Genotype And Phenotype Of Duchenne Muscular Dystrophy And The Evaluation Of Respiratory Function Study

Objective We aimed to describe the genotype distribution and clinical features and their differential responses to glucocorticoid treatments in a large cohort of Chinese Duchenne Muscular Dystrophy（DMD）patients.This is to facilitate future protocol designs and outcome measures for the emerging DMD clinical trials.Progressive respiratory muscle weakness is a major cause of DMD patients’death in China.However,respiratory dysfunction is difficult to evaluate in young patients.The second part of this study aimd to explore the convenient and sensitive assessment methods and predictive indicators of impaired respiratory function in DMD patients.Methods1.Male patients with confirmed DMD diagnosis from nine neuromuscular disorder centers throughout China were enrolled in this cohort study.Patients were followed up for1-4 years.Loss of ambulation（LOA）and survival time were predefined as the primary outcomes.Participants aged five years or older were grouped into glucocorticoid（GC）group and GC-na?ve group.The genetic mutations were categorized as large deletions,large duplications,and small mutations.Large deletions were further classified by the amenability of skipping of exon 44,exon 45,exon 51,and exon 53.2.Patients from our DMD multidisciplinary outpatient clinic were enrolled.Sniff nasal inspiratory pressure（SNIP）,vital capacity（VC）,forced vital capacity（FVC）,forced expiratory volume in one second（FEV1）were analyzed.The expression of TGF-β1 and CTGF were detected by ELISA.Participants were grouped into GC group,GC-na?ve group and Normal Control group.Results1.One thousand one hundred and seventy-one DMD patients were enrolled in our study.One thousand one hundred sixty-three patients were diagnosed by gene analysis,and eight patients were diagnosed only by muscle biopsy.Among the mutations,large deletions,large duplications,and small mutations accounted for 68.8%（800/1163）,7.1%（83/1163）,and 24.1%（280/1163）,respectively.The most common deletion was a deletion of exon 45,and the most common duplication was a duplication of exon 2.The mean age of diagnosis was 4.6 years in this group of DMD patients.The median age at LOA of the GC-na?ve group was 10.2 years,while patients treated with deflazacort was 14.0 years,and patients treated with the prednisone/prednisolone was 12.0years.Patients with deletions amenable to skipping of exon 51 showed earlier age 10.7 years at LOA.The median age at LOA in patients with deletions amenable to skipping of exon 44 was 13.3 while 13.3 years in patients with nonsense mutations.Different genotypes showed differential responses to glucocorticoid treatments.Two hundred and twelve patients provided the precise months of LOA during the year.Forty-eight patients lost their ambulation in September and 29patients in January.A total of 22 patients who were died of DMD has been followed up,and the mean life-span of these patients was 18.6 years.Half of the deceased patients had experienced undergone a pulmonary infection and died of respiratory failure,27%died of circulatory failure,2.SNIP data were collected in three research groups that consists of 581 subjects:125DMD boys who have taken steroid（Age 5.0-13.3,GC group）,145 DMD GC-naive boys（Age 5.0-13.9,GC-naive group）,and 311 healthy controls（Age 5.0-14.0,Control group）.The SNIP for GC-naive group,GC group and Control group were:56.5±14.3 cm H₂O,66.4±15.5 cm H₂O and 78.9±21.5 respectively.The peak value of SNIP in the GC-naive DMD group appeared at age 8.7,and decreased dramatically thereafter,while in GC group and the Control group peaked at 10.2 years and 12.2 years respectively.The expression of TGF-β1 was 122.5±5.1pg/ml（n=51）in patients younger than 10 years while 132.2±1.6pg/ml（n=38）in patients older than 10 years.The expression of CTGF was 370.5±19.6pg/ml（n=51）in patients younger than 10 years while 469.1±42.8 pg/ml（n=38）in patients older than 10 years.In patients younger than 10 years group,CTGF was negatively associated with SNIP sit,meanwhile TGF-β1 is negatively associated with FVC,VC,and FEV1.ConclusionWe recorded the clinical progression of different genotype groups by measuring the ages at LOA and their length of survival.Hot spots of LOA start time during the year were September and January,and the definite reason needs further elucidation.These data provide important baseline for the protocol design of future clinical trial studies.This study strengthens that SNIP can be used to evaluate respiratory dysfunction during the early stage of young patients with neuromuscular disorders,and demonstrates that glucocorticoid is effective in slowing the decrease of SNIP in this group of Chinese DMD boys.The expression levels of TGF-β1 and CTGF are consistent with trend of their motor function.