| Background:Glycogen storage disease type Ⅱ(GSD Ⅱ),also called Pompe disease,is an autosomal recessive lysosomal storage disorder caused by defect of GAA gene.The deficiency of acid a-glucosidase(GAA)leads to the progressive accumulation of glycogen in lysosomes in all tissues mainly including skeletal muscle,heart muscle,and liver,thereby causing corresponding clinical symptoms.Pompe disease is classified into IOPD and LOPD according to the age of onset,affected organs,and disease progression.Patients with infant onset Pompe disease(IOPD),which is characterized by cardiomegaly,feeding difficulties and floppy baby,are diagnosed with an onset before the age of 1 year old,and usually die of cardiorespiratory failure within the first year of life.Patients with late onset Pompe disease(LOPD)refer to individuals with an onset after the age of 1 year old.The symptoms are diverse,mainly manifesting as progressive limb muscle weakness and respiratory insufficiency accompanied by scoliosis or spinal rigidity.It can also present with hyperCKemia at early stage,gastrointestinal symptoms or stroke.The only proven effective treatment for Pompe disease is enzyme replacement therapy(ERT),which is a regular intravenous infusion of recombinant human acid alpha-glucosidase(rhGAA).Although rhGAA can improve the heart function and muscle strength of IOPD infants,it is not ideal for the improvement of serious clinical manifestations in LOPD patients.Objective:Our study was designed to follow up 41 patients with LOPD who were diagnosed and treated between 2001 and 2018 in the Neuromuscular Pathology Laboratory of Qilu Hospital of Shandong University.We analyzed their clinical,pathologic and molecular genetics features in retrospect and gave 13 patients nutrition and exercise instructions.In result,we summarized the characteristics of clinical,pathologic,and molecular genetics of LOPD in Chinese mainland population and observed the effect of nutrition and exercise therapy on the prognosis of LOPD by one-year follow-up of 13 patients,thus provided a reference for the early diagnosis and treatment of LOPD in the future.Materials and methods:41 patients with LOPD were diagnosed and treated in the Neuromuscular Pathology Laboratory of Qilu Hospital of Shandong University from 2001 to 2018.All patients were confirmed diagnosed with LOPD,with detailed medical history,general and neurological physical examinations,and serologic test.All patients received GAA genetic test.32 patients underwent GAA enzyme activity test,and 31 patients underwent muscle biopsy for histochemical staining(H&E,MGT,NADH,SDH,COX,SDH/COX,ORO,PAS,ATPase).28 patients underwent echocardiography,23 patients underwent pulmonary function test,20patients underwent electromyography,and 27 patients underwent brain imaging including CT,MRI and MRA.Results:41 patients with LOPD(23 males and 18 females)were from 31 independent families.Among them,patients 17 and 18,19 and 20,21 and 22,26 and 27,28 and 29,30 and 31 were respectively from the same family.23,24 and 25 were also siblings.The age of onset of 41 patients ranged from 1 to 40 years old with a median age of 15 years.The diagnostic delay was 3 to 47 years,and the median was 22 years.By the time of the study,9 patients had died with the median age of 25 years ranging from 10 to 32 years.30 patients(73.2%)complained of skeletal muscle weakness as their initial symptom.7 patients(17.1%)reported that respiratory insufficiency was the initial clinical symptom.Two patients presented with hyperCKemia as their initialsymptoms noted during a health examination.And two patients began abruptly with stroke and were admitted into hospital.Muscle strength test according to MRC showed that the iliopsoas and gluteus maximus were the most affected,followed by the neck flexors.A total of 21 patients suffered from spine malformation.13 patients presented with scoliosis while 8 patients with rigidity.22 patients underwent 6MWT,the results ranged from 38 to 544 meters with the median of 397 meters.2 people failed to complete the test.One could not walk independently,and another needed intermittent rest.In addition to musculoskeletal system,circulation,respiration,digestion,and nervous systems were affected more or less.To assess cardiac and pulmonary function,28 patients underwent echocardiography and 8 patients(28.6%)had abnormalities.Four patients had moderate pulmonary arterial hypertension and two patients showed pulmonary artery ectasia.23 patients carried out pulmonary function test.The FVC%results were 15.46%to 99.72%with a median of 33.3%.Statistical analysis showed a statistically significant difference in FVC%between patients with spinal rigidity and without(p=0.008).Non-invasive assisted ventilation was required in 18 patients(47.4%),especially at night,5 patients(13.2%)received tracheotomy and invasive ventilation,and 4 patients experienced tracheotomy for the whole life.A total of 16 patients were afflicted by diarrhea.27 patients underwent MRI and MRA.There were 8 patients who showed cerebrovascular abnormalities and the vertebral-basal artery system was involved.The main manifestations were aneurysms,arterial dolichoectasia and stenosis.The median serum CK level was 677.85 IU/L ranging from 66 to 2431 IU/L.Electromyography was performed in 20 patients,and 9 patients(45%)presented with myotonic discharges.31 patients underwent muscle biopsy,all of which showed vacuoles more or less irregularly distributing on the edge of muscle fibers.Partial muscle fibers were filled with basophilic particulate matters.PAS staining indicated glycogen storage.The activity of acid phosphatase increased on acid phosphatase staining which suggested the lysosomal hyperfunction.The median age of biopsy was 19 years.11 patients(35.5%)showed type Ⅱ fibers were involved mostly,and 2 patients type Ⅰ fibers mostly while the rest 18 patients showed no specificity in the type of fibers involved.32 patients were tested for GAA enzyme activity all suggesting the pathologic decreasing in enzyme activity.41 patients all carried out genetic test,and a total of 45 gene mutations were detected.c.2238G>C(p.W746C)was the most common mutation with the allele frequency of 19.70%(13/66),followed by c.2262G>T(p.E888*)with the allele frequency of 6.06%(4/66).Notably,6 patients carried the pseudodeficiency mutation of c.1726G>A(p.G576S).Among the 45 gene mutations,23 have been reported pathogenic,16 are novel.Through Mutation Taster and Polyphen-2,14 mutations of them are disease causing and the 2 are polymorphisms by leading to splicing.By analyzing the clinical manifestations of patients with and without c.2238G>C(p.W746C),we found that the difference of intracranial vascular involvement was statistically significant.In view of the fact that c.2238G>C(p.W746C)is the most common mutation in Chinese mainland population,we statistically analyzed the onset age,gastrointestinal involvement,GAA enzyme activity,FVC%,intracranial vascular involvement and other characteristics inpatients with or without c.2238G>C(p.W746C)respectively in order to further analyze the correlation between genotype and clinical phenotype.The results showed that intracranial vascular involvement was not related to age.Further analysis showed that intracranial vascular involvement was statistically significant with c.2238G>C(p.W746C)(p=0.043(double),p=0.038(unilateral)).In other words,patients carrying c.2238G>C(p.W746C)are more likely to have intracranial vascular involvement,and age of patients with intracranial vascular involvement is no less than 25 years.Other clinical manifestations did not show statistically significant differences.Based on the summary and follow-up,we found that nutrition and exercise therapy.is of vital importance and practicality for patients with LOPD.We preliminary judged that aerobic exercise and low-carbohydrate and high-protein nutrition can help delay the progression of LOPD,especially in delaying the deterioration of respiratory function,but more data are needed to verify the conclusions and the mechanism needs further research.Conclusions:1.Patients with LOPD in this study mostly complained of skeletal muscle weakness at first,followed by respiratory insufficiency,and a small number of patients with hyperCKemia and stroke.2.The difference in FVC%between patients with and without spinal rigidity was statistically significant(p=0.008).We suggest early corrective therapy for patients with spinal malformation to delay the deterioration of pulmonary function.3.Gastrointestinal symptoms,pulmonary artery and cerebrovascular diseases indicated smooth muscle involvement in LOPD patients.4.Genetic test indicated that c.2238G>C(p.W746C)was the most common mutation in mainland Chinese population,followed by c.2262G>T(p.E888*),and several patients had pseudodeficiency c.1726G>A(p.G576S).5.Intracranial vascular involvement was statistically significant with c.2238G>C(p.W746C).The age of patients with intracranial vascular involvement is no less than 25 years.6.We preliminary judged that aerobic exercise and low-carbohydrate and high-protein nutrition can help delay the progression of LOPD,especially in delaying the deterioration of respiratory function,but more data are needed to verify the conclusions and the mechanism needs further research. |
PDF Full Text Request