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Four familial ALS pedigrees discordant for two SOD1 mutations: are all SOD1 mutations pathogenic?

https://arctichealth.org/en/permalink/ahliterature97016
Source
J Neurol Neurosurg Psychiatry. 2010 May;81(5):572-7
Publication Type
Article
Date
May-2010
Author
Ansgar Felbecker
William Camu
Paul N Valdmanis
Anne-Dorte Sperfeld
Stefan Waibel
Peter Steinbach
Guy A Rouleau
Albert C Ludolph
Peter M Andersen
Author Affiliation
Department of Clinical Neuroscience, Umeå University, Umeå SE-901 85, Sweden.
Source
J Neurol Neurosurg Psychiatry. 2010 May;81(5):572-7
Date
May-2010
Language
English
Geographic Location
Finland
Sweden
Multi-National
Publication Type
Article
Keywords
Adult
Age of Onset
Aged
Alleles
Amyotrophic Lateral Sclerosis - genetics - pathology
DNA - genetics
Disease Progression
Female
Finland
Genes, Dominant - genetics
Genes, Recessive - genetics
Germany
Haplotypes
Heterozygote
Humans
Male
Middle Aged
Mutation - genetics - physiology
Mutation, Missense
Pedigree
Phenotype
Reverse Transcriptase Polymerase Chain Reaction
Superoxide Dismutase - genetics
Sweden
Abstract
BACKGROUND: 153 mutations in the Cu/Zn superoxide dismutase (SOD1) gene have been claimed to be associated with amyotrophic lateral sclerosis (ALS) in familial and sporadic ALS in an autosomal dominant or autosomal recessive pattern with complete or reduced penetrance. The authors now report four ALS pedigrees from Finland, France, Germany and Sweden with either the D90A or E100K SOD1 mutations in some but not all affected members. After re-collecting DNA, the non-segregation of the SOD1 mutations with disease was confirmed by three independent laboratories using different PCR primers: while some of the affected patients carry SOD1 mutations, other affected family members have two wildtype/normal SOD1 genes. In addition, some unaffected members within the same families are carriers of SOD1 gene mutations. To exclude other known genetic causes, the authors ruled out mutations within the genes coding for VAPB, ANG, TDP43, FUS and DCTN1 in affected individuals in the four pedigrees. CONCLUSIONS: The authors find that the D90A and E100K SOD1 gene mutations found in some patients are not the exclusive cause of ALS in these pedigrees. Whether this is also the case for the other 151 SOD1 mutations reported in ALS pedigrees is unknown. The findings have consequences for genetic testing in clinical practice when diagnosing ALS and for genetic counselling in ALS. Some SOD1 mutations may be part of an oligo- or epigentic pattern of inheritance. Such a pattern of inheritance may model other oligo- or polygenetic traits responsible for other forms of ALS.
Notes
RefSource: J Neurol Neurosurg Psychiatry. 2010 May;81(5):473
PubMed ID
20460594 View in PubMed
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