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Differences in motor and sensory axonal excitability have been observed between those with and without large fiber neuropathy in hereditary transthyretin amyloidosis polyneuropathy (ATTRv-PN), a new study has shown.¹ Antonia S. Carroll, MD, PhD(cand), with the University of Sydney, in Australia, and colleagues reported their findings in Clinical Neurophysiology.¹

ATTRv-PN is an autosomal dominant, progressive disease characterized by median nerve tenosynovial compression causing carpal tunnel syndrome and lumbar nerve compression causing spinal canal stenosis.¹ Affected patients experience autonomic dysfunction, neuropathic pain, sensory ataxia, and progressive muscle atrophy.¹

Recent treatment advances for ATTRv-PN include gene editing and silencing therapies to reduce hepatic transthyretin production and consequent amyloid deposition.¹

Questions remain, however, about the proper timing of treatment initiation, because current therapeutic approaches are initiated following documentation of neuropathy, which indicates the presence of axonal loss that may be irreversible.¹

The aim of the current study was to identify a biomarker for ATTRv-PN that could help clinicians identify axonal dysfunction non-invasively prior to the onset of irreversible neuropathy.¹

Clinical and neurological assessments

Consecutive patients with a neuropathic ATTRv variant were recruited from the Westmead Amyloidosis Centre in Sydney, Australia. Health, age- and sex-matched controls were recruited from the Westmead Hospital and Brain and Mind Centre, also in Sydney.

Patients with ATTRv variants underwent evaluation with a medical history, family history, body mass index, and clinical staging evaluations using various neuropathy scales. The Familial Amyloidotic Polyneuropathy stage (0 to 3, with higher scores indicating more affected), Polyneuropathy Disability score (0 to 4, with greater score indicating more affected), Karnofsky Performance scale (0 to 100, with greater score indicating less affected). Disease duration, and time to disease onset (in comparison with earliest onset in family) were calculated.

Neuropathy was also assessed using the extended Medical Research Council power grading score (0 to 150, greater score indicating less affected), Overall Neuropathy Limitations Scale (0 to 12, greater score indicating more affected), Neuropathy Impairment Score lower limb subscale (0 to 88, greater score indicating more affected), Rasch-modified CMT Neuropathy score version 2 (0 to 36, greater score indicating more affected), and INCAT sensory sum score (0 to 33, greater score indicating more affected).

Nerve conduction studies were performed on median, ulnar, radial, sural, and superficial peroneal sensory nerves as well as median, ulnar, common peroneal, and tibial motor nerves. Patients were also categorized based on the presence or absence of large fiber neuropathy. Axonal excitability studies were conducted on both motor and sensory axons of the right ulnar nerve.

Patients were grouped as having large fiber neuropathy, not having large fiber neuropathy, or asymptomatic carriers. Age- and sex-matched controls had no evidence of neuropathy.

Observations

Of the 22 participants with an ATTRv variant, 10 had large fiber sensorimotor neuropathy, two had large fiber sensory neuropathy, five had small fiber and autonomic neuropathy, and five were asymptomatic. Median neuropathies were present at the wrist in 11 patients bilaterally and in three patients unilaterally.

Compared with controls, peak ulnar compound muscle action potential latency was prolonged in those with ATTRv. Hyperpolarizing threshold electrotonus and hyperpolarizing slope were also reduced compared with controls; this difference suggests increased accommodation to hyperpolarization in those with ATTRv. Reduced threshold changes across hyperpolarizing threshold electrotonus measures were also noted in the large fiber neuropathy group. At the -40% threshold, threshold electrotonus differed by ATTRv genotype.

Ulnar nerve sensory peak responses were reduced in those with ATTRv compared with controls, as was subexcitability with single and double conditioning pulses. The peak sensory amplitude was also reduced in those with large fiber neuropathy compared with those without large fiber neuropathy.

Both motor and sensory excitability were correlated with clinical severity and prognosis. Refractoriness at 2.5 ms was correlated with familial amyloidotic polyneuropathy stage, modified body mass index, and Neuropathy Impairment Score lower limb scale score, whereas subexcitability was correlated with Polyneuropathy Disability score and modified body mass index. In sensory axons, subexcitability was also correlated with Neuropathy Impairment Score lower limb scale score.

Interpretation

The researchers explained that differences in axonal excitability patterns between patients with and without large fiber neuropathy suggests that membrane excitability changes occur over time in patients with ATTRv-PN. 

鈥淭his study suggests that there are progressive changes in motor and sensory axonal excitability parameters across the disease spectrum,鈥� wrote the authors. Researchers interpret these findings to mean that these axonal changes are associated with disease progression. 

Additionally, the progressive nature of these changes indicate that changes in axonal membrane and channel function occurs early, prior to the onset of large fiber involvement. Thus, these axonal changes have 鈥渢he potential to be used as an early biomarker of transition from asymptomatic carrier to early disease stages.鈥�

Though interindividual excitability is highly variable, individual excitability is relatively stable outside of the disease process. Thus, longitudinal assessment of axonal excitability may help guide treatment initiation with disease modifying therapy and monitor treatment response.

Published: March 20, 2024