QST enables pre-symptomatic carriers of ATTRv to receive disease-modifying treatment

Hereditary transthyretin amyloidosis (ATTRv) is manifested as the mutation of the transthyretin (TTR) gene which creates deposits of amyloid fibrils in various organs of the body. Late onset (above the age of 50) ATTRv amyloidosis is characterized by primarily loss of large nerve fibers, while the small nerve fibers are partially spared. According to Canciello et al. the life-expectancy from disease diagnosis stands at 4-15 years (Canciello, 2022).

Treatment for ATTRv

Until recently, the only treatment available for ATTRv was liver transplant. Since TTR is mainly produced in the liver, a transplanted healthy liver would be able to produce less TTR mutations and thus, slow the disease progression down. In the last decade, disease modifying drugs have been introduced for the treatment of ATTRv amyloidosis, together with the understanding that this multifactorial disease should be diagnosed as early as possible in order to limit damage as much as possible (Russo, 2020). Asymptomatic carriers who are not yet eligible for disease modifying treatment could be treated as soon as the first symptoms of neuropathy would start to appear.

Is quantitative sensory testing sensitive

pre-symptomatically?

Quantitative sensory testing (QST) is considered a sensitive non-invasive test for neuropathy. Thermal QST, which assesses the functionality of small nerve fibers, has been shown to be able to distinguish diminishing sensory nerve function in pre-symptomatic phases in other conditions like diabetic neuropathy, glycemic disorder or metabolic syndrome (Tin, 2019; Lysy, 2014; Farooqi, 2016).

Predicted age-of-onset and quantitative sensory tests

Tozza et al. (Tozza, 2022) reported recently from their experience in QST on asymptomatic ATTRv carriers in Naples, Italy. QST was also performed on 55 healthy subjects which would serve as a reference for the norm values. A computed Z-scored compared to the healthy norm of Z>2 or Z<-2 was considered abnormal. QST consisted of thermal thresholds using Medoc’s TSA-II; cold sensation threshold, warm sensation threshold, cold pain threshold and heat pain threshold using the Limits Method. Testing was conducted on the foot, leg, thigh and hand. For tactile sensation calibrated monofilaments were used. Predicted Age of Onset (PADO) and time-to-PADO were calculated, based on demographic data collected.

Differences between asymptomatic carriers and

healthy controls

Fourteen asymptomatic carriers from eleven different families were recruited, who showed no symptoms of ATTRv and had normal nerve conduction study results. Nine had the Val30Met mutation, while 5 had the Phe64Leu mutation. Time to PADO was in average 10.8 years. All study subjects had at least one abnormal thermal QST result compared to the healthy cohort. The body site in which deviant results were most frequently found was the foot, and least frequently het hand or thigh. The modality in which most abnormal results were found was cold detection threshold, and the modality with least frequent findings was heat pain.

Can we find differences as we near the predicted

age of onset?

Post-hoc analysis of the QST data of carriers vs. healthy cohort, sub-divided in between PADO > 10 years and PADO ≤ 10 years, revealed a significant difference between the both PADO groups and the healthy controls for thermal thresholds, but not for the tactile thresholds. Within the carrier cohort there was also a significant difference in thermal QST results between the two PADO groups: specifically for cold detection and cold pain at the foot, cold pain at the leg and thigh, warm detection, cold pain and heat pain at the hand.

Should QST be used in screening ATTRv carriers?

Even though ATTRv has in the past been described as primarily affecting the large myelinated sensory fibers, in this study all carriers were normal in nerve conduction studies, the gold standard for large fiber testing,. Conversely, in thermal QST in which small fibers are tested, all carriers had at least one deviant test result. This could point to early changes in small fiber function while large fibers, as tested using the monofilaments, appear to have intact function at the preclinical stage.

The body site most differentiating between the PADO phases was the hand, as there differences could be found in most several sensory modalities.

In asymptomatic carriers, for whom according to the consensus statement at least two instrumental findings are needed in order to commence with disease modifying treatment (Conceição, 2019), QST could mean at least one step to advance toward disease modifying, and hopefully life-altering treatment.