Hereditary transthyretin-related amyloidosis is frequent in polyneuropathy and cardiomyopathy of no obvious aetiology

Abstract

Background: Hereditary Transthyretin-Related Amyloidosis, a clinically heterogeneous autosomal dominant disease caused by pathogenic variants in the TTR gene, is characterized by the deposition of insoluble misfolded protein fibrils. The diagnosis, especially in non-endemic areas, is typically delayed by 4-5 years; a misdiagnosis due to clinical heterogeneity is common. The study objective was to define the prevalence of Hereditary Transthyretin-Related Amyloidosis in patients with polyneuropathy and/or cardiomyopathy of no obvious aetiology.

Method: A multicenter observational "Epidemiological analysis for the hereditary Transthyretin-Related AMyloidosis"-TRAM study was performed in Germany, Austria, and Switzerland.

Results: A total of 5141 participants were recruited by 50 neurologic and 27 cardiologic specialized centres. Genetic analysis demonstrated a 1.1% Hereditary Transthyretin-Related Amyloidosis positivity rate among patients with polyneuropathy and/or cardiomyopathy of not obvious aetiology. Twenty-one various TTR variants (TTR-positive) were identified. Body Mass Index was lower in the TTR-positive patients as an indicator for the involvement of the autonomic nervous system; the age of onset of clinical manifestations was higher in TTR-positive patients. There were no other genotype-phenotype correlations or the prevalence of specific clinical manifestations in TTR-positive patients.

Conclusions: Our data support the fact that Hereditary Transthyretin-Related Amyloidosis is underdiagnosed in polyneuropathy and cardiomyopathy patients. Routine implementation of genetic testing is recommended in patients with unexplained polyneuropathy and/or cardiomyopathy to accelerate the earlier diagnosis and the time-sensitive treatment initiation.KEY MESSAGESMore than 5.000 participants with CM and/or PNP of no obvious aetiology were recruited in the observational "Epidemiological analysis for the hereditary Transthyretin-Related AMyloidosis" TRAM study and screened for pathogenic TTR variants.The study demonstrated >1% of patients with CM and/or PNP of unclear aetiology are positive for a pathogenic TTR variant.Routine genetic testing is recommended in patients with unexplained CM and/or PNP to accelerate the initial diagnosis and timely treatment initiation.

Keywords: Hereditary transthyretin-related amyloidosis; cardiomyopathy; genetic testing; polyneuropathy.

Figure 1.

TTR variants as identified by the present study. (A) Fraction of the three relevant classes amongst patients (A’) and variants (A”). Absolute numbers are provided within the charts. (B) Number of observations of individual variants. Colour shade-coding as in (A).

Figure 2.

Comparison of TTR-positive and TTR-negative study participants (TTR-status on the x-axis in all charts). (A) Gender. (B) Ages at disease onset and enrolment. (C) Family history. (D) Manifestation as cardiomyopathy (CM), polyneuropathy (PNP), or both. (E) Body Mass Index (BMI). (F) Number of symptoms.

Figure 3.

Frequency of individual symptoms with TTR-negative (TTR−) depicted in grey and TTR-positive (TTR+) in red colour. Symptoms that show discrepancies between TTR-negative and TTR-positive study participants are depicted on the left. Symptoms in alphabetical order: All: Allodynia; ana: Anaemia; arr: Arrhythmia; bur: “burning feet”; car: History of carpal tunnel syndrome; che: Chest pain; cad: Bouts of constipation that alternate with diarrhoea; con: Constipation; dia: Diarrhoea; dif: Difficulty urinating or holding urine; diz: Dizziness or fainting upon standing; dys: Dyshidrosis; ehc: Enlargement of heart cavities; ehm: Enlargement of heart muscle; hea: Abnormal (fluttering) heartbeat; mlw: Muscle weakness in the legs; mua: Muscle atrophy in the legs; num: Numbness; obm: Inability to obtain or maintain an erection; pai: Pain; pal: Palpitation; sen: Reduced ability to sense temperature; sho: Shortness of breath; tin: Tingling; unw: Unintentional weight loss; wat: Water accumulation in the ankles and lower limbs.