Neurologic and cardiac characteristics associated with hereditary transthyretin amyloidosis (hATTR) variants that are common in the US, including V122I, L58H, and late-onset V30M, have been explored in a study published in Neurology.

The researchers conducted a retrospective case series of patients diagnosed with hATTR between January 2008 and January 2020. Of 56 patients with treatment-naive hATTR and symptoms of peripheral neuropathy or cardiomyopathy, the study included 31 patients with the Val122Ile, 13 with the Leu58His, and 12 with the late-onset Val30Met disease variant.

The researchers analyzed the following data: neurological examinations, EMG and skin biopsy results, echocardiography reports, as well as laboratory assessments including pro-brain-type natriuretic peptide, and reversible neuropathy screens.

According to the results, peripheral neuropathy at diagnosis was present in all 3 disease variants. However, the neurological impairment scores suggest that different variants were not equally affected by it. The V122I group had a neurological impairment score of 22±16, the V30M group of 61±31, and the L58H group scored 57±25.

Read more about hATTR complications

The researchers often found records of strength loss, carpal tunnel syndrome, and positive Romberg sign across the 3 groups.

Patients with the V122I disease variant had the highest pro-brain-type natriuretic peptide levels and interventricular septum thickness (5939±962 pg/mL, 1.70±0.29 cm), whereas those with V30M hATTR were less affected (796±970 pg/mL, 1.42±0.38 cm) and patients with the L58H variant had the lowest results (404±677 pg/mL, 1.23±0.36 cm).

Moreover, 39% of patients with hATTR with the V122I disease variant experienced atrial fibrillation as opposed to 8% of patients with the V30M and L58H variants. Although gastrointestinal symptoms were rarely reported (6%) in patients with V122I, they were common among individuals with V30M (42%) and L58H hATTR (54%).

Only 10% of patients with V122I and 17% of patients with the V30M disease variant reported having an hATTR family history, whereas 69% of patients with L58H confirmed having a family member with the same condition.

Read more about hATTR diagnosis

“Important clinical differences exist between hATTR genotypes. While V122I is perceived to be a cardiac disease, peripheral neuropathy is common and clinically relevant. Most patients with V30M and V122I were diagnosed de-novo and therefore require clinical suspicion for diagnosis. A history of carpal tunnel syndrome and a positive Romberg sign are helpful diagnostic clues, ” Zampino and colleagues concluded.

hATTR is a rare autosomal-dominant systemic disease with a very diverse clinical presentation. The condition may be a challenge to diagnose, especially in the US where it is nonendemic.


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