ABSTRACT
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.
ABSTRACT
Objective To investigate the clinical features,magnetic resonance imaging (MRI),treatment,and follow-up of patients with glutaric aciduria type Ⅰ (GA-1).Methods Four pediatric patients with GA-1 diagnosed in our hospital were included in this study.They were treated with special diets and carnitine supplements.MRI and tandem mass spectrometry (MS/MS) were performed,and the mental development indices were measured.Results GA-1 was confirmed 2 months,13 months,4 months,and 7 months after birth.Seizure had been observed before the disease diagnosis in three patients and disappeared after treatment.In all four patients,T2-weighted brain MRI showed frontotemporal atrophy or hypoplasia and enlarged subarachnoid space in the sylvian fissures and anterior to the temporal lobes.Diffusion weighted imaging revealed high-density lesions over both the putamen and globus pallidus.The patients were followed up for 4 to 5 years.Plasma amino acids and acylcamitine profile were monitored every 3-5 months.The mean C5DC level and C5DC/C8 were kept the higher limits of the normal ranges,especially in case 3.During the follow-up,the body weight was at-2 SD-0 and the height at-1 SD-0.Intellectual development test showed that case 1 and case 4 had mildly abnormal intelligence,whereas case 2 and case 3 had extremely severe intellectual disability.Gene test confirmed the presence of gene mutations in all four cases,including IVS10-2A ＞ C homozygous mutation in cases 1,3,and 4 and [IVS10-2A ＞ C] + [c.245G ＞c(p.Arg82Pro)] hybrid mutation in case 2.Two female children were smoothly enrolled by local kindergarten,while two male children were unable to walk alone due to delayed motor development and spastic paralysis.Conclusions The phenotype of GA-1 patients is not remarkably correlated with its genotype correlation.Newborn screening is essential for identifying GA-1 patients.
ABSTRACT
In previous study,glutaric acid (GA) induced apoptosis of primary striatal neuron in vitro.In order to investigate the neurotoxic effects of GA on neonatal rat corpus striatum and the possible mechanism,34 male pups were randomly assigned to NS group,low dose GA (LGA,5 μmol GA/g body weight) group and high dose GA (HGA,10 μmol GA/g body weight) group.These pups were subcutaneously administered with three injections from postnatal day 3 to 22 at 7:30 am,15:00 pm and 22:30 pm and killed 12 h after the last injection.Microscopic pathology in corpus striatum was evaluated by HE staining.The apoptotic cells were identified by TUNEL staining.The transcript levels of caspase-3,8,9,Bax,Bcl-2 were detected by using real-time PCR and the protein levels of procaspase-3 and the active fraction were evaluated by Westem blotting.In LGA and HGA groups,ventricle collapse,cortical atrophy by a macroscope and interstitial edema,vacuolations,widened perivascular space of bilateral striatum by a microscope were observed.TUNEL assay revealed that the apoptotic cells were increased in LGA and HGA groups.The transcript of caspase-3 was up-regulated to 2.5 fold,accompanied by the up-regulation of caspase-9,Bax and down-regulation of Bcl-2.The protein levels ofprocaspase-3 and the active fraction were up-regulated in LGA and HGA groups.The rat model for GA Ⅰ showed mitochondrial apoptotic pathway may be involved in the GA-induced striatal lesion.Further studies should be taken to investigate the underlying mechanisms.
