Clinical differential factors in patients with hereditary transthyretin amyloidosis with Val142Ile and Ser43Asn mutations

Hereditary transthyretin amyloidosis (hATTR) is a rare autosomal dominant disease with high clinical variability, influenced by both genotype and the geographic origins of carriers. There is a limited understanding of the Val142Ile and Ser43Asn recognised mutations in Ecuador and Colombia. Therefore, the objective of this study is to describe the neurological and functional characteristics of patients with hATTR associated with the Val142Ile and Ser43Asn mutations, as well as to identify possible differentiating factors between the two mutations.

This cross-sectional, multicenter study included 35 hATTR patients from rehabilitation centers in Ecuador and Colombia. Patients had confirmed Val142Ile or Ser43Asn mutations. Neurological and functional assessments included the Neurological Impairment Scale, Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN), Composite Autonomic Symptom Score-31, and various motor function tests as nine-hole peg test (NHP). Quantitative Sensory Testing (QST) evaluating small fiber function, while ultrasound measured the cross-sectional area (CSA) of peripheral nerves. Statistical analysis employed nonparametric tests and random forest classifiers, using SHAP values to identify differentiating variables.

Val142Ile carriers showed lower performance in the right NHP test and greater sensitivity to cold pain in hand and leg. Ultrasound revealed increased CSA of the median nerve at the elbow and arm and the ulnar nerve at the arm in Val142Ile carriers compared to Ser43Asn carriers. The final random forest model identified the NHP test, Norfolk QOL-DN score, and CSA of the median and ulnar nerves as key discriminating variables.

This study identified significant neurophysiological and ultrasound markers differentiating Val142Ile and Ser43Asn mutations in hATTR-PN patients. Increased nerve CSA and specific motor and sensory impairments highlight the need for comprehensive evaluations to guide diagnosis and treatment.