Genotype - phenotype correlation in FAP

Familial Amyloidotic Polyneuropathy (FAP) was initially classified into different types based on the clinical presentation. FAP Type I included patients with predominant upper limb neuropathy, while Type II patients had initial lower limb involvement. Further confusing the issue was the description of FAP Types III and IV, which proved to result from proteins other than Transthyretin (TTR). More recently, molecular classification has superseded clinical classification. It is increasingly clear that the clinical picture of patients with FAP is widely variable. Significant variation in the clinical presentation occurs between individual kindreds with the same mutation and even among family members. The factors that govern this variation are unknown at present. Some general principles have emerged from studying patients with different mutations. Leptomeningeal involvement is rare and occurs predominantly in only a few mutations. Isolated cardiac involvement in African-Americans is invariably associated with the V122I mutation. Given the variability in presentation, it is not possible to accurately classify patients on the basis of neuropathy, either sensorimotor or autonomic. Further, cardiac involvement, which occurs with increased frequency in non-V30M patients, is not a reliable phenotype to distinguish specific mutations. Molecular classification has become the gold standard for classification of the different forms of FAP. While some rare mutations confer a more predictable phenotype, the majority of the known mutations are associated with a wide variation in phenotype.