Late-Onset and Early-Onset Inherited Transthyretin Amyloidosis: Patient Characteristics and Symptoms

Symptomatic disease onset in patients with inherited transthyretin amyloidosis (ATTRv) can develop early (age <50 years) or late (age ≥50 years). Late-onset ATTRv is less common and not well understood.

In an analysis of data from a global longitudinal survey of patients with ATTR, the Transthyretin Amyloidosis Outcomes Survey (THAOS), researchers compared patient and clinical characteristics at the time of enrollment in patients with early-onset versus late-onset ATTRv.

The researchers analyzed records from 1389 patients in the THAOS registry who had the most common inherited mutation, Val30Met. Late-onset disease was evident in 35.3% of patients in THAOS, whereas 64.7% had early-onset disease. In contrast to the full registry, 19 of 21 patients (90.5%) with Val30Met ATTRv from the United States had late-onset disease.

The mean age at enrollment in the registry was 68.1 years for late-onset patients compared with 40.4 years for early-onset patients. Male sex and a longer time between symptom onset and diagnosis were associated with late-onset disease (P <.001 for each).

Almost all patients with early-onset disease had a family history of ATTR (96%), but a family history was found in only 59% of patients with late-onset disease.

Misdiagnosis was more common in late-onset than in early-onset patients (P < .001). Misdiagnosis was reported in 28% of patients with late-onset disease compared with 10% of patients with early-onset disease. Neuropathy and idiopathic neuropathy were the most common misdiagnoses in all patients. Lumbar disc disease and chronic inflammatory demyelinating polyneuropathy were also frequent misdiagnoses in patients with late-onset disease. In contrast, irritable bowel syndrome was a common misdiagnosis in patients with early-onset disease.

Approximately 95% of patients in each group had a history of neurologic disorders at enrollment. Patients with late-onset disease were more likely to have symptoms of motor neuropathy and less likely to have symptoms of autonomic neuropathy compared with patients with early-onset disease (P <.001 for each).

Neurologic impairment, measured by the derived Neuropathy Impairment Score in the Lower Limbs and by Neurologic Composite Score, was significantly worse in patients with late-onset compared with early-onset disease (P <.001 for each).

Cardiovascular symptoms were more common in patients with late-onset disease compared with those with early-onset disease. Electrocardiographic findings were abnormal in 72% of patients with late-onset disease compared with 44% of those with early-onset disease (P <.001). Notably, 70% of late-onset patients had left ventricular thickness >12 mm compared with 15% of patients with early-onset disease (P <.001).

Some limitations of the global registry were differences in the extent of workups, which may have biased detection of some clinical findings.

The researchers stressed that clinicians should realize that ATTRv can be a late-onset disease with heterogeneous presentation, and these patients often do not have a family history of ATTR. These findings may help clinicians diagnose ATTR earlier in the course of the disease.

Source: Waddington-Cruz M, Wixner J, Amass L, et al; for the THAOS Investigators. Characteristics of patients with late- vs. early-onset Val30Met transthyretin amyloidosis from the Transthyretin Amyloidosis Outcomes Survey (THAOS). Neurol Ther. 2021;10:753-766.