title: A novel exon 5 mutation (N139H) in the SOD1 gene in a Spanish family associated with incomplete penetrance.
abstract: BACKGROUND
  Allelic heterogeneity and phenotype variability-especially in age at onset, penetrance and progression-are reported in ALS1 families. For this reason, SOD1 gene mutation data in ALS1 patients are currently being gathered to better understand the genotype-phenotype relationship in this disorder. Here, we report the clinical and molecular characteristics of a Spanish ALS1 family with incomplete penetrance.
  
  
  METHODS
  Clinical data including age at onset, initial topography, progression and survival were available in three affected members. Erythrocyte SOD1 activity was measured in four individuals. Analysis of the SOD1 gene was performed by PCR and direct sequencing.
  
  
  RESULTS
  A novel missense mutation in the exon 5 of the SOD1 gene, an A-to-C transversion at nucleotide position 1485 leading to N139H residue change, was identified in three family members. The phenotype was similar in all cases, with initial symptoms in the distal limb muscles and a mean survival time of around 4 years. Incomplete penetrance was observed in our family, as two obligate carriers did not develop any symptoms of amyotrophic lateral sclerosis (ALS).
  
  
  CONCLUSIONS
  N139H is the fifth SOD1 gene mutation reported in Spain, and the first one presenting with incomplete penetrance. Genetic counseling for at-risk relatives in these low-penetrance families could be difficult as some individuals harbouring the mutation remain asymptomatic throughout their lives. Further genetic characterisation of ALS1 families should provide information regarding the distribution of SOD1 mutants in different ethnic groups.
authors.affiliation: Neurology Department, Hospital General. Universitari Vall d'Hebron, Servicio de Neurologia, Passeig Vall d'Hebron 113-135, 08035 Barcelona, Spain.
authors.forename: Gisela
authors.initials: G
authors.lastname: Nogales-Gadea
authors.forename: Elena
authors.initials: E
authors.lastname: Garcia-Arumi
authors.forename: Antonio L
authors.initials: AL
authors.lastname: Andreu
authors.forename: Carlos
authors.initials: C
authors.lastname: Cervera
authors.forename: Josep
authors.initials: J
authors.lastname: Gamez
mesh_terms: D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000401:mortality; D005091:Exons / Q000235:genetics; D005192:Family Health; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D019683:Penetrance; D017354:Point Mutation; D013030:Spain; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1
chemical_list: C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1