• AMYLOID
• NEUROPATHY
• NEUROPHYSIOLOGY
• NEUROPATHOLOGY

The JNNP paper by Beauvais et al. reports a retrospective study on 130 transthyretin (TTR) mutation carriers with normal nerve conduction studies (indicating no large-fibre neuropathy) irrespective of the presence of symptoms of TTR-related amyloidosis (ATTRv).1 Carriers were submitted to extensive investigations aimed at identifying: amyloid deposits in punch skin biopsies and/or in heart (detected by Technetium-99m-labelled 3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy), evidence of small-fibre involvement, autonomic abnormalities, heart dysfunction employing different tools. Remarkably, only 3/130 carriers had neither neurological nor cardiac abnormalities. Nine carriers had cardiac or small-fibre neuropathy symptoms and amyloid deposits in heart or skin (7 carriers started treatment for ATTRv); 13 carriers, though asymptomatic, had skin and/or heart amyloid deposits, or autonomic dysfunction (3 carriers began therapy immediately and 9 carriers later). The remaining 105 carriers had neither symptoms nor amyloid deposition but had isolated abnormalities with at least one tool.

The series is very large, and results have important implications. As suggested by authors, and previous papers, the impression is that small-fibre loss, as shown by decreased intraepidermal nerve fibre density (occurring in 88.7% of cases) and other tools/questionnaires, starts well before symptom appearance and detectable amyloid deposition; onset of symptoms is truly the iceberg tip and large-fibre abnormalities appear when a large amount of ice has already formed below the surface. Consequences were important for some patients starting treatment before what would have happened without deep investigations, and are relevant for the current debate about the threshold for starting treatment and the age carriers’ monitoring should start, as some patients were considerably younger than the predicted-age-of-disease-onset.

Current criteria for treatment start are ‘symptomatic polyneuropathy and TTR pathogenic mutation’. However, often a minimum Neuropathy Impairment Score value, which, excluding pinprick sensory loss, assesses large-fibre neuropathy signs, is required by national authorities. Should we wait for symptoms and signs of large-fibre neuropathy when we know that early treatment is fundamental, and when small-fibre neuropathy justifies treatment start? Recent papers focused on presymptomatic carriers and investigations able to detect the ‘conversion’ to overt disease.2–5 We cannot rely only on amyloid deposits’ demonstration, as more difficult to detect in late-onset ATTRv.2 Is presymptomatic small-fibre involvement, as revealed by fibre counting in epidermis or cornea, or by autonomic abnormalities, enough for starting treatment? Which is the best method to detect conversion from asymptomatic carrier to patient condition? There is now clear evidence that there are abnormalities preceding overt symptom onset, though they differ from patient to patient and there is no single tool able to indicate conversion with certainty.3 4 Neurofilament light chain assay is promising, but results are still too variable to rely on this (aspecific) parameter only.5 It will be important to continue monitoring presymptomatic carriers until symptom onset to determine predictors of conversion. It is probably wise to consider that two exam abnormalities (preferably including amyloid deposits) are enough to determine conversion and start treatment without waiting for neuropathy symptoms and signs.2 4 An expert consensus or guideline statement will be important to convince authorities to expand the concept of disease onset.