Genotype-phenotype analysis in early-onset Alzheimer's disease due to presenilin-1 mutations at codon 139.

Mutations in the presenilin-1 (PS-1) gene are the main cause of autosomal-dominant early onset Alzheimer's disease (EOAD) and show a high penetrance of symptoms. There are more than 100 mutations in the PS-1 gene. Among them are at present four different missense mutations known at position 139 on exon 5. Lack of genotyping in other family members may lead to the suggestion of sporadic cases. We present the case of a 46-year old German female with EOAD. Cognitive decline started at the age of 32, while myoclonic and tonic-clonic jerks occurred later. Disease symptoms were present in three generations of her family. Genetic analysis revealed the M139V mutation on exon 5 of the PS-1 gene. We compared the clinical data of this family with seven previously reported families and two sporadic cases with mutations at the codon 139. The genotype-phenotype analysis showed marked intrafamilial homogeneity, but interfamilial heterogeneity in relation to the onset, duration, and progression of the disease. Onset and duration were not correlated to the amino acid exchanged. Another modifying genetic or environmental factor is probable.