Widespread Cardiac and Vasomotor Autonomic Dysfunction in Non-Val30Met Hereditary Transthyretin Amyloidosis

Abstract

Objective The autonomic functions of hereditary transthyretin (ATTRm) amyloidosis, traditionally referred to as familial amyloid polyneuropathy, have primarily been investigated in patients with Val30Met mutations, and information regarding non-Val30Met patients is scarce. The aim of this study was to systematically investigate the cardiac and peripheral vasomotor autonomic functions in non-Val30Met patients. Methods The coefficient of variation of R-R intervals (CVR-R), responses to the Valsalva manoeuvre, head-up tilt test results, noradrenaline infusion test results, and the (123) I-metaiodobenzylguanidine (MIBG) uptake on myocardial scintigraphy were assessed in five patients. The predominant manifestations were neuropathy in three patients (Val94Gly, Val71Ala, and Pro24Ser), cardiomyopathy in one (Thr60Ala), and oculoleptomeningeal involvement in one (Tyr114Cys). Results Although one patient with predominant cardiomyopathy did not manifest orthostatic hypotension during the head-up tilt test, the CVR-R, responses to the Valsalva manoeuvre, and myocardial MIBG uptake indicated the presence of cardiac sympathetic and parasympathetic dysfunction in all patients. The total peripheral resistance at 60° tilt did not increase from the baseline values in any of the examined patients. An infusion of low-dose noradrenaline induced an increase in the systolic blood pressure, except in one patient with mild neuropathy. Conclusion Cardiac and peripheral vasomotor autonomic dysfunctions were prevalent in non-Val30Met patients, irrespective of their phenotype, suggesting a common pathology of autonomic involvement. However, the vasoconstrictor function was preserved, even in a patient with advanced neuropathy.

Transthyretin Amyloidosis: Update on the Clinical Spectrum, Pathogenesis, and Disease-Modifying Therapies

“…Although Val30Met is considered the most common mutation among patients predominantly manifesting neuropathy [1,18,24], recent developments in diagnostic techniques led to the discovery of many patients with mutations other than Val30Met (i.e., non-Val30Met mutations) in the TTR gene, in which more than 130 mutations have been reported [1,25]. Cardiomyopathy may be the predominant feature in some of the patients carrying non-Val30Met mutations [18,26]. For example, the Val122Ile (p.Val142Ile) mutation is considered a common cause of heart disease in African Americans originating from West African countries [27,28].…”

Advances in the treatment of hereditary transthyretin amyloidosis: A review

“…Symptoms that may help to distinguish hATTR from other causes of neuropathy include neuropathic pain (often described as lightning pain), autonomic dysfunction, absence of ataxia, small fiber sensory loss above the wrist, and weakness in the upper limbs, and are more common in hATTR (Lozeron et al, 2018). Autonomic neuropathy can manifest as orthostatic hypotension and/or sexual dysfunction but may not be reported (Carr et al, 2016;Koike, Nakamura, et al, 2018;Lozeron et al, 2018;Maurer et al, 2016;Wixner, Tornblom, Karling, Anan, & Lindberg, 2018). Therefore, patients presenting with progressive length-dependent neuropathy of unknown origin, particularly those with concomitant autonomic dysfunction, should be tested for ATTR.…”

Orthostatic hypotension in hereditary transthyretin amyloidosis: epidemiology, diagnosis and management

“…It is frequent, early and severe in patients with the Val30Met mutation and early-onset disease but appears to be less severe in Val30Met cases with late-onset disease [70–72, 74, 108, 138]. OH is also prevalent and severe in patients with some non-Val30Met mutations [12, 15, 20, 24, 25, 27, 49, 53, 57, 60, 69, 73, 78, 79, 95, 96, 113, 115, 119, 136, 137, 142, 145]. For instance, up to 100% of patients with the Ala97Ser mutation have OH, with 71% having frequent syncope, particularly in late stages of the disease [58].…”