Genotype--phenotype correlation in FAP

Area of Science:

• Genetics
• Neurology
• Pathology

Background:

• Familial Amyloidotic Polyneuropathy (FAP) was historically classified into types based on clinical presentation (e.g., upper vs. lower limb neuropathy).
• Previous classifications were complicated by non-Transthyretin (TTR) protein involvement and significant clinical variability within FAP types.
• Recent advances highlight the limitations of clinical classification due to wide phenotypic variation, even among family members with the same mutation.

Purpose of the Study:

• To review the evolution of FAP classification from clinical to molecular approaches.
• To emphasize the significant variability in clinical presentation of FAP, irrespective of mutation.
• To establish molecular classification as the current gold standard for FAP diagnosis and understanding.

Main Methods:

• Review of existing literature and clinical data on Familial Amyloidotic Polyneuropathy.
• Analysis of phenotypic variability across different Transthyretin (TTR) mutations.
• Comparison of clinical classification systems with molecular diagnostic criteria.

Main Results:

• Clinical classification of FAP (Types I-IV) is unreliable due to inconsistent presentation and involvement of non-TTR proteins.
• Significant clinical variability exists between kindreds and individuals with the same TTR mutation.
• Certain mutations have characteristic presentations (e.g., V122I and cardiac involvement in African-Americans), but most show wide phenotypic variation.
• Neuropathy and cardiac involvement are not reliable indicators for distinguishing specific FAP-causing mutations.

Conclusions:

• Molecular classification is the definitive standard for categorizing Familial Amyloidotic Polyneuropathy (FAP) forms.
• Clinical presentation of FAP is highly variable and cannot reliably predict specific Transthyretin (TTR) mutations.
• While some mutations offer predictable phenotypes, most TTR mutations are associated with a broad spectrum of clinical manifestations.