The T60A Variant Is the Most Common Genotype in the Irish Population That Ranges Widely in Clinical Presentation

There is a wide clinical spectrum in the progressive, multisystem disorder known as hereditary transthyretin amyloidosis (hATTR). The T60A variant is the most common genotype in the Irish population. Researchers at Mater Misericordiae University Hospital in Dublin characterized the wide range of patients with T60A hATTR by reviewing the medical, laboratory, and radiologic records of all patients diagnosed with T60A-variant hATTR attending a national amyloid clinic.

The vast majority (94%) of the cases in the hATTR population possessed the T60A mutation. Sixty percent of these patients (N = 15) were male and were diagnosed at a median age of 65 years. The median follow-up for this group was 10 months. Eighty percent of these patients were symptomatic, and 20% had been referred to the clinic for family screening. A family history suggestive of amyloidosis was found in 66% of the patients (N = 10), 6 of whom had a first-degree relative with a T60A mutation.

Ninety-three percent of patients presented with neurologic symptoms at the time of diagnosis (80% with peripheral neuropathy and 95% with autonomic neuropathy), which typically predated the appearance of cardiac symptoms.

A bilateral carpal tunnel release procedure had been performed on one-third of patients (N = 5), a median of 11 years prior to being diagnosed with T60A hATTR.

Symptoms of heart failure were detected in slightly more than half (53%) of patients during follow-up. New York Heart Association stage II was detected in 40% of patients, stage III in 13%, and the remainder were asymptomatic. One-third of patients had been hospitalized for heart failure in the previous year.

Technetium-99m 3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy (Tc-DPD) demonstrated the presence of cardiac involvement in all patients, with Perugini grade 2 in 40% of patients and grade 3 in 60%.

Symptomatic patients had ventricular hypertrophy revealed by echocardiography, with a median left ventricular wall thickness of 2 cm (interquartile range [IQR], 1.5-2.5) and a median right ventricular wall thickness of 0.8 cm (IQR, 0.68-0.92).

Due to abnormalities in hematologic testing, 60% of patients (N = 9) required tissue confirmation of hATTR; these included 1 case of bone marrow aspirate, 5 cases of right ventricular endomyocardial biopsy, and in 3 cases biopsy procedures of fat pad, rectal, or bladder regions were conducted. For the T60A variant, all patients were heterozygous.

Disease-modifying treatment was prescribed for all patients at some point during follow-up. While the majority of patients received diflunisal (80%), some received patisiran (33%), doxycycline (7%), or tafamidis (7%).

On repeat imaging at a median interval of 18 months, all patients with Perugini grade 2 on initial Tc-DPD imaging had progressed to grade 3.

Presenting with a mixed phenotype of polyneuropathy and heart failure, the T60A variant of hATTR is associated with a higher prevalence of neurologic symptoms at earlier stages. Cardiac involvement is often at an advanced stage at the time of diagnosis, regardless of symptoms, and progressed in the study cohort during short-term follow-up.

Source: Hewitt K, McGuckin M, Giblin G, et al. The clinical spectrum of T60a variant hereditary transthyretin amyloidosis in Ireland. Presented at: Heart Failure Society of America Virtual Annual Scientific Meeting 2020; September 30-October 6, 2020. Abstract 088.

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