Hereditary transthyretin amyloidosis (ATTRv) occurs worldwide and is caused by over 140 pathogenic variants in the TTR gene [1]. These variants produce mutant transthyretin proteins, prone to misfolding, and forming amyloid deposits of insoluble fibrils in the organs and tissues. ATTR amyloidosis results in a rapid onset, relentless multisystemic decline, and death within 6–10 years of diagnosis [1]. In endemic areas, patients can often recall the early deaths of blood relatives with similar symptoms of polyneuropathy, cardiomyopathy, and autonomic dysfunction through multiple generations.

In recent years, the landscape for patients with ATTR amyloidosis has advanced rapidly thanks to small molecule stabilizers and mRNA silencers. ATTRv amyloidosis is unique because it has more mRNA silencer therapies with FDA approval than any other condition. However, like all proteinopathies, patients with ATTR amyloidosis benefit from early intervention to safeguard their health and maintain function. This poses a challenge in clinical practice as the disease is heterogeneous, and the initial symptoms may vary or be misattributed to other common causes, such as diabetic neuropathy. As a result, diagnosis can be delayed by 3–4 years [1]. These diagnostic delays have a serious impact on a patient’s functional and vital prognosis, hence they are not insignificant.

Through awareness and more accessible genetic testing, the community of asymptomatic carriers with pathogenic ATTR variants is growing. Yet, the decision to start treatment remains complex and uncertain when it comes to prevention. Although autosomal dominant, ATTR penetrance can vary by variant, ethnicity, and geographical loci. Some carriers may never develop the disease or live symptom-free until their 70s, whereas others see the onset of rapid neurological decline in their 30s. Although there are some excellent reviews with experts’ opinions, there is currently no agreed-upon accurate early biomarkers indicating illness beginning in the prodromal phase. This “wait and see” approach creates understandable frustration, especially for families with highly penetrant variants linked to young-onset disease.

Autonomic dysfunction is very prevalent in ATTR amyloidosis, to varying degrees, but usually early in the course of the disease. This presents a unique window of opportunity to use autonomic biomarkers as signs of disease onset. Patients with ATTR amyloidosis can present with erectile dysfunction, alternating diarrhea and constipation, nausea, vomiting, delayed gastric emptying, anhidrosis, and urinary retention or incontinence. Autopsied cases showed prominent amyloid deposits in the organs and at various levels throughout the sympathetic nervous system within the choroid plexus, posterior and anterior roots of the spinal cord, and spinal ganglia [2]. The vagus nerve shows massive amyloid deposits and degenerative changes [1, 2].

In this issue of Clinical Autonomic Research, Guaraldi et al. [3] use standardized cardiovascular autonomic function tests in a cohort of 37 patients that were carriers of various genetic variants associated with neuropathic, cardiac, and mixed phenotypes. Around half of the subjects were carriers without clinical evidence of disease. Despite this, autonomic function tests revealed that a high majority (74%) had at least one autonomic function test score below the level of age-matched healthy non-carrier controls. Many of these deficits did not rise to the level of clinical significance and symptoms. Around one-third without polyneuropathy had a slow pressure recovery time after the Valsalva. The difference was most striking when it came to cardiac autonomic markers. Heart rate responses to the cold pressor test and hand grip exercise were both blunted. Importantly, they appeared to worsen in the group with polyneuropathy, suggesting this may also be a marker of both disease onset and progression.

The findings are fascinating because they imply that the absence of reflex bradycardia and tachycardia may be early indicators of ATTR amyloidosis and that the sympathetic and parasympathetic nerves that innervate the heart may be affected simultaneously or separately in the prodromal phases.

But before autonomic function tests can be deployed as a screening tool for amyloidosis onset, several hurdles need to be addressed. Currently, our knowledge of autonomic manifestations in ATTR amyloidosis is hampered by small sample sizes, which hasn’t yet allowed us to pinpoint which variants are most likely to have an early autonomic component. Furthermore, autonomic function tests of this nature are limited to specialist testing clinics, each with its own protocols, and often long waiting lists as the field of expertise is small. Interpreting the tests can also be difficult given the background of cardiac involvement with direct deposition of amyloid in the myocardium. All these considerations demonstrate the necessity of a more coordinated cooperative strategy among autonomic centers caring for amyloidosis patients. Significant first steps would be the adoption of standardized testing procedures and a shift toward data sharing.

The study by Guaraldi et al. [3] should perhaps also prompt us to renew our emphasis on finding sensitive autonomic measures that can be obtained from wearable devices and deployed as low-cost screening tools. Heart rate is tracked by most smartwatches, albeit sampled at various frequencies. Unfortunately, no approved devices can accurately obtain beat-to-beat blood pressure at home. This leaves us in the dark about the sympathetic vascular component of the baroreflex arch. We are also unlikely to be able to precisely quantify autonomic function from passive data without additional meta-data that allows precise correlation of a person’s position, activity level, meal time, and sleep–wake cycle – at minimum. This would require processing long noisy data streams and significant machine learning.

Nonetheless, this study from an expert group encourages us to explore ways we can guide our patients through a home version of an autonomic function test protocol. Essentially, collecting autonomic measures with at-home devices that prompt the patients to blow against a closed glottis, breathe at a fixed slow rate, forcefully grippe an object, or place an icepack on the forehead routinary. This may be difficult, but not impossible, and considerably cheaper than imaging studies. The availability of these home tests could potentially be a game changer for screening a broad range of neurological diseases.

Importantly, the study raises awareness about the usefulness of autonomic measures in the early detection of hereditary ATTR amyloidosis. Autonomic dysfunction differentiates ATTR amyloidosis neuropathy from other adult-onset progressive neuropathies as it typically accompanies sensory deficits early in the course of the disease [4]. The study highlights that the timely detection of autonomic neuropathy is crucial for early treatment. Carriers of the ATTR variants may profit by having trustworthy techniques to monitor their autonomic status and capture objective markers of disease onset, enabling them to benefit from the new therapies sooner, shifting the standard of care in symptomatic patients toward preventative medicine.