| BackgroundKennedy disease (KD), also known as spinobulbar muscular atrophy (SBMA), is a rare X-linked recessive hereditary disease, and was first described in detail by Kennedy WR. The prevalence of KD is underestimated to be1-2/100,000in the male population of Western European descent. Clinical presentations may first appear at the3rd-5th decade of the patient’s life. It is characterized by slowly progressive weakness and atrophy in extremities and bulbar, sensory abnormalities and androgen insensitivity. Weakness and waste in limbs can be variable, may present symmetric or asymmetric, proximal or distal prominent, upper limbs or lower limbs prominent. Sensory involvements can be mild or subclinical. Androgen insensitivity can be gynecomastia, testicular atrophy and decreased fertility. Plasma creatine kinase and androgen hormone may elevate to variable degrees. Survival duration in KD individuals after onset may be20-30years and lifespan can be normal or only mild shortened. A prominent feature of KD is sexual specificity. KD fully manifests only in males. While female individuals with disease gene are usually carriers, even female homozygous can only appear with subclinical presentations.In1991, La Spada first reported that the causative mutation of KD was the expansion of a C AG trinucleotide repeat which located on the first exon of androgen receptor (AR) of X chromosome q11-q12. The CAG repeats encode a polyglutamine tract (polyQ). The polyQ tract is polymorphic in length. It ranges between9and36residues in the normal individuals. The pathogenic expansion of CAG can reach38-62repeats. Expanded polyQ tracts form stable and unnative anti-parallel beta-strands which lead to the protein denaturation and result in the deposition of misfold protein into oligomers, microaggregates and inclusions. It was wildly decided the inclusions to be pathogenic. Latest studies give the proof that supports the ideas of inclusions to be protective species for KD patients and the oligomers and microaggregates to be indeed the true pathogenic species. The bindings between polyQ and androgen, usually testosterone and dihydrotestosterone, cause the protein conformational changes. And then, the receptors disassociate from heat shock proteins (Hsps) and translocate into nucleus, resulting in transcriptional disregulation of the hormone response gene. Leuprorelin is a luteinizing hormone-releasing hormone analog. It inhibits the release of gonadotropins from pituitary, followed by decreasing release of testosterone from testis, which resulting in reduction of testosterone in the serum. It protects motor neurons by inhibiting AR’s dislocation in nucleus. It has been reported that leuprorelin can ameliorate the function score and swallowing parameters. These results make it promising in the future treatment for KD individuals. Other agents have been reported remarkable reductions of degenerating motor neurons in KD mice and improvements of motor function by degrading or removing the pathogenic AR. They are17-allylamino-17-demethoxygeldanamycin(17-AAG),17-(dimethylamino-ethylamino)-17-demethoxygeldanamycin(17-DMAG), rapamycin, et al. Another agent,5-[4-(4-chlorobenzoyl)-1-piperazinyl]-8-nitroquinoline (B2), protects KD cells and mices by promoting the oligomers and microaggregates to transform into inclusions. These agents mentioned above provide new strategies for treatments of KD.Amyotrophic lateral sclerosis (ALS) is a motor neuron disease. The upper motor neurons and the lower motor neurons can be involved simutaniously or successively and aggravate progressively. The clinical presentations are usually progressive deteriorations in the extremities and bulbar. Prognosis of ALS patients is poor. Approximate60%of the ALS patients will have died within3years since first symptom appeared. Respiratory failure arising from the involvement of respiratory muscle is the major cause of death.Differential diagnoses between KD and ALS may be difficult in clinical practice when KD patients present atypical symptoms, such as the symptoms of upper motor neurons when they suffer KD combining other central nervous system diseases. It has been reported that some ALS patients present no upper motor neuron symptoms all across the course of the disease. This will increase the difficulties in making diagnosis. Besides, Saunderson RB, et al. do the KD gene tests for the individuals with upper motor neurons or lower motor neurons involved simultaneously or successively or isolately, the positive result is extremely low. KD’s misdiagnosis as ALS will bring huge mental burden on the patients and their families. Moreover, it is of great value to screen KD correctly from ALS-like diseases, which ensures patients get appropriate treatment and gene counseling.Numbers of electrophysiological studies have revealed a decreased amplitude of sensory nerve action potential (SNAP) in KD. There is only one report about electrophysiological comparison between KD and ALS. There are several domestic contrast descriptions for the two diseases but they didn’t compared KD and ALS statistically. Hence, we retrospectively analyzed the clinical features and muscle biopsies of KD in order to further study KD. In addition, we compared the electrophysiological studies between KD and ALS and tried to find the value of electrophysiology in discriminating KD for ALS, which could propose tips for patients whether they needed a gene test for KD.MethodsPart1The clinical presentations and electrophysiological characteristics of patients with Kennedy diseaseⅠ. Case recruitment:9cases of KD admitted to our hospital during Jan.2009to Dec.2013,13cases of ALS during Jan.2001to Dec.2013and26age-match cases with negative neurophysiological tests were recruited.8patients with KD accepted KD gene tests. And the tests revealed numbers that larger than40for the CAG repeats of the AR first exon of X chromosome q11-q12and established the diagnoses of KD. One individual didn’t have the gene test for KD, but the facts that he was an elder brother of one of the8genetically confirmed KD patients and he shared the similar symptoms with his brother supported the diagnosis of KD. The patients with ALS meet the criteria of EFNS guidelines for diagnosis and clinical care of patients and relatives.Ⅱ. Analyses of clinical data:Clinical data of KD individuals had been marked down and analyzed. Clinical symptoms were divided into4regions. They were brainstem, cervical spinal cord, thoracic spinal cord, lumber and sacral spinal cord.Ⅲ. Nerve conduction studies:Motor nerve conductions were tested on median nerves, ulnar nerves and peroneal nerves. And "split hand" phenomena were calculated. Besides, sensory nerve conductions were tested on median nerves and sural nerves.Ⅳ. Electromyography examinations:Needle electromyography tests were conducted on opponens pollicis, abductor digiti minimi, tibialis anterior and sternocleidomastoid muscles.Ⅴ. Statistical analyses:Measurement data were expressed as x±s. Mean among3groups were compared by using One-Way ANOVA analysis. Data which meeting the standard of homogeneity of variance between groups were compared using LSD-ANOVA, while data out of the standard were compared using Dunnett T-ANOVA. Enumeration data were demonstrated as percentages and used Fisher exact probability methods. P<0.05was defined as statistically significant. All data were analyzed by using SPSS13.0Software package.Part2Muscle pathological analyses of patients with Kennedy diseaseⅠ. Preparations for muscle biopsies:Informed consents with signature should be acquired from the patients. Blood coagulation, infectious index and other tests were needed to ensure that the surgery was safe for patients. Ⅱ. Muscle tissue getting:Muscle tissue with the size of soybean should be taken from the biceps or quadriceps or gastrocnemius according to the specific status of the patients.Ⅲ. Preprocessing of muscle tissues:Tissues taken from biopsy were immediately fixed, frozen and stored correctly.Ⅳ. Tissues sectioning:3continuous,9um thick cross-sections were sliced at the temperature between-28℃and-26℃.Ⅴ. Muscle sections staining:Continuous sections from patients were stained with HE, MGT and NADH sequentially and analyzed under the light microscope.Results:Part1Clinical symptoms and electrophysiological characteristics of patients with Kennedy diseaseⅠ. The age when patients admitted to our hospital ranged44-46years and the onset age ranged42-59years. Most of the cases first presented with weakness of extremities, while2cases first presented with the symptoms of bulbar involvements. The prevalence of tongue atrophy was100%in KD patients, while of facial fasciculation was88.9%.44.4%of the patients presented the symptoms of hoarseness, drinking cough and dysphagia.4out of9cases of KD combined other central nervous system diseases and appeared the signs of upper motor neurons.Ⅱ. Compound muscle action potential amplitudes of median nerves, ulnar nerves and peroneal nerves were much lower in patients with ALS than in patients with KD and than in the normal control. Differences were statistically significant. Difference of "split hand" phenomenon between amyotrophic later sclerosis and normal control was statistically significant as well.Ⅲ. The unelicited ratios of sural nerve sensory nerve action potentials in Kennedy disease was56.3%, in amyotrophic lateral sclerosis was0and in normal control was0. The unelicited ratios of sural nerve sensory nerve action potentials was statistically higher in Kennedy disease than in amyotrophic lateral sclerosis (P=0.000) and in normal control (P=0.000). The sensory nerve action potential amplitudes of sural nerve were apparently lower in Kennedy disease (7.9±3.4)uV than in amyotrophic lateral sclerosis (20.0±5.2)uV and than in normal control (26.1±16.8)uV. Differences were statistically significant.Ⅳ.The ratios of prolonged insertional potentials in opponens pollicis, abductor digiti minimi, tibialis anterior, as well as the ratios of fibrillation potentials and positive sharp waves were high in amyotrophic lateral sclerosis. Durations and amplitudes of muscle unit action potentials were also high in amyotrophic lateral sclerosis. The ratios of prolonged insertional potentials in opponens pollicis, abductor digiti minimi, tibialis anterior, as well as the ratios of fibrillation potentials and positive sharp waves were normal in Kennedy disease. While durations and amplitudes of muscle unit action potentials were high in Kennedy disease.Part2Muscle pathological analyses of patients with Kennedy disease6patients with KD had the muscle biopsies.4out of them revealed neurogenic changes dominant combing myogenic damages, while1case displayed myogenic changes dominant. Neurogenic changes were consist of muscle fiber grouping, target fibers or target-like fibers, scattered or small group of small angular or elongated atrophic muscle fibers, nuclear condensation, et al. Myogenic changes included fibers in various sizes, scattered hypertrophic fibers, catenary nuclear, cell degenerating and swelling, muscle fiber splitting, basophilic muscle fibers (regenerated muscle fibers), mild endomysium proliferating, type2muscle fiber dominant, inner nuclear proportion elevating.Conclusion:Clinical symptoms of patients with Kennedy disease express widely and mimic the symptoms of amyotrophic lateral sclerosis. Tongue atrophy and facial fasciculation may occur in the early course and mid-course of Kennedy disease. Plasma creatine kinase may mildly or moderately elevate. Muscle biopsies present neurogenic damages combining myogenic changes, sometimes combing metabolic changes. The unelecited ratios of sural nerve sensory nerve action potentials are high in Kennedy disease individuals. And a decreased sensory nerve action potential amplitude of sural nerve can help make the diagnosis of Kennedy disease. And the gene test of CAG repeat number of the first exon of androgen receptor in X chromosome q11-q12is needed and help confirm the diagnosis of Kennedy disease. |
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