Characteristics of Patients with Late- vs. Early-Onset Val30Met Transthyretin Amyloidosis from the Transthyretin Amyloidosis Outcomes Survey (THAOS)

Abstract

Introduction: Hereditary transthyretin amyloidosis (ATTRv amyloidosis) is a clinically heterogeneous disease caused by mutations in the transthyretin (TTR) gene. The most common mutation, Val30Met, can manifest as an early-or late-onset disease. Methods: The Transthyretin Amyloidosis Outcomes Survey (THAOS) is an ongoing, global, longitudinal, observational survey of patients with transthyretin amyloidosis, including both inherited and wild-type disease and asymptomatic patients with TTR mutations. This is a descriptive analysis of symptomatic patients with ATTRv Val30Met amyloidosis with late-(age at least 50 years) vs. early-onset (age less than 50 years) disease in THAOS (data cutoff August 1, 2019). Results: Of 1389 patients with ATTRv Val30-Met amyloidosis, 491 (35.3%) had late-onset disease. Compared with early-onset, patients with late-onset were more likely to be male (66.2% vs. 53.6%) and have a longer mean (standard deviation [SD]) time from onset to diagnosis (3.8 [3.4] vs. 2.7 [4.1] years). Lateonset disease was associated with more severe neurological impairment at enrollment (median [10th, 90th percentile] derived Neuropathy Impairment Score in the Lower Limbs, 25.0 [4.0, 69.3] vs. 8.0 [0, 54.8]; Neurologic Composite Score, 42.0 [2.0, 155.0] vs. 21.0 [0, 102.0]). Cardiac findings were more prominent in lateonset disease. An overall interpretation of electrocardiogram as abnormal was reported in 72.1% of late-onset patients (vs. 44.3% earlyonset). A left-ventricular septal thickness of at least 12 mm was reported in 69.7% of late-onset patients (vs. 14.6% early-onset). All differences were statistically significant (p \ 0.001). Conclusion: In THAOS, late-onset ATTRv Val30Met amyloidosis is common, presenting with more severe neurologic and cardiac findings at enrollment. Heterogeneity of disease may make it more difficult to diagnose. Increased recognition of late-onset ATTRv Val30Met amyloidosis could lead to moreThe members of the THAOS investigators group was processed under acknowledgements section.

Quantitative Sensory Testing in Late-Onset ATTRv Presymptomatic Subjects: A Single Center Experience

“…The different involvement of sensory nerve fibers was demonstrated depending on mutation type [ 3 ]. The early onset phenotype (<50 years), typical of the endemic regions, is characterized by the predominant small fiber involvement, while the late onset phenotype (≥50 years), typical of non-endemic areas such as Italy [ 4 ], displays a progressive and prevalent large fiber damage with partial sparing of the smallest fibers [ 5 , 6 ].…”

A molecular basis for tetramer destabilization and aggregation of transthyretin Ala97Ser

“…These data might help explain that V30M is early‐onset variant contrary to the late‐onset A97S while V30M and A97S show close stability in acid environments in vitro. However, the rising number of late‐onset V30M cases has been reported, but we cannot clearly explain why V30M patients show different age of disease onset (Pinto et al, 2019; Waddington‐Cruz et al, 2021). It has been hypothesized that the age‐ and symptom‐related variability among TTR variants may be ascribed to the environmental and genetic factors (Pinto et al, 2019; Waddington‐Cruz et al, 2021), thus resulting in differentials in age of onset and clinical phenotypes of V30M patients.…”

“…However, the rising number of late‐onset V30M cases has been reported, but we cannot clearly explain why V30M patients show different age of disease onset (Pinto et al, 2019; Waddington‐Cruz et al, 2021). It has been hypothesized that the age‐ and symptom‐related variability among TTR variants may be ascribed to the environmental and genetic factors (Pinto et al, 2019; Waddington‐Cruz et al, 2021), thus resulting in differentials in age of onset and clinical phenotypes of V30M patients.…”

Hereditary transthyretin amyloidosis: a myriad of factors that influence phenotypic variability

“…As stated in Table 1, individuals with the Val30Met variant and early onset typically have a less severe disease course with neuropathy and considerable autonomic dysfunction. In contrast, late-onset Val30Met patients have more severe symptoms with less autonomic dysfunction and moderate to severe cardiac involvement [27,73].…”