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In transthyretin (ATTR) amyloidosis, the F64L, I107V, and S77Y variants are usually associated with a neurologic phenotype, according to a new study based on data from the Transthyretin Amyloidosis Outcomes Survey (THAOS).¹

ATTR amyloidosis is a heterogeneous disease characterized by transthyretin amyloid fibril deposition throughout the body. It may occur in people with hereditary or wild-type TTR, the gene that encodes transthyretin.¹

Clinical presentations of ATTR amyloidosis include predominantly neurologic, predominantly cardiac, or mixed phenotypes, which vary by age of onset, disease penetrance, and geographic location. More than 130 ATTR variants have been described, with V30M accounting for approximately 70% of them. For individuals with less common ATTR variants, information is limited regarding the natural history of disease.¹

For the current study, an international team of researchers aimed to better characterize the disease phenotypes associated with 4 relatively less common variants: F64L, I68L, I107V, and S77Y. The findings were recently reported in PLoS ONE.¹

The Transthyretin Amyloidosis Outcomes Survey

THAOS is an ongoing, global, longitudinal observational study of patients with ATTR amyloidosis that includes those with hereditary ATTR, wild-type ATTR, and asymptomatic TTR variant carriers. THAOS collects data regarding the natural history of ATTR amyloidosis to better characterize the disease, and in turn, to improve diagnosis and management.

The current analysis was conducted using THAOS data from untreated, symptomatic patients who had 1 of 4 variants (F64L, I68L, I107V, or S77Y) and were enrolled in the study between its start in 2007 and the data cutoff of January 4, 2022. 

Patients were considered symptomatic if they had not previously received treatment with tafamidis and had at least 1 symptom rated by investigators as definitely related to ATTR amyloidosis. 

Phenotypes

Neurologic impairment was evaluated using the Neuropathy Impairment Score in the Lower Limbs (NIS-LL), with higher scores indicating worse impairment, and the modified Polyneuropathy Disability (mPND) score, with higher scores indicating worse disability. For mPND, I indicates lower limb sensory disturbance with preserved ambulation, II indicates ambulatory impairment without the need of a walking stick, IIIa indicates the need for a single walking stick or crutch, IIIb indicates the need for two walking sticks or crutches, and IV indicates confinement to a wheelchair or bed.

Quality of life was evaluated using the Karnofsky Performance Status score (range 0% to 100%) and the EQ-5D-3L (range <0 to 1), with lower scores indicating worse impairment. 

Predominantly neurologic phenotypes were those in which patients had neurologic symptoms or gastrointestinal symptoms and no electrocardiographic rhythm disturbance, heart failure, or dyspnea. In contrast, predominantly cardiac phenotypes were those in which patients had evidence of rhythm disturbance on electrocardiogram, heart failure, or dyspnea, with no more than mild neurologic or gastrointestinal symptoms.

Symptomatic patients not meeting criteria for neurologic or cardiac phenotypes were classified as having an unknown phenotype.

What the investigators discovered

The F64L variant was present in 62 patients, of whom 46 (74.2%) had symptomatic disease. Most were males (67.4%), with 63.0% enrolled in Italy, 32.6% in the U.S., 2.2% in Brazil, and 2.2% in Argentina. At enrollment, the median age was 67.6 years, and patients had a median duration of symptoms of 5 years. 

The neurologic phenotype was most common (73.9%), with no predominantly cardiac phenotypes noted. Typical neurologic symptoms were numbness, tingling, and neuropathic pain/paresthesia. The median NIS-LL score was 23.6, and 40% of patients had an mPND score of 2 or higher. The median EQ-5D-3L score was 0.60, and slightly more than half (53%) of patients could care for themselves.

The I68L variant was found in 77 patients, of whom 45 were symptomatic and 77.8% were male. Most patients were from Italy (86.7%), with 8.9% from the U.S., 2.2% from Germany, and 2.2% from France. At enrollment, their median age was 69.3 years, and the median symptom duration was 3 years. 

In contrast to those with the F64L variant, individuals with the I68L variant had a predominantly cardiac phenotype (42.2%), with 26.7% having a mixed phenotype and 24.4% having a predominantly neurologic phenotype. mPND scores were I, indicating lower limb sensory disturbance with preserved ambulation, for 52.2% of those with a predominantly neurologic or mixed phenotype. The median EQ-5D-3L score was 0.83, with 68.3% of patients being able to care for themselves. 

Another variant that鈥檚 very common in men

The I107V variant was present in 33 patients, 21 (63.6%) of whom had symptoms at enrollment. This variant was associated with the highest proportion of male patients (85.7%). At enrollment, patients鈥� median age was 63.7 years, and the median symptom duration was 3.6 years. These cases were more geographically distributed, with 38.1% from France, 28.6% from Brazil, and the remaining one-third from Germany, Japan, or the U.S. 

The predominant phenotype among patients with the I107V variant was neurologic (42.9%); however, neurologic and mixed phenotypes were equally common (37.5%) in France, and mixed was the most common phenotype in Brazil (66.7%). The median NIS-LL score was 38.9, and 58.8% of patients with a predominantly neurologic or mixed phenotype at enrollment had an mPND score of II (ambulatory impairment but without the need of a walking stick) or higher. The median EQ-5D-3L score was 0.64, and nearly 41% of participants could care for themselves.

A closer look at the S77Y variant

The S77Y variant was present in 58 patients, of whom 29 (50%) were symptomatic at enrollment. Of these 29 patients, 72.4% were male. The median age at enrollment was 57.8 years, and the median symptom duration was 4.7 years. Patients were located primarily in France (55.2%), with smaller proportions in Israel (17.2%) and the U.S. (17.2%).

Most patients (55.2%) with the S77Y variant had the predominantly neurologic phenotype, with 31.0% having a mixed phenotype, 10.3% having an unknown phenotype, and 3.4% having a predominantly cardiac phenotype. Among those with a predominantly neurologic or mixed phenotype, 44.0% had a mPND score of I. The median EQ-5D-3L index score was 0.74, and 57.1% of patients were able to care for themselves. 

Room for more study

Most symptomatic patients with ATTR amyloidosis have wild-type disease or disease caused by V30M or V122I variants, and the corresponding phenotypes for these conditions have been fairly well described in the literature. However, phenotype characterization for the 25% of patients with the less common ATTR variants has been limited.

As for the current analysis, it may have suffered a bit from an overall small number of symptomatic patients (n=141) and the possibility of referral bias, which, the authors wrote, 鈥渕ay have impacted phenotype categorization.鈥�¹

Overall, however, this analysis of data from THAOS provides the largest evaluation of phenotypes to date for the F64L, I68L, I107V, and S77Y genotypes. The study team concluded that these findings 鈥渆nhance the current understanding of the clinical profile of patients with these genotypes and emphasize the importance of comprehensive assessment of all patients.鈥�¹

Published: February 28, 2024