Glutaric aciduria type 1 is an inborn error of lysine, hydroxylysine, and tryptophan metabolism caused by deficiency of glutaryl-coenzyme A dehydrogenase. The disease often appears in infancy with encephalopathy episode that results in acute basal ganglia and white matter degeneration. The majority of patients develop a dystonic-dyskinetic syndrome. This reports 6year-old boy who had been done previous gastrostomy due to swallowing difficulty underwent bilateral pallidotomy with intraoperative electromyography(EMG) monitoring for disabling dystonia. Intraoperative EMG was used to assess stimulation thresholds required for capsular responses and muscle tone. Surface EMG electrodes were placed on the face and cricopharyngeal muscles. Exact target were directly modified according to MRI-visualized anatomy. EMG response was consistently seen prior to visual observation of muscle activity. The surgery improved dystonic symptoms without swallowing difficulty.
Basal Ganglia ; Deglutition ; Dystonia* ; Electrodes ; Gastrostomy ; Glutaryl-CoA Dehydrogenase ; Humans ; Hydroxylysine ; Lysine ; Male ; Metabolism ; Muscles ; Pallidotomy* ; Tryptophan

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

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

A one-year-old girl visited the hospital due to limb torsion and developmental regression for one month after hand, foot and mouth disease. At the age of 11 months, she visited a local hospital due to fever for 5 days and skin rash with frequent convulsions for 2 days and was diagnosed with severe hand, foot and mouth disease, viral encephalitis, and status epilepticus. Brain MRI revealed symmetric abnormal signals in the bilateral basal ganglia, bilateral thalamus, cerebral peduncle, bilateral cortex, and hippocampus. She was given immunoglobulin, antiviral drugs, and anticonvulsant drugs for 2 weeks, and the effect was poor. Blood and urine screening for inherited metabolic diseases were performed to clarify the etiology. The analysis of urine organic acids showed significant increases in glutaric acid and 3-hydroxyglutaric acid, which suggested glutaric aciduria type 1, but her blood glutarylcarnitine was normal, and free carnitine significantly decreased. After the treatment with low-lysine diets, L-carnitine, and baclofen for 1 month, the patient showed a significant improvement in symptoms. Hand, foot and mouth disease is a common viral infectious disease in children, and children with underlying diseases such as inherited metabolic diseases and immunodeficiency may experience serious complications. For children with hand, foot and mouth disease and unexplained encephalopathy, inherited metabolic diseases should be considered.
Amino Acid Metabolism, Inborn Errors ; etiology ; Brain Diseases, Metabolic ; etiology ; Developmental Disabilities ; etiology ; Female ; Glutaryl-CoA Dehydrogenase ; deficiency ; Hand, Foot and Mouth Disease ; complications ; Humans ; Infant ; Torsion Abnormality ; etiology

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

Glutaric aciduria type 1(GA1) is an autosomal recessive disorder of the lysine, hydroxylysine and tryptophan metabolism caused by the deficiency of mitochondrial glutaryl-CoA dehydrogenase. This disease is characterized by macrocephaly at birth or shortly after birth and various neurologic symptoms. Between the first weeks and the 4-5th year of life, intercurrent illness such as viral infections, gastroenteritis, or even routine immunizations can trigger acute encephalopathy, causing injury to caudate nucleus and putamen. But intellectual functions are well preserved until late in the disease course. We report a one-month-old male infant with macrocephaly and hypotonia. In brain MRI, there was frontotemporal atrophy(widening of sylvian cistern). In metabolic investigation, there were high glutarylcarnitine level in tandem mass spectrometry and high glutarate in urine organic acid analysis, GA1 was confirmed by absent glutaryl-CoA dehydrogenase activity in fibroblast culture. He was managed with lysine free milk and carnitine and riboflavin. He developed well without a metabolic crisis. If there is macrocephaly in an infant with neuroradiologic sign of frontotemporal atrophy, GA1 should have a high priority in the differential diagnosis. Because current therapy can prevent brain degeneration in more than 90% of affected infants who are treated prospectively, recognition of this disorder before the brain has been injured is essential for treatment.
Atrophy ; Brain ; Carnitine ; Caudate Nucleus ; Diagnosis, Differential ; Fibroblasts ; Gastroenteritis ; Glutaryl-CoA Dehydrogenase ; Humans ; Hydroxylysine ; Immunization ; Infant ; Lysine ; Macrocephaly* ; Magnetic Resonance Imaging ; Male ; Metabolism ; Milk ; Muscle Hypotonia ; Neurologic Manifestations ; Parturition ; Putamen ; Riboflavin ; Tandem Mass Spectrometry ; Tryptophan

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

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

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