The following is a summary of “Phenotypes Associated With the Val122Ile, Leu58His, and Late-Onset Val30Met Variants in Patients With Hereditary Transthyretin Amyloidosis,” published in the May 09, 2023 issue of Neurology by Zampino, et al.

Hereditary transthyretin amyloidosis (hATTR) is a rare systemic disease with varying clinical presentations and diagnostic challenges, particularly in nonendemic regions like the United States. For a study, researchers sought to describe the neurological and cardiac characteristics of three common hATTR variants (V122I, L58H, and late-onset V30M) at the time of presentation.

A retrospective case series was conducted, including patients with newly diagnosed ATTRv between January 2008 and January 2020. The study aimed to characterize the features of the prominent US variants through neurological examinations, electromyography (EMG), skin biopsy, echocardiography, and laboratory assessments (pro b-type natriuretic peptide [proBNP] and reversible neuropathy screens).

The study included 56 treatment-naïve patients with ATTRv presenting with symptoms/signs of peripheral neuropathy (PN) or cardiomyopathy and confirmed genetic testing. The patients were categorized into Val122Ile (N = 31), late-onset Val30Met (N = 12), and Leu58His ATTRv (N = 13). The age at onset and sex distribution were similar across the variants (V122I: 71.5 ± 8.0, V30M: 64.8 ± 2.6, and L58H: 62.4 ± 9.8 years; 26%, 25%, 31% female). Only a small percentage of patients with V122I (10%) and V30M (17%) were aware of their family history of ATTRv, whereas the majority of patients with L58H (69%) had prior knowledge. PN was present in all three variants at diagnosis (90%, 100%, and 100%), although the neurologic impairment scores differed: V122I: 22 ± 16, V30M: 61 ± 31, and L58H: 57 ± 25. Loss of strength accounted for most deficits. Carpal tunnel syndrome (CTS) and a positive Romberg sign were common among all groups (V122I: 97%, 39%; V30M: 58%, 58%; and L58H: 77%, 77%). ProBNP levels and interventricular septum thickness were highest in patients with V122I (5,939 ± 962 pg/mL, 1.70 ± 0.29 cm), followed by V30M (796 ± 970 pg/mL, 1.42 ± 0.38 cm) and L58H (404 ± 677 pg/mL, 1.23 ± 0.36 cm). Atrial fibrillation was present in 39% of V122I cases and only 8% of V30M and L58H cases. Gastrointestinal symptoms were rare (6%) in patients with V122I but common in patients with V30M (42%) and L58H (54%).

Significant clinical differences existed between hATTR genotypes. While V122I was traditionally considered a cardiac disease, PN was prevalent and clinically relevant. Most patients with V30M and V122I were diagnosed de novo, necessitating clinical suspicion for accurate diagnosis. A history of CTS and a positive Romberg sign can serve as valuable diagnostic clues.

Source: n.neurology.org/content/100/19/e2036