The Relationship Between Genotype And Phenotype Of Chinese Kennedy Disease Patients And The Comparison Between The Clinical Features Of Kennedy Disease And Amyotrophic Lateral Sclerosis

Objective: To assess the genotype-phenotype correlation in Chinese patients with spinal and bulbar muscular atrophy(SBMA) and its clinical characteristics comparing with amyotrophic lateral sclerosis(ALS) patients.Methods: Clinical features of 155 identified Chinese patients with SBMA were retrospectively studied. Genomic DNA was extracted from peripheral blood. PCR amplifications were performed in exon 1 of AR gene. PCR products were directly sequenced to verify the specific number of CAG repeats. The results of sequencing were analyzed together with the clinical material including serum creatase, serum lipid and electromyogram(EMG) by Pearson’s correlation coefficients and analysis of covariance(ANCOVA). 90 cases of ALS were collected, whose clinical data,laboratory examination and electromyographic features were further investigated to look for the differential features of Kennedy disease to provide the clinical identification for clinicians.Results:1. All 155 patients were male with the average age at onset was 44.2±10.2. The average number of CAG repeats in exon 1 of AR was 48.7 ± 3.5. There was an inverse correlation between the length of CAG repeats and the age at onset(r=-0.58,p<0.0001). The number of CAG repeats could explain approximately 34% variance of age at onset.2. Weakness was the main symptoms at onset of the SBMA patients. The symptoms of 4 SBMA patients start from bulbar, 21 from upper limbs,, 61 from lower limb and 67 from extremities. The percentage of SBMA patients finally developed bulbar, upper limbs, lower limb weakness was 35.5%, 65.2% and 75.5% respectively.13.5% and 34.8% of the SBMA patients developed hand tremor and gynecomastiarespectively. Only 22.6% SBMA patients had ascertained family history.3. The serum creatine kinase level was correlated inversely with disease duration and age at examination(p= 0.019 and p= 0.004, respectively).4. EMG revealed diffuse neurogenic damage in all SBMA patients. Nerve conduction studies(NCS) revealed that 28% patients showed decreased amplitude of the median nerve CMAP, and 43% showed decreased amplitude of the peroneal nerve CMAP. 85%, 100% and 52% of patients developed low SNAP amplitudes in the median, ulnar and sural nerves, respectively. All findings of nerve conduction, except the amplitudes of median nerve compound motor action potential, were positively correlated to the length of CAG repeats. Compared to ALS patients, a more significant decline in sensory nerve action potential amplitudes were shown in SBMA patients.5. average age of onset of SBMA is 44.2 ± 10.2 years, whereas that of ALS is52.0 ± 12.2.In terms of initial presentations, bulbar and upper limb abnormalities are more commonly seen in ALS than SBMA6. Almost all SBMA patients have mild to moderate elevation in CK whereas only 55.4% ALS subjects have mild CK elevation, 23.1% subjects have lower-than-normal CK. The average CK is 255 ± 209 U/L, which is lower than CK1024 ± 76 U/L in SBMA. 86% of SMBA subjects have elevated LDH, but only40.3% of ALS subjects have, which is statistically significant7. The variations of Spontaneous potential in EMGs are statistically significant between SBMA and ALS subjects. The frequency of spontaneous potentials are higher in ALS, especially in cervical anterior horn motor neuron, which is highly suggestive of ALS8. The nerve conduction study shows that in median nerve, the amplitude of c MAP is significantly lower in ALS subjects than SBMA subjects. In contrast, the amplitude of SNAP wave of median nerve, ulnar nerve and sural nerve is significantly lower in SBMA subjects than ALS patients. These features of nerve conduction study can be used to differentiate ALS from SMBA in clinical senarios9.The ROC curve of the SNAP amplitude shows that in SBMA, <9.650 in mediannerve, <6.550 in ulnar nerve, <7.3 in sural nerve are most reliable cut-off values for diagnosis of SBMA. When SBMA pts are compared with ALS male patients, the same concl usion can also be verifiedConclusions:1. All 155 patients were male. Similar to the previous reports, the majority of patients started their symptoms with weakness in limb muscle. Few patients have ascertained family history.2. There was an inverse correlation between the length of CAG repeats and the age at first muscle weakness. The number of CAG repeats could explain approximately 34% variance of age at first muscle weakness.3. A major finding in the laboratory tests was the elevation of blood estradiol level. However, the blood testosterone level didn’t showed significant influence in SBMA onset. Another major finding was the elevation of serum triglycerides(TG).4. A more significant decline in sensory nerve action potential amplitudes may be an important feature of patients with SBMA. A more significant decline in SNAP amplitudes than CMAP may be an important feature of SBMA patients. Peroneal nerve CMAP and sensory nerve SNAP amplitudes may be positively correlated with the length of CAG repeats.5. Compared to SBMA patients, ALS patients had a late age at onset, and bulb and upper limb involvement was common in patients than SBMA.6. The muscle enzyme levels in patients with ALS was relatively low when compared to SBMA patients.7.The frequency of insertional activity and spontaneous potential is higher in ALS than SBMA. Especially in cervical anterior horn motor neuron, spontaneous potential highly suggestive of ALS8.In median nerve, the amplitude of CMAP is significantly lower in ALS subjects than SBMA subjects, while that of SNAP is significantly higher in ALS subjects,which can be used to differentiate ALS from SMBA9.In view of prominent discrepancy of SNAP amplitude, ROC curve and the cut off value contributes to the diagnosis of the two diseases.