To determine the incidence and types of inborn errors of metabolism (IEMs) in high-risk children using mass spectrometry techniques.
Children considered high-risk for IEM were screened for metabolic diseases during a 3-y period. Dried blood spots and urine samples were analyzed by tandem mass spectrometry (LC-MS/MS) and gas chromatograph-mass spectrometry (GCMS). Samples with abnormal amino acids were confirmed by high-performance liquid chromatography (HPLC).
Eight hundred and twenty-two suspected cases were evaluated; of which, 87 possible cases of IEMs were identified. Homocystinuria (n = 51) was the most common IEM detected followed by biotinidase deficiency (n = 7), glutaric aciduria type 1 (n = 7), and carnitine uptake defect (n = 6). Overall, there were 45 (51.7%) cases of organic acidemia, 31 cases (35.6%) of amino acid defect, 9 (10.3%) cases of fatty-acid oxidation disorders, and 2 (2.3%) cases of probable mitochondrial disorder.
IEMs are common in India, with a hospital-based incidence of 1 in approximately 6642 among high-risk children. Screening of high-risk children by mass spectrometry techniques is a valuable strategy for early diagnosis of IEMs where universal newborn screening is not yet available.

The aim of the study was a systematic evaluation of cognitive development in individuals with glutaric aciduria type 1 (GA1), a rare neurometabolic disorder, identified by newborn screening in Germany. This national, prospective, observational, multi-centre study includes 107 individuals with confirmed GA1 identified by newborn screening between 1999 and 2020 in Germany. Clinical status, development, and IQ were assessed using standardized tests. Impact of interventional and non-interventional parameters on cognitive outcome was evaluated. The majority of tested individuals (n = 72) showed stable IQ values with age (n = 56 with IQ test; median test age 11 years) but a significantly lower performance (median [IQR] IQ 87 [78-98]) than in general population, particularly in individuals with a biochemical high excreter phenotype (84 [75-96]) compared to the low excreter group (98 [92-105]; p = 0.0164). For all patients, IQ results were homogenous on subscale levels. Sex, clinical motor phenotype and quality of metabolic treatment had no impact on cognitive functions. Long-term neurologic outcome in GA1 involves both motor and cognitive functions. The biochemical high excreter phenotype is the major risk factor for cognitive impairment while cognitive functions do not appear to be impacted by current therapy and striatal damage. These findings implicate the necessity of new treatment concepts.

OBJECTIVE: To determine the incidence of newborn screening (NBS) disorders and to study the key performance indicators of the program.
METHODS: This retrospective single-center study enrolled all infants who underwent NBS from January 2012 to December 2017 at Prince Sultan Military Medical City, Riyadh, Saudi Arabia. We screened 17 NBS disorders. Blood samples were collected 24 hours after birth. If the initial result was positive, a second sample was collected. True positive cases were immediately referred for medical management. Data were extracted from laboratory computerized and non-computerized records using case report forms.
RESULTS: During the study period, 56632 infants underwent NBS with a coverage rate of 100%. Thirty-eight cases were confirmed. The incidence of congenital hypothyroidism was 1:3775. The positive predictive value for the detection of congenital hypothyroidism was 11.8%. Propionic aciduria was the most common metabolic disorder, with an incidence of 1:14158. Very long-chain acyl CoA dehydrogenase deficiency and glutaric aciduria type 1 had an incidence of 1:18877 each. Phenylketonuria, biotinidase deficiency, maple syrup urine disease, and citrullinemia had an incidence of 1:28316 each. However, galactosemia and 3-methyl crotonyl carboxylase deficiency had the lowest incidence of 1:56632.
CONCLUSIONS: The NBS coverage rate at our facility was 100%. Congenital hypothyroidism was the most frequently detected disorder with an incidence that matches worldwide figures. The incidence of other inherited disorders was consistent with regional figures.

Glutaric aciduria type 1 (GA1, deficiency of glutaryl CoA dehydrogenase, glutaric acidemia type 1) (ICD-10 code: E72.3; MIM 231670) is an autosomal recessive disease caused by mutations in the gene encoding the enzyme glutaryl CoA dehydrogenase (GCDH). Herein, we present the biochemical and molecular genetic characteristics of 51 patients diagnosed with GA1 from 49 unrelated families in Russia. We identified a total of 21 variants, 9 of which were novel: c.127 + 1G > T, с.471_473delCGA, c.161 T > C (p.Leu54Pro), c.531C > A (р.Phe177Leu), c.647C > T (p.Ser216Leu), c.705G > A (р.Gly235Asp), c.898 G > A (р.Gly300Ser), c.1205G > C (р.Arg402Pro), c.1178G > A (р.Gly393Glu). The most commonly detected missense variants were c.1204C > T (p.Arg402Trp) and с.1262C > T (р.Ala421Val), which were identified in 56.38% and 11.7% of mutated alleles. A heterozygous microdeletion of the short arm (p) of chromosome 19 from position 12,994,984-13,003,217 (8233 b.p.) and from position 12,991,506-13,003,217 (11,711 b.p.) were detected in two patients. Genes located in the area of imbalance were KLF1, DNASE2, and GCDH. Patients presented typical GA1 biochemical changes in the biological fluids, except one patient with the homozygous mutation p.Val400Met. No correlation was found between the GCDH genotype and glutaric acid (GA) concentration in the cohort of our patients.

Glutaric acidemia type I (GA-1) is an inborn error of metabolism due to deficiency of glutaryl-CoA dehydrogenase (GCDH), which catalyzes the conversion of glutaryl-CoA to crotonyl-CoA. GA-1 occurs in about 1 in 100 000 infants worldwide. The GCDH gene is on human chromosome 19p13.2, spans about 7 kb and comprises 11 exons and 10 introns. Tandem mass spectrometry (MS/MS) was used for clinical diagnosis in a proband from Iran with GA-1. Sanger sequencing was performed using primers specific for coding exons and exon-intron flanking regions of the GCDH gene in the proband. Cosegregation analysis and in silico assessment were performed to confirm the pathogenicity of the candidate variant. A novel homozygous missense variant c.1147C > A (p.Arg383Ser) in exon 11 of GCDH was identified. Examination of variant through in silico software tools determines its deleterious effect on protein in terms of function and stability. The variant cosegregates with the disease in family. In this study, the clinical and molecular aspects of GA-1 were investigated, which showed one novel mutation in the GCDH gene in an Iranian patient. The variant is categorized as pathogenic according to the the guideline of the American College of Medical Genetics and Genomics (ACMG) for variant interpretation. This mutation c.1147C > A (p.Arg383Ser) may also be prevalent among Iranian populations.

To identify the most vulnerable network among typical and three variants of Alzheimer\'s disease (AD) and to link amyloid-β (Aβ) deposition and downstream network dysfunction.
In this study, 38 typical AD, 11 frontal variants, 8 logopenic variants, 6 posterior variants, and 20 normal controls were enrolled. 2-(4\'-[11C] Methylaminophenyl)-6-hydroxybenzothiazole ([11C]PIB) and 2-deoxy-2-[18]fluoro-D-glucose ([18F]FDG) positron emission tomography (PET) imaging were performed. Voxel-wise statistical analysis was used for [18F]FDG analysis, whereas two-sample t test was performed between each AD group and control group. Moreover, the goodness of fit (GOF) of t-maps with brain functional network templates was assessed, and the most vulnerable network in each phenotypic of AD was chosen as volume of interests (VOIs). [11C]PIB binding potential (BPND) of VOIs were generated by using PMOD software. In addition, statistical analysis of BPND among four types of AD in each specific network was calculated by SPSS software.
The hypometabolism patterns indicated that in typical and frontal variants of AD, the most vulnerable network was the left executive control network (GOF score = 4.3, 5.0). For the logopenic variant, the highest GOF score (1.9) belonged to the auditory network. For the posterior variant, the higher visual network was the most vulnerable (GOF score = 6.0). The [11C]PIB BPND showed that there were no significant differences (p > 0.05) among AD groups within the specific networks.
The phenotypic diversity of AD correlates with specific functional network failure; however, Aβ plaques do not associate with specific network vulnerability.

Patients with organic acidemia are prone to different infections, which lead to acidosis episodes. Some studies have evaluated the status of immune system in acidotic phase in these patients, but to the best of our knowledge no study has evaluated the immune system in non-acidotic phase of the disease. In this study, thirty-one patients with organic acidemia were enrolled. For evaluation of humoral immunity, serum IgA, IgG, IgE, IgM, isohemaggltuinin titer, anti tetanus and anti diphtheria IgG were measured. For screening of complement deficiencies, serum C3, C4, and CH50 were assessed. Eleven patients had Maple Syrup Urine Disease (MSUD), 10 had methylmalonic acidemia, 5 had isovaleric acidemia, 4 had glutaric aciduria, and 1 had propionic acidemia. Serum IgM level was less than normal in 2 patients. Serum isohemagglutinin titer was less than 1:8 in 2 other patients. IgA, IgE, and IgG were within normal range for all patients. Anti tetanus and anti diphtheria IgG levels were low in two patients with MSUD. No significant relationship was found between any of the measured parameters and history of recurrent admissions, recurrent infections and the type of their diseases. Five patients had high C3 level, 4 had high C4 level, and 5 had high CH50 percentage. Totally, 10 patients had high complement level, but no remarkable connection was noted between the type of the disease and complement level. Minor insignificant deficiencies in humoral immunity in non-acidotic phase of organic acidemia were found. Some components of complement system showed increase in some patients, which might be due to decreased pH in extracellular fluid.

BACKGROUND: Glutaric aciduria type I (GA-I) is an inherited metabolic disease due to deficiency of glutaryl-CoA dehydrogenase (GCDH). Cognitive functions are generally thought to be spared, but have not yet been studied in detail.
METHODS: Thirty patients detected by newborn screening (n = 13), high-risk screening (n = 3) or targeted metabolic testing (n = 14) were studied for simple reaction time (SRT), continuous performance (CP), visual working memory (VWM), visual-motor coordination (Tracking) and visual search (VS). Dystonia (n = 13 patients) was categorized using the Barry-Albright-Dystonia Scale (BADS). Patients were compared with 196 healthy controls. Developmental functions of cognitive performances were analysed using a negative exponential function model.
RESULTS: BADS scores correlated with speed tests but not with tests measuring stability or higher cognitive functions without time constraints. Developmental functions of GA-I patients significantly differed from controls for SRT and VS but not for VWM and showed obvious trends for CP and Tracking. Dystonic patients were slower in SRT and CP but reached their asymptote of performance similar to asymptomatic patients and controls in all tests. Asymptomatic patients did not differ from controls, except showing significantly better results in Tracking and a trend for slower reactions in visual search. Data across all age groups of patients and controls fitted well to a model of negative exponential development.
CONCLUSIONS: Dystonic patients predominantly showed motor speed impairment, whereas performance improved with higher cognitive load. Patients without motor symptoms did not differ from controls. Developmental functions of cognitive performances were similar in patients and controls. Performance in tests with higher cognitive demand might be preserved in GA-I, even in patients with striatal degeneration.

OBJECTIVE: The sequence bendamustine (B) + Irinotecan (I) followed by etoposide (E) + carboplatin (C) was hypothesized to increase progression-free survival (PFS) and overall survival (OS) in untreated extensive-disease small cell lung cancer (EDSCLC) patients compared to historical controls by exploiting mitotic catastrophe. Absent expression of ERCC-1 and expression of topoisomerases were hypothesized to be predictive for PFS and OS.
METHODS: This was a phase I/IIa trial in 30 patients to determine the maximum tolerated dose (MTD) of B + I and the PFS of B + I E + C with secondary end points including overall response rate (ORR) and OS. Biomarkers measured by immunohistochemistry (IHC) obtained from diagnostic specimens were correlated with outcome.
RESULTS: The MTD of B + I was not reached. During treatment with B + I, there were two grade 5 toxicities from neutropenic sepsis and metabolic encephalopathy. Other toxicities included fatigue, nausea/vomiting, diarrhea, and weight loss. For the sequence, the PFS and OS were 6.0 months and 10 months, respectively. The ORR for B + I and the sequence were 82% and 83%, respectively. Topoisomerase-2 expression was predictive for TTP and OS, but absent ERCC-1 expression was not, contrary to our hypothesis.
CONCLUSIONS: B + I is an active regimen in EDSCLC. Toxicities included two grade 5 events but were otherwise manageable. The novel sequence B + I E + C increased PFS and OS compared to historical controls. Correlative studies are conflicting regarding the mechanism of action of this novel sequence.

BACKGROUND: Glutaric aciduria type I is an autosomal recessive organic acid disorder. The primary defect is the deficiency of Glutaryl-CoA dehydrogenase (EC number 1.3.99.7) enzyme that is involved in the catabolic pathways of the amino acids l-lysine, l-hydroxylysine, and l-tryptophan. It is a treatable neuro-metabolic disorder. Early diagnosis and treatment helps in preventing brain damage.
METHODS: The Glutaryl-CoA dehydrogenase gene (GCDH) gene was sequenced to identify disease causing mutations by direct sequencing of all the exons in twelve patients who were biochemically confirmed with GA I.
RESULTS: We identified eleven mutations of which nine are homozygous mutations, one heterozygous and two synonymous mutations. Among the eleven mutations, four mutations p.Q162R, p.P286S, p.W225X in two families and p.V410M are novel. A milder clinical presentation is observed in those families who are either heterozygous or with a benign synonymous SNP. Multiple sequence alignment (MSA) of GCDH with its homologues revealed that the observed novel mutations are not tolerated by protein structure and function.
CONCLUSIONS: The present study indicates genetic heterogeneity in GCDH gene mutations among South Indian population. Genetic analysis is useful in prenatal diagnosis and prevention. Mutation analysis is a useful tool in the absence of non-availability of enzyme assay in GA I.