Case 5: Diagnosis and discussion:

Familial amyloid polyneuropathy, aka, transthyretin related  amyloidosis (ATTR).

The co-presence of neuropathy, nerve entrapments raised the concern for amyloidosis, which was proven by cardiac MRI and myocardial biopsy.  Tranthyretin Amyloid gene testing showed sequence alteration in Exon 4: DNA Change: c.424G>A, Amino Acid Change: p.V122I (Val122Ile), confirming the diagnosis of ATTR.

TTR is a tetramer which acts as  transport protein  for thyroxine and  retinol-binding protein. It is synthesized by the liver and choroid plexus, and to a lesser extent the retina. In its normal configuration, The mutant TTR forms a less stable tetramer in which monomers may dissociate and aberrantly fold, leading to aggregation and amyloid formation.

ATTR has autosomal dominant inheritance (Chromosome 18q12.1). More than  80 TTR mutations are so far reported, mostly missense point mutations. TTR V122I is the most common mutation in African Americans, carried by 3.9% of this population.  V122I typically causes an isolated cardiomyopathy. In a study comparing the clinical features of ATTR V122I mutation to amyloid light chain (AL) amyloidosis, peripheral neuropathy was present in 10% of V122I mutation cases and 30% of the AL cases.  On the other hand, carpal tunnel syndrome was more frequent in the V122I cases (47%, vs 10% of the AL cases). (1)

Vyndaquel (tafamidis) may delay peripheral neurologic impairment in familial amyloid polyneuropathy by acting as a novel specific stabilizer of TTR (2). Tafamidis is primarily studied in met-30 TTR to date. Combination of heart and liver transplant remain the definitive treatment in severe cardiomyopathy

Reference:

1. Connors LH, Prokaeva T, Lim A, Theberge R, Falk RH, Doros G, et al. Cardiac amyloidosis in African Americans: comparison of clinical and laboratory features of transthyretin V122I amyloidosis and immunoglobulin light chain amyloidosis. Am Heart J. 2009;158(4):607-14.

2. Bulawa CE, Connelly S, Devit M, Wang L, Weigel C, Fleming JA, et al. Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade. Proc Natl Acad Sci U S A;109(24):9629-34.