Screening for hereditary transthyretin amyloidosis
Screening for hereditary transthyretin amyloidosis
Transthyretin amyloidosis (ATTR) is a protein-misfolding disease in which proteins adopt a misfolded state and aggregate into amyloid fibrils that subsequently deposit in the tissues and organs, resulting in progressive organ dysfunction. Early recognition of ATTR amyloidosis is crucial, as treatment is most beneficial when initiated early in the disease course. The aim of this thesis of Milou Berends is to facilitate early diagnosis and thereby improve prognosis by proposing new screening options.
The first part of this thesis focuses on genetic testing in patients with suspected cardiac amyloidosis. Cardiac ATTR amyloidosis is routinely diagnosed using bone scintigraphy in combination with transthyretin (TTR) genotyping. Analysis using a 12-gene multigene panel showed a diagnostic yield of 4.5%. We found that in patients with a positive bone scintigraphy (grade 2-3), multigene panel analysis provides no added diagnostic value compared to TTR genotyping only, except in cases of persistent diagnostic uncertainty. Through genetic testing, patients with hereditary amyloidosis can be identified, enabling presymptomatic testing in family members and identification of individuals at risk.
The second part describes serum neurofilament light chain (sNfL), a biomarker of neuronal damage. We show that sNfL is a sensitive biomarker for screening and monitoring of disease progression and treatment effect of peripheral large fiber neuropathy. The role of sNfL in autonomic neuropathy requires further investigation. Furthermore, we demonstrate that sNfL measurements obtained using different immunoassays can be reliably compared when normalized using Z-scores.
The third part focuses on the early detection of cardiac involvement in ATTRv amyloidosis. Measurement of cardiac troponin T in transthyretin variant (TTRv) carriers can identify those carriers with low troponin T levels who do not need to undergone bone scintigraphy, thereby reducing unnecessary imaging without compromising diagnostic accuracy. Lastly, we show that minimal cardiac tracer uptake (grade 1) on bone scintigraphy is an early marker of cardiac involvement in TTRv carriers, potentially enabling earlier diagnosis and intervention.