Case Report: Identification of a Novel Homozygous Mutation in GPD1 Gene of a Chinese Child With Transient Infantile Hypertriglyceridemia.
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SUBMITTER: Lin H
PROVIDER: S-EPMC8416348 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundTransient infantile hypertriglyceridemia (HTGTI) is an autosomal recessive disorder caused by mutations in the glycerol-3-phosphate dehydrogenase 1 (GPD1) gene.Case presentationWe report a case of HTGTI in a Chinese female infant. She presented with hepatomegaly, hypertriglyceridemia, moderately elevated transaminases, and hepatic steatosis at 3.5 months of age. A novel mutation c.523C>T, p. (Q175*) was identified in GPD1. The patient was a homozygote and her parents were heterozygous for the mutation. Ultrastructural study showed intrahepatocytic lipid droplets.ConclusionsThis is the first reported case of HTGTI in Chinese, expanding the worldwide distribution of HTGTI and the mutation spectrum of GPD1.
| S-EPMC6020200 | biostudies-literature
Project description:Objective : Our study aims to summarize and analyze the clinical characteristics of transient infantile hypertriglyceridemia (HTGTI) and variants in the glycerol-3-phosphate dehydrogenase 1 (GPD1) gene and the effect of HTGTI on the protein structure of GPD1. Methods: Retrospective analysis, using the general data, symptoms, signs, and auxiliary examinations, was performed on patients with HTGTI, which were confirmed by genetic testing in our hospital and reported cases online. The clinical data were analyzed using statistical and bioinformatic approaches. Results: A total of 31 genetically confirmed HTGTI patients were collected from our hospital and cases reported in the literature. The clinical manifestations showed the median age of onset was 6.0 (1.9, 12.0) months. All the patients had normal psychiatric status, but 22.6% of them presented growth retardation and short stature, 93.5% had hepatomegaly, and 16.1% had splenomegaly. Just a few children were reported with jaundice, cholestasis, and obesity (3.2-6.5%). The laboratory investigations showed that 96.8% of them had hypertriglyceridemia (HTG) with a median level of 3.1 (2.1, 5.5) mmol/L, but only 30.0% had returned to normal during follow-up. In addition, 93.5% of patients had elevated alanine aminotransferase (ALT) with an average level of 92.1 ± 43.5 U/L, while 38.7% had hypercholesterolemia. Upon abdominal imaging, all patients presented fatty liver and liver steatosis, with 66.7% of patients showing hepatic fibrosis. Statistical differences in triglyceride (TG) level were observed in the ≤6 months group compared with the older groups and in the 13 months to 6 years group with >6 years group (H = 22.02, P < 0.05). The restricted cubic spline model showed that severe HTG decreased in the early stage of infants to the normal level; however, it rebounded again to a mild or moderate level after the following days. The genetic test revealed that the main variant types of the GPD1 gene were missense variants (51.6%), followed by splicing variants (35.5%) and nonsense variants (12.9%). Of patients, 87.1% had homozygous variants, with the most frequent loci being c.361-1G > C and c.895G > A. Conclusion: The common manifestations of HTGTI were HTG, hepatomegaly, elevated liver transaminases, and hepatic steatosis in early infancy. However, the recurrence of aberrant HTG may pose long-term detrimental effects on HTGTI patients.
| S-EPMC9424621 | biostudies-literature
Project description:The molecular basis for primary hereditary hypertriglyceridemia has been identified in fewer than 5% of cases. Investigation of monogenic dyslipidemias has the potential to expose key metabolic pathways. We describe a hitherto unreported disease in ten individuals manifesting as moderate to severe transient childhood hypertriglyceridemia and fatty liver followed by hepatic fibrosis and the identification of the mutated gene responsible for this condition. We performed SNP array-based homozygosity mapping and found a single large continuous segment of homozygosity on chromosomal region 12q13.12. The candidate region contained 35 genes that are listed in Online Mendelian Inheritance in Man (OMIM) and 27 other genes. We performed candidate gene sequencing and screened both clinically affected individuals (children and adults with hypertriglyceridemia) and also a healthy cohort for mutations in GPD1, which encodes glycerol-3-phosphate dehydrogenase 1. Mutation analysis revealed a homozygous splicing mutation, c.361-1G>C, which resulted in an aberrantly spliced mRNA in the ten affected individuals. This mutation is predicted to result in a truncated protein lacking essential conserved residues, including a functional site responsible for initial substrate recognition. Functional consequences of the mutation were evaluated by measuring intracellular concentrations of cholesterol and triglyceride as well as triglyceride secretion in HepG2 (hepatocellular carcinoma) human cells lines overexpressing normal and mutant GPD1 cDNA. Overexpression of mutant GPD1 in HepG2 cells, in comparison to overexpression of wild-type GPD1, resulted in increased secretion of triglycerides (p = 0.01). This finding supports the pathogenicity of the identified mutation.
| S-EPMC3257852 | biostudies-literature
Project description:The constellation of clinico-pathological and laboratory findings including massive hepatomegaly, steatosis, and marked hypertriglyceridemia in infancy is extremely rare. We describe a child who is presented with the above findings, and despite extensive diagnostic testing no cause could be identified. Whole exome sequencing was performed on the patient and parents' DNA. Mutations in GPD1 encoding glycerol-3-phosphate dehydrogenase that catalyzes the reversible redox reaction of dihydroxyacetone phosphate and NADH to glycerol-3-phosphate (G3P) and NAD(+) were identified. The proband inherited a GPD1 deletion from the father determined using copy number analysis and a missense change p.(R229Q) from the mother. GPD1 protein was absent in the patient's liver biopsy on western blot. Low normal activity of carnitine palmitoyl transferases, CPT1 and CPT2, was present in the patient's skin fibroblasts, without mutations in genes encoding for these proteins. This is the first report of compound heterozygous mutations in GPD1 associated with a lack of GPD1 protein and reduction in CPT1 and CPT2 activity.
| S-EPMC4169545 | biostudies-literature
Project description:BackgroundCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease caused by mutations in NOTCH3 gene with remarkable phenotypic heterogeneity. Cases of CADASIL associated with homozygous NOTCH3 mutations are rare and subsequently understudied. In this study, we investigate the genetic and phenotypic features within patients of CADASIL with homozygous NOTCH3 mutations.Case presentationWe recruited two affected individuals with CADASIL from a mainland Chinese family. The proband (Patient 1), a 60-year-old male, presented with slow progressive gait instability, severe cognitive impairment, and emotional disorder for more than 2 years with a history of ischemic stroke and hypertension. His younger brother (Patient 2) presented with apparent gait difficulties, dysarthria as well as cognitive decline at 59 years old. Brain magnetic resonance imaging (MRI) showed diffused white matter lesions involving bilateral periventricular white matter, semioval center region, and anterior temporal lobes. Molecular genetic testing identified a homozygous variant, c.1759C > T (p.R587C), in NOTCH3 gene in both patients. Pathological analysis revealed granular osmiophilic material (GOM) deposits in small arterial walls of skin from the proband. The diagnosis of CADASIL was confirmed.ConclusionsOur cases of CADASIL with homozygous mutation c.1759C > T (p.R587C) in NOTCH3 share similar manifestation to the patients with heterozygous same mutation reported previously. Other than genetic factors, vascular risk factors or environmental factors might contribute to the phenotypic variation of CADASIL.
| S-EPMC7053106 | biostudies-literature
Project description:Infantile neuroaxonal dystrophy (INAD) is a rare neurodegenerative disorder. Phospholipase A2 group VI (PLA2G6) gene mutations have been identified in the majority of individuals with INAD. The present case report is on a Chinese female pediatric patient (age, 18 months) diagnosed with INAD with deafness. To date, only four cases of INAD with hearing loss have been reported, PLA2G6-association has not been investigated. Next-generation DNA sequencing technology was used to identify disease-associated genes and Sanger sequencing was applied to verify the mutation in the patient's pedigree. Two mutations were identified in the PLA2G6 gene: c.1T>C (E2) and c.497 (E4) to c.496 (E4): Insert C. The distribution frequency of those mutations in the Single Nucleotide Polymorphism, HapMap, 1000 Genomes and Exome Aggregation Consortium databases was 0. However, cases of INAD appear to be underreported, particularly those from China. The identification of two mutations in the present study suggests unique PLA2G6 mutations in Chinese patients, and greatly expands on the spectrum of known mutations in INAD patients.
| S-EPMC6090475 | biostudies-literature
Project description:BACKGROUND:Primary microcephaly is defined as reduced occipital-frontal circumference noticeable before 36?weeks of gestation. Large amount of insults might lead to microcephaly including infections, hypoxia and genetic mutations. More than 16 genes are described in autosomal recessive primary microcephaly. However, the cause of microcephaly remains unclear in many cases after extensive investigations and genetic screening. CASE PRESENTATION:Here, we described the case of a boy with primary microcephaly who presented to a neurology clinic with short stature, global development delay, dyskinetic movement, strabismus and dysmorphic features. We performed microcephaly investigations and genetic panels. Then, we performed whole-exome sequencing to identify any genetic cause. Microcephaly investigations and genetic panels were negative, but we found a new D317V homozygous mutation in TELOE-2 interacting protein 2 (TTI2) gene by whole-exome sequencing. TTI2 is implicated in DNA damage response and mutation in that gene was previously described in mental retardation, autosomal recessive 39. CONCLUSIONS:We described the first French Canadian case with primary microcephaly and global developmental delay secondary to a new D317V homozygous mutation in TTI2 gene. Our report also highlights the importance of TTI2 protein in brain development.
| S-EPMC7023720 | biostudies-literature
Project description:Isolated hyperchloridrosis (HYCHL; OMIM 143860) is a rare autosomal recessive disorder caused by biallelic mutations in the carbonic anhydrase 12 (CA12; OMIM 603263) gene, which is characterized by abnormally high levels of salt in sweat that can lead to dehydration associated with low levels of sodium in the blood. To date, only four variants of the CA12 gene have been identified to be associated with HYCHL. Here, we presented a rare Chinese case of HYCHL in an infant with decreased food intake, mild diarrhea, severe dehydration, and hypovolemic shock who was hospitalized in our department three times. Laboratory tests showed hyponatremia and hypochloremia. Because of recurrent attacks, whole-exome sequencing (WES) was performed and revealed a novel homozygous missense variant c.763A>C (p.Thr255Pro) in the CA12 gene (NM_001218.5). In total 0.9% sodium chloride (NaCl) solution was orally administered until 1 year and 6 months of age. Followed up to 3 years of age, the patient showed good growth and development without similar manifestations. This study reported a novel CA12 gene mutation leading to HYCHL for the first time in China, which enriched the genotype of HYCHL and emphasized the early suspicion and identification of the rare condition to adequate treatment.
| S-EPMC8964059 | biostudies-literature
Project description:BACKGROUND:Cystinosis is an autosomal recessive lysosomal storage disorder characterized by accumulation of cystine in lysosomes throughout the body. Cystinosis is caused by mutations in the CTNS gene that encodes the lysosomal cystine carrier protein cystinosin. CTNS mutations result in either complete absence or reduced cystine transporting function of the protein. The diagnosis of nephropathic cystinosis is generally based on measuring leukocyte cystine level, demonstration of corneal cystine crystals by the slit lamp examination and confirmed by genetic analysis of the CTNS gene. CASE PRESENTATION:A boy born to consanguineous Caucasian parents had the characteristic clinical features of the infantile nephropathic cystinosis including renal Fanconi syndrome (polydipsia/polyuria, metabolic acidosis, hypokalemia, hypophosphatemia, low molecular weight proteinuria, glycosuria, cystine crystals in the cornea) and elevated WBC cystine levels. Initially we performed RFLP analysis of the common in the Northern European population 57-kb deletion of proband's DNA, then a direct Sanger sequencing which revealed no mutations in the coding part of the CTNS gene. To confirm the diagnosis we performed RT-PCR analysis of total RNA obtained from patient-derived fibroblasts in combination with cDNA sequencing. This revealed the skipping of exon 4 and exon 5 in the CTNS in our patient. Therefore, we detected a novel 9-kb homozygous deletion in the CTNS gene at genomic DNA level, spanning region from intron 3 to intron 5. In order to identify the inheritance pattern of the deletion we analyzed DNA of proband's mother and father. Both parents were found to be heterozygous carriers of the CTNS mutation. CONCLUSIONS:Analysis of CTNS gene transcript allowed to identify a large homozygous deletion in the patient with infantile nephropathic cystinosis. Mutational detection at RNA level may be an efficient tool to establish the genetic defect in some cystinosis patients.
| S-EPMC6822415 | biostudies-literature
Project description:BACKGROUND:Neuronal ceroid lipofuscinosis (NCLs) are lysosomal storage disorders characterized by seizures, motor impairment, and loss of vision. Ceroid lipofuscinosis (CLN) gene mutations are the cause, but NCL cases arising from CLN6 mutations have not been described in China to date. The CLN6 protein, which plays a role in lysosomal function, is an endoplasmic reticulum (ER) membrane protein with seven transmembrane (TM) domains. It has a cytosolic-facing amino terminal domain and a luminal-facing carboxyl terminal domain, with six loops between the TM domains. CASE PRESENTATION:Here we report a case involving a Chinese boy whose suspected diagnosis was a hereditary leukoencephalopathy, based on brain MRI imaging and epilepsy symptoms, language articulation disorders, ataxia, and unstable gait. The electroencephalogram showed epileptic discharges, and the brain MRI scan showed high signal intensity adjacent to the bilateral posterior horns of the lateral ventricles on T2-weighted images, along with cerebellar atrophy. Using next-generation sequencing for the genes in a panel for hereditary leukoencephalopathies, we detected a homozygous missense point mutation c.892G?>?A(p.Glu298Lys) in CLN6, and the variant was interpreted as pathogenic on in silico analysis. Absence of this mutation was confirmed in 259 controls. Late infantile NCL and secondary epilepsy were diagnosed, and oral sodium valproate was prescribed. The epilepsy was not well controlled, however, and the other signs had not improved at the 6-month follow-up. We also analyzed the loci of 31 CLN6 missense mutations, including those previously reported and the current one. We found that 22.6% (7/31) of the mutations are in the cytoplasmic domains, about 32.2% (10/31) are in the TM domains, and about 45.2% (14/31) are in the luminal domains. These mutations were mostly located in the TM3-TM4 loop (6/31), TM1-TM2 loop (4/31), and C-terminus (4/31), with none found in the TM4-TM5 loop, TM5-TM6 loop, or TM7. CONCLUSIONS:We report the first case in China of NCL caused by a CLN6 mutation, expanding the genotype options for NCLs. In practice, NCLs generally are not the initial suspected diagnosis for such cases. Use of a gene sequencing panel for investigating unexplained seizures or leukoencephalopathies can help confirm the diagnosis.
| S-EPMC6167792 | biostudies-literature