Scientists have more clearly discerned the phenotypes associated with various mutations in patients with hereditary transthyretin amyloidosis (hATTR), according to a study published in Neurology. 

Researchers have described more than 120 pathogenic variants of hATTR. The 2 most common genetic variants in endemic regions are Val30Met and Thr60Ala. In the United States, the most common genetic mutation is V122I, present in approximately 3% of Black individuals. Studies indicate that the V122I variant mostly results in cardiac pathology; the peripheral nervous system is only sometimes involved. 

The authors of the study sought to better characterize the phenotype of patients with 3 common genetic variants seen at their center: V122I, L58H, and late-onset V30M. They recruited patients who were symptomatic but treatment naive at the Johns Hopkins Amyloid Center between 2008 and 2020. Patients must have had some symptoms of the disease with 1 of the 3 genetic mutations mentioned to have been eligible for the study. 

The research team were focused on 3 main symptoms seen in patients with hATTR: peripheral nerve disease, cardiac pathology, and gastrointestinal involvement. They collected detailed clinical information, such as the year of symptom onset, the earliest abnormal test results, and the progression of the disease. Nerve conduction studies as well as Romberg assessments were conducted. 

Read more about hATTR etiology

They recruited 56 patients with complete medical records: 31 with V122I, 13 with L58H, and 12 with late-onset V30M. The researchers found evidence of extensive disease in all patients with all 3 genetic mutations, although peripheral nerve involvement was not a prominent feature in V122I and L58H. Patients with the L58H mutation were found to mainly have neuropathic pathology with little cardiac involvement; however, gastrointestinal manifestations and spinal stenosis were commonly observed. Cardiac features were more prominent in patients with the V122I and V30M mutations. Patients of all 3 genetic variations of hATTR typically demonstrated a positive Romberg sign. 

“Screening for symptoms across all systems affected (cardiac, peripheral nerve, gastrointestinal, and musculoskeletal) and for imbalance (which disproportionately affects our patients) can improve diagnosis of this rare, progressive, but now treatable disease,” the authors concluded. 


Zampino S, Sheikh FH, Vaishnav J, et al. Phenotypes associated with the Val122Ile, Leu58His, and late-onset Val30Met variants in patients with hereditary transthyretin amyloidosisNeurology. Published online March 20, 2023. doi:10.1212/WNL.0000000000207158