| Background and objectiveSpinal muscular atrophy(SMA)is a rare genetic neuromuscular disease,usually caused by homozygous deletion of the survival motor neuron 1(SMN1)gene or other biallelic pathogenic variants located on chromosome 5q13.2,leading to insufficient SMN protein level and degeneration of spinal anterior horn alpha motor neurons and lower brainstem motor neurons.The main clinical manifestations include progressive muscle weakness,hypotonia and muscle atrophy,with a prevalence of about 1 in 11,000 and a carrier rate of 1/72 to 1/47,making it the most common fatal inherited neuromuscular disease in infants and young children.Significant progress has been made in the drug therapy of SMA.Nusinersen is an improved antisense oligonucleotide(ASO)that increases the complete expression of SMN2,a compensatory gene for SMN1,to increase the amount of SMN protein and achieve therapeutic effects.The drug has been approved by the US FDA for the treatment of SMA patients and was approved in 2019 for use in SMA patients of all ages in China.However,due to the high cost,its clinical application has been limited until January 2022,when nusinersen was significantly reduced in price and entered the Chinese national medical insurance,allowing more SMA patients to receive the drug treatment.The main purpose of this study is to obtain real-world data on the treatment of nusinersen in Chinese adolescent and adult SMA patients,to evaluate its efficacy and safety,and to provide important reference for the diagnosis and management of SMA in China.MethodsThis is a prospective,observational study conducted at two centers.Adolescents and adults with SMA who received standard nusinersen treatment at the neurology department of Qilu Hospital and Qingdao Hospital affiliated with Shandong University from January to October 2022 were included.The follow-up time of treatment was at least 6 months and up to 10 months.General clinical data,clinical characteristics,and genetic testing reports of the included patients were collected,and the Hammersmith Functional Motor Scale Expanded(HFMSE),Revised Upper Limb Module(RULM),and Amyotrophic Lateral Sclerosis Functional Rating Scale Revised(ALSFRS-r)were evaluated at 0,2,6,and 10 months of nusinersen treatment.In addition,the 6-Minute Walk Test(6MWT),pulmonary function,compound muscle action potential(CMAP)amplitude,cerebrospinal fluid protein,bone density,and body composition were measured.The collected data were statistically analyzed.Results1.As of February 28,2023,a total of 29 patients completed the 6-month follow-up evaluation,and 19 patients completed the 10-month follow-up evaluation.The main clinical features:there were 21 males and 8 females with a male to female ratio of 2.6:1.Clinical classification:9 cases(31.0%)were type 2,18 cases(62.1%)were type 3,and 2 cases(6.9%)were type 4.The mean age at treatment initiation was 26 years.The median age of onset was 1.25 years.The average age of genetic diagnosis was 16.29 years,and the average time from onset to diagnosis was 11.42 years.There were 8 patients(27.6%)who could walk,2 patients(6.9%)who could maintain standing,8 patients(27.6%)who could sit independently,and 11 patients(27.9%)who were bedridden.Among them,there were 15 patients(51.7%)with moderate to severe scoliosis and 11 patients(37.9%)with tongue muscle fibrillation.2.Compared with the baseline HFMSE median score of 13.00(3.00-36.00),the median scores at the 2nd,6th,and 10th months of treatment were 16.00(6.00-38.50),22.00(9.0033.50),and 16.00(7.00-44.00),respectively,showing significant improvement.At the 2nd month of treatment,there were 9 out of 29 patients(31%)who had a clinically significant improvement(≥3-point increase)in HFMSE score,with 13 out of 29 patients(44.8%)at the 6th month,and 7 out of 19 patients(36.8%)at the 10th month.3.Compared with the baseline RULM median score of 22.00(9.00-33.50),the median scores at the 2nd,6th,and 10th months of treatment were 24.00(11.50-35.00),27.00(13.5036.00),and 23.00(17.00-36.00),respectively,showing significant improvement.At the 2nd month of treatment,there were 11 out of 29 patients(37.9%)who had a clinically significant improvement(≥2-point increase)in RULM score,with 14 out of 29 patients(48.3%)at the 6th month,and 8 out of 19 patients(42.1%)at the 10th month.4.According to the clinical classification of the patients,including walking ability,degree of spinal curvature,presence of joint contracture,and tongue tremor,they were divided into subgroups.The changes in motor function scores after 2,6,and 10 months of treatment were compared between the groups,and no significant differences were observed between the subgroups.5.Among the 9 SMA patients who could walk,their average 6MWT distance increased by 33.11 meters and 52.33 meters compared to baseline at the 2nd and 6th months of treatment,respectively.Seven of these patients completed the evaluation at the 10th month,with an average increase of 55.94 meters compared to baseline.6.The baseline ALSFRS-r score of the patients was 34.3±8.5.The average scores at the 2nd,6th,and 10th months of treatment were 34.96(mean difference 0.62[95%Cl 0.98-1.14]),35.24(0.89[0.28-1.50]),and 34.78(0.89;0.10-1.68),respectively,all slightly higher than the baseline level.7.Twenty-one patients completed a comparison of Forced Vital Capacity(FVC)at the 6th month of treatment and baseline,with no statistically significant difference.Sixteen patients completed a comparison of Total Body Less Head Bone Mineral Density(TBLH BMD),with a statistically significant decrease in Z value of 0.15 at 6 months of treatment.There was no statistically significant difference in Lumbar Spine Bone Mineral Density(LS BMD),whole-body fat percentage change,or Relative Skeletal Muscle Index(RSMI)between the 6th month of treatment and baseline.8.Thirteen patients in the cohort completed a comparison of compound muscle action potential(CMAP)amplitude before and 6 months after treatment.The average CMAP amplitude of the median nerve increased by 1,33 mV compared to baseline after 6 months of treatment,while the average CMAP amplitude of the peroneal nerve increased by 1.38 mV compared to baseline after 6 months of treatment.There was no statistically significant change in CMAP amplitude of the ulnar nerve and tibial nerve before and after treatment.9.Two adult SMA type 2 patients with severe spinal curvature failed multiple attempts of lumbar puncture under ultrasound guidance.With the informed consent of the patients and their families,a successful subarachnoid Ommaya reservoir implantation was performed,establishing a permanent subcutaneous conduit for intrathecal injection.10.Treatment-related adverse events:11(37.9%)patients experienced a total of 44 adverse events(26.8%),with the most common being headaches(15 events,34.1%),dizziness(11 events,25.0%),and nausea(11 events,25.0%).Conclusions1.Regular intrathecal injections of Nusinersen significantly improve motor function and are relatively safe for Chinese adolescent and adult SMA patients.However,the improvement in respiratory function during 6-10 months of treatment is not ideal.2.Nusinersen treatment for 6-10 months does not significantly improve bone density and body composition in SMA patients.3.For patients with difficult or failed punctures,it is recommended to undergo subarachnoid Ommaya reservoir implantation surgery to establish a permanent subcutaneous conduit for injection. |
