Phenotypes Associated With the Val122Ile, Leu58His, and Late-Onset Val30Met Variants in Patients With Hereditary Transthyretin Amyloidosis

Abstract

Background and Objectives: hATTR is a rare autosomal-dominant systemic disease with variable penetrance and heterogeneous clinical presentation. Several effective treatments can reduce mortality and disability, though diagnosis remains challenging, especially in the US where disease is non-endemic. Our aim is to describe the neurologic and cardiac characteristics of common US ATTR variants V122I, L58H and late-onset V30M at presentation.Methods:We conducted a retrospective case series of patients with a new diagnosis of ATTRv between January 2008 and January 2020 to characterize features of prominent US variants The neurological (examination, EMG, skin biopsy), cardiac (echo) and laboratory assessments (proBNP, reversible neuropathy screens) are described.Results:56 patients with treatment-naïve ATTRv with symptoms/signs of peripheral neuropathy or cardiomyopathy and confirmatory genetic testing presenting with Val122Ile (N=31), late-onset Val30Met (N=12) and Leu58His ATTRv (N=13) were included. The age at onset and gender distributions were similar (V122I: 71.5±8.0, V30M: 64.8±2.6, L58H: 62.4±9.8years; 26, 25, 31% female).Only 10% of patients with V122I and 17% of patients with V30M were aware of an ATTRv family history, while 69% of patients with L58H were. Peripheral neuropathy was present in all three variants at diagnosis (90, 100, 100%) though neurological impairment scores differed: V122I: 22±16, V30M: 61±31 and L58H: 57±25. Most points (deficits) were attributed to loss of strength. Carpal tunnel syndrome (CTS) and a positive Romberg sign were common across all groups (V122I: 97%, 39%; V30M: 58%, 58%; L58H: 77%, 77%).ProBNP levels and interventricular septum thickness were highest among patients with V122I (5939±962pg/mL, 1.70±0.29cm) followed by V30M (796±970pg/mL, 1.42±0.38cm) and L58H (404±677pg/mL, 1.23±0.36cm). Atrial fibrillation was present among 39% of V122I cases and only 8% of V30M and L58H cases. Gastrointestinal symptoms were rare (6%) among patients with V122I and common in patients with V30M (42%) and L58H (54%).Discussion:Important clinical differences exist between ATTRv genotypes. While V122I is perceived to be a cardiac disease, peripheral neuropathy is common and clinically relevant. Most patients with V30M and V122I were diagnosed de-novo and therefore require clinical suspicion for diagnosis.A history of CTS and a positive Romberg sign are helpful diagnostic clues.

Clinical spectrum of Transthyretin amyloidogenic mutations among diverse population origins

“…Similarly, we also observed an AFR-EUR cross-ancestry association between Val122Ile mutation and peripheral nerve disorders (phecode 351). While cardiac amyloidosis is the primary Val122Ile outcome [ 39 ], our finding is consistent with previous reports supporting that Val122Ile may be related to peripheral neuropathy symptoms that are more often reported with respect to other TTR amyloidogenic mutations [ 42 ]. This is in line with the results of a previous phenome-wide analysis in UKB-AFR participants, reporting an association of Val122Ile with polyneuropathy [ 43 ].…”