A 24-year-old male was admitted due to recurrent redness, swelling, fever and pain in the ankle, frequently accompanied by hungry feeling. Dual energy CT scans showed multiple small gouty stones in the posterior edge of the bilateral calcaneus and in the space between the bilateral metatarsophalangeal joints. The laboratory examination results indicated hyperlipidemia, high lactate lipids, and low fasting blood glucose. Histopathology of liver biopsy showed significant glycogen accumulation. The results of gene sequencing revealed the compound heterozygous mutations of the G6PC gene c.248G>A (p.Arg83His) and c.238T>A (p.Phe80Ile) in the proband. The c.248G>A mutation was from mother and the c.238T>A mutation was from father. The diagnosis of glycogen storage disease type Ⅰa was confirmed. After giving a high starch diet and limiting monosaccharide intake, as well as receiving uric acid and blood lipids lowering therapy, the condition of the patient was gradually stabilized. After a one-year follow-up, there were no acute episodes of gout and a significant improvement in hungry feeling in the patient.
Male ; Humans ; Young Adult ; Adult ; Glycogen Storage Disease Type I/genetics* ; Gout/genetics* ; Mutation ; Lipids

Objective: To review the clinical data of 7 patients with Danon disease and analyze their clinical characteristics. Methods: The medical records of 7 patients with Danon disease, who were hospitalized in Peking Union Medical College Hospital of Chinese Academy of Medical Sciences from April 2008 to July 2021, were reviewed and summarized, of which 6 cases were diagnosed as Danon disease by lysosomal-associated membrane protein-2 (LAMP-2) gene mutation detection and 1 case was diagnosed by clinicopathological features. Clinical manifestations, biochemical indexes, electrocardiogram, echocardiography, skeletal muscle and myocardial biopsy and gene detection results were analyzed, and patients received clinical follow-up after discharge. Results: Six patients were male and average age was (15.4±3.5) years and the average follow-up time was (27.7±17.0) months. The main clinical manifestations were myocardial hypertrophy (6/7), decreased myodynamia (2/7) and poor academic performance (3/7). Electrocardiogram features included pre-excitation syndrome (6/7) and left ventricular hypertrophy (7/7). Echocardiography examination evidenced myocardial hypertrophy (6/7), and left ventricular dilatation and systolic dysfunction during the disease course (1/7). The results of skeletal muscle biopsy in 6 patients were consistent with autophagy vacuolar myopathy. Subendocardial myocardial biopsy was performed in 3 patients, and a large amount of glycogen deposition with autophagosome formation was found in cardiomyocytes. LAMP-2 gene was detected in 6 patients, and missense mutations were found in all these patients. During the follow-up period, implantable cardioverter defibrillator implantation was performed in 1 patient because of high atrioventricular block 4 years after diagnosis, and there was no death or hospitalization for cardiovascular events in the other patients. Conclusion: The main clinical manifestations of Danon disease are cardiomyopathy, myopathy and mental retardation. Pre-excitation syndrome is a common electrocardiographic manifestation. Autophagy vacuoles can be seen in skeletal muscle and myocardial pathological biopsies. LAMP-2 gene mutation analysis is helpful in the diagnose of this disease.
Adolescent ; Child ; Female ; Humans ; Male ; Cardiomyopathies/etiology* ; Glycogen Storage Disease Type IIb/complications* ; Hypertrophy, Left Ventricular/etiology* ; Lysosomal-Associated Membrane Protein 2/genetics* ; Pre-Excitation Syndromes/genetics*

Objective: Glycogen storage disease type IX (GSD-IX) is a rare primary glucose metabolism abnormality caused by phosphorylase kinase deficiency and a series of pathogenic gene mutations. The clinical characteristics, gene analysis, and functional verification of a mutation in a child with hepatomegaly are summarized here to clarify the pathogenic cause of the disease. Methods: The clinical data of a child with GSD-IX was collected. Peripheral blood from the child and his parents was collected for genomic DNA extraction. The patient's gene diagnosis was performed by second-generation sequencing. The suspected mutations were verified by Sanger sequencing and bioinformatics analysis. The suspected splicing mutations were verified in vivo by RT-PCR and first-generation sequencing. Results: Hepatomegaly, transaminitis, and hypertriglyceridemia were present in children. Liver biopsy pathological examination results indicated glycogen storage disease. Gene sequencing revealed that the child had a c.285 + 2_285 + 5delTAGG hemizygous mutation in the PHKA2 gene. Sanger sequencing verification showed that the mother of the child was heterozygous and the father of the child was of the wild type. Software such as HSF3.1 and ESEfinder predicted that the gene mutation affected splicing. RT-PCR of peripheral blood from children and his mother confirmed that the mutation had caused the skipping of exon 3 during the constitutive splicing of the PHKA2 gene. Conclusion: The hemizygous mutation in the PHKA2 gene (c.285 + 2_285 + 5delTAGG) is the pathogenic cause of the patient's disease. The detection of the novel mutation site enriches the mutation spectrum of the PHKA2 gene and serves as a basis for the family's genetic counseling.
Child ; Humans ; Exons ; Glycogen Storage Disease/genetics* ; Hepatomegaly/genetics* ; Mutation ; Phosphorylase Kinase/genetics* ; Male ; Female

OBJECTIVE: To explore the clinical features, lysosomal enzymatic [acid α-glucosidase (GAA)] activities and genetic variants in a child with late-onset Pompe disease (LOPD). METHODS: Clinical data of a child who had presented at the Genetic Counseling Clinic of West China Second University Hospital in August 2020 was retrospectively analyzed. Blood samples were collected from the patient and her parents for the isolation of leukocytes and lymphocytes as well as DNA extraction. The activity of lysosomal enzyme GAA in leukocytes and lymphocytes was analyzed with or without addition of inhibitor of GAA isozyme. Potential variants in genes associated with neuromuscular disorders were analyzed, in addition with conservation of the variant sites and protein structure. The remaining samples from 20 individuals undergoing peripheral blood lymphocyte chromosomal karyotyping were mixed and used as the normal reference for the enzymatic activities. RESULTS: The child, a 9-year-old female, had featured delayed language and motor development from 2 years and 11 months. Physical examination revealed unstable walking, difficulty in going upstairs and obvious scoliosis. Her serum creatine kinase was significantly increased, along with abnormal electromyography, whilst no abnormality was found by cardiac ultrasound. Genetic testing revealed that she has harbored compound heterozygous variants of the GAA gene, namely c.1996dupG (p.A666Gfs*71) (maternal) and c.701C>T (p.T234M) (paternal). Based on the guidelines from the American College of Medical Genetics and Genomics, the c.1996dupG (p.A666Gfs*71) was rated as pathogenic (PVS1+PM2_Supporting+PM3), whilst the c.701C>T (p.T234M) was rated as likely pathogenic (PM1+PM2_Supporting+PM3+PM5+PP3). The GAA in the leukocytes from the patient, her father and mother were respectively 76.1%, 91.3% and 95.6% of the normal value without the inhibitor, and 70.8%, 112.9% and 128.2% of the normal value with the inhibitor, whilst the activity of GAA in their leukocytes had decreased by 6 ~ 9 times after adding the inhibitor. GAA in lymphocytes of the patient, her father and mother were 68.3%, 59.0% and 59.5% of the normal value without the inhibitor, and 41.0%, 89.5% and 57.7% of the normal value with the inhibitor, the activity of GAA in lymphocytes has decreased by 2 ~ 5 times after adding the inhibitor. CONCLUSION The child was diagnosed with LOPD due to the c.1996dupG and c.701C>T compound heterozygous variants of the GAA gene. The residual activity of GAA among LOPD patients can range widely and the changes may be atypical. The diagnosis of LOPD should not be based solely on the results of enzymatic activity but combined clinical manifestation, genetic testing and measurement of enzymatic activity.
Humans ; Child ; Male ; Female ; Glycogen Storage Disease Type II/pathology* ; Retrospective Studies ; alpha-Glucosidases/genetics* ; Mothers ; Lysosomes/pathology* ; Mutation

OBJECTIVE: To explore the clinical features and genetic basis of a patient with glycogen storage disease type VI (GSD-VI). METHODS: Clinical data of the patient was collected. Genomic DNA was extracted from peripheral blood samples of the proband and his parents. Genetic variants were detected by using whole exome sequencing. Candidate variants were verified by Sanger sequencing followed by bioinformatics analysis. RESULTS: The proband presented fasting hypoglycemia, hepatomegaly, growth retardation, transaminitis, metabolic acidosis and hyperlactatemia. Liver biopsy indicated GSD. Novel compound heterozygous PYGL gene variants (c.2089A>G/c.158_160delACT) were detected in the proband. Compound heterozygosity was confirmed by Sanger sequencing of the patient's genomic DNA. Provean and MutationTaster predicted the two variants as deleterious and the variant sites are highly conserved. CONCLUSION The compound heterozygous variants (c.2089A>G/c.158_160delACT) of PYGL gene probably underlay the GSD in the patient. The two novel variants have expanded the spectrum of PYGL gene variants and provided the basis for genetic counseling of the family.
Child ; Family ; Genetic Testing ; Glycogen Storage Disease Type VI/genetics* ; Humans ; Mutation ; Whole Exome Sequencing

OBJECTIVE: To explore the clinical and genetic characteristics of a Chinese pedigree affected by glycogen storage disease (GSD) type Ia with gout as the first manifestation. METHODS: Clinical and biochemical data of the pedigree were collected. Available members of the pedigree were subjected to gene sequencing, and the result was analyzed by bioinformatics software. The pedigree was followed up for five years. RESULTS: The proband was a young female manifesting recurrent gout flare, hypoglycemia, and hypertriglyceridemia. One of her younger brothers also presented with dysplasia and hepatic adenoma. Gene sequencing revealed that the proband and her younger brother both harbored c.1022T>A (p.I1e341Asn) and c.230+5G>A compound heterozygous variants of the G6PC gene , which were inherited from their father and mother, respectively. Among these, the c.230+5G>A is an intron region variant which was unreported previously, and bioinformatics analysis showed that it may impact mRNA splicing of the gene. The proband was treated with raw corn starch, allopurinol, and fenofibrate. Gout was well controlled, and she had given birth to a baby girl without GSD. CONCLUSION GSD Ia should be considered among young gout patients with hypoglycemia and hepatomegaly, for which gene sequencing is warranted. GSD Ia has a good prognosis after comprehensive treatment with diet and medicine.
China ; Female ; Glycogen Storage Disease Type I ; Gout/genetics* ; Humans ; Hypoglycemia ; Male ; Pedigree ; Symptom Flare Up

OBJECTIVE: To explore the genetic etiology of a patient with glycogen storage diseases. METHODS: Clinical data of child and his parents were collected. The genes associated with glycogen storage diseases were subjected to high-throughput sequencing to screen the variants. Candidate variant was validated by Sanger sequencing. Pathogenicity of the variant was predicted by bioinformatic analysis. RESULTS: High-throughput sequencing results showed that the boy has carried a hemizygous c.749C>T (p.S250L) variant of the PHKA2 gene. Sanger sequencing verified the results and confirmed that it was inherited from his mother. This variant was unreported previously and predicted to be pathogenic by bioinformatic analysis. CONCLUSION The patient was diagnosed with glycogen storage disease type IXa due to a novel c.749C>T (p.S250L) hemizygous variant of the PHKA2 gene. High-throughput sequencing can facilitate timely and accurate differential diagnosis of glycogen storage disease type IXa.
Child ; Family ; Genetic Testing ; Glycogen Storage Disease/pathology* ; High-Throughput Nucleotide Sequencing/methods* ; Humans ; Male ; Mutation ; Phosphorylase Kinase/genetics*

OBJECTIVE: To explore the clinical features and genetic etiology of a child with glycogen storage disease VI (GSD-VI). METHODS: Clinical data and laboratory results of the patient were collected. Whole exome sequencing (WES) was carried out for the patient. Candidate variant and its parental origin was verified by Sanger sequencing. RESULTS: The patient was a 3-year-and-9-month old boy whom has featured abdominal distention, hepatomegaly, short stature and elevated hepatic transaminase. WES revealed the he has harbored compound heterozygous variants of the PYGL gene, namely c.697G>A (p.Gly233Ser) and c.320dupA (p.Asn107fs). Sanger sequencing has verified that the two variants have derived from his father and mother, respectively. The c.320dupA (p.Asn107fs) variant was unreported previously. CONCLUSION The compound heterozygous variants of the PYGL gene probably underlay the GSD-VI in this patient. Above finding has enriched the spectrum of PYGL gene variants and provided a basis for the treatment and genetic counseling.
Child ; Genetic Testing ; Glycogen Storage Disease Type VI/genetics* ; Humans ; Infant ; Male ; Mutation ; Transaminases/genetics* ; Exome Sequencing

OBJECTIVE: To explore the clinical features and genetic basis of two children with glycogen storage disease type III (GSD III). METHODS: The probands and their parents were subjected to genetic testing, and the pathogenity of candidate variants was analyzed by using bioinformatic tools. RESULTS: Sequencing has identified compound heterozygous variants of the AGL gene in both children, namely c.1423+1G>A and c.3701-2A>G in case 1, and c.4213_c.4214insA (p.Glu1405Glufs*17) and c.3589-3C>G in case 2. Both children were diagnosed with GSD III. Literature review suggested that the main type variant among Chinese patients with GSD III involve splice sites of the AGL gene, with c.1735+1G>T being the most common. Based on the American College of Medical Genetics and Genomics standards and guidelines,c.1423+1G>A, c.3701-2A>G and c.4213_c.4214insA variants of AGL gene were predicted to be of pathogenic (PVS1+PM2+PM3, PVS1+PM2+PM3, PVS1+PM2+PP5), and c.3589-3C>G variant was predicted to be of uncertain significance (PM2+PM3+PP3). CONCLUSION The compound heterozygous variants of the AGL gene probably underlay the GSD III in both children. Above findings have enriched the spectrum of genetic variants underlying this disease.
Child ; Genetic Testing ; Genomics ; Glycogen Storage Disease Type III/genetics* ; Humans ; Mutation

BACKGROUND: Abnormally activated mechanistic target of rapamycin (mTOR) pathway has been reported in several model animals with inherited metabolic myopathies (IMMs). However, the profiles of mTOR pathway in skeletal muscles from patients are still unknown. This study aimed to analyze the activity of mTOR pathway in IMMs muscles. METHODS: We collected muscle samples from 25 patients with mitochondrial myopathy (MM), lipid storage disease (LSD) or Pompe disease (PD). To evaluate the activity of mTOR pathway in muscle specimens, phosphorylation of S6 ribosomal protein (p-S6) and p70S6 kinase (p-p70S6K) were analyzed by Western blotting and immunohistochemistry. RESULTS: Western blotting results showed that p-p70S6K/p70S6K in muscles from LSD and MM was up-regulated when compared with normal controls (NC) (NC vs. LSD, U = 2.000, P = 0.024; NC vs. MM: U = 6.000, P = 0.043). Likewise, p-S6/S6 was also up-regulated in muscles from all three subgroups of IMMs (NC vs. LSD, U = 0.000, P = 0.006; NC vs. PD, U = 0.000, P = 0.006; NC vs. MM, U = 1.000, P = 0.007). Immunohistochemical study revealed that p-S6 was mainly expressed in fibers with metabolic defect. In MM muscles, most p-S6 positive fibers showed cytochrome C oxidase (COX) deficiency (U = 5.000, P = 0.001). In LSD and PD muscles, p-S6 was mainly overexpressed in fibers with intramuscular vacuoles containing lipid droplets (U = 0.000, P = 0.002) or basophilic materials (U = 0.000, P = 0.002). CONCLUSION The mTOR pathway might be activated in myofibers with various metabolic defects, which might provide evidence for mTOR inhibition therapy in human IMMs.
Adolescent ; Adult ; Aged ; Blotting, Western ; Child ; Child, Preschool ; Female ; Glycogen Storage Disease Type II ; genetics ; metabolism ; Humans ; Immunohistochemistry ; In Vitro Techniques ; Lipid Metabolism, Inborn Errors ; genetics ; metabolism ; Male ; Middle Aged ; Mitochondrial Myopathies ; genetics ; metabolism ; Muscular Diseases ; genetics ; metabolism ; Signal Transduction ; genetics ; physiology ; TOR Serine-Threonine Kinases ; metabolism ; Young Adult