Pompe Disease In Children: Clinical Characteristics,GAA Gene Mutations And Enzyme Replacement Therapy(ERT)

Objective:The clinical features,gene mutations and valuable experience of standardized enzyme replacement therapy(ERT)of Pompe disease(PD)in children were systematically summarized in order to provide reference for early identification,diagnosis,treatment and prognosis of PD.Methods:The children diagnosed with PD in the Heart Center and PICU of Qingdao Women and Children’s Hospital from December 2016 to March 2021 were divided into infantile-onset(IOPD)group and late-onset(LOPD)group according to the age of onset.At the same time,according to whether recombinant human acid α-glucosidase(rh GAA)was used,they were divided into ERT group and non-ERT group,and ERT group was divided into standard ERT group and non-standard ERT group.The clinical data of children in each group were collected and analyzed,including demographic data,medical history and physical examination,laboratory examination,cardiac imaging examination and gene analysis,treatment and follow-up.Results:1.Clinical data:There were 12 cases of PD,including 9 cases of IOPD and 3 cases of LOPD.The average age of onset and diagnosis in IOPD group was(4.49±3.14)months and(6.54±2.01)months,respectively.The average age of onset in LOPD group was 17 months,24 months,42 months,respectively,and the age of diagnosis was 17 months,25 months,42 months,respectively.In IOPD group,cardiac involvement was the most common cause of initial consultation,accounting for 55.6%,followed by abnormal creatine kinase(CK)and repeated cough.The causes of first consultation for 3 cases in LOPD group were myasthenia,cardiac involvement and respiratory tract infection,respectively.All children with PD have growth retardation at the time of diagnosis.There were 5 cases with abnormal face,7 cases with hepatomegaly,8 cases with muscle weakness in IOPD group.2 cases with hepatomegaly and 3 cases with normal muscle strength were in LOPD group.2.Auxiliary examination:The serum level of CK in all cases increased in varying degrees.Acid α-glucosidase(GAA)activity was completely deficient in 1 case and decreased in 11 cases.All the children in IOPD group showed myocardial hypertrophy,of which 4 cases showed biventricular myocardial hypertrophy.In LOPD group,1 case showed enlargement of left atrium and left ventricle,uniform thickening of interventricular septum and anterior wall of right ventricle,and non-compaction of left ventricular myocardium in 1 case.In IOPD group,electrocardiograph(ECG)showed short PR interval,left ventricular high voltage and extensive T-wave inversion,while only 1 case in LOPD group had abnormal ECG.A total of23 mutations were found in 12 cases,including 10 nonsense mutations,9 missense mutations,2 frameshift mutations and 2 splice mutations.Only one case of LOPD had homozygous mutation of GAA,which was c.2105G>A(p.R702H).The other 11 cases carried compound heterozygous mutations from their parents.Three new mutation were found: c.1861T>G(p.Trp621Gly),c.2278A>T(p.K760X),c.949G>A(p.A317T).Prediction of status of cross-reactive immunologic material(CRIM): 4 cases were CRIM positive and 5 cases were CRIM negative in IOPD group,and 3 cases were CRIM positive in LOPD group.3.Treatment and prognosis:5 cases in IOPD group were given ERT,of which 2 cases were given standard ERT 52 weeks,and the other 3 cases were treated with non-standard ERT.At the end of follow-up,2cases treated with standardized ERT survived and the remaining 7 cases died,of which 2cases died of heart failure and 5 died of respiratory failure.In LOPD group,only 1 case was given ERT one time,2 cases survived and 1 died of respiratory failure.The total mortality rate was 66.7%.4.ERT efficacy assessment:The muscle strength and motor development of children with standardized ERT were significantly improved.CK and left ventricular mass index(LVMI)decreased significantly after treatment.At the same time,the hypertrophic myocardium became thinner and the heart size decreased.In the patients with non-standard ERT,there were 3 cases of IOPD,of which1 case had improvement of the muscle strength of the extremities and 2 cases had no significant improvement in muscle strength.1 case of LOPD,using household ventilator to maintain survival,had no significant decreased in CK and LVMI,and the changes of myocardial thickness and heart size were not obvious.The survival curve of ERT group and standard ERT group was significantly different from that of non-ERT group(Log Rank P=0.037,0.044),so the survival rate of ERT group and standard ERT group was significantly higher than that of non-ERT group.Conclusion:1.Children less than 1 year old have progressive muscle weakness,hypotonia,abnormal CK,and myocardial hypertrophy,and attention should be paid to the possibility of IOPD.Children older than 1 year have muscle weakness,dyspnea,and/or respiratory failure,and abnormal CK,it is necessary to guard against the possibility of LOPD.2.The level of CK in children with PD can significantly increased,while the levels of LDH,AST and ALT can increased,especially in children with IOPD.GAA activity examination and GAA gene analysis are important for clinical diagnosis of PD.3.Standardized ERT can significantly improve the symptoms of myasthenia,delay the progression of the disease,and even reverse myocardial hypertrophy in children with IOPD.