from three to seven different, voluntarily recruited motor units of the extensor digitorum communis muscle (EDC) in each patient. The onset latency, number of excess bins, duration and synchrony of the primary peak were analysed. All measurements differed significantly between healthy controls and the D90A patients (P < 0.0007). The mean onset latency of the primary peak in D90A patients was 35.3 ms, compared with 24.2 ms for non-hereditary ALS patients and 19.3 ms for normal subjects (P < 0.0000). Delayed primary peaks in the D90A patients were desynchronized and characteristically preceded by a marked suppression phase. This suppression phase was not seen in non-hereditary ALS patients. We conclude that the mainly slow conducting and/or polysynaptic corticomotoneuronal connections are preserved in the D90A homozygous cases, and that the cortical and possibly spinal inhibitory circuitry is preserved. These events may partially protect the motor neurons, slowing down the degenerative process.

Identifiers
urn:nbn:se:umu:diva-4837 (URN)10.1093/brain/123.7.1505 (DOI)10869061 (PubMedID)
Available from: 2005-11-17 Created: 2005-11-17Bibliographically approved
5. The physiological basis of conduction slowing in ALS patients homozygous for the autosomal recessive D90A CuZn-SOD mutation
Open this publication in new window or tab >>The physiological basis of conduction slowing in ALS patients homozygous for the autosomal recessive D90A CuZn-SOD mutation
Show others...
2001 (English)In: Muscle and Nerve, ISSN 0148-639X, Vol. 24, no 1, 89-97 p.Article in journal (Refereed) Published
Abstract [en]

Familial amyotrophic lateral sclerosis (ALS) with the autosomal-recessively inherited D90A CuZn-superoxide dismutase (CuZn-SOD) mutation is characterized by a stereotypic slowly progressive, distinctive phenotype and very slow central motor conduction. To determine the basis of this slowing, we assessed corticomotoneuronal function using peristimulus time histograms (PSTHs) in 8 ALS patients homozygous for the D90A CuZn-SOD mutation. The results were compared with findings in 10 patients with multiple sclerosis (MS), in which slowing of central motor conduction is common, and 11 healthy subjects. PSTHs were constructed from 3-7 different, voluntarily recruited motor units recorded in each patient from the extensor digitorum communis muscle (EDC). In D90A and MS patients, the stimulus threshold, onset latency, number of excess bins, duration, amplitude, and synchrony of the primary peak differed significantly from controls (P < 0.0004). The mean onset latency of the primary peak in D90A patients was 35.3 ms, compared to 23.6 ms for MS patients and 19.3 ms for normal subjects (P < 0.0001). In the D90A patients, the onset latencies of the primary peak had a bimodal distribution, whereas in MS the distribution showed a continuum. Loss of synchrony was similar in D90A and MS patients, but the threshold, number of excess bins, and duration differed significantly (P < 0.0057), which suggests that either axonal loss or demyelination can result in delayed and desynchronized primary peaks. We propose that conduction slowing in the D90A homozygotes results from selective loss of fast-conducting large pyramidal cells with preservation of slow-conducting mono- or polysynaptic corticomotoneuronal connections. Copyright 2001 John Wiley & Sons, Inc.

Identifiers
urn:nbn:se:umu:diva-4838 (URN)10.1002/1097-4598(200101)24:1<89::AID-MUS10>3.0.CO;2-I (DOI)11150970 (PubMedID)
Available from: 2005-11-17 Created: 2005-11-17Bibliographically approved
6. Corticomotoneuronal dysfunction in ALS patients with different SOD1 mutations.
Open this publication in new window or tab >>Corticomotoneuronal dysfunction in ALS patients with different SOD1 mutations.
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.

Keyword
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
Identifiers
urn:nbn:se:umu:diva-7128 (URN)10.1016/j.clinph.2006.04.004 (DOI)16793335 (PubMedID)
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2009-11-27Bibliographically approved

Open Access in DiVA

fulltext(1636 kB)1889 downloads
File information
File name FULLTEXT01.pdfFile size 1636 kBChecksum SHA-1
6252cce519f162cda3a7503aa76c5b0014154c6a887a85a33b010e5100cf3001e2635026
Type fulltextMimetype application/pdf

By organisation
Pharmacology and Clinical Neuroscience

Search outside of DiVA

GoogleGoogle Scholar
Total: 1889 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 765 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf