Clinical And Genetic Analysis Of Seven Cases Of Late-Onset Glycogen Storage Disease Type Ⅱ

Background:Glycogen storage disease typeⅡ(GSDⅡ), is an autosomal recessive disorder caused by mutations in the gene encoding the the acid alpha-glucosidase enzyme (GAA), which is essential for the degradation of glycogen to glucose in lysosomes. Two broad categories have been described in the literatures:infantile and late-onset forms. The former is a rapidly progressive disease typically associated with cardiac hypertrophy, and the latter mainly presents with chronic progressive skeletal muscle weakness. The GAA gene is located to human chromosome 17q25 and contains 20 exons,19 of which are coding. More than 351 mutations and sequence variants have been identified, and the most frequent mutation in late-onset patients is c.-32-13T->G (IVS1-13T->G). In china, D645E and D615R are two common mutations; little investigations have been performed in patients from mainland.Purpose:To summarize the clinical features and gene mutations of 7 cases of late-onset GSDⅡ, and to investigate the genotype-phenotype correlations in our series of patients.Methods:The clinical and pathological data of 7 patients diagnosed as late-onset GSDⅡclinically and pathologically in Qilu hospital of our department between March 2001 and March 2010 were collected, and the genomic DNA were extracted from the patients'frozen muscle specimens and the coding regions and the exon-intron boundaries of GAA gene were amplified by polymerase chain reaction (PCR), direct sequencing. All of the mutation alleles were confirmed by bidirectional DNA sequencing, and the novel missense mutations were analyzed by Restriction Fragment Length Polymorphism in 50 normal controls.Results:There were 3 males and 4 females with a mean onset age of 12.6, and a mean diagnostic age of 19.4, and two cases had family history. All of these 7 patients mainly manifested as proximal muscle weakness in their lower extremities, but 1 case presented with a sudden onset of respiratory failure,2 cases with a juvenile-onset age, 2 cases with dominant gastrointestinal symptoms (intestinal obstruction or reflux), and 1 case with paroxysmal vertigo which indicated ischemic attacks in the posterior cerebral arteries. Laboratory finding:6 cases had a mildly to moderately increased CK level; 5 cases had a myogenic change in the EMG; 1 case was found hepatosplenomegaly; 1 case occupied with CNS damage, cerebrovascular abnormalities (multiple stenosis and dilation of intracranial artery, and fusiform basilar artery aneurysm formation). The light microscopic feature of 6 of the 7 cases was a vacuolar myopathy with high glycogen content and acid phospatase activity in the vacuoles; the other one case only showed an atypical vacuolar myopathy change and had to be further confirmed by electron microscopy.11 different mutations were identified, including 5 missense mutations (c.2167 G>A, c.1309 C＜T, c.1409 A>G, c.1316 T>A, c.1114 C＞G),3 nonsense mutations (c.2130 C＞G, c.C1822 C＞T, c.2662 G>T),3 delete mutations (c.827del 19, c.829del 19, c.1388del 19).3 mutations have been reported (c.1309 C＞T and c.1316 T>A: pathogenic; c.2167 G>A:unknown), the other 8 mutations were novel.Conclusions:1. Late-onset Pompe patients mainly presented with chronic progressive skeletal muscle weakness, always in a symmetric pattern, lower extremities worse than upper extremities, proximal muscles worse than distal muscles. Cerebrovasular abnormalities and gastrointestinal dysfunctions could be undergone by small number of patients. Respiratory insufficieny was an important cause of death in the patients.2. Muscle biopsy typically showed a vacuolar myopathy with high glycogen cotent and acid phosphatase activity in the vacuoles. Eletron microscopy could be helpful for diagnosis if the light microscopic manifestations were not typical enough.3. GAA mutations were identified in all of our 7 patients, including 5 compound missense mutations,3 compound nonsense mutations, and 3 compound delete mutations.3 missense mutations(c.1309 C＞T, c.1316 T>A and c.2167 G>A) have been reported; other 8 mutations were novel.4. GA A mutations in this group of patients showed a remarkable heterogeneity, and the genotype-phenotype correlation needed more samples analyzed to be confirmed.