Chronic Creatine Kinase Is Elevated In Children With Clinical Analysis-cum-juvenile Onset Of The Clinical And Genetic Analysis Of Late-onset Pompe Disease

objective Elevation of serum creatine kinase(CK)levels are related to a variety of diseases including muscle injury,infections,toxins,endocrine diseases,etal.,but persistently increased serum CK levels were considered a hallmark of neuromuscular disease.Different causes have different treatment and prognosis.The aim of our study is to establish the diagnosis of juvenile patients with chronic elevation of serum creatine kinase(CK) levels.Methods We made a retrospective evaluation of 25 juvenile patients with hyperCKemia over three months in the genetic clinic of our department between January 2005 and March 2007.Clinical data,neurological examination and laboratory examinations were analysized.All the patients underwent open muscle biopsy.Biochemical and genetic investigation were added in selected cases.Results There were 7 females and 18 males aged between 2 year 9 month and 15 years [mean 7.8y].The disease duration were beween 3 months and 7 years. Serum CK leverls were between 285 and 15720 U/L(18-198).We made a diagnosis in 16 patients.The diagnosis included dystrophinopathies in 8 patients;Pompe disease in 2 patients;glycogenosis typeⅢin 1 patient;mitochondrial myopathies in 1 patient;glutaric aciduria typeⅡin 1 patient;spinal muscular atrophy in 1 patients;inflammatory myopathies in 2 patients.Diagnosis were not able to confirm in 9 patients, pathological but not conclusive muscle changes were found in 5 patients. Conclusion Neurological and metabolic myopathies disease were the main causes of pesistent hyperckemia in children,muscle biopsy as well as biochemical and genetic investigations were essential to the diagnosis. Backgrounds and ObjectiveGlycogen-storage disease typeⅡ(GSDⅡ,Pompe's disease) is an autosomal recessive disorder caused by a functional deficiency of acid alpha-glucosidase(GAA) that leads to glycogen accumulation within lysosomes in most tissues.The GAA gene is located to human chromosome 17q25 and contains 20 exons,19 of which are coding, Clinically,patients with the severe infantile form of GSDⅡhave muscle weakness and cardiomyopathy eventually leading to death before the age of two years.Patients with the juvenile or the adult form of GSDⅡpresent with myopathy with a slow progression over several years or decades,symptoms may start at any age and are related to progressive dysfunction of skeletal muscles.With disease progression,patients become confined to wheelchairs and require artificial ventilation. Respiratory failure is the cause of significant morbidity and mortality in this form of disease.The age of death varies from early childhood to late adulthood,depending on the rate of disease progression and the extent of respiratory muscle involvement.A broad genetic heterogeneity has been described in GSDⅡin Europe,South Africa,USA,Japan and Korea, hower,the investigation has not been performed in the patients from the mainland of China.In this study,clinical analysis and mutations detection were done on Chinese patients.MethodsTwo unrelated juvenile patients with late onset GSDⅡ(one boy,3 year old and one girl,9 year old)were included in the study with the informed consents.The diagnosis was confirmed byα-glucosidase determination in cultured fibroblasts.In addition,their clinical presentation,laboratory findings,electrophysiologic studies and muscle biopsy findings were analyzed in detail.Genomic DNA samples were extracted from fibroblasts of the probands,Genomic DNA samples were extracted from peripheral bloods of their parents and 50 unrelated,normal individuals.All the coding 19 exons and exon-intron boundaries of GAA were detected in the proband by polymerase chain reaction(PCR),direct sequencing.Resultsone patient presented decrease of muscle strength,limb-girdle hypotonia,the other patient presented reduced size of muscle volumes and respiratory problems.Both had increased serum creatinine phosphokinase(CPK) value,myopathic pattern on EMG;vacuoles on muscle biopsy,and deficiency of 1,4-alpha-glucosidase activity.After 1 year follow up,the girl died after pneumonia at 10 year old.One patient was found to be compound heretozygote for the novel mutation Arg702His,and Pro266Ser,previously reported in korean population, with the late-onset phenotype.Two novel missense mutations Thr711Arg, Va1723Met were found on the other patients.As for three new mutations, we were not able to observe the same changes among 100 control chromosomes.ConclusionsThe two cases of juvenile Pompe patients in our study had different characters in the clinical,the involvement of respiratory muscle seems a pronostic factor.We did not find the most commont mutation in the late-onset patients in the white people,and the most prevalent mutation Asp654Glu in the infantile form found in Taiwan district of China were not detected in our patients.The three mutations identified in the patients were new missense mutations causing late onset GSDⅡ,which had not been reported elsewhere before.There is currently no treatment other than supportive care for Pompe disease.With enzyme replacement therapy likely to become available in the near future and other therapies on the horizon,early disease recognition is increasingly important so the patients can receive prompt and appropriate therapy.