Screening For Deficiency Research Articles

Quantitative G6PD Deficiency Screening in Routine Malaria Diagnostic Units in the Brazilian Amazon (SAFEPRIM): An Operational Mixed-Methods Study.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency testing is not routinely performed before primaquine treatment in most Plasmodium vivax endemic areas, despite the risk of primaquine-associated hemolysis. This is due to the operational challenges associated with pragmatic G6PD testing and as such needs to be addressed. This mixed-methods operational study was aimed at implementing the quantitative point-of-care StandardTM G6PD (SD Biosensor, Korea) screening test in malaria treatment units (MTUs) in the municipalities of Rio Preto da Eva and Mâncio Lima, in the Brazilian Amazon, between mid-January 2020 and December 2020. In total, 1286 P. vivax cases were treated based on the Standard G6PD test: 1230 had activity equal to or greater than 4.0 U/g Hb, and 56 less than 4.0 U/g Hb. No G6PD deficient (G6PDd) genotypes were found in 96 samples from the 1230, and only 21 of the 56 G6PDd cases had confirmed G6PDd genotypes. Evaluations were conducted on the proficiency of health care professionals (HCPs) training to perform the test, the reliability of testing performed in the field, and the perceptions of HCPs and patients about the implementation. Post-training proficiency was 73.4% after a 4-hour training session. This study revealed that locations with lower malaria caseloads will need regular refresher training. The test was well accepted by both HCPs and patients. Signs and symptoms of hemolysis were not always associated with malaria treatment drugs by HCPs and patients. Point-of-care quantitative G6PD testing can be performed at MTUs in the Brazilian Amazon to inform treatment decisions with primaquine. Limitations related to technical and cultural aspects need to be addressed further when expanding screening to larger areas.

Quantification of lysosphingomyelin and lysosphingomyelin-509 for the screening of acid sphingomyelinase deficiency

BackgroundAcid sphingomyelinase deficiency (ASMD) is a lysosomal disorder caused by deficiency of acid sphingomyelinase (ASM) leading to the accumulation of sphingomyelin (SM) in a variety of cell types. Lysosphingomyelin (LysoSM) is the de-acetylated form of SM and it has been shown as a biomarker for ASMD in tissues, plasma, and dried blood spots (DBS) and lysosphingomyelin-509 (LysoSM509) is the carboxylated analogue of LysoSM. High levels of Lysosphingomyelin 509 (LysoSM509) have also been shown in ASMD patients. In this study, we report the utility of the quantification of LysoSM and LysoSM509 in DBS of patients from Latin America with ASMD by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS).ResultsDBS samples from 14 ASMD patients were compared with 15 controls, and 44 general newborns. All patients had their diagnosis confirmed by the quantification of ASM and the measurement of the activity of chitotriosidase. All patients had significantly higher levels of lysoSM and lysoSM509 compared to controls and general newborns.ConclusionsThe quantification of lysosphingolipids in DBS is a valuable tool for the diagnosis of ASMD patients and lysoSM can be useful in the differential diagnosis with NPC. This method is also valuable in the ASMD newborn screening process.

Incorporating second-tier genetic screening for multiple acyl-CoA dehydrogenase deficiency

BackgroundNewborn screening (NBS) for multiple acyl-CoA dehydrogenase deficiency (MADD) has poor sensitivity. This study aimed to evaluate the feasibility of incorporating second-tier genetic screening for MADD. MethodsA total of 453,390 newborns were screened for inherited metabolic disorders using tandem mass spectrometry from January 2017 to May 2022. A matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) assay was developed to identify 23 common ETFDH variants and used for second-tier screening of MADD. ResultsOverall, 185 newborns with suspected MADD received second-tier genetic screening. Thirty-three (17.8 %) newborns with positive results, of which 7 were homozygotes, 5 were compound heterozygotes, 21 were heterozygotes. Further genetic analysis revealed that 6 of the 21 newborns had a second ETFDH variant. Therefore, 18 patients were finally diagnosed with MADD, with a positive predictive value of 9.73 %. The detection rate and diagnostic rate of MALDI-TOF MS assay were 83.33 % and 66.67 %, respectively. Thus the incidence of MADD in our population was estimated at 1:25,188. Nine different ETFDH variants were identified in MADD patients. The most common ETFDH variant being c.250G > A with an allelic frequency of 47.22 %, followed by c.524G > A (13.89 %) and c.998A > G (13.89 %). All patients had elevation of multiple acylcarnitines at NBS. However, seven patients had normal acylcarnitine levels and two patients showed mild elevation of only two acylcarnitines during the recall review. ConclusionWe have established a high throughput MALDI-TOF MS assay for MADD screening. Half of the MADD patients would not be detected under conventional screening protocols. Incorporating second-tier genetic screening into the current NBS could improve the performance of MADD NBS.

A Rare Biotinidase Deficiency in the Pediatrics Population: Genotype-Phenotype Analysis.

Biotinidase (BTD) deficiency is a rare autosomal recessive metabolic disorder caused by insufficient biotin metabolism, where it cannot recycle the vitamin biotin. When this deficiency is not treated with supplements, it can lead to severe neurological conditions. Approximately 1 in 60,000 newborns are affected by BTD deficiency. The BTD deficiency causes late-onset biotin-responsive multiple carboxylase deficiency, which leads to acidosis or lactic acidosis, hypoglycemia, and abnormal catabolism. BTD deficiency is of two types based on the amount of BTD Enzyme present in the serum. A wide range of pathogenic mutations in the BTD gene are reported worldwide. Mutations in the BTD gene lead to profound and partial BTD deficiency. Profound BTD deficiency results in a severe pathogenic condition. A high frequency of newborns are affected with the partial deficiency worldwide. They are mostly asymptomatic, but symptoms may appear during stressful conditions such as fasting or viral infections. Several pathogenic mutations are significantly associated with neurological, ophthalmological, and skin problems along with several other clinical features. This review discusses the BTD gene mutation in multiple populations detected with phenotypic features. The molecular-based biomarker screening is necessary for the disease during pregnancy, as it could be helpful for the early identification of BTD deficiency, providing a better treatment strategy. Moreover, implementing newborn screening for the BTD deficiency helps patients prevent several diseases.

Reduction of Missed Diagnosis of G6PD Deficiency in Heterozygous Females by G6PD/6PGD Ratio Assay Combined with Amplification Refractory Mutation System PCR

Objective: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked genetic disorder that results in impaired enzyme activity. The G6PD/6PGD ratio assay was routinely used for G6PD deficiency screening in China, but there is an apparent defect of missed diagnosis in heterozygous females. The study aims to explore the means to improve its accuracy. Methods: A total of 4,161 Chinese females of childbearing age were collected in this retrospective study. All samples were first subjected to G6PD/6PGD ratio assay and then screened by amplification refractory mutation system PCR (ARMS-PCR) for six hotspot mutants in Chinese population (c.1376G>T, c.1388G>A, c.95A>G, c.1024C>T, c.392G>T, and c.871G>A). For the samples with G6PD/6PGD ratio<1.0 and no mutations were found by ARMS-PCR, next-generation sequencing (NGS) was performed. Sanger sequencing was finally used to verify all the variants. Results: The prevalence of G6PD deficiency in Shenzhen females of childbearing age was 7.31%. The proportion of the six hotspot mutations accounted for 98.03% of all 304 G6PD variants carriers. Taking the ARMS-PCR/NGS results as a reference, the missed diagnosis rate of the G6PD/6PGD ratio assay was 33.88%. Using ARMS-PCR to retest the samples with a G6PD/6PGD ratio between 1.00 and ∼1.10 or 1.00 and ∼1.15 could reduce the missed diagnosis rate from the original 33.88% to 18.09% or 12.05% separately. Conclusion: ARMS-PCR is an appropriate supplementary method for discovering most carriers missed by the G6PD/6PGD ratio assay.

Multiple 17-OHP Cutoff Co-Variates Fail to Improve 21-Hydroxylase Deficiency Screening Accuracy.

To improve the positive predictive value (PPV) of newborn screening for 21-hydroxylase deficiency (21OHD), co-variates have been used to modify 17-hydroxyprogesterone (17OHP) cutoffs. The objective of this study is to evaluate whether 17OHP screening cutoffs adjusted for both collection time (CT) and birth weight (BW) improved the sensitivity and PPV of 21OHD screening. Unaffected newborn screening samples were stratified based on BW and CT to establish 17OHP concentration cutoffs at the 95th and 99th percentile. These cutoffs were applied to a cohort of confirmed cases of 21OHD to determine the sensitivity and PPV of the modified screening parameters. 17OHP cutoffs at the 99th percentile, adjusted for BW and CT, had a sensitivity of 96.3% and a specificity of 98.9%, but a relatively low PPV (0.130) for the identification of 21OHD and did not detect all cases. Use of the 95th percentile further increased sensitivity to 98.1% but resulted in a notably lower PPV (0.027). Alternative approaches that do not rely exclusively on 17OHP are needed to improve newborn screening accuracy for 21OHD.

Incorporating Nutrition-Based Strategies into IBD Treatment.

Diet and nutrition have emerged as key factors in the development and course of inflammatory bowel disease (IBD), including the approach to therapy. We present an overview of evidence-based recommendations and recent research in dietary therapy and nutrition management for patients with IBD. Patients with IBD should undergo a comprehensive nutrition assessment with the assistance of a registered dietitian (RD), including screening for micronutrient deficiencies. Multiple specialized whole foods and liquid formula diets have been evaluated as part of induction and maintenance therapy for IBD. Nutritional status should ideally be optimized in the perioperative setting as well. Nutritional issues are prevalent among IBD patients and should be addressed by a multidisciplinary team, tailored to each patient's disease type, severity and course, including response to medical therapy and need for surgical management, as well as relevant psychosocial considerations.

Screening for Iron Deficiency in Early Childhood Using Serum Ferritin

Introduction: The iron deficiency is an important public health problem widely prevalent in the early childhood period. Iron is very important for various body processes like monoamine metabolism, synthesis of myelin, and metabolic function of the brain. It has many detrimental effects on the cognition, emotional, social, and motor development.‍ Serum ferritin is an easily available, non invasive, inexpensive with high specificity for iron deficiency.&#x0D; Aim: The present study was conducted with the aim to estimate the levels of hemoglobin and serum ferritin in young children in the age group of 1-5 years irrespective of their sex. &#x0D; Materials and Methods: Laboratory data of serum ferritin and hemoglobin levels were prospectively collected of apparently healthy children, 1 to 5 years of age coming to Pediatrics OPD of Acharya Shri Chander College of Medical Sciences, Jammu. The ferritin levels were estimated in roche chemiluminescent immunoassay. The haemoglobin levels were estimated. Children with serum ferritin level &lt; 12 µg/L was considered as deficiency. The statistical analysis was conducted using SPSS version 20.&#x0D; Results: A total of 100 children, 1 to 5 years of age were enrolled in the study. The mean hemoglobin level in children is 12.2gm%. The mean serum ferritin level in children is 29.2µg/L. In our study, it was observed that the mean Hb levels are higher in the reference age group, than decreases in the 2-3 year age group and then again increases in the 3-5 years age group. It was further observed that the serum ferritin levels were higher in the reference age group and then decreases in the 2-3 year age group. The serum ferritin levels further rises in the 3-4 years, 4-5 years age group.&#x0D; Conclusion: In our study, it was observed that serum ferritin is a more reliable test than hemoglobin for screening iron deficiency in early childhood. The most favorable age group for screening for iron deficiency appears to be 2 to 3 years of age in which maximum number of children with iron deficiency was observed, but other associated conditions should also be kept in mind.

Prevalence of G6PD deficiency and G6PD variants amongst the southern Thai population.

BackgroundGlucose-6-phosphate dehydrogenase (G6PD) is an enzyme essential for NADPH production and protecting cells, especially red blood cells, from free radicals. The oxidative stress from drugs, chemicals, and infections can induce red blood cell hemolysis in G6PD deficiency patients, causing a genetic disorder.ObjectivesThis study aims to provide more information on G6PD deficiency prevalence and the G6PD variants in the southern Thai population.MethodsFive hundred and twenty healthy subjects in 14 provinces in the southern part of Thailand participated in the study. EDTA-blood samples were collected for a hematological parameters study, G6PD deficiency screening, and a molecular study for G6PD mutation. G6PD deficiency screening was tested using a fluorescent spot test. The types of G6PD mutation were identified by the allele-specific PCR method.ResultsThe prevalence of G6PD deficiency in southern Thailand was 6.1% (14/228) in males and 9.6% (28/292) in females. Two homozygous and 26 heterozygous G6PD deficiencies were found in females. G6PD Viangchan (871G>A) was the most common variant with 43%, followed by G6PD Mahidol (487G>A), 24% with an allele frequency of 0.025 and 0.012, respectively. Uncharacterized mutations existed in three samples. The study volunteers had anemia in 36.6% (107/292) females and 7.5% (17/228) males. Among G6PD deficiency subjects, only ten partial G6PD deficiency females had mild anemia.ConclusionsThis study suggests that the prevalence of G6PD deficiency in southern Thailand aligns with that of other parts of Thailand. Newborn screening for G6PD deficiency is recommended for personal information and medical reference to prevent acute hemolysis from oxidative stressors.

Impact of Guidelines Regarding Dihydropyrimidine Dehydrogenase (DPD) Deficiency Screening Using Uracil-Based Phenotyping on the Reduction of Severe Side Effect of 5-Fluorouracil-Based Chemotherapy: A Propension Score Analysis.

Dihydropyrimidine dehydrogenase (DPD) deficiency is associated with severe fluoropyrimidines-induced toxicity. As of September 2018, French recommendations call for screening for DPD deficiency by plasma uracil quantification prior to all fluoropyrimidine-based chemotherapy. A dose reduction of fluoropyrimidine is recommended when uracil concentration is equal to or greater than 16 ng/mL. This matched retrospective study assessed the impact of DPD screening on the reduction of severe side effects and on the management of DPD-deficient patients. Using a propensity score, we balanced the factors influencing 5-Fluorouracil (5-FU) toxicity. Then, the severity scores (G3 and G4 severity as well as their frequency) of patients who did not benefit from DPD screening were compared with those of patients who benefited from DPD screening for each treatment cycle (from 1 to 4). Among 349 screened patients, 198 treated patients were included. Among them, 31 (15.7%) had DPD deficiency (median uracilemia 19.8 ng/mL (range: 16.1–172.3)). The median toxicity severity score was higher in the unscreened group for each treatment cycle (0 vs. 1, p < 0.001 at each cycle from 1 to 4) as well as the cumulative score during all courses of treatment (p = 0.028). DPD-deficient patients received a significantly lower dose of 5-FU (p < 0.001). This study suggests that pretherapeutic plasmatic uracil assessment, along with 5-FU dosage adjustment, may be beneficial in reducing 5-FU toxicity in real-life patients.

Iron Deficiency in the United States: Limitations in Guidelines, Data, and Monitoring of Disparities.

Iron deficiency and the more severe sequela, iron deficiency anemia, are public health problems associated with morbidity and mortality, particularly among pregnant women and younger children. The 1998 Centers for Disease Control and Prevention recommendations for prevention and control of iron deficiency in the United States is old and does not reflect recent evidence but is a foundational reference for many federal, clinical, and program guidelines. Surveillance data for iron deficiency are sparse at all levels, with critical gaps for pregnant women and younger children. Anemia, iron deficiency, and iron deficiency anemia are often conflated but should not be. Clinical guidelines for anemia, iron deficiency, and iron deficiency anemia give inconsistent recommendations, causing nonsystematic assessment of iron deficiency. Screening for iron deficiency typically relies on identifying anemia, despite anemia's low sensitivity for iron deficiency. In the National Health and Nutrition Examination Survey, more than 70% of iron deficiency is missed among pregnant women and children by relying on hemoglobin for iron deficiency screening. To improve assessment and diagnosis and strengthen surveillance, better and more complete data and updated foundational guidance on iron deficiency and anemia are needed that consider new evidence for measuring and interpreting laboratory results. (Am J Public Health. 2022;112(S8):S826-S835. https://doi.org/10.2105/AJPH.2022.306998).

DIAGNOSTIC ACCURACY COMPARISON OF THE QUANTITATIVE POINT-OF-CARE ECO G6PD AND BREWERS TEST FOR ASSESSMENT OF G6PD DEFICIENCY IN INFECTIOUS DISEASES

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked, hereditary condition caused by mutations in the G6PD gene, that results in protein variants with different enzyme activity levels. G6PD provides reducing power to NADPH (reduced form of nicotinamide adenine dinucleotide phosphate). NADPH effect is critical in red blood cells (RBC) due to the absence of a nucleus. Clinical manifestations are usually mild and are induced by an exogenous agent, such as drugs, infections, or dietary (fava beans). The G6PD deficiency diagnosis is crucial in infectious diseases because both infections and treatment can induce acute hemolysis. Rarely, life-threatening cases can require transfusions of RBC and hemodialysis. The gold standard for the measurement of G6PD activity is a quantitative UV spectrophotometric assay, however, it is inaccessible in most cases. Methemoglobin reduction test (Brewer's test) is a qualitative spot test most used for G6PD deficiency screening, but is imprecise, requires a cold chain, some laboratory infrastructure, trained personnel, and is time-costing. Point-of-care (POC) is a simple and fast semi-quantitative test that is becoming increasingly important when a prompt diagnosis is required and in health care of out-of-reach communities. To compare the diagnostic accuracy of the quantitative POC ECO and Brewers test for assessment of G6PD deficiency. A cross-sectional diagnostic accuracy study was enrolled between May 2020 and December 2021 at the Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz. Individuals older than 17 years old with a suspicious diagnosis of an infectious disease were eligible. 125 convenience blood samples were tested to compare concordance analysis between Brewers test and POC STANDARD G6PD. The exclusion criteria were hemoglobin concentration < 7.0 g/dL due to technical device limitations. A total of 125 subjects (38 females and 87 males) were recruited. The median age was 42.0 years (range 18–76) in females and 45.0 years (range 19–78) in males. The median of G6PD activity was 7.1 U/g Hb (0.2-17.5). We observed a trend of concordance between the G6PD status (deficient or normal), with low frequencies of discordances in the screenings. The strength of agreement between G6PD tests was classified as almost perfect in all participants (k = 0.82, IC95% = 0.66,0.97) and in subgroups female (k = 0.83, IC95% = 0.59,1.00) and male (k = 0.81, IC95% = 0.59,1.00). The total concordance percentage (number of concordances/total) was 95% in females, 97% in males, and 96% in all participants. Here, we demonstrate POC ECO G6PD test could be performed during medical consultation, guiding the most appropriate therapy almost immediately. In addition to saving time and having comparable results to Brewer's test, it could be performed even in remote areas and with scarce resources, dispensing minimum laboratory requirements. Our findings will be of value to diagnose conditions that could have life-threatening consequences if not timely recognized, such as before initiating primaquine for the treatment of malaria. Therefore, it can improve healthcare in vulnerable isolated communities. We observed a high concordance result between Brewers test and POC STANDARD G6PD, which is becoming the reference test to diagnose G6PD deficiency worldwide.

Screening for Color Vision Deficiency in Health Science Students

Purpose: Various professions require employees to be able to detect different shades of color accurately when visually reading test results with colorimetric end points. To prepare health science students to better meet this requirement, a screening test for color vision deficiency (CVD) was administered to detect any major or minor errors as part of the undergraduate student experience. Method: Screening for color vision deficiency was administered using the Farnsworth D-15 Color Vision Test. Students completed the test and their results were scored and interpreted at the time of completion. Results: Students (n=85) from nine different health science programs completed the Farnsworth D-15 Color Vision Test. Ages of the participants ranged from 18-63 years with 70% of the participants in the age range of 18-23 years. Seventy-one percent of the participants identified as female, 28% identified as males, and 1% identified as non-binary. Two students (one female and one male) had a minor error resulting in a crossover within the test circle on the Gulden test score sheet. There were no major errors identified in the 85 participants. Conclusion: While two minor errors were detected in this population, this data is not consistent with other CVD studies. This most likely is due to screening predominately female students, and/or the amount of time allotted for each individual test to be completed. Future studies will include expanding the participant numbers, with a focus on testing more male participants, limiting the number of minutes to complete the screening process, and collecting additional demographic data.

Iron deficiency and common neurodevelopmental disorders-A scoping review.

A wealth of human and experimental studies document a causal and aggravating role of iron deficiency in neurodevelopmental disorders. While pre-, peri-, and early postnatal iron deficiency sets the stage for the risk of developing neurodevelopmental disorders, iron deficiency acquired at later ages aggravates pre-existing neurodevelopmental disorders. Yet, the association of iron deficiency and neurodevelopmental disorders in childhood and adolescence has not yet been explored comprehensively. In this scoping review, we investigate 1) the association of iron deficiency in children and adolescents with the most frequent neurodevelopmental disorders, ADHD, ASD, and FASD, and 2) whether iron supplementation improves outcomes in these disorders. Scoping review of studies published between 1994 and 2021 using "iron deficiency / iron deficiency anemia" AND "ADHD" OR "autism" OR "FASD" in four biomedical databases. The main inclusion criterion was that articles needed to have quantitative determination of iron status at any postnatal age with primary iron markers such as serum ferritin being reported in association with ADHD, ASD, or FASD. For ADHD, 22/30 studies and 4/4 systematic reviews showed an association of ADHD occurrence or severity with iron deficiency; 6/6 treatment studies including 2 randomized controlled trials demonstrated positive effects of iron supplementation. For ASD, 3/6 studies showed an association with iron deficiency, while 3/6 and 1/1 systematic literature review did not; 4 studies showed a variety of prevalence rates of iron deficiency in ASD populations; 1 randomized controlled trial found no positive effect of iron supplementation on behavioural symptoms of ASD. For FASD, 2/2 studies showed an association of iron deficiency with growth retardation in infants and children with prenatal alcohol exposure. Evidence in favor of screening for iron deficiency and using iron supplementation for pediatric neurodevelopmental disorders comes primarily from ADHD studies and needs to be further investigated for ASD and FASD. Further analysis of study methodologies employed and populations investigated is needed to compare studies against each other and further substantiate the evidence created.

Evaluation of strategies for identification of infants with pathogenic glucose-6-phosphate dehydrogenase variants in China.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, which is caused by pathogenic variants of G6PD that result in decreased G6PD activity, is an X-linked inherited inborn error of metabolism that occurs worldwide. Individuals with G6PD deficiency and heterozygous females with normal G6PD activity (i.e., all individuals with pathogenic G6PD variants) are at risk of developing hemolytic anemia under increased oxidative challenge. However, this risk can be minimized by timely diagnosis. Currently, two assays are used to diagnose G6PD deficiency in China: evaluation of enzymatic activity and targeted genotyping. In terms of identification of all individuals with pathogenic G6PD variants, the performance and cost of different diagnostic strategies (isolated or combined evaluation of G6PD activity and G6PD genotyping) can vary, and these factors should be comprehensively evaluated. In this study, we examined 555 infants (437 males and 118 females) who were positive for the newborn screening of G6PD deficiency. We first evaluated the diagnostic performances of enzymatic testing and targeted genotyping. Both assays attained 100% specificities and positive predictive values for both male and female infants. In contrast, the sensitivities and negative predictive values (NPVs) of the diagnostic tests were different for male and female infants. For male infants, the sensitivities were 99.8 and 98.3%, and the NPVs were 94.1% and 69.6%, for enzymatic testing and targeted genotyping, respectively. For female infants, the sensitivities were 62.5% and 97.9%, and the NPVs were 37.9% and 91.7%, for enzymatic testing and targeted genotyping, respectively. We also evaluated the cost of the five different diagnostic strategies. The combination of G6PD activity testing of all infants, followed by genotyping of female infants with normal G6PD activity, attained high diagnostic sensitivity (99.8%) at a low cost (8.60 USD per diagnosed case). In the future, simultaneous examination of G6PD activity and whole-exon or whole-gene G6PD sequencing could become a standard clinical practice. Our data provide references for clinical practice on the standardization of current and future interventions for G6PD deficiency in China.

Newborn screening for propionic, methylmalonic acidemia and vitamin B12 deficiency. Analysis of 588,793 newborns.

We present the results of our experience in the diagnosis and follow up of the positive cases for propionic, methylmalonic acidemias and cobalamin deficiencies (PA/MMA/MMAHC) since the Expanded Newborn Screening was implemented in Madrid Region. Dried blood samples were collected 48h after birth. Amino acids and acylcarnitines were quantitated by MS/MS. Newborns with alterations were referred to the clinical centers for follow-up. Biochemical and molecular genetic studies for confirmation of a disease were performed. In the period 2011-2020, 588,793 children were screened, being 953 of them were referred to clinical units for abnormal result (192 for elevated C3 levels). Among them, 88 were false positive cases, 85 maternal vitamin B12 deficiencies and 19 were confirmed to suffer an IEM (8PA, 4 MMA, 7 MMAHC). Ten out 19 cases displayed symptoms before the NBS results (6PA, 1 MMA, 3 MMAHC). C3, C16:1OH+C17 levels and C3/C2 and C3/Met ratios were higher in newborns with PA/MMA/MMAHC. Cases diagnosed with B12 deficiency had mean B12 levels of 187.6±76.9pg/mL and their mothers 213.7±95.0; 5% of themothers were vegetarian or had poor eating while 15% were diagnosed of pernicious anemia. Newborns and their mothers received treatment with B12 with different posology, normalizing their levels and the secondary alterations disappeared. Elevated C3 are a frequent cause for abnormal result in newborn screening with a high rate of false positive cases. Presymptomatic diagnosis of most of PA and some MMA/MMAHC is difficult. Vitamin B12 deficiency secondary to maternal deprivation is frequent with an heterogenous clinical and biochemical spectrum.

Glucose 6 phosphate dehydrogenase deficiency quantitative test in dried blood spot- a potential marker for adult unknown G6PD deficiency.

Glucose 6 Phosphate Dehydrogenase (G6PD) enzyme activity estimation in a freshly collected blood sample is the most widely used diagnostic method for the diagnosis of G6PD deficiency. The objective is to evaluate the need for newborn screening for G6PD deficiency over post-malarial diagnosis and the feasibility and reliability of using dried blood spots (DBS) as samples for screening. A total of 562 samples were analyzed for G6PD and parallel measurement of G6PD activity by the colorimetric method in whole blood and DBS was carried out in the neonatal subset. Among 466 adults, 27 (5.7%) showed G6PD deficiency, out of whom 22 (81.48%) were diagnosed after the malarial encounter. In the pediatric group, 8 neonates showed G6PD deficiency. G6PD activity estimated from DBS samples agreed with whole blood, with a statistically significant strong positive correlation. Screening of G6PD deficiency at birth to prevent future unwarranted complications, using DBS is feasible.

Newborn screening and genetic variation of medium chain acyl-CoA dehydrogenase deficiency in the Chinese population.

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is an autosomal recessive disorder of thefatty acid oxidative metabolism. This study aimed toinvestigate the epidemiological characteristics, the spectrum of variation, clinical phenotype, and prognosis ofMCADD in Chinese newborns. We retrospectively analysed newborn screening (NBS) data in the Zibo area from January 2016 to March 2022 and summarized 42 cases recently reported in Chinese neonates. High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and next-generation sequencing (NGS) were used to detect the concentrations ofcarnitine in the blood spots and for diagnosis. A total of 183,082 newborns were detected, andsix patients were diagnosed with MCADD (1/3,0514). The primary octanoylcarnitine (C8) and the octanoylcarnitine/decanoylcarnitine ratio (C8/C10) were elevated in allpatients. Gene analysis revealed four known and four novel variants of the ACADM gene. Five patients were asymptomatic and developed normally under dietary guidance. One child died of vaccination-induced MCADD, presenting with hypoglycemia and elevated acylcarnitines. The incidence of MCADD in Chinese newborns varies geographically from 1/222,903 to 1/30,514, andthe most common pathogenic variant isc.449_452 delCTGA (p. T150Rfs∗4) in ACADM gene with a frequency of 27.7%. HPLC-MS/MS and genetic analysis are beneficial for early prevention and good prognosis of MCADD.

The High Relevance of 21-Deoxycortisol, (Androstenedione + 17α-Hydroxyprogesterone)/Cortisol, and 11-Deoxycortisol/17α-Hydroxyprogesterone for Newborn Screening of 21-Hydroxylase Deficiency.

There are limited reports on the detailed examination of steroid profiles for setting algorithms for 21-hydroxylase deficiency (21OHD) screening by liquid chromatography-tandem mass spectrometry (LC-MS/MS). We aimed to define an algorithm for newborn screening of 21OHD by LC-MS/MS, measuring a total of 2077 dried blood spot samples in Tokyo. Five steroids (17α-hydroxyprogesterone [17αOHP], 21-deoxycortisol [21DOF], 11-deoxycortisol [11DOF], androstenedione [4AD], and cortisol [F]) were included in the panel of LC-MS/MS. Samples from 2 cohorts were assayed: Cohort A, 63 "screening positive" neonates who were referred to an endocrinologist (n = 26 with 21OHD; n = 37 false-positive; obtained from 2015 to 2020); and Cohort B, samples (n = 2014) with 17αOHP values in the 97th percentile or above, in the first-tier test with 17αOHP ELISA from 2020 to 2021. Analysis of Cohort A revealed that the 3 indexes 21DOF, 11DOF/17αOHP, and (4AD + 17αOHP)/F had higher area under the curve (AUC) values (0.999, 0.997, 0.989, respectively), while the 17αOHP AUC was lower (0.970). Accordingly, in addition to 17αOHP, the 3 markers were included for defining the screening algorithm. The assay of Cohort B revealed that the new algorithm gave 92% of predicted positive predictive value without false-negative cases. We also determined the reference values for the 5 steroids at 4 to 7 days after birth, according to sex and gestational age (GA), revealing extremely low levels of 21DOF at any GA irrespective of sex differences. Our study demonstrated the high relevance of 21DOF, (4AD + 17αOHP)/F, and 11DOF/17αOHP, rather than 17αOHP, for 21OHD screening.

Systemic primary carnitine deficiency induces severe arrhythmias due to shortening of the QT interval

Systemic primary carnitine deficiency is a rare genetic disease characterized by severe hypokinetic dilated cardiomyopathy and/or severe rhythm disorders. Without carnitine supplementation, evolution is usually towards a fatal cardiac decompensation. While the cardiomyopathy is most likely secondary to the energy deficiency, the mechanism of the rhythm disturbance is unclear, and may be related to a significant shortening of the QT interval. The aim of this work was to describe rhythmic manifestations at the diagnosis of primary carnitine deficiency and their evolution with carnitine supplementation. We conducted a retrospective multicenter study, including all French patients with a confirmed diagnosis of primary carnitine deficiency. Clinical and paraclinical data at diagnosis and during follow-up were collected. QT interval were measured by two pediatric cardiologists according to international recommendations and corrected with the Bazett formula (QTc). Nineteen patients (median age at diagnosis 2.3 years) followed in 8 French centers were included. At diagnosis, 22% of the patients (4/18) had arrhythmia (1 sudden death, 1 ventricular tachycardia and 2 ventricular fibrillations), and 78% (14/18) had a cardiomyopathy. Seven electrocardiograms before initiation of treatment out of the 9 available displayed a QTc < 340 ms indicating the diagnosis of short QT. The mean QTc after carnitine supplementation was 385 ± 24 ms versus 334 ± 21 ms before treatment ( P < 0.01). No patient reached the criteria of short QT syndrome with carnitine supplementation. Three patients died during the survey, which included one sudden death before carnitine supplementation, one non-recoverable rhythmic storm also before initiation of supplementation, and one sudden death in a patient who stopped carnitine supplementation 16 years after diagnosis. Primary carnitine deficiency is associated with a short QT interval that induces severe arrhythmias and sudden death. Carnitine supplementation normalizes the QTc and avoids arrhythmias. The screening of primary carnitine deficiency in neonates would prevent neonatal death.