Late-onset hereditary ATTR V30M amyloidosis with polyneuropathy: Characterization of Brazilian subjects from the THAOS registry

Abstract

Background: Despite growing numbers of patients diagnosed with late-onset hereditary ATTR V30M amyloidosis with polyneuropathy (ATTRv-PN), this condition remains poorly characterized in Brazil. Objective: Characterize late-onset V30M ATTRv-PN in Brazil. Material and methods: Demographic and clinical data at the time of enrolment for Brazilian subjects with symptomatic V30M ATTRv-PN were extracted from the ongoing, multinational, longitudinal, observational Transthyretin Amyloidosis Outcomes Survey (THAOS; cut-off date: January 30, 2017). Subjects were divided into those with symptom onset at age < 50 years (EO-V30M), and at age ≥50 years (LO-V30M). Results: A total of 96 Val30Met patients were symptomatic. LO-V30M (n = 25, 26.0%) had a longer time to diagnosis (mean 5.1 vs. 2.8 yrs.; p = 0.006) and less frequently positive family history (40% vs. 95.8%; p < 0.0001) than EO-V30M. Clinically, subjects with LO-V30M had more imbalance (92% vs. 54.9%; p = 0.006), deep sensory loss (100% vs. 80%; p = 0.0178), electrocardiogram abnormalities (88.9% vs. 59.4; p = 0.0241), and interventricular septum hypertrophy (69.2% vs. 0%; p < 0001) and less frequently sensory dissociation (12% vs. 74%; p < 0.0001). Also, LO-V30M tended to have more severe mean Neurologic Composite Score (101 vs. 70 pts.; p = 0.1136). Conclusions: LO-V30M ATTRv-PN is not unusual in Brazil, tending to be more difficult to diagnose and present with a more severe phenotype, with more large nerve fibers and cardiac involvement than EO-V30M.Trial Registration: ClinicalTrials.gov: NCT00628745

Real-world outcomes in non-endemic hereditary transthyretin amyloidosis with polyneuropathy: a 20-year German single-referral centre experience

“…The results of our study largely confirm a number of essential findings from previous studies conducted in other countries: Late-onset ATTRv-PN was found to be more difficult to diagnose and to be associated with higher neurologic disease severity and frequent cardiac involvement [19,21,27]. Muscle weakness and impairment of gait, both clinical indicators of advanced polyneuropathy, were also frequently met in our patient cohort.…”

Neurological involvement in Ile68Leu (p.Ile88Leu) ATTR amyloidosis: not only a cardiogenic mutation

“…Few patients spontaneously report neurologic symptoms, and there is a risk that the neurologic involvement could escape notice as patients are generally referred to the cardiologist for severe heart failure or arrhythmias. Our patients do not show the typical small fiber painful neuropathy and the typical 'sensory dissociation' of Val30Met (p.Val50Met) patients [35]. The phenotypic characterization of the neurologic involvement (considering both baseline and follow-up) is a mild, non-painful, mainly sensory neuropathy.…”

“…One of the first neurophysiologic signs of neuropathic involvement is a mild and diffuse increment of F wave latencies with normal motor distal latencies and normal conduction velocities: the association rules out the typical features of demyelination. On the other hand, prolongation of F wave minimal latency is indicated in the literature as a sensitive predictor of polyneuropathy [35].…”

Neuromuscular amyloidosis: Unmasking the master of disguise

“…Val50Met (Val30Met) mutation from Portugal, Brazil, and the southern part of Japan usually present with early-onset (<50 years) profound autonomic neuropathy and small fiber sensory loss in the second or third decade of life, 120,121,27 whereas patients with same mutation from other regions present with late-onset (>50 years) panmodality sensory loss and mild or no autonomic disturbance. 15,122,123 In ATTRv amyloidosis, the sensitivity of biopsy may vary with genotype and phenotype, but in general, fat aspirate is positive in approximately 45%, 110 lip biopsy in 75%-91%, 124,125 and skin biopsy in 70%. 126 The average life expectancy for patients with untreated ATTRv polyneuropathy is 10 years.…”