Impaired sensorimotor control of the hand in congenital absence of functional muscle spindles

Abstract

Patients with hereditary sensory and autonomic neuropathy type III (HSAN III) exhibit marked ataxia, including gait disturbances. We recently showed that functional muscle spindle afferents in the leg, recorded via intraneural microelectrodes inserted into the peroneal nerve, are absent in HSAN III, although large-diameter cutaneous afferents are intact. Moreover, there is a tight correlation between loss of proprioceptive acuity at the knee and the severity of gait impairment. We tested the hypothesis that manual motor performance is also compromised in HSAN III, attributed to the predicted absence of muscle spindles in the intrinsic muscles of the hand. Manual performance in the Purdue pegboard task was assessed in 12 individuals with HSAN III and 11 age-matched healthy controls. The mean (±SD) pegboard score (number of pins inserted in 30 s) was 8.1 ± 1.9 and 8.6 ± 1.8 for the left and right hand, respectively, significantly lower than the scores for the controls (15.0 ± 1.3 and 16.0 ± 1.1; P < 0.0001). Performance was not improved after kinesiology tape was applied over the joints of the hand. In 5 patients we inserted a tungsten microelectrode into the ulnar nerve at the wrist. No spontaneous or stretch-evoked muscle afferent activity could be identified in any of the 11 fascicles supplying intrinsic muscles of the hand, whereas touch-evoked activity from low-threshold cutaneous mechanoreceptor afferents could readily be recorded from 4 cutaneous fascicles. We conclude that functional muscle spindles are absent in the short muscles of the hand and most likely absent in the long finger flexors and extensors, and that this largely accounts for the poor manual motor performance in HSAN III.

NEW & NOTEWORTHY We describe the impaired manual motor performance in patients with hereditary sensory and autonomic neuropathy type III (Riley-Day syndrome), who exhibit congenital insensitivity to pain, poor proprioception, and marked gait ataxia. We show that functional muscle spindles are absent in the intrinsic muscles of the hand, which we argue contributes to their poor performance in a task involving the precision grip.

INTRODUCTION

Hereditary sensory and autonomic neuropathy type III (HSAN type III), also known as Riley-Day syndrome or, more commonly, familial dysautonomia, is an autosomal recessive genetic mutation on chromosome 9q that causes a deficiency of IκB kinase complex-associated protein (IKAP; Anderson et al. 2001; Blumenfeld et al. 1993; Slaugenhaupt et al. 2001). The systems affected in the phenotype are diverse, with many sensory systems exhibiting deficits (for review see Axelrod 2002; Norcliffe-Kaufmann et al. 2017). Affected individuals develop a progressively ataxic gait, ultimately requiring walking aids. The cause of the ataxia is not known: muscle tone and strength are normal, and there is little evidence of cerebellar atrophy (Axelrod et al. 2010; Brown et al. 1964; Cohen and Solomon 1955; Yatsu and Zussman 1964). Tendon and H-reflexes are absent (Aguayo et al. 1971; Macefield et al. 2011; Mahloudji et al. 1970; Riley 1974), and recent work from our laboratory has shown that functional muscle spindle afferents, as recorded via intraneural microelectrodes inserted into muscle fascicles of the common peroneal nerve, are absent (Macefield et al. 2011). Compared with the ongoing neural activity one encounters when impaling muscle fascicles of this nerve in healthy subjects, the complete neural silence in these muscle fascicles was striking; not only was spontaneous and stretch-evoked muscle afferent activity completely absent, so too were the spontaneous and evoked bursts of muscle sympathetic nerve activity (MSNA) one normally encounters (Macefield et al. 2013b). Given that muscle spindles provide our primary source of proprioceptive information (Macefield and Knellwolf 2018; Proske 1997; Proske and Gandevia 2009, 2012), although cutaneous afferents can contribute (see below), the lack of muscle spindles may largely account for the disturbed proprioception, as measured by passive joint-angle matching at the knee (Macefield et al. 2013a). Indeed, we recently demonstrated a tight linear relationship between loss of proprioceptive accuracy and the severity of gait impairment, and argued that the ataxia seen in these individuals is of the sensory, rather than central, type (Macefield et al. 2013a). However, despite an absence of functional muscle spindle afferents, at least in the leg, proprioception was not affected equally in all; a few individuals exhibited almost normal proprioceptive acuity (Macefield et al. 2013a).

Interestingly, despite the marked absence of ongoing afferent activity in muscle fascicles of the common peroneal nerve, microelectrode recordings from cutaneous fascicles revealed apparently normal tactile afferent activity (Macefield et al. 2011). We reasoned that those few individuals with essentially normal proprioception at the knee may be relying more on proprioceptive information from the skin: it is known that cutaneous afferents can provide signals of joint movement in the hand (Burke et al. 1988; Collins et al. 2005; Edin 1992, 2004; Hulliger et al. 1979), ankle (Aimonetti et al. 2007, 2012), and knee (Edin 2001), with the slowly adapting type II (SA II) and type III (SA III) (Edin 2001) afferents, both of which are sensitive to skin stretch, being the most likely candidates responsible for signaling joint movement and position (Chambers et al. 1972; Edin 1992, 2001, 2004). Indeed, we recently showed that increasing signals of tensile strain in the skin, by applying longitudinal strips of elastic tape across the anterior and posterior aspects of the knee joint, improved proprioception in HSAN III, apparently making up for the loss of muscle spindles in these individuals (Macefield et al. 2016). What is not known is whether increasing tactile afferent feedback can improve motor performance. Moreover, although we assume that muscle spindles are absent throughout the body in HSAN III, without data from other sites this remains conjecture.

The aim of this study was to assess motor performance in the upper limb in patients with HSAN III and to determine whether muscle spindles are absent in the upper as well as lower limbs in these patients. Specifically, we used a standard test of manual dexterity, the Purdue Pegboard Test, to assess hand function. Participants use their thumb and index finger to pick up pins from a well and place them sequentially in holes in a pegboard. Performance in the set of tasks is based on the number of pins placed in a set time, using one or both hands and using each hand alternately. The test has been used clinically to demonstrate reductions in manual dexterity in, for example, carpal tunnel syndrome (Amirjani et al. 2011), and Parkinson’s disease (Růžička et al. 2016), and to document improvements in manual motor performance in older individuals following muscle training (Kornatz et al. 2005) or following pallidotomy in patients with Parkinson’s disease (Jankovic et al. 1999). In addition, based on the prediction that increasing tactile afferent feedback would improve manual performance in HSAN III, we repeated these tasks after applying longitudinal strips of elastic adhesive (kinesiology) tape over the joints of the hand, elbow, and shoulder. Finally, given that these tasks require use of the precision grip between thumb and index finger, we attempted to record from muscle spindles supplying the intrinsic muscles of the hand.

MATERIALS AND METHODS

Twelve patients (8 women, 4 men) with HSAN III and a mean (±SD) age of 26.1 ± 6.1 yr were recruited from the database of the Dysautonomia Center, where the initial diagnoses had been performed in infancy or early childhood. All patients had a genetic mutation of chromosome 9q with molecular confirmation of diagnosis. All patients had an ataxic, broad-based gait but were not confined to a walking aid, such as a walker or wheelchair, and had a positive Romberg sign (loss of balance when standing with eyes closed) and absent tendon and H reflexes in the upper and lower limbs, as described previously (Macefield et al. 2011). For comparison, 11 age-matched healthy control participants (7 women, 4 men; age 26.2 ± 4.1 yr) were also studied. All participants gave informed written consent to the procedures, which were approved by the Institutional Review Board of the New York University Medical Center. All studies were performed in accordance with the Declaration of Helsinki. For all experimental procedures the participants were seated.

Assessment of manual motor performance.

The Purdue Pegboard (Lafayette Instrument, Lafayette, IN) was used to assess motor performance of the hands. This requires participants to use a precision grip between thumb and index finger to pick up a small metal cylinder (pin), with a length of 25 mm and diameter of 2.5 mm, from a shallow well and insert it into a hole of the same diameter in the pegboard, which is composed of 2 rows of 25 holes, each separated by 10 mm. Participants had to pick and place the maximum number of pins in 30 s by using the right hand to insert them into the right column of holes and then repeat the procedure using the left hand. The procedure was then undertaken with participants using the right and left hand concurrently, placing the pins in two parallel rows of holes. Finally, the participants were instructed to 1) pick up a pin and place it in a hole with the right hand, 2) pick up a washer with the left hand and place it over the pin, 3) pick up a collar and place it over the washer with the right hand, and then complete the assembly by 4) placing a washer on the collar using the left hand; 60 s were allowed for this task. For each task the score was simply the number of pins placed in the required time. Naturally, subjects could see the pegboard and performed all tasks with vision.

Following completion of all pegboard tasks, 10 × 5-cm strips of adhesive kinesiology tape (RockTape, Campbell, CA) were applied longitudinally to the dorsal and palmar surfaces of both hands, extending across the wrist, as well as across the anterior and posterior aspects of the elbow joints and on the lateral surface of the shoulder joints on both sides. The elasticity of the tape is unidirectional, which allows the tape to be stretched beyond its form at baseline, but only in the longitudinal axis. Before placement, the tape was stretched over the surface of the wrists, elbows, and shoulder to ensure the maximum possible tensile strain in the skin. A sham application was also made in which a 5-cm length of tape was placed horizontally across the dorsal surface of the wrist. All pegboard tasks were repeated either with the normal placement of the tape or in the sham condition, with the order of taping being randomized.

Microneurography.

In five patients, the ulnar nerve at the wrist was located by external electrical stimulation (0.2-ms pulses, 1 Hz, 1.5–3.0 mA; Stimulus Isolator; ADInstruments, Sydney, Australia). Intraneural recordings were made from muscle and cutaneous fascicles via tungsten microelectrodes (FHC, Bowdoin, ME) inserted percutaneously into the ulnar nerve. Impedances of the recording microelectrodes ranged from ~300 to 700 kΩ; an uninsulated tungsten microelectrode inserted subcutaneously 1 cm away served as the reference electrode. As described previously, at the level of the wrist, the ulnar nerve is composed of distinct fascicles that supply either muscles in the hand (with the exception of the 3 thenar muscles supplied by the median nerve) or skin of the hypothenar eminence, the little finger (digit V), or the medial side of the ring finger (digit IV; Burke et al. 1988; Gandevia et al. 1990; Macefield 2005; Macefield et al. 1990; McNulty and Macefield 2001). Muscle fascicles were identified according to the movements of the digits produced by intraneural stimulation at 10–20 μA; we know from experience that such currents indicate that the microelectrode tip is located within the fascicle. Cutaneous fascicles were identified by the absence of muscle twitches and reports of paresthesias projecting along the skin of the hypothenar eminence, digit V, or the medial aspect of digit IV. Neural activity was amplified (gain 20,000; bandpass 0.3–5.0 kHz) using an isolated amplifier (NeuroAmp EX; ADInstruments) and stored on computer (10-kHz sampling) using a computer-based data acquisition and analysis system (PowerLab 16SP hardware and LabChart 7 software; ADInstruments). Afferent activity was discriminated using Spike Histogram software (ADInstruments), and instantaneous frequencies were calculated. All statistical analyses were performed using Prism 6 for Macintosh (GraphPad Software). All data were normally distributed, so unpaired (between groups) or paired (within groups) t-tests were used; P < 0.05 was considered significant.

RESULTS

Assessment of manual motor performance.

Patients were rather clumsy when performing the pegboard tasks; there was a noticeable difficulty in picking up the pin from the well as well as difficulty in inserting the pin into the pegboard hole. The mean (±SD) pegboard score (number of pins inserted in 30 s) was 8.1 ± 1.9 and 8.6 ± 1.8 for the left and right hand, respectively, which was significantly lower than the scores for the controls (15.0 ± 1.3 and 16.0 ± 1.1; P < 0.0001). When participants were instructed to perform the task using both hands at the same time, the scores were 6.1 ± 1.8 for the patients and 12.6 ± 1.3 for the controls (P < 0.0001), significantly lower than when participants used either the left or right hand alone (P < 0.001). Scores for the assembly task, in which participants had to alternate between the left and right hand to construct a tower in 60 s, were also significantly lower in the patients (7.1 ± 2.0) than in the controls (19.7 ± 3.2; P < 0.0001). Across patients, performance in a given task was linearly correlated to performance in another task, with correlation coefficients ranging from 0.738 to 0.817 (P = 0.001–0.006). The same was true for the controls (0.710–0.816; P = 0.002–0.014) when using either one or both hands, but correlations were poorer when the assembly task was included (0.375–0.377; P = 0.057–0.256).

When kinesiology tape was applied to the anterior and posterior aspects of the hands and wrist, the anterior and posterior surfaces of the elbow, and the lateral aspect of the shoulder, there were no significant differences in manual dexterity of the patients when using the left and right hand separately, together or alternating when performing the assembly task. Likewise, taping had no effect on manual performance of the control participants. Mean data are shown for all conditions for patients and controls in Fig. 1. Given that longitudinal taping across the joints had no significant effect on performance in any of the tasks, it is not surprising that sham (horizontal) taping also had no effect.

Fig. 1.

Pegboard scores (means ± SD) during each of the tasks for the 12 patients with hereditary sensory and autonomic neuropathy type III (HSAN) and 11 age-matched controls (CTL), without and with kinesiology tape (+tape) applied longitudinally across the wrist, elbow, and shoulder joints and tape applied horizontally (+sham) across the wrist. Across all tasks, scores were significantly lower for the patients than for controls (P < 0.001), but there were no significant effects of taping for either the patients or controls.

Intraneural recordings from the ulnar nerve.

An attempt was made to record from muscle spindles within the intrinsic muscles of the hand in five patients. Intraneural stimulation at currents <0.02 mA evoked twitches in specific muscles. Eleven muscle fascicles were investigated, identified according to the type of movement and the digit moved: the third and fourth lumbricals (n = 4), abductor digiti minimi (n = 2), opponens pollicis (n = 2), first dorsal interosseous (n = 1), fourth dorsal interosseous (n = 1), and fourth palmar interosseous (n = 1). Recordings from three separate muscle fascicles were made in three patients, whereas the other two patients contributed only one fascicle each. Despite the clear muscle twitches evoked at these low currents, indicating that the tip of the microelectrode had impaled a muscle fascicle, there was no spontaneous neural activity in any of the fascicles. Moreover, palpation over the muscle bellies (or digital interspaces) and passive movements of the digits that would evoke stretch of the short muscle acting on that digit failed to evoke any sensory activity. Indeed, after palpation or stretch of the specific muscle failed to reveal any evoked activity, a systematic exploration of the entire hand was undertaken, with palpation of the thenar and hypothenar eminences and each digital interspace in turn, as well as extension, abduction, or adduction at the metacarpophalangeal joint of each digit. In addition, no spontaneous bursts of muscle sympathetic nerve activity could be detected in any of the muscle fascicles.

A recording of a muscle spindle secondary ending from a healthy control subject is shown in Fig. 2A. This ending, located in the fourth palmar interosseous muscle, was spontaneously active at rest, was unloaded during passive adduction of digit V (i.e., toward digit IV), and increased its discharge during passive abduction of digit V, which stretched the parent muscle, the adductor of digit V. Such spontaneous and stretch-evoked activity of muscle spindles can readily be found within muscle fascicles of the ulnar nerve at the wrist; its complete absence in patients with HSAN III is striking, as illustrated in a recording from the same fascicle in an HSAN III patient in Fig. 2B.

Fig. 2.

A: microelectrode recording from a muscle fascicle of the ulnar nerve, supplying the fourth palmar interosseous muscle, in a healthy control subject (unpublished data, Macefield VG). This muscle spindle secondary ending was spontaneously active at rest, and its firing rate could be decreased by passive movement of digit V toward digit IV, which unloaded the muscle spindle ending, and increased by passive abduction of digit V, which stretched the receptor-bearing muscle and hence loaded the muscle spindle. B: a recording from the same fascicle in a patient with hereditary sensory and autonomic neuropathy type III (HSAN III) failed to reveal any spontaneous or stretch-evoked afferent activity.

Unlike the complete neural silence we encountered when exploring muscle fascicles of the ulnar nerve, in four patients in whom cutaneous fascicles were explored, rich sensory activity from large myelinated axons could readily be found by stroking the skin of the innervation territory. Two fascicles supplied digit IV, one digit V, and one the skin overlying the hypothenar eminence. Figure 3 shows examples of unitary recordings from a cutaneous fascicle supplying digit IV in one HSAN III patient: a slowly adapting type I afferent (SA I) responding to repeated sustained indentations of one of three hotspots identified within its receptive field (Fig. 3A) and a fast-adapting type I afferent (FA I) responding to repetitive stroking across its receptive field (Fig. 3C). Note that both sensory endings could generate very high discharge frequencies, exceeding 200 Hz. Similar recordings from two control subjects are also shown in Fig. 3: an SA I afferent in the distal phalanx of the thumb (recorded from the median nerve) responding to punctate indentation over its hot spot (Fig. 3B) and an FA I afferent responding to stroking across its receptive field on the hypothenar eminence (Fig. 3D).

Fig. 3.

Microelectrode recordings from the cutaneous fascicle of the ulnar nerve supplying the medial aspect of digit IV in a patient with hereditary sensory and autonomic neuropathy type III (HSAN III). A: responses of a slowly adapting type I (SA I) afferent located on the finger pad during repeated and sustained indentations with a 1-mm probe of one of the hot spots within its receptive field. C: responses of a fast-adapting type I (FA I) afferent located on the middle phalanx during repeated back-and-forth stroking over its receptive field. B and D: similar recordings from 2 control subjects show responses of an SA I afferent in the distal phalanx of the thumb (recorded from the median nerve) responding to punctate indentation over its hot spot (B) and an FA I afferent responding to stroking across its receptive field on the hypothenar eminence (D).

Pain evoked by intraneural stimulation.

Interestingly, intraneural stimulation at intensities approaching 1 mA only ever induced paresthesias when the microelectrode was in a cutaneous fascicle, whereas intrafascicular currents much lower than this induce strong pain in neurologically intact subjects. This indicates that cutaneous nociceptors are essentially absent in HSAN III. Conversely, electrical stimulation within a muscle fascicle induced a deep dull ache at currents that would produce similar pain in intact individuals (>0.1 mA), indicating that muscle nociceptors are present in HSAN III. One patient also reported a local dull ache at the microelectrode insertion site, before the tip had impaled the fascicle.

DISCUSSION

We have documented that motor performance in the upper limb is poor in patients with HSAN III and also have shown that muscle spindle afferents appear to be absent in the upper as well as lower limbs in these patients. As described previously, our use of intraneural microelectrodes to record from a peripheral nerve allowed us to undertake “functional in vivo biopsy” of the territories supplied by the nerve (Macefield et al. 2011). We can now confirm that functional muscle spindle afferents are absent in the intrinsic hand muscles in HSAN III. We use the term “functional” to indicate that the muscle spindle endings may be present but either do not function or lack sensory innervation. It is likely that functional muscle spindles are also absent in other muscles of the upper limb, including the long flexors and extensors of the fingers and wrist, which are involved in the tasks of manual motor performance studied here. Indeed, although our previous microneurography study demonstrated that functional muscle spindles were absent in the ankle and toe extensor muscles (Macefield et al. 2011), the fact that proprioception at the knee was very poor (Macefield et al. 2013a) would support the conclusion that muscle spindles supplying the flexors and extensors of the knee were also absent. Thus, by examining the common peroneal nerve, and now the ulnar nerve, we can reasonably conclude that functional muscle spindles are absent from all limbs of patients with HSAN III.

Furthermore, it is not unreasonable to conclude that functional muscle spindles are absent throughout the body, which would fit with the embryological model of Hamburger and Levi-Montalcini (1949), in which muscle spindle afferents fail to develop because of the failed second wave of migration of neural crest cells from the dorsal root ganglion. It would appear that the preservation of cutaneous mechanoreceptors, established from the first wave of migration, accounts for the normal tactile sensibility in HSAN III, whereas failure of the second wave of migration accounts for the loss of temperature and pain sensitivity in the skin as well as the loss of muscle spindles. Interestingly, mice with a specific genetic mutation that results in a deficiency in transcription factor EGR3, which prevents muscle spindles from forming, exhibit a waddling, uncoordinated gait and abnormal positioning of the limbs, suggestive of impaired proprioception (Tourtellotte and Milbrandt 1998). These mice also develop scoliosis, which is a common feature of HSAN III (Riley et al. 1954; Yoslow et al. 1971) and which suggests that muscle spindles in the axial musculature are also absent in HSAN III. Like these EGR3-deficient mice, another mouse model with spindle agenesis, produced by a deletion in the cytoplasmic dynein heavy chain 1 gene (Dync1h1), has a pure proprioceptive sensory neuropathy without any motor involvement (Chen et al. 2007). These animals also walk with an unsteady “jerky and wobbling gait” and splay their hindlimbs, again pointing to the importance of muscle spindles in both proprioception and gait.

Clearly, patients with HSAN III exhibited poor manual dexterity: they were rather clumsy at performing the Purdue Pegboard Tests and completed significantly fewer placements in these timed tests than the age-matched controls. Perhaps this is not surprising, but this is the first time that manual motor performance has been quantified in these patients. What is surprising from our results is that taping, which we would expect would increase sensory information from the skin, and clearly improved proprioception at the knee (Macefield at al. 2016), had no effect on manual motor performance. Although proprioception at the finger joints is impaired in HSAN III, at least as assessed clinically (i.e., qualitatively), we would have thought that manual motor performance could be improved by taping through an increase in proprioceptive acuity, as demonstrated at the knee (Macefield et al. 2016). The movements were relatively slow, yet subjects had to be accurate and to perform as many placements as possible in the time available. Of course, these were active movements, so perhaps there is a limit to how much sensory feedback from the skin can assist in performing these tasks. Moreover, unlike those rare cases of complete large-fiber sensory neuropathy, in which large-diameter cutaneous as well as muscle afferents are lost but small-diameter afferents are preserved (Cole and Sedgwick 1992; Lajoie et al. 1996), our patients had access to sensory input from the skin, which could potentially offer proprioceptive information. We know that unlike mechanoreceptors in the interphalangeal joints, those in the skin surrounding the joints can encode joint movements (Burke et al. 1988; Collins et al. 2005; Edin 1992, 2004; Hulliger et al. 1979). Moreover, we know that proprioceptive cues can be obtained from tactile afferents in the absence of changes in muscle (or joint) afferent input (Collins et al. 2005; Edin and Johansson 1995) and that essentially normal mechanoreceptors have been identified histologically in the skin of the fingers and toes (Pearson et al. 1971; Winkelmann et al. 1966). In the present study we could record from single FA I and SA I cutaneous afferents, and from our experience in recording from these afferents in healthy individuals, their behavior seemed absolutely normal: as shown in Fig. 3, tactile afferents with small receptive fields could generate very high instantaneous frequencies when mechanically stimulated at one of their hot spots, just as in the controls.

Small-diameter cutaneous afferents are reduced in HSAN III, such that cutaneous pain thresholds are elevated and patients exhibit a relative indifference to pain. None of our patients reported sharp or burning pain during high-intensity intraneural stimulation within cutaneous fascicles at currents that would be painful in healthy individuals; all they felt were “pins and needles” projected to the innervation territory of the fascicle. In other words, high-intensity electrical stimulation of large-diameter cutaneous afferents evoked paresthesias but, because of the apparent lack of small-diameter afferents, no cutaneous pain. We had reported the same in the common peroneal nerve (Macefield et al. 2011). Histological studies have shown that the sural nerve has a profoundly reduced complement of unmyelinated axons in HSAN III, as well as fewer myelinated axons and a reduced cross-sectional area of the nerve (Aguayo et al. 1971; Pearson et al. 1971). Moreover, we had previously shown that there is a reduction in amplitude of the compound sensory nerve action potential, and a small slowing of conduction velocity, of the sural and ulnar nerves, indicating that there is some loss of large-diameter cutaneous afferents in HSAN III; vibration thresholds are also elevated (Macefield et al. 2011). Nevertheless, despite this partial loss, those cutaneous afferents that remained did appear normal.

The purpose of the study was not to characterize the perception of electrically induced pain in the upper limb in HSAN III, but we nevertheless did confirm our earlier observations in the leg that individuals with HSAN III can feel muscle pain (Macefield et al. 2011). Unlike the absence of electrically evoked cutaneous pain in HSAN III, all patients reported pain when intraneural stimulation was delivered within muscle fascicles of the ulnar nerve, as we had also seen in the common peroneal nerve. These painful sensations were felt as a diffuse, poorly localized dull ache in the muscle belly, which often referred into the hand, suggesting that some small-diameter afferents may remain despite the apparent absence of large-diameter muscle afferents. Interestingly, in addition to a reduced density of nociceptive afferents in the skin, another class of unmyelinated cutaneous afferent, the C-tactile afferents, which mediate affective touch, were functionally absent or reduced in HSAN III when assessed in the forearm and leg (Macefield et al. 2014).

Limitations.

Although the findings of poor manual sensorimotor performance were obtained in only 12 patients with HSAN III, who clearly demonstrated poor manual dexterity, the microneurography data were obtained in only 5 patients. This is because many of the participants found it difficult to stay still for the nerve recording experiments, and some of those in whom we had made recordings from the common peroneal nerve a few years ago were reluctant to participate again in this part of the study. Nevertheless, the absolute neural silence we encountered when entering a muscle fascicle, which contrasted with the rich sensory activity one finds in intact individuals, was striking. Within each recording session, we sampled two or three separate muscle fascicles, and we were systematic in our search for spontaneous or stretch-induced afferent activity. Of course, we had also seen this lack of functional muscle spindles in recordings of the common peroneal nerve, in which we explored 21 muscle fascicles within 10 patients, so we do not feel that because we only recorded from the ulnar nerve in 5 patients this is a major weakness. It is highly unlikely that had we recorded from more patients we would encounter functional muscle spindle afferents; based on the principle of parsimony, the most likely explanation for our lack of recording muscle spindles in the intrinsic muscles of the hand in HSAN patients is that they are not present. Indeed, it is highly likely that they are absent throughout the body. Moreover, the absence of muscle afferent activity contrasts with the presence of rich cutaneous afferent activity during stroking of the skin of the fascicular innervation zone. In all patients we could record strong multiunit tactile afferent activity, and in one patient we also managed to impale two individual axons, one supplying an FA I afferent and the other an SA I afferent. Naturally, it was beyond the scope of this study to assess the firing properties of all large-diameter cutaneous afferents, which would require much longer and multiple recording sessions. However, as noted above, we do feel that the behavior of the cutaneous afferents we did record appeared to be normal.

Conclusions.

We have confirmed that motor performance of the hand in a precise sensorimotor task is impaired in HSAN III, which we attribute to the absence of functional muscle spindles and hence sensory feedback of their movements. Clearly, visual feedback was available but inadequate to allow the fine sensorimotor control required of the tasks. We were surprised that taping did not improve manual performance, because we had reasoned that an increase in feedback of tensile strain in the skin around the joints might have offset to some extent the loss of muscle length feedback from the muscle spindles. Unlike the extremely rare complete large-fiber sensory neuropathy, HSAN III provides a natural model in which to study proprioception and sensorimotor performance in a genetic mutation that selectively abolishes the sensory feedback provided by muscle spindles yet preserves that provided by mechanoreceptors in the skin.

GRANTS

This work was supported by the National Health and Medical Research Council of Australia Grant GTN1100038 (to V. G. Macefield).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

V.G.M. conceived and designed research; L.J.S. and V.G.M. performed experiments; L.J.S. and V.G.M. analyzed data; L.J.S., L.N.-K., J.-A.P., H.K., and V.G.M. interpreted results of experiments; V.G.M. prepared figures; L.J.S. and V.G.M. drafted manuscript; L.J.S., L.N.-K., J.-A.P., H.K., and V.G.M. edited and revised manuscript; L.J.S., L.N.-K., J.-A.P., H.K., and V.G.M. approved final version of manuscript.