[Genetics of amyotrophic lateral sclerosis].
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Amyotrophic Lateral Sclerosis↗
Biomedical subjects
P M Andersen
Publications and source records attributed to P M Andersen.
Founder effect in spinal and bulbar muscular atrophy (SBMA) in Scandinavia.
We haplotyped 13 Finnish, 10 Swedish, 12 Danish and 2 Norwegian SBMA (spinal and bulbar muscular atrophy, Kennedy disease) families with a total of 45 patients and 7 carriers for 17 microsatellite markers spanning a 25.2 cM region around the androgen receptor gene on chromosome Xq11-q12 in search of a genetic founder effect. In addition, the haplotypes of 50 Finnish, 20 Danish and 22 Swedish control males were examined. All the Scandinavian SBMA families shared the same 18 repeat allele for the intragenic GGC repeat, which was present in only 24% of the controls. Linkage disequilibrium was also seen for the closest microsatellite markers. In addition, extended haplotypes of the Finnish, Swedish and Danish SBMA families revealed country-specific common founder haplotypes, which over time became gradually shortened by recombinations. No common haplotype was found among the controls. The data suggest that the SBMA mutation was introduced into western Finland 20 generations ago. Haplotype analysis implies a common ancestor for the majority of Scandinavian SBMA patients.
Alleles↗
Genetic factors in the early diagnosis of ALS.
The frequency of familial amyotrophic lateral sclerosis (ALS) is usually reported as 5-10% of all ALS cases. This figure is probably an underestimate, primarily due to inadequate recording of family history in the patients' charts, and to the not infrequent occurrence of reduced disease penetrance in pedigrees with familial ALS. The true familial ALS frequency may be at least double this. Familial ALS is heterogenetic. The only known ALS-causing gene is the CuZn-superoxide dismutase gene (CuZn-SOD). Mutations in this gene account for a fifth of all familial ALS cases and a few percent of apparent sporadic ALS cases. Genetic testing for CuZn-SOD mutations can help confirm a diagnosis of ALS, especially in cases with atypical features that have been reported in some cases with CuZn-SOD mutations. Genetic testing should only be performed after thorough clinical examination and in cases with a proven or uncertain family history of ALS. It is not warranted in cases with no proven family history for three generations, unless the patient shows the characteristic phenotype associated with recessive inheritance of the D90A CuZn-SOD mutation.
Gene Frequency↗
Preserved slow conducting corticomotoneuronal projections in amyotrophic lateral sclerosis with autosomal recessive D90A CuZn-superoxide dismutase mutation.
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.
Adult↗
Vertebrogenic dysphagia and gait disturbance mimicking motor neuron disease.
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Cervical Vertebrae↗
Motor system abnormalities in heterozygous relatives of a D90A homozygous CuZn-SOD ALS patient of finnish extraction.
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.
Aged↗
[Treatment of amyotrophic lateral sclerosis].
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Amyotrophic Lateral Sclerosis↗
Manganese-containing superoxide dismutase signal sequence polymorphism associated with sporadic motor neuron disease.
An alanin-9valin (Ala-9Val) polymorphism in the mitochondrial targeting sequence of manganese-containing superoxide dismutase (Mn-SOD) has recently been described. We studied this polymorphism in 72 Swedish patients with sporadic motor neuron diseases (MND) and controls using an oligonucleotide ligation assay. There were significant differences in genotype between MND patients and controls (P = 0.025), and between male and female MND patients (P = 0.009). Individuals homozygous for the Ala allele had a higher risk for MND [odds ratio, 2.9; 95% confidence interval (CI), 1.3-6.6], which was increased when including only females in the analysis (odds ratio, 5.0; 95% CI, 1.8-14.0). In classical amyotrophic lateral sclerosis, the odds ratio was 3.8 (95% CI, 1.3-10.0), and 5. 5 (95% CI, 1.5-19.9) when including only females. The results suggest that mutations influencing the cellular allocation of Mn-SOD may be a risk factor in MND, especially in females, and that MND may be a disease of misdistribution of the superoxide dismutase enzymes.
Alanine↗
Deletions of the heavy neurofilament subunit tail in amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron degeneration resulting in paralysis and death, usually within 3 years of onset. Pathological and animal studies implicate neurofilament involvement in ALS, but whether this is primary or secondary is not clear. The heavy neurofilament subunit (NFH) tail is composed of a repeating amino acid motif, usually X-lysine-serine-proline-Y-lysine (XKSPYK), where X is a single amino acid and Y is one to three amino acids. There are two common polymorphic variants of 44 or 45 repeats. The tail probably regulates axonal calibre, with interfilament spacing determined by phosphorylation of the KSP motifs. A previous study suggested an association between sporadic cases of ALS and NFH tail deletions, but two subsequent studies have found none. We have analysed samples from two different populations (UK 207, Scandinavia 323) with age-matched controls for each group (UK 219, Scandinavia 228) and have found four novel NFH tail deletions, each involving a whole motif. These were found in three patients with sporadic ALS and a family with autosomal dominant ALS, although another was also found in two young controls. In all cases motif deletions were only associated with disease when paired with the long NFH allele. The deletions all occurred within a small region of the NFH tail. This has allowed us to propose a structural organization of the tail as well as allowing observed deletions both from this study and previous reports to be organized into logical groups. These results strongly suggest that NFH motif deletions can be a primary event in ALS but that they are not common.
Adult↗
Localized eddy current compensation using quantitative field mapping.
Eddy current effects induced by switched gradients in proximal conducting structures are traditionally reduced by applying preemphasis currents whose amplitudes and decay characteristics must be set to offset the eddy current fields. We present an expeditious, localized, and quantitative method for mapping and adjusting the parameters for eddy current compensation. Mapping is based on analysis of projections as used in the fast automatic shimming technique by mapping along projections (FASTMAP). Adjustment methods are demonstrated in high-field horizontal bore systems. The proposed localized eddy current mapping technique may also be used for localized measurements in situations where asymmetric conducting structures may cause nonlinear eddy current fields, such as in interventional MRI and open magnet designs.
Algorithms↗
CuZn-superoxide dismutase, extracellular superoxide dismutase, and glutathione peroxidase in blood from individuals homozygous for Asp90Ala CuZu-superoxide dismutase mutation.
The Asp90Ala CuZn-superoxide dismutase mutation is associated with amyotrophic lateral sclerosis (ALS) in both homo- and heterozygous form. We analyzed antioxidant enzymes in blood from 44 individuals homozygous and 114 individuals heterozygous for the Asp90Ala mutation as well as 66 blood relatives carrying the wild-type allele only. Erythrocyte CuZn-superoxide dismutase activity was reduced by 9% in the homozygous individuals, confirming previous findings on a smaller cohort. The specific activity of Asp90Ala mutant CuZn-superoxide dismutase in erythrocytes was equal to that of isolated mutant enzyme and slightly higher than that of isolated wild-type enzyme. There was no evidence for the presence of inactive mutant molecules in erythrocytes, and the lower activity is due to the occurrence of fewer active molecules. There were no significant differences between the groups in plasma extracellular superoxide dismutase content, and the erythrocyte glutathione peroxidase activities were virtually identical. Also, there were no differences in these parameters between homozygous individuals with or without ALS. There was no evidence for any association with ALS of a polymorphic extracellular superoxide dismutase mutation, Arg213Gly. The absence of response of the blood antioxidant enzymes to the Asp90Ala CuZn-superoxide dismutase mutation does not support the theory that the ALS-linked CuZn-superoxide dismutase mutations cause disease by increased oxidant stress.
Alanine↗
Recessive amyotrophic lateral sclerosis families with the D90A SOD1 mutation share a common founder: evidence for a linked protective factor.
Amyotrophic lateral sclerosis (ALS) is a progressive motor neurodegeneration resulting in paralysis and death from respiratory failure within 3-5 years. About 20% of familial cases are associated with mutations in the gene for copper/zinc superoxide dismutase ( SOD1 ), which catalyses the dismutation of the superoxide radical to hydrogen peroxide and oxygen. Experimental evidence suggests mutations act by a toxic gain of function but the mechanism is unknown. There are >60 known SOD1 mutations associated with ALS and all are dominant except for one in exon 4, a D90A substitution which is recessive. D90A pedigrees with dominant inheritance have now been reported and this apparent contradiction needs to be explained. We performed a worldwide haplotype study on 28 D90A pedigrees using six highly polymorphic microsatellite markers. We now show that all 20 recessive families share the same founder (alpha = 0.999), regardless of geographical location, whereas several founders exist for the eight dominant families (alpha = 0.385). This finding confirms that D90A can act in a dominant fashion in keeping with all other SOD1 mutations, but that on one occasion, a new instance of this mutation has been recessive. We propose a tightly linked protective factor which modifies the toxic effect of mutant SOD1 in recessive families.
Amino Acid Substitution↗
Sequential activity in human motor areas during a delayed cued finger movement task studied by time-resolved fMRI.
Activity in the human primary motor cortex, the premotor cortex and the supplementary motor area during a delayed cued finger movement task was measured by time-resolved functional magnetic resonance imaging. Activity during movement preparation can be resolved from activity during movement execution in a single trial. All three areas were active during both movement preparation and movement execution. Activity in the primary motor cortex was considerably weaker during movement preparation than during movement execution; in the premotor cortex and the supplementary motor area, activity was of similar intensity during both periods. These observations are consistent with results from single neuronal recording studies in primates.
Brain Mapping↗
[Amyotrophic lateral sclerosis and superoxide dismutase--a review].
The recent observation that mutations in cytosolic CuZn-superoxide dismutase (CuZn-SOD) are associated with amyotrophic lateral sclerosis (ALS) suggests that the disease arises from a perturbation of the homeostasis of free radicals resulting in neuronal degeneration by reactive oxygen species. The stability is altered in these mutant molecules, but without necessarily reducing the specific activity of the CuZn-SOD molecule. Substantial evidence argues that the disease arises not from the loss of CuZn-SOD function, but rather from an adverse or novel property of the mutant enzyme molecule. The mechanism for this acquired adverse function is, as yet, completely unknown. SOD research is an important step for a better understanding of the pathogenesis of ALS.
Amyotrophic Lateral Sclerosis↗
Effects of riluzole on symptom progression in amyotrophic lateral sclerosis.
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Amyotrophic Lateral Sclerosis↗
Normal binding and reactivity of copper in mutant superoxide dismutase isolated from amyotrophic lateral sclerosis patients.
In some families with amyotrophic lateral sclerosis (ALS), the disease is linked to mutations in the gene encoding CuZn-superoxide dismutase. The mutant CuZn-superoxide dismutases appear to cause motor neuron degeneration by a toxic property, suggested to be linked to an altered reactivity of the active-site Cu ions. Asp90Ala mutant CuZn-superoxide dismutase was isolated from six patients with ALS, allowing properties of the mutant enzyme synthesized and conditioned in patients with ALS to be examined. The molecular mass of the Asp90Ala mutant CuZn-superoxide dismutase was 45 Da lower than that of the wild-type enzyme, as expected from the amino acid exchange. The mobility after sodium dodecyl sulfate-polyacrylamide gel electrophoresis was markedly increased, however, suggesting altered properties of the polypeptide. The mutant CuZn-superoxide dismutase showed a minimal reduction in stability but did not differ significantly from the wild-type enzyme in enzymic activity, in content and affinity for active-site Cu ions and in the propensity to catalyze formation of hydroxyl radicals. Our findings suggest that the deleterious effect of mutant CuZn-superoxide dismutases on motor neurons in ALS is not related to altered reactivity of active-site Cu ions, resulting in increased oxidant stress. Attention should therefore also be directed at other mechanisms and properties of the mutant polypeptides and their degradation products.
Amyotrophic Lateral Sclerosis↗
Phenotypic heterogeneity in motor neuron disease patients with CuZn-superoxide dismutase mutations in Scandinavia.
Four-hundred and fifty-one blood samples from Scandinavian patients with motor neuron disease were analysed for mutations in the CuZn-superoxide dismutase gene. Forty-one (9.6%) of the 427 patients with the amyotrophic lateral sclerosis (ALS) form of the disease were found to have a disease-associated mutation, and 14 of these patients were apparently sporadic cases. A mutation was found in 12 of the 51 families with recognized familial ALS. The five different mutations found (Ala4Val, Val14Gly, Asp76Tyr, Asp90Ala, Gly127insTGGG) have different genetic characteristics and are associated with very variable phenotypes spanning from rapidly progressing disease with only lower motor neuron signs to very slowly progressing disease with both the upper and lower motor neuron systems affected. The patients showed different sites of onset, though the progressive bulbar palsy form of the disease appears to be rare among patients with a CuZn-superoxide dismutase mutation. The progression of motor signs and symptoms followed the same basic pattern in patients with different mutations. Extra-motor system symptoms were frequent among patients with a CuZn-superoxide dismutase mutation. The results suggest that patients with mutations in the CuZn-superoxide dismutase gene constitute one disease entity. The Val14Gly and Asp76Tyr mutations have not been reported before, and the latter is the first mutation to be found in exon 3 of the CuZn-superoxide dismutase gene.
Adult↗
Autoimmunity and ALS: studies on antibodies to acetylcholinesterase in sera.
The involvement of the immune system in the pathogenesis of amyotrophic lateral sclerosis is controversial. It has been suggested that ALS patients develop specific antibodies against acetylcholinesterase (AChE) and that these antibodies by retrograde axonal transport may be the cause of death of the spinal motor neurons. It has also been argued that these antibodies elicit hemolysis of erythrocytes. However, using recombinant human AChE as antigen in ELISA and Western blot analysis, we have been unable to find any evidence for the existence of specific AChE antibodies in ALS patients.
Acetylcholinesterase↗