Split hand and motor axonal hyperexcitability in spinal and bulbar muscular atrophy

Abstract

ObjectiveThe ‘split hand’ sign refers to preferential wasting of the thenar and first dorsal interosseous muscles with relatively sparing of the hypothenar muscles in amyotrophic lateral sclerosis (ALS) and both cortical and spinal/peripheral excitotoxic mechanisms have been proposed. We aimed to study split hand and axonal excitability in spinal and bulbar muscular atrophy (SBMA) in which cortical motor neurons are intact.MethodsIn 35 patients with genetically confirmed SBMA, 55 with ALS, 158 with other neuromuscular diseases and 90 normal controls; split hand was strictly determined by amplitudes of compound muscle action potentials. Nerve excitability testing of median motor axons was performed in 35 SBMA and 55 patients with ALS and 45 normal controls.ResultsSplit hand was as frequently found for patients with SBMA (57%) and ALS (62%), compared with disease (20%) and normal (0%) controls. Excitability testing showed that in both SBMA and ALS, strength-duration time constant was longer, and threshold changes in depolarising threshold electrotonus and superexcitability in the recovery cycle were greater than in normal controls (p<0.01).ConclusionsSplit hand is not specific to ALS and can be caused by the peripheral mechanism alone in SBMA, whereas the effect of upper motor neuron lesion cannot be excluded in ALS. Our results also suggest that SBMA and ALS share common axonal excitability changes; increased nodal persistent sodium and reduced potassium currents that may accelerate motor neuronal death and differently affect axons-innervating different muscles. Ion channel modulators could be a therapeutic option for both SBMA and ALS.

Fatigue and activity-dependent conduction block in neuromuscular disorders

“…Briefly, the excitability properties of CIDP were characterized by greater threshold changes in threshold electrotonus, presumably due to decreased myelin resistance by demyelination ( Cappelen-Smith et al, 2001 ). Patients with SBMA showed longer SDTC, suggesting increased persistent nodal sodium currents, possibly due to collateral sprouting ( Shibuya et al, 2020 ), consistent with previous reports.…”

Split-hand and split-limb phenomena in amyotrophic lateral sclerosis: pathophysiology, electrophysiology and clinical manifestations

“…Although split-hand syndrome is primarily associated with ALS, split-hand has been observed in other conditions, such as spinal muscular atrophy (SMA), spinocerebellar ataxia type-3, Kennedy's disease (SBMA) or postpolio syndrome. [11][12][13][14] A recent study suggested that the split-hand syndrome may be a feature of SBMA, although this finding was discordant when compared with a previous study from this group. 4 14 'Reverse split-hand syndrome', which refers to the predominant wasting of ADM and the relative sparing of APB, may suggest the diagnosis of Hirayama disease (HD) in the appropriate clinical context (box 1).…”

Mexiletine in spinal and bulbar muscular atrophy: a randomized controlled trial

“…Low temperatures slow the kinetics of the Na/K‐pump due to a reduction in its ATPase activity, leading to slow conduction velocity and muscle weakness 11,37,38 . Electrophysiological studies have suggested that upregulation of persistent nodal sodium conductance causes changes in axonal excitability, leading to motor neuron death 39 . Similarly, the depolarization of muscle fibers depends on the influx of Na+ ions; therefore, lower temperatures prolong the depolarization of each muscle fiber.…”

“…11,37,38 Electrophysiological studies have suggested that upregulation of persistent nodal sodium conductance causes changes in axonal excitability, leading to motor neuron death. 39 Similarly, the depolarization of muscle fibers depends on the influx of Na+ ions; therefore, lower temperatures prolong the depolarization of each muscle fiber. In a biological study, immunofluorescence revealed downregulation of CLCN1 protein in the muscles in a knock-in mouse model of SBMA, leading to abnormal sodium currents.…”