Autosomal Dominant Familial Amyotrophic Lateral Sclerosis Research Articles

No mutations in hnRNPA1 and hnRNPA2B1 in Dutch patients with amyotrophic lateral sclerosis, frontotemporal dementia, and inclusion body myopathy

Inclusion body myopathy (IBM) associated with Paget disease of the bone, frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), sometimes called IBMPFD/ALS or multi system proteinopathy, is a rare, autosomal dominant disorder characterized by progressive degeneration of muscle, brain, motor neurons, and bone with prominent TDP-43 pathology. Recently, 2 novel genes for multi system proteinopathy were discovered; heterogenous nuclear ribonucleoprotein (hnRNP) A1 and A2B1. Subsequently, a mutation in hnRNPA1 was also identified in a pedigree with autosomal dominant familial ALS. The genetic evidence for ALS and other neurodegenerative diseases is still insufficient. We therefore sequenced the prion-like domain of these genes in 135 familial ALS, 1084 sporadic ALS, 68 familial FTD, 74 sporadic FTD, and 31 sporadic IBM patients in a Dutch population. We did not identify any mutations in these genes in our cohorts. Mutations in hnRNPA1 and hnRNPA2B1 prove to be a rare cause of ALS, FTD, and IBM in the Netherlands.

Clinical phenotypes of a large Chinese multigenerational kindred with autosomal dominant familial ALS due to Ile149Thr SOD1 gene mutation

About 10% of amyotrophic lateral sclerosis (ALS) cases are familial. We identified a five-generation Chinese family with autosomal dominant familial ALS (FALS). We performed a detailed family study, clinical and electromyographic validation, and SOD1, VEGF and CNTF mutation analyses. Forty-five living members (16 affected) were studied and DNA samples collected. Genealogical data were collected for deceased members. Based on the duration between symptom onset to ventilator dependence, they were divided into rapidly progressive (range 1-18 months, mean (SD) duration = 12.08 (+/-6.10) months, mean (SD) age of symptom onset = 39.75 (+/-9.84) years) and slowly progressive groups (>18 months; mean (SD) age of onset = 37.25 (+/-5.32) years old). We identified a heterozygous mutation of ATT to ACT of SOD1 gene at codon 149 in exon 5 resulting in substitution of isoleucine to threonine. It co-segregated with all affected members and 11 non-symptomatic members. We report a large multigenerational Chinese FALS kindred with I149T mutation in SOD1. No polymorphisms or mutations were found to date in two known modifier genes, namely, VEGF and CNTF, which were associated with heterogeneity in the phenotype within this kindred. Follow-up of the family will be helpful to explore any potential disease markers.

Formation of high molecular weight complexes of mutant Cu, Zn-superoxide dismutase in a mouse model for familial amyotrophic lateral sclerosis.

Deposition of aggregated protein into neurofilament-rich cytoplasmic inclusion bodies is a common cytopathological feature of neurodegenerative disease. How-or indeed whether-protein aggregation and inclusion body formation cause neurotoxicity are presently unknown. Here, we show that the capacity of superoxide dismutase (SOD) to aggregate into biochemically distinct, high molecular weight, insoluble protein complexes (IPCs) is a gain of function associated with mutations linked to autosomal dominant familial amyotrophic lateral sclerosis. SOD IPCs are detectable in spinal cord extracts from transgenic mice expressing mutant SOD several months before inclusion bodies and motor neuron pathology are apparent. Sequestration of mutant SOD into cytoplasmic inclusion bodies resembling aggresomes requires retrograde transport on microtubules. These data indicate that aggregation and inclusion body formation are mechanistically and temporally distinct processes.

A novel mutation (Cys6Gly) in the Cu/Zn superoxide dismutase gene associated with rapidly progressive familial amyotrophic lateral sclerosis

Autosomal-dominant familial amyotrophic lateral sclerosis (FALS) is associated with mutation in the gene that encodes Cu/Zn superoxide dismutase (SOD1). We identified a novel missense mutation of SOD-1 (Cys6Gly) in exon 1 in a Japanese woman and her family. The illness showed rapid progression similarly to the FALS with a mutation of Cys6Phe that was reported by Morita et al. (1996) (Morita, M., Aoki, M., Abe, K., Hasegawa, T., Sakuma, R., Onodera, Y., Ichikawa, N., Nishizawa, M. and Itoyama, Y., A novel two-base mutation in the Cu/Zn superoxide dismutase gene associated with familial amyotrophic lateral sclerosis in Japan. Neurosci. Lett., 205 (1996) 79–82). Mutation of the cystein at amino acid 6 might be associated with the rapid progression of ALS.

Superoxide dismutase concentration and activity in familial amyotrophic lateral sclerosis.

Some cases of autosomal-dominant familial amyotrophic lateral sclerosis (FALS) have been associated with mutations in SOD1, the gene that encodes Cu/Zn superoxide dismutase (Cu/Zn SOD). We determined the concentrations (microgram of Cu/Zn SOD/mg of total protein), specific activities (U/microgram of total protein), and apparent turnover numbers (U/mumol of Cu/Zn SOD) of Cu/Zn SOD in erythrocyte lysates from patients with known SOD1 mutations. We also measured the concentrations and activities of Cu/Zn SOD in FALS patients with no identifiable SOD1 mutations, sporadic ALS (SALS) patients, and patients with other neurologic disorders. The concentration and specific activity of Cu/Zn SOD were decreased in all patients with SOD1 mutations, with mean reductions of 51 and 46%, respectively, relative to controls. In contrast, the apparent turnover number of the enzyme was not altered in these patients. For the six mutations studied, there was no correlation between enzyme concentration or specific activity and disease severity, expressed as either duration of disease or age of onset. No significant alterations in the concentration, specific activity, or apparent turnover number of Cu/Zn SOD were detected in the FALS patients with no identifiable SOD1 mutations, SALS patients, or patients with other neurologic disorders. That Cu/Zn SOD concentration and specific activity are equivalently reduced in erythrocytes from patients with SOD1 mutations suggests that mutant Cu/Zn SOD is unstable in these cells. That concentration and specific activity do not correlate with disease severity suggests that an altered, novel function of the enzyme, rather than reduction of its dismutase activity, may be responsible for the pathogenesis of FALS.

Decrease in [formula omitted] and Mn-superoxide dismutase activities in brain and spinal cord of patients with amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a degenerative disorder of motor neurons in the central nervous system (CNS). Mutation of the Cu Zn-superoxide dismutase (SOD) gene on chromosome 21 has been found in some families with autosomal dominant familial ALS (FALS). We sought to determine whether there may be differences in the distribution and activity of SOD in the CNS of patients with sporadic ALS, and of control patients without neurological disorders. The frontal cortex, cerebellum, and spinal cord were obtained at autopsy on 5 patients with ALS and from 10 controls. Immunohistochemically, in the controls, the cytosols of the large pyramidal neurons of the cerebral cortex, anterior and posterior horn cells, and neurons of the nucleus thoracicus of spinal cord were stained homogeneously with anti-human Cu Zn-SOD antibody, and in a granular manner with anti-human Mn-SOD antibody. Pia mater and epithelial cells of choroid plexus also stained well. Conversely, in the CNS of the ALS patients, most neurons were stained faintly, or not at all with both anti-Cu Zn- and Mn-SOD antibodies, whereas the pia mater and the epithelial cells of choroid plexus stained intensely. There was no difference in total SOD activity in the entire CNS between ALS patients and controls, as determined by enzyme assay. Results suggest that, in cases of sporadic ALS, the activities of Cu Zn- and Mn-SOD are decreased and superoxide produced within the neurons accumulates because of an insufficient elimination, leading to the development or acceleration of cell damage, ultimately producing neuronal degeneration and necrosis.

Identification of flanking markers for the familial amyotrophic lateral sclerosis gene ALS1 on chromosome 21

Amyotrophic lateral sclerosis (ALS) is a progressive, adult-onset, neurodegenerative disorder characterized by the death of large motor neurons from the cerebral cortex, brainstem, and spinal cord, The etiology of ALS remains unknown; however, approximately 10% of the cases are familial in nature. In the majority of these families, the mode of transmission is autosomal dominant. Recently, linkage of an autosomal dominant familial ALS (FALS) gene to the locus ALS1 on chromosome 21q was established. In addition, evidence was provided for genetic heterogeneity, with approximately 55% of families most likely linked to chromosome 21. The development of a number of highly informative simple sequence repeat polymorphisms in the region of linkage - 21q21 through 21q22.1 - has permitted us to confirm both the assignment of ALS1 to 21q and the genetic heterogeneity of FALS. In addition, we have been able to refine the mapping of ALS1, based on recombination events in two of the linked families. Flanking markers for the FALS gene are D21S213 on the centromeric side and D21S219 on the telomeric side. The candidate region is approximately 4 Mb and contains the genes copper/zinc superoxide dismutase (CuZnSOD); the fourth member of the class II cytokine receptor family (CRF2-4); and the interferon-alpha receptor (IFNAR).

Superoxide Dismutase Activity, Oxidative Damage, and Mitochondrial Energy Metabolism in Familial and Sporadic Amyotrophic Lateral Sclerosis

The cause of neuronal death in amyotrophic lateral sclerosis (ALS) is unknown. Recently, it was found that some patients with autosomal-dominant familial ALS (FALS) have point mutations in the gene that encodes Cu/Zn superoxide dismutase (SOD1). In this study of postmortem brain tissue, we examined SOD activity and quantified protein carbonyl groups, a marker of oxidative damage, in samples of frontal cortex (Brodmann area 6) from 10 control patients, three FALS patients with known SOD1 mutations (FALS-1), one autosomal-dominant FALS patient with no identifiable SOD1 mutations (FALS-O), and 11 sporadic ALS (SALS) patients. Also, we determined the activities of components of the electron transport chain (complexes I, II-III, and IV) in these samples. The cytosolic SOD activity, which is primarily SOD1 activity, was reduced by 38.8% (p < 0.05) in the FALS-1 patients and not significantly altered in the SALS patients or the FALS-O patient relative to the control patients. The mitochondrial SOD activity, which is primarily SOD2 activity, was not significantly altered in the FALS-1, FALS-O, or SALS patients. The protein carbonyl content was elevated by 84.8% (p < 0.01) in the SALS patients relative to the control patients. Finally, the complex I activity was increased by 55.3% (p < 0.001) in the FALS-1 patients relative to the control patients. These results from cortical tissue demonstrate that SOD1 activity is reduced and complex I activity is increased in FALS-1 patients and that oxidative damage to proteins is increased in SALS patients.