Spinal And Bulbar Muscular Atrophy (SBMA):an Electrophysiological, Genetic And Correlation Study In Chinese Patients

Kennedy disease (KD) or spinal and bulbar muscular atrophy (SBMA) is a rare neurodegenerative disorder characterized by adult onset, slowly progressive, proximal limb muscular atrophy and bulbar involvement. Clinical or subclinical sensory disorder is not uncommon. The prevalence is around1/40,000-50,000men in western countries. SBMA is caused by a trinucleotide CAG-repeat expantion in the first exon of the androgen receptor (AR) gene on the X-chromosome (Xqll-12). Mutated AR gene leads to a cytotoxic elongation of polyglutamine tract in AR protein. Several studies have demonstrated an inverse relationship between the length of the CAG and GGC repeat and the transactivaton function as well as ligand-binding ability of AR. Further more, correlation was also found between CAG repeat size and electrophysiological changes.We made an electrophysiological and genetic study in46Chinese patients with SBMA. Among them,42underwent electrophysiological studies and43patients from different pedigrees had there CAG and GGC copies sequenced. The purpose of our studies was to find the hallmark in electrodiagnosis and differential diagnosis in Chinese SBMA patients. In addition, we analyzed the size of the CAG repeats and the polymorphism of GGC repeats to demonstrate the distribution, difference of distribution as well as allelic association of CAG and GGC repeats in normal controls and SBMA patients. Finally, possible influence factors of electrophysiological changes such as age, age at onset, course of disease and CAG/GGC size were also analyzed.Part Ⅰ:Characteristics of electrophysiological findings in SBMA patientsObjective:To demonstrate the characteristics of electrophysiological findings in SBMA patients as well as the difference in intrinsic hand muscle involvement in SBMA, ALS and Hirayama disease. Methods:Nerve conduction studies including F-wave and tibial H-reflex as well as needle EMG were performed in42patients with genetically confirmed SBMA and77normal control subjects.52ALS patients and75cases with Hirayama disease were recruited as disease control. We examined motor conduction in median, ulnar, peroneal and tibial nerve. Sensory conduction studies were done in median, ulnar, superficial and sural nerve. Needle EMG included muscles in all four lower motor neuron regions. Results:In the42patients, the average age at evaluation was51years (51.1±10.8years), age at onset44years (44.5±10.8years), mean disease course79.6±61.0months. Motor conduction velocities (MCV), compound muscle action potentials (CMAP), sensory conduction velocities (SCV) and sensory nerve action potentials (SNAP) were significantly decreased in all nerves in SBMA patients compared with the findings in normal controls. Latencies of F-wave and H-reflex as well as distal motor latencies were significantly prolonged. Decreased SNAP and CMAP amplitudes were found in92.9%and64.3%SBMA patients respectively. The extent of amplitude changes was more profound in SNAPs (21.3-34.6%of normal mean value) than in CMAPs (61.1-77.5%of normal mean value). The occurrence and extent of abnormal CMAPs were of no significant difference among the four nerves in upper and lower extremities while the decrease of SNAPs in superficial and sural nerve was more prominent than that in median nerve (P<0.05). Needle EMG revealed widespread chronic denervation and reinnervation in all the muscles in the four lower motor neuron regions including the masseter which is innervated by trigeminal motor nucleus. Patients with SBMA showed less selective change in intrinsic hand muscles. In ALS patients, APB was more severely involved compared with ADM while in patients with Hirayama disease, ADM was preferentially affected. Conclusion:The characteristics of electrophysiological findings in SBMA patients were widespread chronic neurogenic changes in the four lower motor neuron regions accompanied with/without sensory or motor conduction abnormalities. Sensory nerve conduction was more involved than motor nerve in terms of both occurrence and extent of electrophysiological abnormalities. Recognition of the hallmark of electrophysiological changes in SBMA patients will be very useful in the early diagnosis of SBMA and shorten the course between disease onset and gene analysis. It also proposes a new concept of electrodiagnosis of SBMA in areas where gene study is not available. Different pattern in intrinsic hand muscle involvement might also help in the early diagnosis and differential diagnosis among SBMA, ALS and Hirayama disease.Part Ⅱ:Size of the CAG repeats and the polymorphism of GGC repeats in ExonI of AR gene in Chinese SBMA patients and normal controlsObjective:To analyze the difference of distribution, polymorphism and allelic association of CAG and GGC repeats in Chinese SBMA patients and normal controls. Methods:(CAG)n and (GGC)n were sequenced in43unrelated SBMA X chromosomes and102control X chromosomes in Chinese males. Results:The normal group had an average CAG repeat number of23±3.2which was ranged from14-31and the most frequent size was22. The range of CAG repeat size in SBMA chromosomes was41-59with a mean of47.3±3.5and the most frequent copies were48and46. The controls had8different alleles of the GGC repeats with the range from13to20. In SBMA chromosomes four different alleles were seen. In both controls and SBMA patients, the most frequent repeat of GGC was17which account for73.4%in normal chromosomes and69.0%in SBMA. The most frequent CAG/GGC haplotype in controls was22/17(16.3%) and that in SBMA patients was46/17(16.7%). There was no allelic association between the CAG and GGC microsatellites among normal controls and SBMA patients. The (GGC)n distribution was significantly different between SBMA patients and control subjects.(GGC)14was more frequent in SBMA chromosomes than in normal chromosomes (P<0.01). Conclusion:The size and distribution of CAG microsatellites in Chinese normal controls and SBMA patients were similar with other Asian reports while were different with other racial. GGC repeats in both Chinese normal subjects and SBMA patients was different from other Asian countries and different racial.(GGC)14was more common in Chinese SBMA patients compared with normal controls.Part III Correlation study between (CAG)n/(GGC)n microsatellites and electrophysiological changes in Chinese SBMA patientsObjective:To study the influence factors of electrophysiological changes in SBMA patients especially the correlation between (CAG)n/(GGC)n repeat size and nerve conduction abnormities. Methods:Data derived from nerve conduction studies and clinical information such as the age, age at onset and the course of disease were recorded and analyzed from42SBMA patients. Results:CAG repeats correlated inversely with age, age at onset and correlated positively with the course of the disease (r=-0.503,-0.668and0.349respectively with P value<0.01and0.05). Among motor conduction studies, CMAP amplitude and motor conduction velocities correlated with both the course of disease and the age of patients while CAG size had no relationship with either amplitudes or velocities. Among the factors that influenced the sensory conduction, CAG copies correlated positively with SNAP amplitudes and sensory conduction velocities in median and ulnar nerve. A close relationship existed between age/age at onset and SNAP amplitudes in all four sensory nerves. Whiling controlling age and age at onset, partial correlation analysis failed to reveal a definite relationship between CAG length and sensory abnormities. Age and age at onset also correlated with median and ulnar sensory conduction velocities. A mild relationship was found between course of disease and conduction velocities in sensory nerves of lower limbs. Age of the patients was the main factor which influenced the elicitation of tibial H-reflexes. Although no significant difference of electrophysiological changes was found among3subgroups of SBMA patients with different GGC repeats, a tendency of decreasing CMAP amplitude with smaller GGC repeats was noticed especially in median nerve. Conclusion:Electrophysiological changes and correlation factors between motor and sensory involvement were different. Main influence factors for motor and sensory nerve conduction studies are course of the disease and age of the patient respectively. These findings might suggest differences in pathophysiological processes between motor and sensory neurons or their axons. Although closely correlates with the onset of the disease, CAG repeat size has no relation with any electrophysiological changes. GGC polymorphism might be a potential factor influencing clinical and electrophysiological phenotype in SBMA patients but further studies with larger patient samples are needed.