Letter to the editor: Comment on “Involvement of cranial nerves in ATTR Ile127Val amyloidosis” by Silva Batista JAD et al. (Eur J Med Genet. 2022 Jul;65(7):104524) and report of 3 new patients

Cranial nerve involvement in hereditary transthyretin amyloidosis (ATTRv) remains an underrecognized manifestation, particularly in carriers of atypical variants. Silva Batista et al. (2022) expanded the phenotypic spectrum of the p.Ile127Val mutation by reporting cranial neuropathies in approximately 21% of p.Ile127Val individuals. Motivated by these findings, we conducted a retrospectively analysis of our cohort of p.Ile127Val carriers followed at the Neuromuscular/Peripheral Neuropathies Unit of Hospital Geral de Fortaleza, Ceará, Brazil. This hospital is located in the same northeastern region where the original cases were first described. Among 31 p.Ile127Val carriers evaluated up to May 2025, three patients (10%) exhibited some kind of cranial nerve involvement, at a median age of 61 years, which is approximately 10 years later than previously reported. All 3 affected individuals presented with some degree of axonal peripheral neuropathy, but cardiac involvement was observed in only one case. Cranial manifestations appear to be more common in p.Ile127Val carriers than individuals with other ATTRv variants or than the same variant from other regions, which suggests the existence of a potential regional founder effect. Proposed mechanisms include amyloid fibril deposition, inflammation, fibrosis, ischemic injury to cranial nerve vasculature, and, more recently, leptomeningeal amyloid infiltration. Our findings corroborate those of Silva Batista JAD et colleagues and reinforce the importance of distinguishing ATTRv amyloidosis from bulbar motor neuron disease. Recognizing associated features such as sensory axonal neuropathy and dysautonomia in order to ensure timely intervention, which can significantly modify disease progression.