Familial Amyloid Polyneuropathy: Impact of Biopsies and Mutations on Diagnostic Considerations (P3.4-033)

Abstract

Objective: To characterize the symptoms, signs and skin biopsy neuropathological findings in a cohort of individuals with TTR Mutations.

Background: Familial amyloid polyneuropathy is due to one of many mutations in the transthyretin(TTR) gene, resulting in a progressive fatal disease with sensory, motor and autonomic involvement.

Design/Methods: Individuals with a variety of TTR mutations underwent detailed neurological examinations including the Neuropathy Impairment Score in the Lower Limb(NIS-LL), the Utah Early Neuropathy Score(UENS), Coutinho staging, autonomic testing, symptom scores (using the EuroQol, Brief Pain Symptom Inventory, and the orthostatic hypotension Questionnaire). All subjects had 3mm punch skin biopsies at the distal leg and distal thigh with analysis of amyloid burden by Congo Red, and neuropathy severity by staining with protein gene product 9.5.

Results: A total of 88 subjects participated with the following TTR mutations: 43-Val30Met, 30-Ser50Arg, 6- Gly47Ala, 5- Ser52Pro, 2- F64L, 1- I73V and 1 with Y136H. Coutinho staging included 47 stage 0, 32 stage 1, 8 stage 2 and 1 stage 3. The diagnostic sensitivity for amyloid detection from a single skin biopsy was 72%, the diagnostic yield increased to 89% with 2 biopsies. Biopsies were positive for amyloid in 78% of individuals with no clinical evidence of neuropathy (NIS-LL scores of 0) and 94% for individuals with any evidence of neuropathy. Amyloid burden was inversely correlated with nerve density at the distal leg (R=0.59, P<0.01) and distal thigh(R=−0.53, P<0.01), and correlated with the NIS-LL (R=0.48, P<0.05), and UENS (R=0.49, P<0.05).

Conclusions: Skin biopsy is a sensitive and specific pathological marker for tissue diagnosis of familial amyloid polyneuropathy across multiple mutations, even in individuals with no clinical evidence of disease. Amyloid burden correlates with neuropathy severity, both pathologically and by examination criteria; skin biopsies may prove informative for studies that seek to alter the natural history of the disease.