High Incidence of Neonatal Inborn Errors of Metabolism in Bahrain Revealed by Tandem Mass Spectrometry

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Diab, Anfal A. Jasim, Zahra Alsahlawi, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6716073/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 12 You are reading this latest preprint version Abstract Background Inborn errors of metabolism (IEM) are individually rare but collectively common. If not detected early, they can cause severe morbidity and death. The study aimed to determine the incidence and types of IEM among healthy newborns in Bahrain. Methods Between January 2019 and May 2020, approximately 5,000 full-term asymptomatic newborns delivered at three major hospitals in Bahrain were enrolled. All newborns began breastfeeding and/or formula milk a few hours after birth. Dried blood spots were collected within 24–72 hours after birth and analyzed using tandem mass spectrometry (TMS. The initial positive screening results were confirmed through repeat testing, analyte ratio evaluation, and additional biochemical analyses. Results The initial metabolic lab tests were followed by further confirmatory tests. Nineteen of the screened newborns had true positive test results, resulting in an IEM incidence of 3.81 per 1,000 live births. Of the identified cases, only two (10.5%) were born to consanguineous marriages. Fatty acid oxidation disorders were the most prevalent (52.6%), followed by amino acid disorders (42.1%) and organic acidemias (5.3%). CPT-I deficiency and tyrosinemia were the most frequently observed conditions. Conclusion The study showed a high incidence of IEM in Bahrain, surpassing rates reported in other Arab and global populations. These findings underscore the urgent need to establish a national newborn screening program to enable early diagnosis and intervention, reducing the burden of metabolic disorders in the Bahraini population. Newborn screening fatty acid oxidation aminoacidopathies organic acidemia inherited metabolic disorders Gulf countries Introduction Inborn Errors of Metabolism (IEM) are a heterogeneous group of rare genetic disorders caused by enzymatic or transporter deficiencies that disrupt normal metabolic pathways. These disruptions can lead to the accumulation of toxic metabolites or the deficiency of essential products, resulting in severe clinical outcomes if undiagnosed, including irreversible neurological damage, multiorgan failure, and death [ 1 ]. Globally, the incidence of IEM ranges from 0.03 to 1.76 per 1,000 live births as reported from China and Saudi Arabia, respectively [ 2 , 3 ]. Although individually rare, collectively they present a significant burden, particularly in regions with high rates of consanguineous marriages [ 4 ]. IEM are commonly grouped into disorders of small molecule metabolism (e.g., aminoacidopathies, organic acidemias), energy metabolism (e.g., fatty acid oxidation defects), and complex molecules (e.g., lysosomal storage disorders) [ 5 ]. Newborn screening programs have proven effective in reducing IEM-related morbidity and mortality by facilitating early diagnosis and treatment. The utilization of tandem mass spectrometry (TMS) in diagnosing IEM has revolutionized the NBS by allowing real-time analysis of over 50 metabolic markers from a single dried blood spot with high sensitivity and specificity [ 6 ]. TMS has become the cornerstone of modern NBS programs due to its reliability, accuracy, rapid turnaround, and cost-effectiveness in detecting multiple conditions [ 7 ]. In Bahrain, selective screening efforts began in the mid-1980s, initially targeting congenital hypothyroidism and common hematological disorders [ 8 , 9 ]. Later expansions included limited metabolic disorders such as phenylketonuria and galactosemia [ 10 ]. Despite these efforts, Bahrain has yet to implement a national NBS program for IEM. A previous study conducted in 2013 at the Aljawhara Center reported an IEM incidence of approximately 1.3 per 1,000 live births using TMS, with amino acid disorders as the most common group [ 9 ]. Given the limitations of earlier data and the lack of national-level screening, updated epidemiological insights are urgently needed. The findings from such insights may encourage health policymakers to support the establishment of a comprehensive, government-led NBS initiative in Bahrain, ultimately reducing preventable morbidity and improving neonatal health outcomes across the kingdom. The study aimed to determine the incidence and types of IEM among Bahraini newborns using TMS in a prospective hospital-based screening initiative. Materials and Methods Patient and Study Design From January 2019 to May 2020, approximately 5,000 full-term healthy newborn infants were recruited for screening from three major hospitals in Bahrain: Salmanyia Medical Center (SMC), King Hamad University Hospital (KHUH), and Bahrain Defense Force Hospital (BDF). Newborn data, including gender, gestational age, maternal age, type of delivery, family history of consanguinity, and family history of IEM, were collected. Sample collection Dried blood samples (DBS) were collected 24–72 hours after birth. Four spots of whole blood were collected from a heel prick. Blood was dripped on Guthrie filter cards (903 Whatman paper) and allowed to dry. Blood spot cards were then dispatched to the newborn screening laboratory at Al-Jawhara Center (AJC) in zipped plastic biohazard envelopes to avoid humidity and contamination. Samples of blood that had not soaked through on both sides were rejected. Sample preparation A 3 mm punch of dry blood spot (DBS) was obtained using a semi-automated puncture machine. Each punch contains 3 µl of whole blood. A deuterated internal standard was used to avoid interference with ion suppression effects and to allow precise quantification. One hundred µl of internal standard was added to the DBS, then shaken for 20 minutes, and the solution was subsequently transferred to another plate for introduction to the TMS. The run lasts 1.8 minutes per sample, enabling a very short processing time. Due to high selectivity, the application does not require an HPLC column. Newborn Screening using Tandem Mass Spectrometer (TMS) The tandem mass spectrometer system consists of two mass spectrometers connected in series (MS/MS). In the first mass spectrometer (MS1), the ions are separated based on their mass-to-charge ratio (m/z). Following this, the ions enter a collision cell where they collide with an inert gas (argon) and dissociate into fragments. The characteristics of these fragments are then analyzed by the second mass spectrometer (MS2) based on their mass-to-charge ratio. TMS is interfaced with Ultra Performance Liquid Chromatography (UPLC/MS/MS), employing the soft ionization technique known as positive ion mode Electro-Spray Ionization (ESI). The Acquity TQD quadruple mass analyzer (Waters, USA) is utilized to analyze the ionized metabolites. A multiple reaction monitoring acquisition mode (MRM) was implemented to identify and simultaneously detect various target metabolites. The MRM mode ensures both high selectivity and high sensitivity. Thirty-eight biochemical parameters were measured, including 13 amino acids, 5 organic acids, and 20 acylcarnitines. Analysis was performed using a commercially available LC-MS/MS kit (Non-derivatized MassChrom®, Chromsystems, Germany). To exclude false-positive results, a second run from a second blood spot was performed for all positive cases.. The analyte ratio was calculated as a confirmatory test. The United States Centers for Disease Control and Prevention (CDC) cutoff values were used for metabolic analytes [ 11 ]. Research Ethics The research adhered to the Helsinki Declaration on ethical principles for medical research involving human participants. The research proposal was reviewed and approved by the ethics committees of the participating hospitals and the Research Ethics Committee of the Arabian Gulf University (Ref. E001-PI-10/18). Before screening, informed written consent was obtained from the parents of the newborn. Statistical analysis Data was entered into Excel sheets and processed using SPSS software, version 22.0 (Chicago, IL, USA). The arithmetic means and standard deviations were computed, and the significance level was defined at P < 0.05 Results Approximately 5,000 newborn infants were screened in this study (Table 1 ). The gender distribution was nearly balanced, with a slight male predominance (51%). The infants were healthy, born at term (> 37 weeks' gestation), and began milk feeds shortly after birth. The prevalence of parental consanguinity among the cohort was reported in 16.8% of cases. A family history of IEM, usually a sibling, was reported by 514 mothers (10.3%) of the total number of newborns studied. Tables 2 & 3 represent the applied cut-off values, the number of cases falling outside these thresholds, gender-based differences among the reported cases, and the associated suspected conditions. The cut-off values applied in this study were based on US CDC-approved reference ranges. Initial screening identified 2,314 newborns with out-of-range results, but confirmatory testing proved only 19 truly positive cases. These huge false-positive initial tests suggest that the cutoff levels we currently use for analytes (US-CDC values) may not be suitable for Bahraini newborns and call for the development of local standards, as has been done in some other countries [ 12 ]. Table 1 Characteristics of the studied newborns (n = 4991) Variable Category/Statistic n (%) or mean ± SD Gender Male 2545 (51%) Female 2446 (49%) Gestational Age Term (37–40 weeks) 4973 (99.62) > 40 weeks 19 (0.38%) Birth Weight (kg) Total 3.07 ± 0.59 Male 3.12 ± 0.60 Female 3.02 ± 0.58 Mode of delivery Vaginal 3403 (68.18%) Cesarean Section 1588 (31.82%) Parental Consanguinity Yes 838 (16.80%) No 4153 (83.21%) Family history of IEMs Present 514 (10.3%) Absent 4477 (89.7%) Table 2 Cut-off Values and Preliminary Positive Amino Acids Case Profiles Analytes Cut-off level (µmol/L) Positive Cases Mean ± SD Gender (P)* Suspected Conditions Proline < 440 8 553.1 ± 114.6 M: 4, F: 4 (P = 0.874) Prolinemia Glycine < 1000 1 1100 F:1 (P = 0.317) Nonketotic Hyperglycinemia (NKHG) Alanine < 583 53 678.3 ± 84.7 M: 24, F: 31 (P = 0.069) Secondary marker of PC and LACTIC Ornithine < 210 44 255.2 ± 61.4 M: 26, F: 18 (P = 0.228) Urea Cycle Disorders Valine < 300 2 355.1 ± 16.2 M: 1, F: 1 (P = 1) MSUD, Valinemia Leucine/ Isoleucine < 300 2 351.2 ± 55 M: 1, F: 1 (P = 1) MSUD, OH PRO Phenylalanine < 120 79 175.1 ± 105.8 M: 39, F: 40 (P = 0.910) PKU, H-PHE, BIOPT-BIO, BIOPT-REG Citrulline < 55 3 68.8 ± 12.7 M: 3 (P = 0.083) ASA, CIT I, PC Tyrosine < 350 3 452.7 ± 96.3 M: 2, F: 1 (P = 0.564) TYR * PC: Pyruvate carboxylase deficiency, LACTIC: Primary lactic acidemia, MSUD: Maple syrup urine disease, OH PRO: Hydroxyprolinemia, PKU: Phenylketonuria, H-PHE: Hyperphenylalaninemia (variant, benign), BIOPT-BIO: Disorders of biopterin, biosynthesis, BIOPT-REG: Disorders of biopterin regeneration, CIT I: Citrullinemia type I, ASA: Argininosuccinic aciduria, TYR: Tyrosinemia. Table 3 Cut-off Values and Preliminary Positive Fatty and Organic Acids Case Profiles Analytes Cut-off level (µmol/L) Positive Cases Mean ± SD Gender (P) Suspected Conditions High C0 8.0 24 6.88 ± 1.03 M: 10, F: 14 (P = 0.414) CUD Low C2 > 7.0 1893 4.37 ± 1.72 M: 905, F: 988 (P = 0.056) CUD C3 < 5.0 12 5.63 ± 0.39 M: 5, F: 7 (P = 0.564) PA, MUT, CBL A & B, CBL C & D, SUCLA 2 C4 < 1.3 4 1.51 ± 0.14 M: 2, F: 2 (P = 1) SCAD, GA II, IBD, EE C5 < 0.70 1 0.86 F: 1 (P = 0.317) IVA, GA II, 2MBG C5OH < 1.0 1 1.22 F: 1 (P = 0.317) MCD, 3MCC, BKT, HMG, 2M3HBA, 3MGA, 3MCC (mat) C8 < 0.50 1 0.7 F: 1 (P = 0.317) MCAD, GA II C10 < 0.45 4 0.53 ± 0.04 M: 2, F: 2 (P = 1) MCAD, GA II C14 < 0.75 1 1.3 F: 1 (P = 0.317) VLCAD C14:1 < 0.60 2 1.07 ± 0.30 F: 2 (P = 0.157) VLCAD C16 < 7.50 2 7.99 ± 0.49 M: 1, F: 1 (P = 1) VLCAD, LCHAD, TFP, CACT, CPT I & II & III C16OH < 0.10 13 0.14 ± 0.05 M: 3, F: 10 (P = 0.052) LCHAD, TFP C18 < 2.30 27 2.56 ± 0.18 M: 17, F: 10 (P = 0.178) CACT, CPT I & II, & III C18:1 < 3.5 62 4.27 ± 0.66 M: 32, F: 30 (P = 0.799) CACT, CPT I & II, & III C18: OH < 0.10 7 0.16 ± 0.04 M: 2, F: 5 (P = 0.257) LCHAD, TFP C5:1 < 0.25 2 13.8 ± 10.9 F: 2 (P = 0.157) BKT, 2M3HBA C10:1 < 0.30 1 1.58 F: 1 (P = 0.317) MCAD, GA II CPT-I: carnitine palmitoyl transferase type I deficiency, CUD: Carnitine uptake defect, PA: Propionic acidemia, MUT: Methylmalonic acidemia (mut), CBL A & B: Methylmalonic acidemia (Cbl A & B), CBL C & D: Methylmalonic aciduria and homocystinuria, SUCLA 2: Succinyl-CoA ligase deficiency, SCAD: Short-chain acyl-CoA dehydrogenase deficiency, GA II: Glutaric acidemia type II, IBD: Isobutyrylglycinuria, EE: Ethylmalonic encephalopathy, IVA: Isovaleric acidemia, 2MBG: 2-Methylbutyrylglycinuria, MCD, Multiple carboxylase deficiency, 3MCC: 3-Methylcrotonyl-CoA carboxylase deficiency, BKT: β-Ketothiolase deficiency, HMG: 3-Hydroxy-3-methylglutaric aciduria, 2M3HBA: 2-Methyl-3-hydroxybutyric aciduria, 3MGA: 3-Methylglutaconic aciduria, 3MCC (mat): Maternal 3-Methylcrotonyl-CoA carboxylase deficiency, CACT: Carnitine-acylcarnitine translocase deficiency, MCAD: Medium-chain acyl-CoA dehydrogenase deficiency, VLCAD: Very long-chain acyl-CoA dehydrogenase deficiency, LCHAD: Long-chain L-3-Hydroxy dehydrogenase deficiency, TFP: Trifunctional protein deficiency, BKT: β-Ketothiolase deficiency. In the current analysis, 195 preliminary positive cases of amino acid disorders were identified, as summarized in Table 2 . Among these, phenylalanine, alanine, and ornithine were the most frequently elevated amino acids, with 79, 53, and 44 positive cases, respectively. These three analytes demonstrated a notably higher prevalence than other amino acids, indicating their potential as common indicators in the spectrum of amino acid-related metabolic abnormalities among Bahraini newborns. Proline was the next most elevated amino acid, with 8 positive cases recorded. Despite these observations, statistical evaluation revealed no significant gender-based differences in the occurrence of elevated levels for any of the amino acids within this subgroup, suggesting that amino acid disorders, at least at the preliminary screening level, may affect males and females at relatively similar rates. It is noteworthy that several other amino acids included in the screening panel did not yield any preliminary positive cases. These included aspartic acid, methionine, and arginine. The absence of detected abnormalities in these amino acids may reflect their lower prevalence among Bahraini newborns. In contrast, the proportion of preliminary positive cases associated with fatty acid and organic acid metabolism disorders was markedly higher (Table 3 ). Fatty acid-related analytes accounted for most of these findings, with a total of 2,103 positive cases, representing approximately 86.4% of all preliminary positive results. This substantial proportion underscores the high frequency and possible clinical relevance of disturbances in fatty acid oxidation pathways among newborns in Bahrain. Among these, low levels of acylcarnitine (C2) were the most prevalent abnormality, identified in 1,893 cases, which constitutes 90% of the total acylcarnitine-related positive findings. Statistical comparison between sexes revealed that this abnormality was more frequently observed in females than in males, although the difference approached but did not reach conventional levels of statistical significance (P = 0.056), indicating a potential gender-related trend that warrants further investigation in a larger cohort. Elevated free carnitine (C0) levels represented the second most observed abnormality among the acylcarnitine analytes, with 62 positive cases, accounting for 2.95% of all fatty acid-related preliminary findings. In contrast to low C2 levels, this abnormality demonstrated a statistically significant gender difference, with elevated C0 levels occurring more frequently in males compared to females (P = 0.002), highlighting a potential sex-specific variation in carnitine metabolism that may have diagnostic or pathophysiological implications. Similarly, elevated levels of oleic acid (C18:1) were detected in 62 cases (2.95%), matching the frequency of elevated C0 levels. However, unlike C0, the distribution of C18:1 abnormality did not differ significantly between genders (P > 0.05), suggesting a uniform distribution across sexes for this specific fatty acid. Elevated levels of hydroxy-palmitoyl-carnitine (C16OH) were less common, found in 13 cases, but appeared to be more frequent in females. This observation approached statistical significance (P = 0.052), indicating a borderline gender-related trend that, although not definitive, may be clinically meaningful and should be explored further in future studies. On the other hand, a relatively small number of preliminary positive cases were attributed to disorders associated with organic acid metabolism. Only 16 such cases were identified, constituting the lowest proportion of all detected abnormalities in the screening cohort. Among these, elevated propionyl carnitine (C3) levels were the most frequently observed, present in 12 cases, which corresponds to 75% of the organic acid-related abnormalities. Analysis of gender distribution within this subgroup revealed no statistically significant differences (P = 0.564), indicating that elevated C3 levels were similarly prevalent in males and females. Conversely, a single fatty acid-related and a single organic acid-related analyte included in the screening did not yield any preliminary positive findings. Notably, no elevations were detected for hexanoic acid (C6) or urine glutaryl-carnitine (C5DC), among others. This lack of positive detection could reflect their lower diagnostic yield in the screened Bahraini newborns. Overall, these findings suggest that while amino acid-related disorders occur with moderate frequency and exhibit no strong gender association, fatty acid metabolism disturbances are significantly more prevalent and may demonstrate sex-specific patterns, particularly regarding certain acylcarnitines. In contrast, organic acid metabolism disorders were rare in this cohort and did not display any evident gender predilection. To verify the accuracy of initial positive newborn screening results, selected cases underwent comprehensive confirmatory procedures. This included repeat analysis using either the original or a second dried blood spot (DBS) card, the calculation of additional diagnostic analyte ratios, and, where appropriate, supplementary biochemical testing (Table 4 ). Through these rigorous confirmatory measures, a total of 19 true positive cases were validated. Table 4 Biochemical Parameters of Confirmed Positive Cases (n. 19) Confirmed Cases N of Cases Analyte Normal Cutoff Value (µmol/l) Secondary Marker Normal Cutoff 2 Ratio or Value (µmol/l) Amino Acids 8 PKU 1 Phenylalanine < 120 1075.68 Phe/Tyr < 3 30.7 MSUD 1 Leu/isoleucine < 300 312.34 Leu/Phe, Leu/Tyr < 4 7.76 Valine < 300 366.5 Val/Phe, Val/Tyr < 4 9.1 ASA 1 Citrulline < 55 55 Cit/Arg 0.60 CIT 2 Citrulline < 55 74 ± 10.1 Cit/Arg 1.02, 1.60 Tyrosinemia 3 Tyrosine < 350 Fatty Acids 10 CPT-I 5 C0 < 57 94.4 ± 9.2 C0/(C16 + C18) < 15 (15.5–35.9) CACT 2 C16 < 7.5 7.64, 8.33 C14 < 0.36 0.44, 0.32 C18 < 2.3 2.5, 2.68 C16/C2 < 0.65 0.30,0.97 C18:1 < 2.75 2.93, 1.9 (C16 + C18:1)/C2 < 0.75 0.41,1.21 VLCAD 2 C14 < 0.75 0.71, 1.33 C14:1/C2 < 0.03 0.033,0.30 C14:1 < 0.60 1.28, 0.86 C14:1/C16 < 0.30 0.54, 0.25 MCAD 1 C8 < 0.50 0.7 C5OH < 1.0 1.22 C10 < 0.45 0.56 C8/C10 < 1.6 1.3 Among the confirmed cases, fatty acid oxidation defects represented the largest group, accounting for 10 cases (52.6%). This was followed by amino acid disorders, with 8 cases (42.1%), and a single case (5.3%) of an organic acid disorder, specifically isovaleric acidemia (IVA). Within the fatty acid oxidation disorders, Carnitine Palmitoyl Transferase Type I (CPT-I) deficiency emerged as the most prevalent individual condition, with an observed incidence of 1 per 1,000 newborns. Tyrosinemia was the second most frequently diagnosed disorder, with an incidence of 0.6 per 1,000 newborns. Further breakdown of the confirmed conditions revealed two cases each of citrullinemia type I (CIT-I), carnitine-acylcarnitine translocase deficiency (CACT), and very long-chain acyl-CoA dehydrogenase deficiency (VLCAD), corresponding to an incidence of 0.4 per 1,000 newborns for each disorder. Additionally, there was one confirmed case each of phenylketonuria (PKU), maple syrup urine disease (MSUD), argininosuccinic aciduria (ASA), and medium-chain acyl-CoA dehydrogenase deficiency (MCAD), all with an incidence of 0.2 per 1,000 newborns. Most of the confirmed cases were identified in otherwise healthy infants born to non-consanguineous parents, suggesting a broad population-wide distribution. However, two cases out of nineteen (10.5%), one involving elevated citrulline (CIT) levels and another of CPT-I deficiency, were detected in infants born to consanguineous parents, highlighting the potential influence of autosomal recessive inheritance patterns. These findings reflect an overall incidence of 3.81 per 1,000 screened newborns, which is high compared to the reported incidence of IEM in other Arab countries (Table 5 ). Table 5 Incidence of IEM per 100,000 live births in Arab countries Country Incidence/100,000 Reference # Bahrain 381 This study Libya 193 [ 17 ] Saudi Arabia 176 [ 14 ] Qatar 111 [ 19 ] Tunisia 61 [ 18 ] United Arab Emirates 55 [ 15 ] Egypt 51 [ 20 ] Discussion Bahrain is one of the six Gulf Cooperation Council (GCC) countries. The reported incidence of IEM in GCC countries and some other Arab nations is higher than that reported from various regions around the world [ 13 – 15 ]. Since most IEM disorders follow an autosomal recessive pattern of inheritance, the high prevalence of these disorders in the GCC countries can be explained by population genetics and the high rate of consanguineous marriages [ 4 ]. A total of 4991 Bahraini newborns were screened in this study. Nineteen true-positive cases were identified, resulting in an overall incidence of 3.81 per 1000 live births. The incidence of IEM in this study is higher than the reported incidence of these disorders in GCC countries and other Arab nations [ 16 – 20 ]. Moreover, this incidence is nearly three times greater than the IEM incidence reported in countries within Europe, the UK, the US, and China [ 2 , 3 , 21 ]. We believe this is the highest reported incidence of IEM worldwide. When different metabolic categories are considered, the highest incidence of IEM in this study was that of fatty acid oxidation defects, followed by the aminoacidopathies and urea cycle disorders. Organic acidemias had the lowest incidence, as we detected only one case of isovaleric acidemia. These findings are strikingly different from those of a previous study conducted at our center in 2013. In that report, 1986 sick symptomatic Bahraini newborns were investigated at our lab (AJC) for IEM using TMS [ 9 ]. Twenty-five of them had confirmed disorders. Aminoacidopathies were the most common in that series, comprising 44% of cases, followed by organic acidemias (36%). Fatty acid oxidation defects comprised 20% of cases in that group. The finding that fatty acid oxidation defects were the most encountered type of IEM in this study contradicts the findings of many studies from the GCC countries and other Arab countries [ 22 – 24 ]. However, the incidence of aminoacidopathies and urea cycle disorders is comparable to those reported from Saudi Arabia [ 12 , 13 ]. The incidence of organic acidurias in our series is very close to the findings of a study from Tunisia [ 18 ]. However, it was lower than that reported in a previous study from our center [ 10 ], and much lower than that reported from other Arab countries [ 18 , 20 , 23 ]. A family history of IEM was reported in 10.3% of the screened newborns, and in 21% of the positive cases, a finding comparable to what was reported from other GCC countries [ 19 , 2 ]. The consanguinity rate observed among the families of the screened babies in this study (16.8%) agrees with the reported rate of consanguineous marriages in Bahrain (16–25%). Among the confirmed positive cases, however, parental consanguinity is reported in only two cases (10.5%), a finding much lower than that of the previous study from our center on symptomatic infants, which found that 94% of IEM patients were products of consanguineous marriages [ 10 ]. Due to their chronic and progressive nature, inborn errors of metabolism (IEM) necessitate lifelong medical care, specialized management, and often costly supportive and symptomatic therapies. These disorders impose a substantial burden on healthcare delivery systems. The expenses associated with the confirmatory metabolic and genetic testing required for diagnosis, in addition to the costs of treatment modalities including high-priced medications, specialized nutritional formulas, enzyme replacement therapies, liver transplantation, prolonged hospitalizations, and ongoing supportive care, represent a significant economic challenge. Early detection of IEM through newborn screening (NBS) programs is the most cost-effective strategy to mitigate the severe complications, morbidity, and mortality linked to delayed diagnosis, ultimately enhancing patient outcomes and quality of life. The successful implementation of national NBS programs remains essential to achieving these goals. Conclusion This study showed that IEM disorders are prevalent in Bahrain, with an estimated incidence that is higher than those reported from the GCC countries and other Arab countries and far higher than the incidence described from the different regions of the world. Early detection of these disorders is essential to prevent severe morbidity and death among the affected infants [ 25 ]. Most GCC countries have established national newborn screening programs for IEM and other hereditary diseases. We believe it is timely for Bahrain to initiate a national newborn screening program for IEM to reduce infant mortality and improve health care for affected babies. Such a program is feasible because all births occur in hospitals, making 100% coverage granted, and the specialized medical personnel and the lab facilities needed are available in the country. Declarations Ethics approval and consent to participate: The research adhered to the Helsinki Declaration on ethical principles for medical research involving human participants. The research proposal was reviewed and approved by the ethics committees of the participating hospitals and the Research Ethics Committee of the Arabian Gulf University (Ref. E001-PI-10/18). Before screening, informed written consent was obtained from the parents of the newborns. Consent for publication : The parents of the screened newborns agreed to the publication of the research data and signed informed consent forms. Data Availability: The raw data of this study are available upon request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Competing interests: The authors declare that they have no conflict of interest. Funding: The Arabian Gulf University in Bahrain covered the costs of the lab tests. None of the authors has received any funds or benefits. Clinical trial number : not applicable. Authors’ contributions : (1) Abdelaziz Elamin: planning of research and writing the manuscript. (2 and 3) Diab E. Diab and Anfal A. Jasim did the tandem mass spectrometry and other laboratory investigations and assisted in writing the results section. (4-9) Zahra Alsahlawi, Hadhami Benturkia, Salman M. Alkhalifa, Shatha H. Osman, Abdulraoof Almadhoob and Mona Aljufairi are the physicians who recruited the newborns, obtained informed consents from parents, revised the lab results, and contributed to writing the results section. (10) Moiz Bakhiet: contributed to the research proposal, revised the manuscript, and contributed to the discussion section of the article. Acknowledgements : not applicable. References Saudubray JM, Garcia-Cazorla A. Inborn Errors of Metabolism Overview: Pathophysiology, Manifestations, Evaluation, and Management. Pediatr Clin North Am. 2018;65(2):179–208. Kanungo S, Patel D, Neelakantan M, et al. Newborn screening and changing face of inborn errors of metabolism in the United States. Ann Transl Med. 2018;6(24):468–72. Hao L, Liang L, Gao X, et al. Screening of 1.17 million newborns for inborn errors of metabolism using tandem mass spectrometry in Shanghai, China: A 19-year report. Mol Genet Metab. 2021;141(1):108098. Afzal RM, Lund AM, Skovby F. 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JIMD Rep. 2016;28:127–35. Moammar H, Cheriyan G, Mathew R, Al-Sannaa N. Incidence and patterns of inborn errors of metabolism in the Eastern province of Saudi Arabia. Ann Saudi Med. 2010;30:271–7. Alobaidy H. Patterns of inborn errors of metabolism: A 12-year single-center hospital- A based study in Libya. Qatar Med J. 2013; 2013(2):57–65. Chioukh FZ, Chaabane A, Khamis T, Jlassi A, Kaabachi N, Monastiri K. Inborn errors of metabolism in the neonatal period: A Challenging management in Tunisia. Tunis Med. 2019;97(5):681–4. Lindner M, Abdoh G, Fang-Hoffmann J, et al. Implementation of extended neonatal Screening and a metabolic unit in the State of Qatar: developing and optimizing strategies in cooperation with the Neonatal Screening Center in Heidelberg. J Inherit Metab Dis. 2007;30(4):522–9. Hassan FA, El-Mougy F, Sharaf SA, et al. Inborn errors of metabolism detectable by tandem mass spectrometry in Egypt: The first newborn screening pilot study. J Med Screen. 2016;23(3):124–9. Sanderson S, Green A, Preece MA, Burton H. The incidence of inherited metabolic disorders in the West Midlands, UK. Arch Dis Child. 2006;91:896–902. Joshi SN, Venugopalan P. Clinical characteristics of neonates with inborn errors of metabolism detected by Tandem MS analysis in Oman. Brain Dev. 2007;29(9):543–6. Meiouet F, El-Kabbaj S, Abilkassem R, Boemer F. Moroccan Experience of Targeted Screening for Inborn Errors of Metabolism by Tandem Mass Spectrometry. Pediatr Rep. 2023;15(1):227–36. Jelassi A, Nasrallah F, Talbi A, et al. Spectrum of Organic Aciduria Diseases in Tunisia: A 35-year Retrospective Study. Saudi J Med Sci. 2024;12(1):27–34. Bakhiet M, Alawadi AMI, Alhammadi MM, Ali MF, Butti N. A case report of neurological complications owing to. lately diagnosed hyperargininemia, emphasizing the role of national neonatal screening policies in the Kingdom of Bahrain. Med (Baltim). 2018;97(20):e10780. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6716073","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":477457994,"identity":"da0689c4-949c-420d-962c-0a742b298b50","order_by":0,"name":"Abdelaziz Elamin","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAklEQVRIiWNgGAWjYDACCQYDhgcMDDxgzgeImAEDY8MB/FoSoFoYZ5CiBQyYeYjRwj+7eeODhJo6Gfn27sTHNjW1iQ3szdskGHfcwW3JnWPFBgnH2HgYe85uNs45djyxgedYmQTjmWe4HXYjx0wigY2Hh1kid5t0DtuxxAYJoAhj22GcOuRv5Jj/SPgnwcMm/3b7b4t/QC3yb/BrMQDawpDYZsDDI8G7jZmxrQZoCw9+LYZAv0gk9iXwSPDkbpbs7Ttg3MaTVmyReAa3FrnbzRs/fPhWZy/ffnbjhx/f6mT72Q9vvPFxB24t6OAwAxuISiBaAwNDHQlqR8EoGAWjYKQAALdiWEAxn8oAAAAAAElFTkSuQmCC","orcid":"","institution":"Arabian Gulf University","correspondingAuthor":true,"prefix":"","firstName":"Abdelaziz","middleName":"","lastName":"Elamin","suffix":""},{"id":477457995,"identity":"96ba5f17-37b3-44a3-821d-d5519382829c","order_by":1,"name":"Diab E. Diab","email":"","orcid":"","institution":"Aljawhara Centre, Arabian Gulf University","correspondingAuthor":false,"prefix":"","firstName":"Diab","middleName":"E.","lastName":"Diab","suffix":""},{"id":477457996,"identity":"ad0880be-d9af-4058-bf7d-5a601349cee5","order_by":2,"name":"Anfal A. Jasim","email":"","orcid":"","institution":"Aljawhara Centre, Arabian Gulf University","correspondingAuthor":false,"prefix":"","firstName":"Anfal","middleName":"A.","lastName":"Jasim","suffix":""},{"id":477457997,"identity":"271a89f9-a381-4876-b88a-4f514ef4e13d","order_by":3,"name":"Zahra Alsahlawi","email":"","orcid":"","institution":"Salmaniya Medical Complex","correspondingAuthor":false,"prefix":"","firstName":"Zahra","middleName":"","lastName":"Alsahlawi","suffix":""},{"id":477457998,"identity":"5b9548a8-26f0-4623-81df-9517d0d937a3","order_by":4,"name":"Hadhami Benturkia","email":"","orcid":"","institution":"King Hamad University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hadhami","middleName":"","lastName":"Benturkia","suffix":""},{"id":477457999,"identity":"b42722ac-ec08-4260-9954-e43da748e718","order_by":5,"name":"Salman M. Alkhalifa","email":"","orcid":"","institution":"King Hamad University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Salman","middleName":"M.","lastName":"Alkhalifa","suffix":""},{"id":477458000,"identity":"e6cb2f41-0685-410b-8969-46ccb9d74f56","order_by":6,"name":"Shatha H. Osman","email":"","orcid":"","institution":"King Hamad University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shatha","middleName":"H.","lastName":"Osman","suffix":""},{"id":477458001,"identity":"40a6dde5-60b1-4b9c-a27f-cc346df11a8c","order_by":7,"name":"Abdulraoof Almadhoob","email":"","orcid":"","institution":"Salmaniya Medical Complex","correspondingAuthor":false,"prefix":"","firstName":"Abdulraoof","middleName":"","lastName":"Almadhoob","suffix":""},{"id":477458002,"identity":"16754f87-4f36-41af-bde9-79df6db6f60d","order_by":8,"name":"Muna Aljufairi","email":"","orcid":"","institution":"Salmaniya Medical Complex","correspondingAuthor":false,"prefix":"","firstName":"Muna","middleName":"","lastName":"Aljufairi","suffix":""},{"id":477458003,"identity":"e860c5f7-2be3-42ae-955e-fc0f49ca443a","order_by":9,"name":"Moiz Bakhiet","email":"","orcid":"","institution":"Arabian Gulf University","correspondingAuthor":false,"prefix":"","firstName":"Moiz","middleName":"","lastName":"Bakhiet","suffix":""}],"badges":[],"createdAt":"2025-05-21 11:38:04","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6716073/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6716073/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":85690668,"identity":"f61f4457-8384-4ded-a311-d5c5ae8a2d5c","added_by":"auto","created_at":"2025-06-30 16:50:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1000556,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6716073/v1/52dae830-c2f4-481b-98d3-d1a18cc483d0.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"High Incidence of Neonatal Inborn Errors of Metabolism in Bahrain Revealed by Tandem Mass Spectrometry","fulltext":[{"header":"Introduction","content":"\u003cp\u003eInborn Errors of Metabolism (IEM) are a heterogeneous group of rare genetic disorders caused by enzymatic or transporter deficiencies that disrupt normal metabolic pathways. These disruptions can lead to the accumulation of toxic metabolites or the deficiency of essential products, resulting in severe clinical outcomes if undiagnosed, including irreversible neurological damage, multiorgan failure, and death [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Globally, the incidence of IEM ranges from 0.03 to 1.76 per 1,000 live births as reported from China and Saudi Arabia, respectively [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Although individually rare, collectively they present a significant burden, particularly in regions with high rates of consanguineous marriages [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. IEM are commonly grouped into disorders of small molecule metabolism (e.g., aminoacidopathies, organic acidemias), energy metabolism (e.g., fatty acid oxidation defects), and complex molecules (e.g., lysosomal storage disorders) [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNewborn screening programs have proven effective in reducing IEM-related morbidity and mortality by facilitating early diagnosis and treatment. The utilization of tandem mass spectrometry (TMS) in diagnosing IEM has revolutionized the NBS by allowing real-time analysis of over 50 metabolic markers from a single dried blood spot with high sensitivity and specificity [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. TMS has become the cornerstone of modern NBS programs due to its reliability, accuracy, rapid turnaround, and cost-effectiveness in detecting multiple conditions [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn Bahrain, selective screening efforts began in the mid-1980s, initially targeting congenital hypothyroidism and common hematological disorders [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Later expansions included limited metabolic disorders such as phenylketonuria and galactosemia [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Despite these efforts, Bahrain has yet to implement a national NBS program for IEM. A previous study conducted in 2013 at the Aljawhara Center reported an IEM incidence of approximately 1.3 per 1,000 live births using TMS, with amino acid disorders as the most common group [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eGiven the limitations of earlier data and the lack of national-level screening, updated epidemiological insights are urgently needed. The findings from such insights may encourage health policymakers to support the establishment of a comprehensive, government-led NBS initiative in Bahrain, ultimately reducing preventable morbidity and improving neonatal health outcomes across the kingdom. The study aimed to determine the incidence and types of IEM among Bahraini newborns using TMS in a prospective hospital-based screening initiative.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient and Study Design\u003c/h2\u003e \u003cp\u003eFrom January 2019 to May 2020, approximately 5,000 full-term healthy newborn infants were recruited for screening from three major hospitals in Bahrain: Salmanyia Medical Center (SMC), King Hamad University Hospital (KHUH), and Bahrain Defense Force Hospital (BDF). Newborn data, including gender, gestational age, maternal age, type of delivery, family history of consanguinity, and family history of IEM, were collected.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSample collection\u003c/h3\u003e\n\u003cp\u003eDried blood samples (DBS) were collected 24\u0026ndash;72 hours after birth. Four spots of whole blood were collected from a heel prick. Blood was dripped on Guthrie filter cards (903 Whatman paper) and allowed to dry. Blood spot cards were then dispatched to the newborn screening laboratory at Al-Jawhara Center (AJC) in zipped plastic biohazard envelopes to avoid humidity and contamination. Samples of blood that had not soaked through on both sides were rejected.\u003c/p\u003e\n\u003ch3\u003eSample preparation\u003c/h3\u003e\n\u003cp\u003eA 3 mm punch of dry blood spot (DBS) was obtained using a semi-automated puncture machine. Each punch contains 3 \u0026micro;l of whole blood. A deuterated internal standard was used to avoid interference with ion suppression effects and to allow precise quantification. One hundred \u0026micro;l of internal standard was added to the DBS, then shaken for 20 minutes, and the solution was subsequently transferred to another plate for introduction to the TMS. The run lasts 1.8 minutes per sample, enabling a very short processing time. Due to high selectivity, the application does not require an HPLC column.\u003c/p\u003e\n\u003ch3\u003eNewborn Screening using Tandem Mass Spectrometer (TMS)\u003c/h3\u003e\n\u003cp\u003eThe tandem mass spectrometer system consists of two mass spectrometers connected in series (MS/MS). In the first mass spectrometer (MS1), the ions are separated based on their mass-to-charge ratio (m/z). Following this, the ions enter a collision cell where they collide with an inert gas (argon) and dissociate into fragments. The characteristics of these fragments are then analyzed by the second mass spectrometer (MS2) based on their mass-to-charge ratio. TMS is interfaced with Ultra Performance Liquid Chromatography (UPLC/MS/MS), employing the soft ionization technique known as positive ion mode Electro-Spray Ionization (ESI). The Acquity TQD quadruple mass analyzer (Waters, USA) is utilized to analyze the ionized metabolites. A multiple reaction monitoring acquisition mode (MRM) was implemented to identify and simultaneously detect various target metabolites. The MRM mode ensures both high selectivity and high sensitivity. Thirty-eight biochemical parameters were measured, including 13 amino acids, 5 organic acids, and 20 acylcarnitines. Analysis was performed using a commercially available LC-MS/MS kit (Non-derivatized MassChrom\u0026reg;, Chromsystems, Germany). To exclude false-positive results, a second run from a second blood spot was performed for all positive cases.. The analyte ratio was calculated as a confirmatory test. The United States Centers for Disease Control and Prevention (CDC) cutoff values were used for metabolic analytes [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eResearch Ethics\u003c/h3\u003e\n\u003cp\u003e The research adhered to the Helsinki Declaration on ethical principles for medical research involving human participants. The research proposal was reviewed and approved by the ethics committees of the participating hospitals and the Research Ethics Committee of the Arabian Gulf University (Ref. E001-PI-10/18). Before screening, informed written consent was obtained from the parents of the newborn.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eData was entered into Excel sheets and processed using SPSS software, version 22.0 (Chicago, IL, USA). The arithmetic means and standard deviations were computed, and the significance level was defined at \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eApproximately 5,000 newborn infants were screened in this study (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The gender distribution was nearly balanced, with a slight male predominance (51%). The infants were healthy, born at term (\u0026gt;\u0026thinsp;37 weeks' gestation), and began milk feeds shortly after birth. The prevalence of parental consanguinity among the cohort was reported in 16.8% of cases. A family history of IEM, usually a sibling, was reported by 514 mothers (10.3%) of the total number of newborns studied.\u003c/p\u003e \u003cp\u003eTables\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e \u0026amp; \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e represent the applied cut-off values, the number of cases falling outside these thresholds, gender-based differences among the reported cases, and the associated suspected conditions. The cut-off values applied in this study were based on US CDC-approved reference ranges. Initial screening identified 2,314 newborns with out-of-range results, but confirmatory testing proved only 19 truly positive cases. These huge false-positive initial tests suggest that the cutoff levels we currently use for analytes (US-CDC values) may not be suitable for Bahraini newborns and call for the development of local standards, as has been done in some other countries [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of the studied newborns (n\u0026thinsp;=\u0026thinsp;4991)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCategory/Statistic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003en (%) or mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2545 (51%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2446 (49%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGestational Age\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTerm (37\u0026ndash;40 weeks)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4973 (99.62)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;40 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (0.38%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBirth Weight (kg)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.07\u0026thinsp;\u0026plusmn;\u0026thinsp;0.59\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.12\u0026thinsp;\u0026plusmn;\u0026thinsp;0.60\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.02\u0026thinsp;\u0026plusmn;\u0026thinsp;0.58\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMode of delivery\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVaginal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3403 (68.18%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCesarean Section\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1588 (31.82%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eParental Consanguinity\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e838 (16.80%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4153 (83.21%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFamily history of IEMs\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePresent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e514 (10.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAbsent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4477 (89.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCut-off Values and Preliminary Positive Amino Acids Case Profiles\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnalytes\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCut-off level (\u0026micro;mol/L)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePositive Cases\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGender (P)*\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSuspected Conditions\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;440\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e553.1\u0026thinsp;\u0026plusmn;\u0026thinsp;114.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eM: 4, F: 4\u003c/p\u003e \u003cp\u003e(P\u0026thinsp;=\u0026thinsp;0.874)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eProlinemia\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlycine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;1000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eF:1\u003c/p\u003e \u003cp\u003e(P\u0026thinsp;=\u0026thinsp;0.317)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNonketotic Hyperglycinemia (NKHG)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlanine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;583\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e678.3\u0026thinsp;\u0026plusmn;\u0026thinsp;84.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eM: 24, F: 31\u003c/p\u003e \u003cp\u003e(P\u0026thinsp;=\u0026thinsp;0.069)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSecondary marker of PC and LACTIC\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOrnithine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;210\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e255.2\u0026thinsp;\u0026plusmn;\u0026thinsp;61.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eM: 26, F: 18\u003c/p\u003e \u003cp\u003e(P\u0026thinsp;=\u0026thinsp;0.228)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eUrea Cycle Disorders\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eValine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;300\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e355.1\u0026thinsp;\u0026plusmn;\u0026thinsp;16.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eM: 1, F: 1\u003c/p\u003e \u003cp\u003e(P\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMSUD, Valinemia\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeucine/ Isoleucine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;300\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e351.2\u0026thinsp;\u0026plusmn;\u0026thinsp;55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eM: 1, F: 1\u003c/p\u003e \u003cp\u003e(P\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMSUD, OH PRO\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhenylalanine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;120\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e175.1\u0026thinsp;\u0026plusmn;\u0026thinsp;105.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eM: 39, F: 40\u003c/p\u003e \u003cp\u003e(P\u0026thinsp;=\u0026thinsp;0.910)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePKU, H-PHE, BIOPT-BIO, BIOPT-REG\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCitrulline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e68.8\u0026thinsp;\u0026plusmn;\u0026thinsp;12.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eM: 3\u003c/p\u003e \u003cp\u003e(P\u0026thinsp;=\u0026thinsp;0.083)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eASA, CIT I, PC\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTyrosine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;350\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e452.7\u0026thinsp;\u0026plusmn;\u0026thinsp;96.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eM: 2, F: 1\u003c/p\u003e \u003cp\u003e(P\u0026thinsp;=\u0026thinsp;0.564)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eTYR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e* PC: Pyruvate carboxylase deficiency, LACTIC: Primary lactic acidemia, MSUD: Maple syrup urine disease, OH PRO: Hydroxyprolinemia, PKU: Phenylketonuria, H-PHE: Hyperphenylalaninemia (variant, benign), BIOPT-BIO: Disorders of biopterin, biosynthesis, BIOPT-REG: Disorders of biopterin regeneration, CIT I: Citrullinemia type I, ASA: Argininosuccinic aciduria, TYR: Tyrosinemia.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCut-off Values and Preliminary Positive Fatty and Organic Acids Case Profiles\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnalytes\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCut-off level (\u0026micro;mol/L)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePositive Cases\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGender (P)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSuspected Conditions\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHigh C0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e66.8\u0026thinsp;\u0026plusmn;\u0026thinsp;10.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eM: 43, F: 19\u003c/p\u003e \u003cp\u003e(P\u0026thinsp;=\u0026thinsp;0.002)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCPT-I\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLow C0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;8.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.88\u0026thinsp;\u0026plusmn;\u0026thinsp;1.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eM: 10, F: 14\u003c/p\u003e \u003cp\u003e(P\u0026thinsp;=\u0026thinsp;0.414)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCUD\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLow C2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;7.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1893\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.37\u0026thinsp;\u0026plusmn;\u0026thinsp;1.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eM: 905, F: 988\u003c/p\u003e \u003cp\u003e(P\u0026thinsp;=\u0026thinsp;0.056)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCUD\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;5.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.63\u0026thinsp;\u0026plusmn;\u0026thinsp;0.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eM: 5, F: 7\u003c/p\u003e \u003cp\u003e(P\u0026thinsp;=\u0026thinsp;0.564)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePA, MUT, CBL A \u0026amp; B, CBL C \u0026amp; D, SUCLA 2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.51\u0026thinsp;\u0026plusmn;\u0026thinsp;0.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eM: 2, F: 2\u003c/p\u003e \u003cp\u003e(P\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSCAD, GA II, IBD, EE\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eF: 1\u003c/p\u003e \u003cp\u003e(P\u0026thinsp;=\u0026thinsp;0.317)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eIVA, GA II, 2MBG\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC5OH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eF: 1\u003c/p\u003e \u003cp\u003e(P\u0026thinsp;=\u0026thinsp;0.317)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMCD, 3MCC, BKT, HMG, 2M3HBA, 3MGA, 3MCC (mat)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eF: 1\u003c/p\u003e \u003cp\u003e(P\u0026thinsp;=\u0026thinsp;0.317)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMCAD, GA II\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.53\u0026thinsp;\u0026plusmn;\u0026thinsp;0.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eM: 2, F: 2\u003c/p\u003e \u003cp\u003e(P\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMCAD, GA II\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eF: 1\u003c/p\u003e \u003cp\u003e(P\u0026thinsp;=\u0026thinsp;0.317)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eVLCAD\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC14:1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.07\u0026thinsp;\u0026plusmn;\u0026thinsp;0.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eF: 2\u003c/p\u003e \u003cp\u003e(P\u0026thinsp;=\u0026thinsp;0.157)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eVLCAD\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;7.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.99\u0026thinsp;\u0026plusmn;\u0026thinsp;0.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eM: 1, F: 1\u003c/p\u003e \u003cp\u003e(P\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eVLCAD, LCHAD, TFP, CACT, CPT I \u0026amp; II \u0026amp; III\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC16OH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.14\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eM: 3, F: 10\u003c/p\u003e \u003cp\u003e(P\u0026thinsp;=\u0026thinsp;0.052)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLCHAD, TFP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;2.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.56\u0026thinsp;\u0026plusmn;\u0026thinsp;0.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eM: 17, F: 10\u003c/p\u003e \u003cp\u003e(P\u0026thinsp;=\u0026thinsp;0.178)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCACT, CPT I \u0026amp; II, \u0026amp; III\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC18:1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;3.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.27\u0026thinsp;\u0026plusmn;\u0026thinsp;0.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eM: 32, F: 30\u003c/p\u003e \u003cp\u003e(P\u0026thinsp;=\u0026thinsp;0.799)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCACT, CPT I \u0026amp; II, \u0026amp; III\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC18: OH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.16\u0026thinsp;\u0026plusmn;\u0026thinsp;0.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eM: 2, F: 5\u003c/p\u003e \u003cp\u003e(P\u0026thinsp;=\u0026thinsp;0.257)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLCHAD, TFP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC5:1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13.8\u0026thinsp;\u0026plusmn;\u0026thinsp;10.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eF: 2\u003c/p\u003e \u003cp\u003e(P\u0026thinsp;=\u0026thinsp;0.157)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBKT, 2M3HBA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC10:1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eF: 1\u003c/p\u003e \u003cp\u003e(P\u0026thinsp;=\u0026thinsp;0.317)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMCAD, GA II\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eCPT-I: carnitine palmitoyl transferase type I deficiency, CUD: Carnitine uptake defect, PA: Propionic acidemia, MUT: Methylmalonic acidemia (mut), CBL A \u0026amp; B: Methylmalonic acidemia (Cbl A \u0026amp; B), CBL C \u0026amp; D: Methylmalonic aciduria and homocystinuria, SUCLA 2: Succinyl-CoA ligase deficiency, SCAD: Short-chain acyl-CoA dehydrogenase deficiency, GA II: Glutaric acidemia type II, IBD: Isobutyrylglycinuria, EE: Ethylmalonic encephalopathy, IVA: Isovaleric acidemia, 2MBG: 2-Methylbutyrylglycinuria, MCD, Multiple carboxylase deficiency, 3MCC: 3-Methylcrotonyl-CoA carboxylase deficiency, BKT: β-Ketothiolase deficiency, HMG: 3-Hydroxy-3-methylglutaric aciduria, 2M3HBA: 2-Methyl-3-hydroxybutyric aciduria, 3MGA: 3-Methylglutaconic aciduria, 3MCC (mat): Maternal 3-Methylcrotonyl-CoA carboxylase deficiency, CACT: Carnitine-acylcarnitine translocase deficiency, MCAD: Medium-chain acyl-CoA dehydrogenase deficiency, VLCAD: Very long-chain acyl-CoA dehydrogenase deficiency, LCHAD: Long-chain L-3-Hydroxy dehydrogenase deficiency, TFP: Trifunctional protein deficiency, BKT: β-Ketothiolase deficiency.\u003c/p\u003e \u003cp\u003eIn the current analysis, 195 preliminary positive cases of amino acid disorders were identified, as summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Among these, phenylalanine, alanine, and ornithine were the most frequently elevated amino acids, with 79, 53, and 44 positive cases, respectively. These three analytes demonstrated a notably higher prevalence than other amino acids, indicating their potential as common indicators in the spectrum of amino acid-related metabolic abnormalities among Bahraini newborns. Proline was the next most elevated amino acid, with 8 positive cases recorded. Despite these observations, statistical evaluation revealed no significant gender-based differences in the occurrence of elevated levels for any of the amino acids within this subgroup, suggesting that amino acid disorders, at least at the preliminary screening level, may affect males and females at relatively similar rates.\u003c/p\u003e \u003cp\u003eIt is noteworthy that several other amino acids included in the screening panel did not yield any preliminary positive cases. These included aspartic acid, methionine, and arginine. The absence of detected abnormalities in these amino acids may reflect their lower prevalence among Bahraini newborns.\u003c/p\u003e \u003cp\u003eIn contrast, the proportion of preliminary positive cases associated with fatty acid and organic acid metabolism disorders was markedly higher (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Fatty acid-related analytes accounted for most of these findings, with a total of 2,103 positive cases, representing approximately 86.4% of all preliminary positive results. This substantial proportion underscores the high frequency and possible clinical relevance of disturbances in fatty acid oxidation pathways among newborns in Bahrain. Among these, low levels of acylcarnitine (C2) were the most prevalent abnormality, identified in 1,893 cases, which constitutes 90% of the total acylcarnitine-related positive findings. Statistical comparison between sexes revealed that this abnormality was more frequently observed in females than in males, although the difference approached but did not reach conventional levels of statistical significance (P\u0026thinsp;=\u0026thinsp;0.056), indicating a potential gender-related trend that warrants further investigation in a larger cohort.\u003c/p\u003e \u003cp\u003eElevated free carnitine (C0) levels represented the second most observed abnormality among the acylcarnitine analytes, with 62 positive cases, accounting for 2.95% of all fatty acid-related preliminary findings. In contrast to low C2 levels, this abnormality demonstrated a statistically significant gender difference, with elevated C0 levels occurring more frequently in males compared to females (P\u0026thinsp;=\u0026thinsp;0.002), highlighting a potential sex-specific variation in carnitine metabolism that may have diagnostic or pathophysiological implications.\u003c/p\u003e \u003cp\u003eSimilarly, elevated levels of oleic acid (C18:1) were detected in 62 cases (2.95%), matching the frequency of elevated C0 levels. However, unlike C0, the distribution of C18:1 abnormality did not differ significantly between genders (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05), suggesting a uniform distribution across sexes for this specific fatty acid. Elevated levels of hydroxy-palmitoyl-carnitine (C16OH) were less common, found in 13 cases, but appeared to be more frequent in females. This observation approached statistical significance (P\u0026thinsp;=\u0026thinsp;0.052), indicating a borderline gender-related trend that, although not definitive, may be clinically meaningful and should be explored further in future studies.\u003c/p\u003e \u003cp\u003eOn the other hand, a relatively small number of preliminary positive cases were attributed to disorders associated with organic acid metabolism. Only 16 such cases were identified, constituting the lowest proportion of all detected abnormalities in the screening cohort. Among these, elevated propionyl carnitine (C3) levels were the most frequently observed, present in 12 cases, which corresponds to 75% of the organic acid-related abnormalities. Analysis of gender distribution within this subgroup revealed no statistically significant differences (P\u0026thinsp;=\u0026thinsp;0.564), indicating that elevated C3 levels were similarly prevalent in males and females.\u003c/p\u003e \u003cp\u003eConversely, a single fatty acid-related and a single organic acid-related analyte included in the screening did not yield any preliminary positive findings. Notably, no elevations were detected for hexanoic acid (C6) or urine glutaryl-carnitine (C5DC), among others. This lack of positive detection could reflect their lower diagnostic yield in the screened Bahraini newborns.\u003c/p\u003e \u003cp\u003eOverall, these findings suggest that while amino acid-related disorders occur with moderate frequency and exhibit no strong gender association, fatty acid metabolism disturbances are significantly more prevalent and may demonstrate sex-specific patterns, particularly regarding certain acylcarnitines. In contrast, organic acid metabolism disorders were rare in this cohort and did not display any evident gender predilection.\u003c/p\u003e \u003cp\u003eTo verify the accuracy of initial positive newborn screening results, selected cases underwent comprehensive confirmatory procedures. This included repeat analysis using either the original or a second dried blood spot (DBS) card, the calculation of additional diagnostic analyte ratios, and, where appropriate, supplementary biochemical testing (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Through these rigorous confirmatory measures, a total of 19 true positive cases were validated.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBiochemical Parameters of Confirmed Positive Cases (n. 19)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConfirmed Cases\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN of Cases\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAnalyte\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNormal Cutoff\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eValue\u003c/p\u003e \u003cp\u003e(\u0026micro;mol/l)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSecondary Marker\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNormal Cutoff 2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eRatio or Value (\u0026micro;mol/l)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAmino Acids\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePKU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePhenylalanine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;120\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1075.68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePhe/Tyr\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e30.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eMSUD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLeu/isoleucine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;300\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e312.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLeu/Phe, Leu/Tyr\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e7.76\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eValine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;300\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e366.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eVal/Phe, Val/Tyr\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e9.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eASA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCitrulline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCit/Arg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;6.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e2.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCit/Phe\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.56\u0026gt;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.60\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCIT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCitrulline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e74\u0026thinsp;\u0026plusmn;\u0026thinsp;10.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCit/Arg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;6.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e14.8, 9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCit/Phe\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.56\u0026gt;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1.02, 1.60\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTyrosinemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTyrosine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;350\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFatty Acids\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e10\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCPT-I\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eC0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e94.4\u0026thinsp;\u0026plusmn;\u0026thinsp;9.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eC0/(C16\u0026thinsp;+\u0026thinsp;C18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e(15.5\u0026ndash;35.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eCACT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eC16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;7.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7.64, 8.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eC14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.44, 0.32\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eC18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;2.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.5, 2.68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eC16/C2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.30,0.97\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eC18:1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;2.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.93, 1.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(C16\u0026thinsp;+\u0026thinsp;C18:1)/C2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.41,1.21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eVLCAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eC14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.71, 1.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eC14:1/C2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.033,0.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eC14:1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.28, 0.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eC14:1/C16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.54, 0.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eMCAD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eC8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eC5OH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1.22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eC10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eC8/C10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;1.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAmong the confirmed cases, fatty acid oxidation defects represented the largest group, accounting for 10 cases (52.6%). This was followed by amino acid disorders, with 8 cases (42.1%), and a single case (5.3%) of an organic acid disorder, specifically isovaleric acidemia (IVA). Within the fatty acid oxidation disorders, Carnitine Palmitoyl Transferase Type I (CPT-I) deficiency emerged as the most prevalent individual condition, with an observed incidence of 1 per 1,000 newborns. Tyrosinemia was the second most frequently diagnosed disorder, with an incidence of 0.6 per 1,000 newborns.\u003c/p\u003e \u003cp\u003eFurther breakdown of the confirmed conditions revealed two cases each of citrullinemia type I (CIT-I), carnitine-acylcarnitine translocase deficiency (CACT), and very long-chain acyl-CoA dehydrogenase deficiency (VLCAD), corresponding to an incidence of 0.4 per 1,000 newborns for each disorder. Additionally, there was one confirmed case each of phenylketonuria (PKU), maple syrup urine disease (MSUD), argininosuccinic aciduria (ASA), and medium-chain acyl-CoA dehydrogenase deficiency (MCAD), all with an incidence of 0.2 per 1,000 newborns.\u003c/p\u003e \u003cp\u003eMost of the confirmed cases were identified in otherwise healthy infants born to non-consanguineous parents, suggesting a broad population-wide distribution. However, two cases out of nineteen (10.5%), one involving elevated citrulline (CIT) levels and another of CPT-I deficiency, were detected in infants born to consanguineous parents, highlighting the potential influence of autosomal recessive inheritance patterns.\u003c/p\u003e \u003cp\u003eThese findings reflect an overall incidence of 3.81 per 1,000 screened newborns, which is high compared to the reported incidence of IEM in other Arab countries (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eIncidence of IEM per 100,000 live births in Arab countries\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCountry\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIncidence/100,000\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eReference #\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBahrain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e381\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eThis study\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLibya\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e193\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSaudi Arabia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e176\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eQatar\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e111\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTunisia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnited Arab Emirates\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEgypt\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eBahrain is one of the six Gulf Cooperation Council (GCC) countries. The reported incidence of IEM in GCC countries and some other Arab nations is higher than that reported from various regions around the world [\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Since most IEM disorders follow an autosomal recessive pattern of inheritance, the high prevalence of these disorders in the GCC countries can be explained by population genetics and the high rate of consanguineous marriages [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA total of 4991 Bahraini newborns were screened in this study. Nineteen true-positive cases were identified, resulting in an overall incidence of 3.81 per 1000 live births. The incidence of IEM in this study is higher than the reported incidence of these disorders in GCC countries and other Arab nations [\u003cspan additionalcitationids=\"CR17 CR18 CR19\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Moreover, this incidence is nearly three times greater than the IEM incidence reported in countries within Europe, the UK, the US, and China [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. We believe this is the highest reported incidence of IEM worldwide.\u003c/p\u003e \u003cp\u003eWhen different metabolic categories are considered, the highest incidence of IEM in this study was that of fatty acid oxidation defects, followed by the aminoacidopathies and urea cycle disorders. Organic acidemias had the lowest incidence, as we detected only one case of isovaleric acidemia. These findings are strikingly different from those of a previous study conducted at our center in 2013. In that report, 1986 sick symptomatic Bahraini newborns were investigated at our lab (AJC) for IEM using TMS [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Twenty-five of them had confirmed disorders. Aminoacidopathies were the most common in that series, comprising 44% of cases, followed by organic acidemias (36%). Fatty acid oxidation defects comprised 20% of cases in that group.\u003c/p\u003e \u003cp\u003eThe finding that fatty acid oxidation defects were the most encountered type of IEM in this study contradicts the findings of many studies from the GCC countries and other Arab countries [\u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. However, the incidence of aminoacidopathies and urea cycle disorders is comparable to those reported from Saudi Arabia [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The incidence of organic acidurias in our series is very close to the findings of a study from Tunisia [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. However, it was lower than that reported in a previous study from our center [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], and much lower than that reported from other Arab countries [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. A family history of IEM was reported in 10.3% of the screened newborns, and in 21% of the positive cases, a finding comparable to what was reported from other GCC countries [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe consanguinity rate observed among the families of the screened babies in this study (16.8%) agrees with the reported rate of consanguineous marriages in Bahrain (16\u0026ndash;25%). Among the confirmed positive cases, however, parental consanguinity is reported in only two cases (10.5%), a finding much lower than that of the previous study from our center on symptomatic infants, which found that 94% of IEM patients were products of consanguineous marriages [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDue to their chronic and progressive nature, inborn errors of metabolism (IEM) necessitate lifelong medical care, specialized management, and often costly supportive and symptomatic therapies. These disorders impose a substantial burden on healthcare delivery systems. The expenses associated with the confirmatory metabolic and genetic testing required for diagnosis, in addition to the costs of treatment modalities including high-priced medications, specialized nutritional formulas, enzyme replacement therapies, liver transplantation, prolonged hospitalizations, and ongoing supportive care, represent a significant economic challenge. Early detection of IEM through newborn screening (NBS) programs is the most cost-effective strategy to mitigate the severe complications, morbidity, and mortality linked to delayed diagnosis, ultimately enhancing patient outcomes and quality of life. The successful implementation of national NBS programs remains essential to achieving these goals.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study showed that IEM disorders are prevalent in Bahrain, with an estimated incidence that is higher than those reported from the GCC countries and other Arab countries and far higher than the incidence described from the different regions of the world. Early detection of these disorders is essential to prevent severe morbidity and death among the affected infants [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Most GCC countries have established national newborn screening programs for IEM and other hereditary diseases. We believe it is timely for Bahrain to initiate a national newborn screening program for IEM to reduce infant mortality and improve health care for affected babies. Such a program is feasible because all births occur in hospitals, making 100% coverage granted, and the specialized medical personnel and the lab facilities needed are available in the country.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe research adhered to the Helsinki Declaration on ethical principles for medical research involving human participants. The research proposal was reviewed and approved by the ethics committees of the participating hospitals and the Research Ethics Committee of the Arabian Gulf University (Ref. E001-PI-10/18). Before screening, informed written consent was obtained from the parents of the newborns.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe parents of the screened newborns agreed to the publication of the research data and signed informed consent forms.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe raw data of this study are available upon request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eArabian Gulf University in Bahrain covered the costs of the lab tests. None of the authors has received any funds or benefits.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e: not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(1) Abdelaziz Elamin: planning of research and writing the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(2 and 3) Diab E. Diab and Anfal A. Jasim did the tandem mass spectrometry and other laboratory investigations and assisted in writing the results section.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(4-9) Zahra Alsahlawi, Hadhami Benturkia, Salman M. Alkhalifa, Shatha H. Osman,\u003c/p\u003e\n\u003cp\u003eAbdulraoof Almadhoob and Mona Aljufairi are the physicians who recruited the newborns, obtained informed consents from parents, revised the lab results, and contributed to writing the results section.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(10) Moiz Bakhiet: contributed to the research proposal, revised the manuscript, and contributed to the discussion section of the article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e: not applicable.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003e\u003cspan\u003eSaudubray JM, Garcia-Cazorla A. Inborn Errors of Metabolism Overview: Pathophysiology, Manifestations, Evaluation, and Management. Pediatr Clin North Am. 2018;65(2):179\u0026ndash;208.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eKanungo S, Patel D, Neelakantan M, et al. Newborn screening and changing face of inborn errors of metabolism in the United States. Ann Transl Med. 2018;6(24):468\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eHao L, Liang L, Gao X, et al. Screening of 1.17 million newborns for inborn errors of metabolism using tandem mass spectrometry in Shanghai, China: A 19-year report. Mol Genet Metab. 2021;141(1):108098.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eAfzal RM, Lund AM, Skovby F. The impact of consanguinity on the frequency of inborn errors of metabolism. Dan Med J. 2018;65(10):A5508.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eFerreira CR, Rahman S, Keller M, Zschocke J. An International Classification of Inherited Metabolic Disorders (ICIMD). J Inherit Metab Dis. 2021;44(1):164\u0026ndash;77.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eClarke S. Tandem mass spectrometry: the tool of choice for diagnosing inborn errors of metabolism. Br J Biomed Sci. 2002;59(1):42\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eTang C, Li L, Chen T, et al. Newborn Screening for Inborn Metabolism by Next-Generation Sequencing Combined with Tandem Mass Spectrometry. Int J Neonatal Screen. 2024;10(2):28\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eGolbahar J, Al-Khayat H, Hassan B, et al. Neonatal screening for congenital hypothyroidism: a retrospective hospital-based study from Bahrain. J Pediatr Endocrinol Metab. 2010;23(1\u0026ndash;2):39\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eGolbahar J, Al-Jishi EA, Altayab D, et al. Selective newborn screening of inborn errors of amino acids, organic acids, and fatty acids metabolism in Bahrain. Mol Genet Metab. 2013;110(1\u0026ndash;2):98\u0026ndash;101. [[28]].\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eAl-Arrayed S. Campaign to control genetic blood diseases in Bahrain. Community Genet. 2005;8(1):52\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eMcHugh DMS, Cameron CA, Abdenur JE, et al. Clinical validation of cutoff target ranges in newborn screening of metabolic disorders by tandem mass spectrometry: a worldwide collaborative project. Genet Med. 2011;13(3):230\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eKhan A, Alothaim A, Alfares A, et al. Cut-off values in newborn screening for inborn errors of metabolism in Saudi Arabia. Ann Saudi Med. 2022;42(2):107\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eMohamed S, Elsheikh W, Al-Aqeel A, et al. Incidence of newborn screening disorders among 56632 infants in Central Saudi Arabia. A 6-year study. Saudi Med J. 2020;41(7):703\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eAlfadhel M, Alothaim A, Al-Saif S, et al. Expanded Newborn Screening Program in Saudi Arabia: Incidence of screened disorders. Paediatr Child Health. 2017;53(6):585\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eAl-Jasmi FA, Al-Shamsi A, Hertecant JL, Al-Hamad SM, Souid AK. Inborn Errors of Metabolism in the United Arab Emirates: Disorders Detected by Newborn Screening (2011\u0026ndash;2014). JIMD Rep. 2016;28:127\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eMoammar H, Cheriyan G, Mathew R, Al-Sannaa N. Incidence and patterns of inborn errors of metabolism in the Eastern province of Saudi Arabia. Ann Saudi Med. 2010;30:271\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eAlobaidy H. Patterns of inborn errors of metabolism: A 12-year single-center hospital- A based study in Libya. Qatar Med J. 2013; 2013(2):57\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eChioukh FZ, Chaabane A, Khamis T, Jlassi A, Kaabachi N, Monastiri K. Inborn errors of metabolism in the neonatal period: A Challenging management in Tunisia. Tunis Med. 2019;97(5):681\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eLindner M, Abdoh G, Fang-Hoffmann J, et al. Implementation of extended neonatal Screening and a metabolic unit in the State of Qatar: developing and optimizing strategies in cooperation with the Neonatal Screening Center in Heidelberg. J Inherit Metab Dis. 2007;30(4):522\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eHassan FA, El-Mougy F, Sharaf SA, et al. Inborn errors of metabolism detectable by tandem mass spectrometry in Egypt: The first newborn screening pilot study. J Med Screen. 2016;23(3):124\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eSanderson S, Green A, Preece MA, Burton H. The incidence of inherited metabolic disorders in the West Midlands, UK. Arch Dis Child. 2006;91:896\u0026ndash;902.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eJoshi SN, Venugopalan P. Clinical characteristics of neonates with inborn errors of metabolism detected by Tandem MS analysis in Oman. Brain Dev. 2007;29(9):543\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eMeiouet F, El-Kabbaj S, Abilkassem R, Boemer F. Moroccan Experience of Targeted Screening for Inborn Errors of Metabolism by Tandem Mass Spectrometry. Pediatr Rep. 2023;15(1):227\u0026ndash;36.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eJelassi A, Nasrallah F, Talbi A, et al. Spectrum of Organic Aciduria Diseases in Tunisia: A 35-year Retrospective Study. Saudi J Med Sci. 2024;12(1):27\u0026ndash;34.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eBakhiet M, Alawadi AMI, Alhammadi MM, Ali MF, Butti N. A case report of neurological\u0026nbsp;\u003c/span\u003e\u003cspan\u003ecomplications owing to. lately diagnosed hyperargininemia, emphasizing the role of national neonatal screening policies in the Kingdom of Bahrain. Med (Baltim). 2018;97(20):e10780.\u003c/span\u003e\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Newborn screening, fatty acid oxidation, aminoacidopathies, organic acidemia, inherited metabolic disorders, Gulf countries","lastPublishedDoi":"10.21203/rs.3.rs-6716073/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6716073/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eInborn errors of metabolism (IEM) are individually rare but collectively common. If not detected early, they can cause severe morbidity and death. The study aimed to determine the incidence and types of IEM among healthy newborns in Bahrain.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eBetween January 2019 and May 2020, approximately 5,000 full-term asymptomatic newborns delivered at three major hospitals in Bahrain were enrolled. All newborns began breastfeeding and/or formula milk a few hours after birth. Dried blood spots were collected within 24\u0026ndash;72 hours after birth and analyzed using tandem mass spectrometry (TMS. The initial positive screening results were confirmed through repeat testing, analyte ratio evaluation, and additional biochemical analyses.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe initial metabolic lab tests were followed by further confirmatory tests. Nineteen of the screened newborns had true positive test results, resulting in an IEM incidence of 3.81 per 1,000 live births. Of the identified cases, only two (10.5%) were born to consanguineous marriages. Fatty acid oxidation disorders were the most prevalent (52.6%), followed by amino acid disorders (42.1%) and organic acidemias (5.3%). CPT-I deficiency and tyrosinemia were the most frequently observed conditions.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe study showed a high incidence of IEM in Bahrain, surpassing rates reported in other Arab and global populations. These findings underscore the urgent need to establish a national newborn screening program to enable early diagnosis and intervention, reducing the burden of metabolic disorders in the Bahraini population.\u003c/p\u003e","manuscriptTitle":"High Incidence of Neonatal Inborn Errors of Metabolism in Bahrain Revealed by Tandem Mass Spectrometry","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-30 16:34:36","doi":"10.21203/rs.3.rs-6716073/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-02-06T05:12:04+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-17T18:16:25+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"107195870213175895955301741881059988077","date":"2025-07-08T09:39:54+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"93716904689440311424710808485521029506","date":"2025-07-08T06:47:31+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-07T11:06:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"115835739878469171767261947718465819458","date":"2025-07-05T21:24:52+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"10324588231712906337069459307887290913","date":"2025-06-27T14:42:21+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-26T04:59:36+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-18T10:12:59+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-06-02T14:06:47+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-01T08:31:31+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pediatrics","date":"2025-06-01T08:28:46+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1a436c5e-67eb-497c-882b-a1675291872e","owner":[],"postedDate":"June 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-02T00:08:13+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-30 16:34:36","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6716073","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6716073","identity":"rs-6716073","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}