1.Clinical phenotype and novel mutation in one of twins with glutaric acidemia type I.
Ying WANG ; Shujun FU ; Yuqi YANG ; Huaiyan WANG ; Yuping ZHANG ; Hong ZHOU ; Bin YU
Chinese Journal of Medical Genetics 2019;36(6):602-605
OBJECTIVE:
To review the clinical features of a male twin affected with glutaric academia type I (GA-I) and analyze the variations of glutaryl-CoA dehydrogenase (GCDH) gene.
METHODS:
Clinical data of the pair of twins and their parents were collected. Genomic DNA was extracted from peripheral blood samples, and variants of GCDH genes were detected by capture sequencing using a customized panel. Variants of the twins and their parents were verified by Sanger sequencing.
RESULTS:
The level of glutaric acyl carnitine (C5DC + C6OH) was 3.26 μmol/L in the male twin. The relative level of glutaric acid in urine was 547.51 by gas chromatography mass spectrometry analysis. Cerebral ultrasonography showed that the patient had subependymal hemorrhage, but no serious clinical manifestation was noted. After treating with special formula milk powder and L-carnitine, the boy showed good growth and development. Two heterozygous variants of the GCDH gene were detected in the patient, among which c.416C>G was suspected to be pathogenic, while c.109_110delCA was unreported. The variants were respectively inherited from his parents. The twin girl only carried the c.416C>G variant.
CONCLUSION
GA-I can be diagnosed by mass spectrometry, urine gas chromatographic mass spectrometry, imaging as well as genetic diagnosis. Early diagnosis and intervention is important.
Amino Acid Metabolism, Inborn Errors
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genetics
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Brain Diseases, Metabolic
;
genetics
;
Female
;
Glutaryl-CoA Dehydrogenase
;
deficiency
;
genetics
;
Humans
;
Male
;
Mutation
;
Phenotype
2.Analysis of CGDH gene variants and clinical features in three patients with glutaric aciduria type Ⅰ.
Jianqiang TAN ; Dayu CHEN ; Tizhen YAN ; Jun HUANG ; Ren CAI
Chinese Journal of Medical Genetics 2019;36(9):882-885
OBJECTIVE:
To screen for potential variants of GCDH gene in 3 patients clinically diagnosed as glutaric aciduria type Ⅰ.
METHODS:
GCDH gene variants was detected by Sanger sequencing among the three children and their family members.
RESULTS:
Sanger sequencing showed that patient 1 carried compound heterozygosity variants of c.532G>A (p.Gly178Arg) and c.655G>A (p.Ala219Thr) of the GCDH gene, while his father and mother respectively carried heterozygous c.532G>A(p.Gly178Arg) and c.655G>A (p.Ala219Thr) variants. Patient 2 carried c.532G>A (p.Gly178Arg) and a novel c.1060G>T (p.Gly354Cys) compound heterozygous variant, while his father and mother respectively carried heterozygous c.532G>A (p.Gly178Arg) and c.1060G>T (p.Gly354Cys) variant. Patient 3 carried homozygous c.532G>A (p.Gly178Arg) variant of the GCDH gene, for which both of his parents were heterozygous carriers.
CONCLUSION
The GCDH gene variant probably underlie the glutaric aciduria type Ⅰ among the 3 patients. Identifcation of the novel variant has enriched the spectrum of GCDH gene variants.
Amino Acid Metabolism, Inborn Errors
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genetics
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Brain Diseases, Metabolic
;
genetics
;
Female
;
Glutaryl-CoA Dehydrogenase
;
deficiency
;
genetics
;
Heterozygote
;
Humans
;
Male
3.Clinical and variation analysis of three Chinese families affected with glutaric acidemia type 1.
Xiaorong SHI ; Zhonglin KE ; Aidong ZHENG ; Wenhuang XIE ; Guiling MO
Chinese Journal of Medical Genetics 2018;35(6):796-799
OBJECTIVE:
To detect potential variation in glutaryl-CoA dehydrogenase (GCDH) gene among three Chinese families affected with glutaric acidemia type Ⅰ(GA-1) and correlate the genotypes with phenotypes.
METHODS:
Genomic DNA was extracted from peripheral blood samples derived from three patients with GA-1 and their family members. The coding regions of the GCDH gene were amplified with PCR and subjected to Sanger sequencing.
RESULTS:
The clinical manifestation of the patients varied from macrocephaly to severe encephalopathy, with notable phenotypic difference between siblings carrying the same variation. In pedigrees 1 and 2, the probands have carried compound heterozygous variations c.1133C>T(p.Ala378Val) and c.1244-2A>C, which were derived their fathers and mothers, respectively. In pedigree 3, the proband has carried compound heterozygous variation c.339delT (p.Tyr113) and c.406G>T (p.Gly136Cys). Among these, variations c.339delT and c.1133C>T were verified as novel by retrieval of dsSNP, HGMD and 1000 genome database. Bioinformatic analysis suggested that above variations can affect protein function and are probably pathogenic.
CONCLUSION
Above discovery has expanded the mutation spectrum of the GCDH gene. No correlation was found between the clinical phenotype and genotype of GA-1 patients.
Amino Acid Metabolism, Inborn Errors
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diagnosis
;
genetics
;
Brain Diseases, Metabolic
;
diagnosis
;
genetics
;
China
;
DNA Mutational Analysis
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Glutaryl-CoA Dehydrogenase
;
deficiency
;
genetics
;
Humans
;
Mutation
4.Analysis of GCDH gene variant in a child with Glutaric aciduria type I.
Hanjun YIN ; Qiong XUE ; Suyue ZHU
Chinese Journal of Medical Genetics 2022;39(1):39-42
OBJECTIVE:
To explore the genetic basis for a neonate affected with Glutaric aciduria type I (GA-I).
METHODS:
Targeted capture and high-throughput sequencing was carried out for the proband and her parents. Candidate variants were verified by Sanger sequencing.
RESULTS:
The proband was found to harbor compound heterozygous variants of the GCDH gene, namely c.523G>A and c.1190T>C, which was derived from her father and mother, respectively.
CONCLUSION
The compound heterozygous variants of the GCDH gene probably underlay the GA-I in the patient.
Amino Acid Metabolism, Inborn Errors/genetics*
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Brain Diseases, Metabolic/genetics*
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Child
;
Female
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Glutaryl-CoA Dehydrogenase/genetics*
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High-Throughput Nucleotide Sequencing
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Humans
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Infant, Newborn
;
Mutation
5.Mutation analysis of GCDH gene in eight patients with glutaric aciduria type I.
Jing CHEN ; Zhao-xia WANG ; Jin-li ZHANG ; Yan-ling YANG ; Jing CHEN ; Yi-ning HUANG
Chinese Journal of Medical Genetics 2011;28(4):374-378
OBJECTIVETo investigate the mutations of glutaryl-CoA dehydrogenase (GCDH) gene in patients with glutaric aciduria type I(GA-1).
METHODSGenomic DNA was extracted from peripheral blood cells of the eight probands with GA-1 who were diagnosed by urine and blood analyses. By PCR and direct sequencing, all 11 exons and their flanking sequences of the GCDH gene were examined. Mutation search was also performed in some of their family members.
RESULTSAmong the eight patients diagnosed by metabolic screening, seven patients belonged to classical infantile-onset. One patient, however, was adult-onset, who was admitted to the hospital because of suffering from ischemic cerebral stroke. The GCDH gene mutations were identified in all the eight probands with GA-1: five of them had compound heterozygous mutations, while the other three harbored only one heterozygous mutation. Totally, nine different mutations of the GCDH gene were identified in the eight probands, four of them were novel, i.e., c.148T>C, c.371G>A, 909delC and c.263G>A.
CONCLUSIONGCDH gene mutations are identified in 8 patients with GA-1 in mainland China, including one adult patient with late onset. Four novel mutations of GCDH gene are found which expanded the mutational spectrum of the GCDH gene.
Adult ; Amino Acid Metabolism, Inborn Errors ; enzymology ; genetics ; Amino Acid Sequence ; Animals ; Base Sequence ; Brain Diseases, Metabolic ; enzymology ; genetics ; DNA Mutational Analysis ; Exons ; genetics ; Female ; Glutaryl-CoA Dehydrogenase ; chemistry ; deficiency ; genetics ; Humans ; Infant ; Male ; Molecular Sequence Data
6.Complex heterogeneity phenotypes and genotypes of glutaric aciduria type 1.
Chinese Journal of Contemporary Pediatrics 2016;18(5):460-465
Glutaric aciduria type 1 is a rare autosomal recessive disorder. GCDH gene mutations cause glutaryl-CoA dehydrogenase deficiency and accumulation of glutaric acid and 3-hydroxyglutaric acid, resulting in damage of striatum and other brain nucleus and neurodegeneration. Patients with glutaric aciduria type 1 present with complex heterogeneous phenotypes and genotypes. The symptoms are extremely variable. The ages of the clinical onset of the patients range from the fetus period to adulthood. The patients with mild glutaric aciduria type 1 are almost asymptomatic before onset, however, severe glutaric aciduria type 1 may cause death or disability due to acute encephalopathy. Acute metabolic crisis in patients with underlying glutaric aciduria type 1 is often triggered by febrile illnesses, trauma, hunger, high-protein foods and vaccination during a vulnerable period of brain development in infancy or early childhood. The early-onset patients usually have a poor prognosis. Urinary organic acids analysis, blood acylcarnitines analysis and GCDH study are important for the diagnosis of this disorder. Neonatal screening is essential for the early diagnosis and the improvement of prognosis.
Amino Acid Metabolism, Inborn Errors
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diagnosis
;
genetics
;
therapy
;
Brain Diseases, Metabolic
;
diagnosis
;
genetics
;
therapy
;
Genotype
;
Glutaryl-CoA Dehydrogenase
;
deficiency
;
genetics
;
Humans
;
Infant, Newborn
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Neonatal Screening
;
Phenotype
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Prenatal Diagnosis
;
Prognosis
7.Analysis of clinical features and GCDH gene mutations in four patients with glutaric academia type I.
Peng -qiang WEN ; Guo-bing WANG ; Xiao-hong LIU ; Zhan-ling CHEN ; Yue SHANG ; Dong CUI ; Ping SONG ; Quan YUAN ; Shu-li CHEN ; Jian-xiang LIAO ; Cheng-rong LI
Chinese Journal of Medical Genetics 2012;29(6):642-647
OBJECTIVETo review clinical features of four male patients with glutaric academia type I and screen glutaryl-CoA dehydrogenase (GCDH) gene mutations.
METHODSThe 4 patients underwent brain computer tomography (CT) and magnetic resonance imaging (MRI) analyses. Blood acylcarnitine and urine organic acid were analyzed with tandem mass spectrometry and gas chromatographic mass spectrometry. Genomic DNA was extracted from peripheral blood samples. The 11 exons and flanking sequences of GCDH gene were amplified with PCR and subjected to direct DNA sequencing.
RESULTSAll patients have manifested macrocephaly, with head circumference measured 50 cm (14 months), 47 cm (9 months), 46 cm (5 months) and 51 cm (14 months), respectively. Imaging analyses also revealed dilation of Sylvian fissure and lateral ventricles, frontotemporal atrophy, subarachnoid space enlargement and cerebellar vermis abnormalities. All patients had elevated glutarylcarnitine (5.8 umol/L, 7.5 umol/L, 8.3 umol/L and 7.9 umol/L, respectively) and high urinary excretion of glutaric acid. Seven mutations were identified among the patients, among which c.146_149del4, IVS6-4_Ex7+4del8, c.508A>G (p.K170E), c.797T>C (p.M266T) and c.420del10 were first discovered.
CONCLUSIONMacrocephaly and neurological impairment are the most prominent features of glutaric academia type I. Blood tandem mass spectrometry and urine gas chromatographic mass spectrometry analysis can facilitate the diagnosis. The results can be confirmed by analysis of GCDH gene mutations.
Amino Acid Metabolism, Inborn Errors ; diagnosis ; genetics ; metabolism ; Amino Acid Sequence ; Base Sequence ; Brain Diseases, Metabolic ; diagnosis ; genetics ; metabolism ; Glutaryl-CoA Dehydrogenase ; deficiency ; genetics ; metabolism ; Humans ; Infant ; Male ; Molecular Sequence Data ; Mutation ; Sequence Alignment
8.Effect of glutaryl-CoA dehydrogenase gene silencing and high-concentration lysine on the viability of BRL hepatocytes.
Jin-Zhi GAO ; Cai ZHANG ; Qin YI ; Yan-Qin YING ; Xiao-Ping LUO
Chinese Journal of Contemporary Pediatrics 2017;19(9):1014-1019
OBJECTIVETo investigate the effect of glutaryl-CoA dehydrogenase (GCDH) gene silencing and accumulation of lysine metabolites on the viability of hepatocytes.
METHODSBRL cells were divided into normal control group, negative control group, and GCDH silencing group. The shRNA lentiviral vector for silencing GCDH gene was constructed, and the BRL hepatocytes in the GCDH silencing group and the negative control group were infected with this lentivirus and negative control virus respectively, and then cultured in a medium containing 5 mmol/L lysine. Immunofluorescence assay was used to measure the infection efficiency of lentivirus. Western blot was used to measure the expression of GCDH protein. MTT assay was used to evaluate cell viability. Hoechest33342 staining was used to measure cell apoptosis. Western blot was used to measure the expression of Caspase-3, an index of cell apoptosis.
RESULTSThe lentivirus constructed effectively silenced the GCDH gene in hepatocytes (P<0.01). MTT assay and Hoechest 33342 staining showed no significant differences in cell viability and apoptosis between groups (P>0.05). There was also no significant difference in the expression of Caspase-3 protein between groups (P>0.05).
CONCLUSIONSGCDH gene silencing and accumulation of lysine metabolites may not cause marked hepatocyte injury.
Amino Acid Metabolism, Inborn Errors ; pathology ; therapy ; Animals ; Apoptosis ; Brain Diseases, Metabolic ; pathology ; therapy ; Caspase 3 ; metabolism ; Cell Survival ; Cells, Cultured ; Fluorescent Antibody Technique ; Gene Silencing ; Glutaryl-CoA Dehydrogenase ; deficiency ; genetics ; Hepatocytes ; pathology ; Lysine ; metabolism ; Rats
9.Progress of glutaric aciduria type I.
Chinese Journal of Pediatrics 2012;50(12):912-914
Amino Acid Metabolism, Inborn Errors
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diagnosis
;
genetics
;
therapy
;
Brain
;
diagnostic imaging
;
metabolism
;
pathology
;
Brain Diseases, Metabolic
;
diagnosis
;
genetics
;
therapy
;
Child, Preschool
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Diagnosis, Differential
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Glutarates
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metabolism
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Glutaryl-CoA Dehydrogenase
;
deficiency
;
genetics
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Humans
;
Infant
;
Infant, Newborn
;
Lysine
;
metabolism
;
Magnetic Resonance Imaging
;
Multiple Acyl Coenzyme A Dehydrogenase Deficiency
;
diagnosis
;
genetics
;
therapy
;
Mutation
;
Neonatal Screening
;
methods
;
Radiography
10.Mutation analysis of GCDH gene in four patients with glutaric academia type I.
Qi LIU ; Yiping CHEN ; Wei CHEN
Chinese Journal of Medical Genetics 2015;32(2):187-191
OBJECTIVETo report on clinical features of four patients with glutaric academia type Ⅰ (GA-1) and mutations identified in the glutaryl-CoA dehydrogenase (GCDH) gene.
METHODSAll of the patients underwent magnetic resonance imaging (MRI) analysis. Blood acylcarnitine and urine organic acid were analyzed with tandem mass spectrometry and gas chromatographic mass spectrometry. Genomic DNA was extracted from peripheral blood samples. The 11 exons and flanking sequences of the GCDH gene were amplified with PCR and subjected to direct DNA sequencing.
RESULTSMutations of the GCDH gene were identified in all of the patients. Three had homozygous mutations. A recurrent mutation, IVS10-2A>C, was found in the four unrelated families, while the mutation of c.245G>C (p.Arg82Pro) was novel.
CONCLUSIONIVS10-2A>C is likely a founder mutation for Chinese population in Wenzhou.
Amino Acid Metabolism, Inborn Errors ; diagnostic imaging ; enzymology ; genetics ; Amino Acid Sequence ; Asian Continental Ancestry Group ; genetics ; Base Sequence ; Brain Diseases, Metabolic ; diagnostic imaging ; enzymology ; genetics ; DNA Mutational Analysis ; Exons ; Female ; Glutaryl-CoA Dehydrogenase ; chemistry ; deficiency ; genetics ; metabolism ; Humans ; Infant ; Magnetic Resonance Imaging ; Male ; Molecular Sequence Data ; Point Mutation ; Radiography ; Sequence Alignment