glutaryl-CoA Dehydrogenase Research Articles

Protective effects of L-carnitine on behavioral alterations and neuroinflammation in striatum of glutaryl-COA dehydrogenase deficient mice

Glutaric acidemia type 1 (GA1) is caused by glutaryl-CoA dehydrogenase deficiency that leads to a blockage in the metabolic route of the amino acids lysine and tryptophan and subsequent accumulation of glutaric acid (GA), 3-hydroxyglutaric acids and glutarylcarnitine (C5DC). Patients predominantly manifest neurological symptoms, associated with acute striatal degeneration, as well as progressive cortical and striatum injury whose pathogenesis is not yet fully established. Current treatment includes protein/lysine restriction and l-carnitine supplementation of (L-car). The aim of this work was to evaluate behavior parameters and pro-inflammatory factors (cytokines IL-1β, TNF-α and cathepsin-D levels), as well as the anti-inflammatory cytokine IL10 in striatum of knockout mice (Gcdh−/-) and wild type (WT) mice submitted to a normal or a high Lys diet. The potential protective effects of L-car treatment on these parameters were also evaluated. Gcdh−/- mice showed behavioral changes, including lower motor activity (decreased number of crossings) and exploratory activity (reduced number of rearings). Also, Gcdh−/- mice had significantly higher concentrations of glutarylcarnitine (C5DC) in blood and cathepsin-D (CATD), interleukin IL-1β and tumor factor necrosis alpha (TNF-α) in striatum than WT mice. Noteworthy, L-car treatment prevented most behavioral alterations, normalized CATD levels and attenuated IL-1β levels in striatum of Gcdh−/- mice. Finally, IL-1β was positively correlated with CATD and C5DC levels and L-car was negatively correlated with CATD. Our results demonstrate behavioral changes and a pro-inflammatory status in striatum of the animal model of GA1 and, most importantly, L-car showed important protective effects on these alterations.

Glutaric Aciduria Type I Missed by Newborn Screening: Report of Four Cases from Three Families.

Glutaric aciduria type I (GA-1) is a rare autosomal-recessive disorder of the degradation of the amino acids lysine and tryptophan caused by mutations of the GCDH gene encoding glutaryl-CoA-dehydrogenase. Newborn screening (NBS) for this condition is based on elevated levels of glutarylcarnitine (C5DC) in dried blood spots (DBS). Here we report four cases from three families in whom a correctly performed NBS did not detect the condition. Glutarylcarnitine concentrations were either normal (slightly below) or slightly above the cut-off. Ratios to other acylcarnitines were also not persistently elevated. Therefore, three cases were defined as screen negative, and one case was defined as normal, after a normal control DBS sample. One patient was diagnosed after an acute encephalopathic crisis, and the other three patients had an insidious onset of the disease. GA-1 was genetically confirmed in all cases. Despite extensive efforts to increase sensitivity and specificity of NBS for GA-1, by adjusting cut-offs and introducing various ratios, the biological diversity still leads to false-negative NBS results for GA-1.

Blood Transcriptome Profiling Reveals Diet-Induced Changes in Metabolic Pathway Gene Expression

ObjectivesThis study explored the effects of diet-induced (almonds vs. crackers) changes on blood transcriptome profiles of young adults. MethodsYoung adults (age: 18–22 years) were randomly assigned to consume either almonds (2 oz./d, n = 13) or an isocaloric control snack of graham crackers (325 kcal/d, n = 10) daily for 4 weeks. Blood samples were collected at baseline and 4 weeks after intervention. Total leukocyte RNA was extracted and sequenced. Gene expression profiling was carried out using a 3′ Tag-RNA-Seq protocol. Barcoded sequencing libraries were prepared using the QuantSeq FWD kit for multiplexed sequencing. Data were preprocessed, STAR aligned, and count tables generated using the QuantSeq FWD-UMI pipeline. Differential expression (DE) analysis was conducted on the time x diet model using the limma-voom packages in R. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis on the DE p-values was conducted using the Wilcoxon rank-sum test in R. P-values were adjusted for false discovery rate correction (FDR). ResultsOut of 13,018 filtered genes, 69 were differentially expressed (FDR < 0.1). Glutamic-oxaloacetic transaminase 2 (GOT2), diacylglycerol kinase alpha (DGKA), and glutaryl-CoA dehydrogenase (GCDH) genes were upregulated with almond consumption. GOT2 plays a role in amino acid metabolism and the urea and tricarboxylic acid cycles, DGKA is involved in lipid metabolism, and GCDH is involved in lysine degradation and tryptophan metabolism. Cracker consumption resulted in greater upregulation of TGF-beta activated kinase 1 gene (MAP3K7) binding protein 3 (TAB3) gene which is involved in the NF-kappaB signal transduction pathway and a greater downregulation in the immunoglobulin superfamily member 8 (IGSF8) gene. Enrichment analyses indicate gene annotations to 341 KEGG pathways. Thermogeneic and ribosomal pathways were significantly enriched (FDR < 0.1). Pathways related to oxidative phosphorylation, sphingolipid signaling, and tryptophan, propanoate, and starch and sucrose metabolism were also differentially enriched (P < 0.05, FDR < 0.3). ConclusionsThese findings indicate that diet (almond vs cracker) potentially alters metabolism through changes in gene transcription. The implications of these findings and associations with health and disease outcomes need to be investigated further. Funding SourcesNIH

The first knock-in rat model for glutaric aciduria type I allows further insights into pathophysiology in brain and periphery

Glutaric aciduria type I (GA-I, OMIM # 231670) is an inborn error of metabolism caused by a deficiency of glutaryl-CoA dehydrogenase (GCDH). Patients develop acute encephalopathic crises (AEC) with striatal injury most often triggered by catabolic stress. The pathophysiology of GA-I, particularly in brain, is still not fully understood.We generated the first knock-in rat model for GA-I by introduction of the mutation p.R411W, the rat sequence homologue of the most common Caucasian mutation p.R402W, into the Gcdh gene of Sprague Dawley rats by CRISPR/CAS9 technology. Homozygous Gcdhki/ki rats revealed a high excretor phenotype, but did not present any signs of AEC under normal diet (ND). Exposure to a high lysine diet (HLD, 4.7%) after weaning resulted in clinical and biochemical signs of AEC.A significant increase of plasmatic ammonium concentrations was found in Gcdhki/ki rats under HLD, accompanied by a decrease of urea concentrations and a concomitant increase of arginine excretion. This might indicate an inhibition of the urea cycle. Gcdhki/ki rats exposed to HLD showed highly diminished food intake resulting in severely decreased weight gain and moderate reduction of body mass index (BMI). This constellation suggests a loss of appetite. Under HLD, pipecolic acid increased significantly in cerebral and extra-cerebral liquids and tissues of Gcdhki/ki rats, but not in WT rats. It seems that Gcdhki/ki rats under HLD activate the pipecolate pathway for lysine degradation. Gcdhki/ki rat brains revealed depletion of free carnitine, microglial activation, astroglyosis, astrocytic death by apoptosis, increased vacuole numbers, impaired OXPHOS activities and neuronal damage. Under HLD, Gcdhki/ki rats showed imbalance of intra- and extracellular creatine concentrations and indirect signs of an intracerebral ammonium accumulation.We successfully created the first rat model for GA-I. Characterization of this Gcdhki/ki strain confirmed that it is a suitable model not only for the study of pathophysiological processes, but also for the development of new therapeutic interventions. We further brought up interesting new insights into the pathophysiology of GA-I in brain and periphery.

Neurological manifestations in glutaric acidemia type 1 and the impact of expanded neonatal screening in Brazil

Glutaric acidemia type 1 (GA1) is an inborn error of metabolism caused by the deficiency of the enzyme glutaryl-CoA dehydrogenase, with consequent accumulation of the aminoacids lysine, hydroxylsine and tryptophan. About 1 in every 100,000 individuals are affected by the disease. Neurological manifestations are variable and include acute and chronic encephalopathic crises, dystonia, motor and cognitive deficits, as well as neuroimaging findings such as brain hypoplasia, striatal, white matter and subdural effusions. Early diagnosis is crucial for specific therapy, which includes a diet with restricted amino acids and carnitine replacement. The present work describes the variability of neurological manifestations in four patients with glutaric acidemia type 1, diagnosed in different age groups, through mass spectrometry, technology of the expanded neonatal screening available in the Ministry of Health program in Federal District, Brazil. Complications of GA1 were more severe in cases with later diagnosis, which justifies the use of the enlarged neonatal screening as an important resource in the early diagnosis and treatment of inborn errors of metabolism.

The outcome of 41 Late-Diagnosed Turkish GA-1 Patients: A Candidate for the Turkish NBS

Glutaric aciduria type 1(GA-1) is an inherited cerebral organic aciduria. Untreated patients with GA-1 have a risk of acute encephalopathic crises during the first 6 years of life. In so far as GA-1 desperately does not exist in Turkish newborn screening (NBS) program, most patients in our study were late-diagnosed. This study included 41 patients diagnosed with acylcarnitine profile, urinary organic acids, mutation analyses in the symptomatic period. We presented with clinical, neuroradiological, and molecular data of our 41 patients. The mean age at diagnosis was 14.8 ± 13.9 (15 days to 72 months) and, high blood glutaconic acid, glutarylcarnitine and urinary glutaric acid (GA) levels in 41 patients were revealed. Seventeen different mutations in the glutaryl-CoA dehydrogenase gene were identified, five of which were novel. The patients, most of whom were late-diagnosed, had a poor neurological outcome. Treatment strategies made a little improvement in dystonia and the frequency of encephalopathic attacks. All GA-1 patients in our study were severely affected since they were late-diagnosed, while others show that GA-1 is a treatable metabolic disorder if it is diagnosed with NBS. This study provides an essential perspective of the severe impact on GA-1 patients unless it is diagnosed with NBS. We immediately advocate GA-1 to be included in the Turkish NBS.

Expert consensus for the diagnosis and treatment of glutaricacidemia type 1

Glutaricacidemia type 1(GA1) is an autosomal recessive disease caused by reduced or missing glutaryl-CoA dehydrogenase activity which hamps metabolism of lysine, hydroxylysine and tryptophan. The catabolic products of glutarylcarnitine and glutaric acid are abnormally accumulated in the body, resulting in metabolic disorders which primarily lead to damage to the nervous system. Clinical manifestations of patients include macrocephaly, dystonia, dyskinesia, and developmental retardation. Acute encephalopathy may be induced in infants and young children due to infection, vaccination and surgery. For GA1 is a rare disease and its clinical manifestations are similar to other neurological diseases, it may be easily missed or misdiagnosed. To facilitate early diagnosis and treatment and improve the prognosis, this consensus was formulated by pediatric experts from the fields of endocrinology and genetic metabolism through full discussion and reference to the latest literature and guidelines home and abroad.

Genetic, Prenatal, and Preimplantation Genetic Diagnosis of Glutaric Aciduria Type I

Purpose: Glutaric Acid Type I (GA-I) is an inherited metabolic disorder. Although the treatment guidelines for GA-I were established a decade ago, they cannot block the vertical heredity. We aim to apply genetic methods to block the inheritance of GA-I and verifies the efficiency of Next-Generation Sequencing (NGS)-based Preimplantation Genetic Testing for Monogenic disease (PGT-M) of GA-I.Materials and methods: A non-consanguineous Chinese family was diagnosed with GA-I by Sanger sequencing. PGT-M and prenatal diagnosis (PND) were performed for the carrier. 5 blastocysts were used for the trophectoderm biopsy. After Whole-Genome Amplification (WGA), the WGA products were used for Sanger sequencing, NGS-based PGT-M and PGT-A. Sanger sequencing-based PND was performed in second trimester to confirm the results of PGT-M.Results: A compound heterozygous mutation was diagnosed in the GCDH gene with co-segregation. One is [c.533G&gt;A (p.G178E)] and another is [c.914C&gt;T (p.S305L)]. 2 blastocysts were diagnosed as normal and one of them was transferred into the mother’s uterus. Finally, a healthy female was born 39 weeks after transplantation.Conclusion: Our study successfully applied NGS-based PGT-M to avoid GA-I and highlights the efficiency of genetic diagnoses. It has significant implications on genetic counseling and genetic diagnosis for GA-I.

Microencephaly in macrocephaly: Rare report of two siblings with glutaric aciduria type 1

Glutaric aciduria type 1 is an autosomal recessive disorder caused by mutations in GCDH gene on chromosome 19 leading to the deficiency of glutaryl-CoA dehydrogenase which causes an abnormal metabolism of lysine, hydroxylysine and tryptophan with resultant accumulation of glutaric acid and 3-hydroxy glutaric acid. Usual presentations include macrocephaly with recurrent dystonic episodes, along with developmental regression. The diagnosis is based on characteristic magnetic resonance imaging finding of widening of sylvian fissures and urinary tandem mass spectroscopic analysis of excess glutarylcarnitine and hydroxyglutaric acid. Management includes lysine-free diet and carnitine supplementation.

Clinical and Nutritional Evolution of 24 Patients with Glutaric Aciduria Type 1 in Follow-up at a Center Specialized in Inborn Errors of Metabolism in Chile

Introduction: Glutaric Aciduria Type 1 (GA-1) is produced by the enzymatic deficiency of glutaryl-CoA-dehydrogenase (GCDH), leading to the accumulation of glutaric acid (GA). 90% of patients without early treatment present acute encephalopathic crisis (AEC), followed by disabling neurological symptoms. The treatment consists of a low lysine (Lys) diet, protein substitute lys-free, tryptophan-reduced (PS) and L-carnitine. Objectives: Describe the clinical and nutritional evolution of a cohort of GA-1 patients at a national referral center in Chile. Methodology: Retrospective study of 24 patients diagnosed with GA-1 between 1998-2020 and referred to the Institute of Nutrition and Food Technology (INTA) of University of Chile. Results: Age at diagnosis was 19±27 months; 10/24 presented AEC and neurological sequelae. The cases without AEC (14/24) 8 presented neurological compromise: psychomotor development delay, abnormal movements and pyramidal syndrome. Nutritional evaluation: 12/24 were malnourished by deficiency, <6 years old group (12/24): 11 cases were found to have Lys and PS, ≥6 years old (12/24): 9/12 did not receive PS. All had normal free carnitine levels. Conclusion: GA-1 has variable symptoms with neurological involvement AEC or insidious start. Is essential to maintain a long-term follow-up and consider its inclusion in neonatal screening programs.

Pediatric Glutaric Aciduria Type 1: 14 Cases, Diagnosis and Management.

Introduction:Glutaric aciduria type I is an autosomal recessive disorder of lysine metabolism due to the defect of the enzyme glutaryl-CoA dehydrogenase. The regression of milestones following an intercurrent infection with disabling dystonia is the common presentation. We report the clinical features, diagnosis, and management of 14 south Indian children with glutaric aciduria type I.Results:Males predominated the study (57.1%). The mean age of onset of the symptoms was 8.57 ± 3.57 months. The mean age at the time of diagnosis was 35.21 ± 48.31 months. The history of consanguinity was noted in 57.1%. Development was normal prior to the onset of acute crises in nearly three fourths. Acute crises triggered by infection followed by the regression of milestones was the major presenting feature in 10 children (71.4%). Macrocephaly was another prominent feature in an equal number. Bat's wing appearance (fronto temporal atrophy) was present in all children. Nearly 80% had moderate to severe disability in the form of dystonic movement disorder and spastic quadriparesis.Conclusion:Glutaric aciduria type Ihas to be identified and managed early to have a better outcome.

A rare case of type i glutaric aciduria in an early child

Glutaric aciduria type I (deficiency of glutaryl-COA dehydrogenase, glutaric acidemia type I) is a rare autosomal recessive disease caused by mutations in the gene encoding the enzyme glutaryl – COA - dehydrogenase (GCDH). Cerebral organic aciduria, caused by a deficiency of glutaryl-COA - dehydrogenase, is generally considered a neurological disorder.The phenotypic spectrum of untreated GA-1 varies from a more common and pronounced form (a disease with infancy) to a low-symptom and less common form. In people with the same genotype, the clinical manifestations and depth of CNS damage can vary widely depending on the age of manifestation of acute encephalopathic crises. It is assumed that with early detection and treatment of “asymptomatic” newborns (in the context of screening for this disease), most people who would have developed manifestations of GA-1 with childhood or late onset will remain asymptomatic.

Impact of interventional and non-interventional variables on anthropometric long-term development in glutaric aciduria type 1: A national prospective multi-centre study.

Glutaric aciduria type 1 (GA1) is a rare neurometabolic disorder, caused by inherited deficiency of glutaryl-CoA dehydrogenase, mostly affecting the brain. Early identification by newborn screening (NBS) significantly improves neurologic outcome. It has remained unclear whether recommended therapy, particular low lysine diet, is safe or negatively affects anthropometric long-term outcome. This national prospective, observational, multi-centre study included 79 patients identified by NBS and investigated effects of interventional and non-interventional parameters on body weight, body length, body mass index (BMI) and head circumference as well as neurological parameters. Adherence to recommended maintenance and emergency treatment (ET) had a positive impact on neurologic outcome and allowed normal anthropometric development until adulthood. In contrast, non-adherence to ET, resulting in increased risk of dystonia, had a negative impact on body weight (mean SDS -1.07; P = .023) and body length (mean SDS -1.34; P = -.016). Consistently, longitudinal analysis showed a negative influence of severe dystonia on weight and length development over time (P < .001). Macrocephaly was more often found in female (mean SDS 0.56) than in male patients (mean SDS -0.20; P = .049), and also in individuals with high excreter phenotype (mean SDS 0.44) compared to low excreter patients (mean SDS -0.68; P = .016). In GA1, recommended long-term treatment is effective and allows for normal anthropometric long-term development up to adolescence, with gender- and excreter type-specific variations. Delayed ET and severe movement disorder result in poor anthropometric outcome.

Clinical, biochemical and molecular findings of 24 Brazilian patients with glutaric acidemia type 1: 4 novel mutations in the GCDH gene.

Glutaric aciduria type 1 (GA-1) is a rare but treatable inherited disease caused by deficiency of glutaryl-CoA dehydrogenase activity due to GCDH gene mutations. In this study, we report 24 symptomatic GA-1 Brazilian patients, and present their clinical, biochemical, and molecular findings. Patients were diagnosed by high levels of glutaric and/or 3-hydroxyglutaric and glutarylcarnitine. Diagnosis was confirmed by genetic analysis. Most patients had the early-onset severe form of the disease and the main features were neurological deterioration, seizures and dystonia, usually following an episode of metabolic decompensation. Despite the early symptomatology, diagnosis took a long time for most patients. We identified 13 variants in the GCDH gene, four of them were novel: c.91 + 5G > A, c.167T > G, c.257C > T, and c.10A > T. The most common mutation was c.1204C > T (p.R402W). Surprisingly, the second most frequent mutation was the new mutation c.91 + 5G > A (IVS1 ds G-A + 5). Our results allowed a complete characterization of the GA-1 Brazilian patients. Besides, they expand the mutational spectrum of GA-1, with the description of four new mutations. This work reinforces the importance of awareness of GA-1 among doctors in order to allow early diagnosis and treatment in countries like Brazil where the disease has not been included in newborn screening programs.

Molecular identification of glutaryl CoA dehydrogenase gene variations and clinical course in three glutaric aciduria type I patients

Glutaric aciduria type-I (GA-I) is a rare autosomal recessive organic-aciduria caused due to glutaryl-CoA-dehydrogenase (GCDH) gene mutations leading to the accumulation of neurotoxins. In this article, we describe the molecular study of three GA-I families from southern India. Clinical features and biochemical parameters were examined. DNA was isolated from dried blood spots and GCDH gene analysis was performed using polymerase chain reaction and Sangers sequencing. Computational assessment of the mutations was performed to analyse their pathogenicity. Median age of the patients was 8 months and parental consanguinity was seen in all the three families. All GA-I patients had a mild clinical course, with brain atrophies. Macrocephaly was not noted. Mutation analysis identified three likely pathogenic mutations including two novel GCDH gene variants (S189T and W225S) and one previously reported variant (R386P). In-silico tools determined R386P and W225S mutations to be deleterious, while S189T to be neutral to the GCDH protein. The S189T was associated with a low excretor phenotype. In conclusion, identification of mutations by genotyping tests in distinct populations can accomplish early DNA based GA-I screening and is useful in definitive diagnosis of GA-I without the prior need of biochemical or enzyme assay.

Lipopolysaccharide-Elicited Systemic Inflammation Induces Selective Vulnerability of Cerebral Cortex and Striatum of Developing Glutaryl-CoA Dehydrogenase Deficient (Gcdh−/−) Mice to Oxidative Stress

We investigated redox homeostasis in cerebral and peripheral tissues of wild type (WT) and glutaryl-CoA dehydrogenase knockout mice (Gcdh-/-) submitted to inflammation induced by lipopolysaccharide (LPS) since patients with glutaric aciduria type I (GA I) manifest acute encephalopathy during catabolic events triggered by inflammation. WT and Gcdh-/- mice fed a low (0.9%) or high (4.7%) Lys chow were euthanized 4h after LPS intraperitoneal injection. Cerebral cortex of Lys-restricted Gcdh-/- animals presented no alterations of redox homeostasis, whereas those fed a high Lys chow showed increased malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity, compared to WT mice. Furthermore, Gcdh-/- mice receiving low Lys and injected with LPS presented elevated MDA levels and decreased reduced glutathione (GSH) concentrations, glutathione peroxidase (GPx), and glutathione reductase (GR) activities in cerebral cortex. LPS administration also decreased GSH values, as well as GPx and GR activities in cerebral cortex of Gcdh-/- mice receiving Lys overload. Further experiments performed in WT and Gcdh-/- mice injected with LPS and receiving either a low or high Lys chow revealed increased MDA levels and decreased GSH concentrations in cerebral cortex and striatum, but not in hippocampus, liver and heart of Gcdh-/- mice, suggesting a selective vulnerability of these cerebral structures to oxidative stress during an inflammatory process. LPS administration also increased S100B and NF-κF protein levels in brain of Gcdh-/- mice receiving high Lys. These data support the hypothesis that low Lys diet is beneficial in GA I by preventing redox imbalance, whereas a high Lys diet or systemic inflammation per se or combined induce oxidative stress in striatum and cerebral cortex that are mainly damaged in this disorder.

Inherited Disorders of Lysine Metabolism: A Review

Lysine is an essential amino acid, and inherited diseases of its metabolism therefore represent defects of lysine catabolism. Although some of these enzyme defects are not well described yet, glutaric aciduria type I (GA1) and antiquitin (2-aminoadipic-6-semialdehyde dehydrogenase) deficiency represent the most well-characterized diseases. GA1 is an autosomal recessive disorder due to a deficiency of glutaryl-CoA dehydrogenase. Untreated patients exhibit early onset macrocephaly and may present a neurological deterioration with regression and movement disorder at the time of a presumably “benign” infection most often during the first year of life. This is associated with a characteristic neuroimaging pattern with frontotemporal atrophy and striatal injuries. Diagnosis relies on the identification of glutaric and 3-hydroxyglutaric acid in urine along with plasma glutarylcarnitine. Treatment consists of a low-lysine diet aiming at reducing the putatively neurotoxic glutaric and 3-hydroxyglutaric acids. Additional therapeutic measures include administration of ʟ-carnitine associated with emergency measures at the time of intercurrent illnesses aiming at preventing brain injury. Early treated (ideally through newborn screening) patients exhibit a favorable long-term neurocognitive outcome, whereas late-treated or untreated patients may present severe neurocognitive irreversible disabilities. Antiquitin deficiency is the most common form of pyridoxine-dependent epilepsy. α-aminoadipic acid semialdehyde (AASA) and ∆-1-piperideine-6-carboxylate (P6C) accumulate proximal to the enzymatic block. P6C forms a complex with pyridoxal phosphate (PLP), a key vitamer of pyridoxine, thereby reducing PLP bioavailability and subsequently causing epilepsy. Urinary AASA is a biomarker of antiquitin deficiency. Despite seizure control, only 25% of the pyridoxine-treated patients show normal neurodevelopment. Low-lysine diet and arginine supplementation are proposed in some patients with decrease of AASA, but the impact on neurodevelopment is unclear. In summary, GA1 and antiquitin deficiency are the 2 main human defects of lysine catabolism. Both include neurological impairment. Lysine dietary restriction is a key therapy for GA1, whereas its benefits in antiquitin deficiency appear less clear.

Clinical Characteristics, Molecular Profile, and Outcomes in Indian Patients with Glutaric Aciduria Type 1.

Glutaric acidemia type 1 (GA-1, OMIM 231670) is an autosomal recessive inborn error of metabolism caused by the deficiency of glutaryl-coenzyme A (CoA) dehydrogenase with most children presenting in infancy with encephalopathy, dystonia, and macrocephaly. In this article, we presented the clinical characteristics, molecular profile, and outcomes in 29 unrelated families with affected children (30 cases total). The mean age at onset of illness was 10 months (±14.58), whereas the mean age at referral for molecular diagnosis was 29.44 months (±28.11). Patients were residents of nine different states of India. Clinical presentation varied from acute encephalitis followed by neuroregression and chronic/insidious developmental delay. Neurological sequelae varied from asymptomatic (no sequelae, 2 patients) to moderate (5 patients) and severe (23 patients) sequelae. All patients underwent blood tandem mass spectrometry (TMS on dried blood spots) and/or urine gas chromatography mass spectrometry (GCMS). Neuroimaging demonstrated batwing appearance in 95% cases. Sanger's sequencing of GCDH , covering all exons and exon-intron boundaries, was performed for all patients. Variants identified include 15 novel coding variants: p.Met100Thr, p.Gly107Ser, p.Leu179Val, p.Pro217Ser, p. Phe236Leufs*107, p.Ser255Pro, p.Met266Leufs*2, p.Gln330Ter, p.Thr344Ile, p.Leu345Pro, p.Lys377Arg, p.Leu424Pro, p.Asn373Lys, p.Lys377Arg, p.Asn392Metfs*9, and nine known genetic variants such as p.Arg128Gln, p.Leu179Arg, p.Trp225Ter, p.Met339Val, p.Gly354Ser, p.Arg402Gln, p.Arg402Trp, p.His403Tyr, and p.Ala433Val (Ensembl transcript ID: ENST00000222214). Using in silico analysis, genetic variants were shown to be affecting the residues responsible for homotetramer formation of the glutaryl-CoA dehydrogenase protein. Treatment included oral carnitine, riboflavin, protein-restricted diet, lysine-deficient special formulae, and management of acute crises with intravenous glucose and hydration. However, the mortality (9/30, 27.58%) and morbidity was high in our cohort with only two patients affording the diet. Our study is the largest multicentric, genetic variant-proven series of glutaric aciduria type 1 from India till date.

Clinical, Biochemical, and Radiologic Characteristics of Filipino Patients with Glutaric Aciduria Type 1

Introduction. Glutaric Aciduria Type 1 (GA1) is an inborn error of metabolism included in the expanded newborn screening of the Philippines. This inborn error of metabolism is caused by glutaryl-CoA dehydrogenase deficiency which is important in the catabolism of lysine, hydroxylysine and tryptophan.Objective. This paper aimed to present the baseline data of patients with GA1 in the Philippines by describing the clinical, biochemical, and radiologic characteristics of Filipino patients with biochemically-confirmed GA1 seen at the Philippine General Hospital from January 2010 to December 2017. The cases of this condition have been increasing and are expected to increase even more with the full coverage of the expanded newborn screening.Methods. This study was a review of the medical records of the GA1 patients managed by the Division of Clinical Genetics, Department of Pediatrics of the Philippine General Hospital (PGH). Biochemical parameters, developmental assessment, neurologic assessment, and radiologic features of the patients were reviewed and analyzed.Results. There were a total of 7 patients with GA1 at the PGH from January 2010 to December 2017. Of the 7 patients, 4 were diagnosed by expanded newborn screening (ENBS) and 3 patients had disease onset prior to diagnosis. Clinical features noted in screened patients include global developmental delay (75%), seizures (50%), dystonia (50%), truncal hypotonia (25%) and macrocephaly (25%). In unscreened patients, macrocephaly was present in 66.67 %, while the other clinical features were present in all of them. Four of the 7 patients had infection and one had vaccination, which may have led to a metabolic crisis and subsequent onset of symptoms. The plasma levels of glutarylcarnitine (C5DC) range from 2.81 to 4.58 umol/L. Grossly elevated urinary excretion of glutarylcarnitine were noted in all patients. Urinary glutaconic acid and 3-hydroxyglutaric acid were also detected in all patients. Both striatal and extra-striatal abnormalities were present in screened and unscreened patients on neuroimaging. The most common being the widening of the sylvian fissure, cerebral atrophy, and white matter abnormalities.Conclusion. Although newborn screening of GA1 and initiation of early management of this condition have been seen important, it is still prudent to continue the appropriate management and to provide timely aggressive emergency treatment in order to improve outcome of patients with GA1. With the recent Philippine Health Insurance (PhilHealth) coverage of the expanded newborn screening, it is expected that physicians will encounter more of the metabolic disorders, including GA1. Hence, it is important that physicians be more aware of the presenting signs and symptoms of this disorder, as well as its management, which can further improve the neurologic and developmental outcomes of these patients.

Proteome-Wide Analyses Provide New Insights into the Compatible Interaction of Rice with the Root-Knot Nematode Meloidogyne graminicola.

The root-knot nematode Meloidogyne graminicola is an important pathogen in rice, causing huge yield losses annually worldwide. Details of the interaction between rice and M. graminicola and the resistance genes in rice still remain unclear. In this study, proteome-wide analyses of the compatible interaction of the japonica rice cultivar “Nipponbare” (NPB) with M. graminicola were performed. In total, 6072 proteins were identified in NPB roots with and without infection of M. graminicola by label-free quantitative mass spectrometry. Of these, 513 specifically or significantly differentially expressed proteins were identified to be uniquely caused by nematode infection. Among these unique proteins, 99 proteins were enriched on seven Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. By comparison of protein expression and gene transcription, LOC_Os01g06600 (ACX, a glutaryl-CoA dehydrogenase), LOC_Os09g23560 (CAD, a cinnamyl-alcohol dehydrogenase), LOC_Os03g39850 (GST, a glutathione S-transferase) and LOC_Os11g11960 (RPM1, a disease resistance protein) on the alpha-linolenic acid metabolism, phenylpropanoid biosynthesis, glutathione metabolism and plant–pathogen interaction pathways, respectively, were all associated with disease defense and identified to be significantly down-regulated in the compatible interaction of NPB with nematodes, while the corresponding genes were remarkably up-regulated in the roots of a resistant rice accession “Khao Pahk Maw” with infection of nematodes. These four genes likely played important roles in the compatible interaction of rice with M. graminicola. Conversely, these disease defense-related genes were hypothesized to be likely involved in the resistance of resistant rice lines to this nematode. The proteome-wide analyses provided many new insights into the interaction of rice with M. graminicola.