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 investigate the clinical pathology and gene mutation characteristics of patients with glycogen storage disease type Ⅳ (GSD Ⅳ). Methods: The clinical data, liver histopathology and ultrastructural morphology, and gene sequencing results of 5 GSD Ⅳ cases diagnosed in the Children's Hospital Affiliated to Shanghai Jiaotong University School of Medicine and the Children's Hospital of Fudan University from January 2015 to February 2022 were collected and analyzed retrospectively. Results: Among the 5 cases, 3 were male and 2 were female, ranging in age from 4 months to 1 year and 9 months. The clinical manifestations included fever, hepatosplenomegaly, liver insufficiency, growth retardation and hypotonia. Four cases had liver biopsy showing ground-glass-like changes in hepatocytes with intracytoplasmic inclusion bodies and varying degrees of fibrosis. Liver electron microscopy in 2 cases showed that the level of glycogen increased to varying degrees, and the cytoplasm was filled with low electron density substances. Genetic testing revealed that 3 cases had compound heterozygous variants in GBE1 gene; 1 case had a single pathogenic variant in GBE1 gene; and 1 case was deceased with no genetic testing, but each parent was tested for a heterozygous variant in the GBE1 gene. A total of 9 GBE1 gene mutations were detected, 3 of which were reported mutations and 6 novel mutations. One case died of liver cirrhosis, and 1 case underwent autologous liver transplantation. After transplantation, the liver function basically returned to normal, and the growth and development improved; the other 3 cases were managed through diet control and symptomatic treatment. Conclusions: CSD Ⅳ is an extremely rare inherited metabolic disease caused by GBE1 gene mutation, often presenting with hepatic and neuromuscular disorders, with heterogeneous clinical manifestations. The diagnosis mainly depends on histopathology and a pedigree gene analysis.
Infant ; Child ; Humans ; Male ; Female ; Glycogen Storage Disease Type IV/pathology* ; Retrospective Studies ; China ; Mutation ; Genetic Testing/methods*

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*

OBJECTIVETo summarize clinical features and diagnosis of Chinese infantile patients with glycogen storage disease type II (GSD II).

METHODSix infant patients with GSD II diagnosed from January 2012 to June 2014 in the Department of Pediatrics, Peking University First Hospital were enrolled into this study. Clinical information of the 6 patients, including clinical manifestation, blood biochemistry, chest X-ray, echocardiogram, electrocardiogram, acid alpha-glucosidase (GAA) activity and GAA gene mutation analysis by direct sequencing of polymerase chain reaction (PCR) product were reviewed.

RESULTOf the 6 patients, five were female and one was male, five of whom were classic infantile type while the other one was atypical. The age of onset ranged from birth to 3-month-old. All patients had varying degrees of generalized muscle weakness, hypotonia and development retardation or retrogression. Other common findings were feeding difficulties in two patients, tongue weakness in two patients, respiratory distress in four patients, macroglossia in one patient, and hepatomegaly in two patients. Left ventricular hypertrophy and cardiomegaly were obvious in all the six patients. All six patients were found to have a enlarged heart in physical examination, and three patients who underwent a chest X-ray examination had an enlarged heart shadow. Four patients who had an echocardiography were found to have myocardial hypertrophy. The electrocardiogram in three patients showed short PR intervals and high voltage. The creatine kinase (CK) levels were three to seven times elevated. The mildest elevated CK was 441 IU/L, and the highest CK level was 1 238 U/L. Assay of GAA enzyme activity in whole blood showed significantly reduced activity (1.3 nmol/ (spot·d) to 2 nmol/(spot·d)) in the patients tested. Gene sequencing in 4 patients showed 8 pathogenic mutations, including 6 missense mutations, one nonsense mutation and one frameshift mutation. The missense mutations were c.998C > A (p.Thr333Lys), c.1280T > C (p.Met427Thr), c.1760T > C (p.Leu587Pro), c.1924G > T (p.Val642Phe), c.2012T > A (p.Met671Lys) and c.2105G > A (p.Arg702His). The nonsense mutation was c2662G > T (p.Glu888X), and the frameshift mutation was c2812_2813delTG (p.Cys938fs). The 5 classic infantile patients died at the age of 7 to 22 months. The atypical infantile patient was 2 years and five months old according to our latest follow up.

CONCLUSIONInfantile GSD II had similar motor manifestations and cardiac involvements, blood biochemical test, imaging findings, enzyme assays, though there were slight differences. The probability of GSD II should be taken into consideration if an infant has both muscular disease and cardiac involvement.

Asian Continental Ancestry Group ; Female ; Glycogen Storage Disease Type II ; diagnosis ; pathology ; Humans ; Infant ; Infant, Newborn ; Macroglossia ; congenital ; Male ; Muscle Weakness ; Mutation ; Mutation, Missense ; Polymerase Chain Reaction ; alpha-Glucosidases ; genetics ; metabolism

Glycogen storage disease type V (GSD-V) is the most common disorder of muscle glycogenosis with characteristic clinical and laboratory findings. A 32-yr-old woman complained of exercise intolerance and myoglobulinuria since early adolescence. She reported several episodes of second-wind phenomenon. Physical examination did not show any neurological abnormality, including fixed muscle weakness or atrophy. Serum creatine kinase level was 1,161 IU/L at rest. The result of the non-ischemic forearm exercise test was compatible with GSD-V. Mutation analysis identified the compound heterozygous mutations of the PYGM, p.D510fs and p.F710del, which has not yet been reported in Korea. The present case recognizes that detail clinical and laboratory analysis is the first step in the diagnosis of GSD-V.
Adult ; Base Sequence ; Creatine Kinase/blood ; Exons ; Female ; Frameshift Mutation ; Gene Deletion ; Genotype ; Glycogen Phosphorylase, Muscle Form/genetics ; Glycogen Storage Disease Type V/*diagnosis/genetics/pathology ; Humans ; Pedigree ; Sequence Analysis, DNA

Bronchopulmonary Dysplasia ; diagnostic imaging ; pathology ; therapy ; Female ; Glycogen Storage Disease ; diagnosis ; pathology ; therapy ; Humans ; Infant ; Infant, Newborn ; Lung ; diagnostic imaging ; growth & development ; pathology ; Lung Diseases, Interstitial ; classification ; diagnosis ; pathology ; therapy ; Male ; Neurosecretory Systems ; pathology ; Pediatrics ; Tomography, X-Ray Computed

Glycogenic hepatopathy (GH) is an uncommon cause of serum transaminase elevation in type I diabetes mellitus (DM). The clinical signs and symptoms of GH are nonspecific, and include abdominal discomfort, mild hepatomegaly, and transaminase elevation. In this report we describe three cases of patients presenting serum transaminase elevation and hepatomegaly with a history of poorly controlled type I DM. All of the cases showed sudden elevation of transaminase to more than 30 times the upper normal range (like in acute hepatitis) followed by sustained fluctuation (like in relapsing hepatitis). However, the patients did not show any symptom or sign of acute hepatitis. We therefore performed a liver biopsy to confirm the cause of liver enzyme elevation, which revealed GH. Clinicians should be aware of GH so as to prevent diagnostic delay and misdiagnosis, and have sufficient insight into GH; this will be aided by the present report of three cases along with a literature review.
Acute Disease ; Adult ; Alanine Transaminase/blood ; Aspartate Aminotransferases/blood ; Delayed Diagnosis ; Diabetes Mellitus, Type 1/complications/*pathology ; Diagnostic Errors ; Female ; Glycogen Storage Disease/complications/*diagnosis/ultrasonography ; Hepatitis/diagnosis ; Hepatomegaly/complications/*diagnosis/ultrasonography ; Humans ; Liver/pathology ; Recurrence ; Young Adult

OBJECTIVES: Dental technicians are exposed to methyl methacrylate(MMA) and hard metal dusts while working, and several cases of hypersensitivity pneumonitis caused by the exposure have been reported. The authors experienced a case of hypersensitivity pneumonitis in a female dental technician who had 10 years' work experience and report the case with clinical evidence. METHOD: The patient's work, personal, social, and past and present medical histories were investigated based on patient questioning and medical records. Furthermore, the workplace conditions and tools and materials the patient worked with were also evaluated. Next, the pathophysiology and risk factors of pneumonitis were studied, and studies on the relationship between hypersensitivity pneumonitis and a dental technician's exposure to dust were reviewed. Any changes in the clinical course of her disease were noted for evaluation of the work-relatedness of the disease. RESULTS: The patient complained of cough and sputum for 1 year. In addition, while walking up the stairs, the patient was not able to ascend without resting due to dyspnea. She visited our emergency department due to epistaxis, and secondary hypertension was incidentally suspected. Laboratory tests including serologic, electrolyte, and endocrinologic tests and a simple chest radiograph showed no specific findings, but chest computed tomography revealed a centrilobular ground-glass pattern in both lung fields. A transbronchial biopsy was performed, and bronchoalveolar washing fluid was obtained. Among the findings of the laboratory tests, microcalcification, noncaseating granuloma containing foreign body-type giant cells, and metal particles within macrophages were identified histologically. Based on these results, hypersensitivity pneumonitis was diagnosed. The patient stopped working due to admission, and she completely quit her job within 2 months of restarting work due to reappearance of the symptoms. CONCLUSION: In this study, the patient did not have typical radiologic findings, but pathological evaluation of the lung biopsy from the bronchoscope led to the suspicion of pneumonitis. Under the microscope, the sample contained fibrotic changes in the lung, multinucleated giant cells, and particles in macrophages and was diagnosed as dental technician pneumoconiosis by the pathology. Working as a dental technician had directly exposed her to light metal dust and MMA, and her clinical symptoms and radiologic findings subsided after withdrawal from exposure to the workplace. These outcomes led to the diagnosis of hypersensitity pneumonitis due to MMA exposure and strong work-relatedness.
Alveolitis, Extrinsic Allergic* ; Biopsy ; Bronchoscopes ; Cough ; Dental Technicians* ; Diagnosis ; Dust ; Dyspnea ; Emergencies ; Epistaxis ; Female* ; Giant Cells* ; Giant Cells, Foreign-Body ; Glycogen Storage Disease Type VI ; Granuloma ; Humans ; Hypersensitivity* ; Hypertension ; Lung ; Macrophages ; Medical Records ; Pathology ; Pneumoconiosis ; Pneumonia ; Radiography, Thoracic ; Risk Factors ; Sputum ; Thorax ; Walking

OBJECTIVETo analyze and summarize the characteristics of glycogen storage disease type II (Pompe disease) patients according to the clinical description and prognosis.

METHODSeventeen Chinese patients diagnosed by acid alpha-glucosidase (GAA) enzyme activity test were reviewed. Clinical data tables were designed. Interviews were made via phone calls. Information was collected to reach the objective.

RESULTFour of 17 patients diagnosed by acid alpha-glucosidase are infantile-onset, symptoms started between 2 to 6 months after birth with increased serum creatine kinase and cardiac problems, with or without respiratory concerns. Other 13 patients were later-onset cases, and their symptoms started between 2 to 22 years of age with increased serum creatine kinase. Eleven later-onset patients started with muscle weakness, 2 patients developed respiratory insufficiency, 2 patients showed scoliosis, and 1 patient expressed increased serum creatine kinase with abnormal liver function. Just 3 of the later-onset patients were treated with mechanical ventilator and adjuvant therapy, others were not. All patients' acid alpha-glucosidase (GAA) enzyme activity analysis showed lower than 10% of normal. Fourteen patients were tested by muscle biopsy pathology, and 9 of them progressed to glycogen storage disease type II; 10 patients received genetic analysis, and 6 of them had two mutations which cause the disorder. Twelve of the 17 patients were interviewed successfully. In 3 of the infant-onset patients the disease resulted in death from respiratory failure, and 1 is still alive at the age of 1 year and 7 months. In 4 of 8 later-onset patients the disease resulted in death from respiratory failure between 3 to 5 years after onset of symptoms. Three of 4 survivors had increased muscle weakness, and 1 patient kept alive with ventilator without any changes. Seven of 12 interviewed patients died, the mortality rate was 58.3%.

CONCLUSIONGlycogen storage disease type II (Pompe disease) present differently in the clinic. Infant-onset Pompe disease is mainly characterized by generalized muscle weakness and obvious cardiac involvement. It's a dangerous disease, with high mortality rate. Later-onset Pompe disease is characterized by chronic proximal muscle weakness and respiratory insufficiency. GAA enzyme activity analysis, muscle biopsy and genetic analysis used to support the diagnosis of Pompe disease. Prognosis of the disease depends on age of onset and respiratory muscle involvement.

Adolescent ; Biopsy ; Cardiomyopathies ; epidemiology ; etiology ; Child ; Child, Preschool ; Clinical Enzyme Tests ; Creatine Kinase ; blood ; Female ; Follow-Up Studies ; Glucan 1,4-alpha-Glucosidase ; genetics ; metabolism ; Glycogen Storage Disease Type II ; diagnosis ; genetics ; pathology ; Humans ; Infant ; Male ; Muscle Weakness ; epidemiology ; etiology ; Prognosis ; Respiratory Insufficiency ; epidemiology ; Retrospective Studies ; Young Adult

Adult ; Diagnosis, Differential ; Female ; Glycogen ; metabolism ; Glycogen Storage Disease Type II ; pathology ; Humans ; Liver ; metabolism ; pathology ; Muscle, Skeletal ; metabolism ; pathology ; Muscular Dystrophies, Limb-Girdle ; pathology ; Pyomyositis ; pathology ; Young Adult