OBJECTIVE: To explore the genetic basis for a child affected with cerebral creatine deficiency syndrome 1 (CCDS1). METHODS: High-throughput sequencing was carried out to screen pathogenic variant associated with the clinical phenotype of the proband. The candidate variant was verified by Sanger sequencing. RESULTS: High-throughput sequencing revealed that the proband has carried heterozygous c.327delG variant of the SLC6A8 gene, which was verified by Sanger sequencing.Neither parent was found to carry the same variant. CONCLUSION The de novo heterozygous c.327delG variant of the SLC6A8 gene probably underlay the CCDS1 in this child.
Brain Diseases, Metabolic, Inborn/genetics* ; Creatine ; Genetic Testing ; Heterozygote ; Humans ; Mental Retardation, X-Linked ; Mutation

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 ; genetics ; Brain Diseases, Metabolic ; genetics ; Female ; Glutaryl-CoA Dehydrogenase ; deficiency ; genetics ; Heterozygote ; Humans ; Male

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 ; genetics ; Brain Diseases, Metabolic ; genetics ; Female ; Glutaryl-CoA Dehydrogenase ; deficiency ; genetics ; Humans ; Male ; Mutation ; Phenotype

OBJECTIVETo explore pathogenic mutation in a family affected with 2-hydroxyglutaric aciduria.

METHODSExons of 3 candidate genes, including L2HGDH, D2HGDH and SLC25A1, were amplified with polymerase chain reaction and subjected to direct sequencing.

RESULTSDNA sequencing has found that the proband and his affected younger brother have both carried a heterozygous mutation c.845G>A (p.R282Q) in the exon 7 of the L2HGDH gene. The same mutation was not detected in the his sister who was healthy. Pedigree analysis has confirmed that the above mutation was inherited from the mother. No mutation was detected in exons and flanking sequences of the D2HGDH and SLC25A1 genes.

CONCLUSIONMutation of the L2HGDH gene probably underlies the 2-hydroxyglutaric aciduria in this family.

Alcohol Oxidoreductases ; genetics ; Base Sequence ; Brain ; diagnostic imaging ; Brain Diseases, Metabolic, Inborn ; diagnostic imaging ; enzymology ; genetics ; Child ; Female ; Humans ; Male ; Molecular Sequence Data ; Mutation ; Pedigree ; Radiography ; Young Adult

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 ; diagnosis ; genetics ; Brain Diseases, Metabolic ; diagnosis ; genetics ; China ; DNA Mutational Analysis ; Glutaryl-CoA Dehydrogenase ; deficiency ; genetics ; Humans ; Mutation

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* ; Brain Diseases, Metabolic/genetics* ; Child ; Female ; Glutaryl-CoA Dehydrogenase/genetics* ; High-Throughput Nucleotide Sequencing ; Humans ; Infant, Newborn ; Mutation

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

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

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 ; diagnosis ; genetics ; therapy ; Brain Diseases, Metabolic ; diagnosis ; genetics ; therapy ; Genotype ; Glutaryl-CoA Dehydrogenase ; deficiency ; genetics ; Humans ; Infant, Newborn ; Neonatal Screening ; Phenotype ; Prenatal Diagnosis ; Prognosis

Amino Acid Metabolism, Inborn Errors ; diagnosis ; genetics ; therapy ; Brain ; diagnostic imaging ; metabolism ; pathology ; Brain Diseases, Metabolic ; diagnosis ; genetics ; therapy ; Child, Preschool ; Diagnosis, Differential ; Glutarates ; metabolism ; Glutaryl-CoA Dehydrogenase ; deficiency ; genetics ; Humans ; Infant ; Infant, Newborn ; Lysine ; metabolism ; Magnetic Resonance Imaging ; Multiple Acyl Coenzyme A Dehydrogenase Deficiency ; diagnosis ; genetics ; therapy ; Mutation ; Neonatal Screening ; methods ; Radiography