National Newborn Screening Program Research Articles

Insights into Central Congenital Hypothyroidism: A Multicenter Retrospective Analysis.

Central congenital hypothyroidism (CCH) is a thyroid hormone deficiency at birth caused by inadequate pituitary stimulation of the thyroid gland. Although primary CH has been studied extensively, studies on CCH are sparse. To assess the prevalence of CCH in Israel and describe its clinical features, neonatal screening results, and outcomes. Multicenter cross-sectional retrospective chart review. Nine pediatric endocrine units throughout Israel. Patients diagnosed with CCH in 1987-2021 were categorized into early (within 14 days of life) and late (after 14 days) diagnosis groups. Newborn screening (NBS) results were retrospectively retrieved from the national NBS program dataset. CCH prevalence in Israel was about 1:42,800 live births. Subjects were 94 patients (54 males), of these, 84% had multiple pituitary hormone deficiencies and 16% had isolated CCH. The median age at diagnosis was 50 days (range, 1-8760), with 66% having moderate to severe hypothyroidism. NBS detected only three infants. Early diagnosis occurred in 34% due to hypopituitarism, while 66% were diagnosed later due to growth and developmental delays. Neurodevelopmental sequelae included mental retardation (12%), learning difficulties (18%), delayed speech (27%), and motor clumsiness (19%), with no significant differences in outcomes between early and late diagnosis. Despite high rates of neurodevelopmental sequelae, no differences were found between early and late diagnosis groups. Further research is needed to assess the impact of delayed diagnosis on neurological outcomes in newborns with CCH. Improved strategies for detecting CHH in newborns are also necessary.

Enzymatic testing for mucopolysaccharidosis type I in Kuwaiti newborns: a preliminary study toward newborn screening.

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive lysosomal storage disorder characterized by deficient or absent α-L-iduronidase (IDUA) enzyme activity due to pathogenic variants in the IDUA gene. Early treatment with hematopoietic stem cell transplantation and/or enzyme replacement therapy is associated with improved outcomes in this progressive multisystem disease. The diagnosis is usually delayed due to late presentation and non-specific symptoms, which result in high morbidity and mortality. The incidence of MPS I is unknown in Kuwait. This pilot study was undertaken to screen MPS I in all Kuwaiti neonates born at Farwaniya Hospital (FH), a major center in Kuwait, over 12 months. This study examined the incidence of MPS I for inclusion in the national newborn screening (NBS) to enable its early detection and adequate treatment. All Kuwaiti neonates born at FH between December 2021 and December 2022 were screened for MPS I. The screening consisted of determining IDUA enzyme activity in dried blood spot-derived samples using tandem mass spectrometry. A follow-up genetic analysis of the IDUA gene has been planned to screen the cases with diminished IDUA enzyme activity as second-tier testing. A total of 618 newborns, including 331 (54%) boys and 287 (46%) girls, were screened. Of them, 20 had deficient IDUA enzyme activity but showed negative genetic testing. However, we have diagnosed one additional female infant with MPS I who belonged to FH, but the parents chose to deliver in a private hospital. The molecular genetic study revealed the presence of a previously reported pathogenic nonsense variant in the IDUA c.1882C>T, which is associated with severe phenotype. That being included, MPS I is estimated to be approximately 0.2% of all screened cases in Kuwait. Our study is the first to evaluate the incidence of MPS I in Kuwait. Given the single center, small number of screened infants, and the short study duration thus far, it is premature to calculate the incidence. It is anticipated that as the study continues, we would be able to estimate the incidence in our population correctly. Screening newborns in all maternity hospitals in Kuwait is necessary to calculate the actual incidence of this severe disorder. Still, our preliminary data support the inclusion of MPS I in national NBS program to allow early initiation of treatment and thus improve disease outcome.

Point-of-Care Newborn Screening for Sickle Cell Disease at Selected Health Facilities in the Gambia

Sickle cell disease (SCD) contributes significantly to childhood morbidity and mortality in sub-Saharan Africa. Early diagnosis through newborn screening (NBS) and subsequent comprehensive follow-up care will reduce the burden. Up till now, the prevalence of SCD among newborns remains unknown in The Gambia and there is no national NBS programme to address this significant public health issue. We assessed the real-time frequency of SCD in the country and determined differences in the pattern of SCD phenotypes among different ethnic groups. A preliminary prospective feasibility study was done in eight purposively selected hospitals in the seven Health Administrative Regions and Banjul. Consecutive newborn babies delivered or managed in these facilities were screened using HemoTypeSC, a sensitive and specific ELISA-based point-of-care test (POCT). Babies identified as SCD with HemoTypeSC were retested at age ≥6 months using alkaline cellulose acetate hemoglobin electrophoresis (ACAE). Head-to-head comparison between HemoType screening and gold standard HPLC could not be done. 1,168 newborn babies were screened from April 14 to August 12, 2023. Fifteen (1.3%) had homozygous HbS (HbSS), two (0.2%) heterozygous for HbS and HbC (HbSC), 204 (17.5%) had sickle cell trait (HbAS), four (0.3%) heterozygous for HbA and HbC (HbAC), and 943 (80.7%) had normal hemoglobin (HbAA). The 17 with SCD (HbSS and HbSC) comprised of 7 (2.2%) of 324 Fula; 6 (1.4%) of 426 Mandinka; 2 (1.6%) of 125 Jola and 2 (1.3%) of 150 Wolof. Fourteen (82.4%) of the 17 accepted the diagnosis and were enrolled into the SCD program. For these 14, HemoTypeSC had 100% sensitivity with ACAE when repeated at age ≥6 months. In addition to determining the real-time newborn prevalence of SCD and trait in The Gambia for the first time, this pilot study showed that SCD-POCT is feasible in Gambian health facilities.

Integrated Approaches and Practical Recommendations in Patient Care Identified with 5q Spinal Muscular Atrophy through Newborn Screening.

In recent years, significant progress has been made in 5q Spinal Muscular Atrophy therapeutics, emphasizing the importance of early diagnosis and intervention for better clinical outcomes. Characterized by spinal cord motor neuron degeneration, 5q-SMA leads to muscle weakness, swallowing difficulties, respiratory insufficiency, and skeletal deformities. Recognizing the pre-symptomatic phases supported by screening and confirmatory genetic tests is crucial for early diagnosis. This work addresses key considerations in implementing 5q-SMA screening within the Brazilian National Newborn Screening Program and explores Brazil's unique challenges and opportunities, including genetic tests, time-to-patient referral to specialized centers, program follow-up, and treatment algorithms. We aim to guide healthcare professionals and policymakers, facilitating global discussions, including Latin American countries, and knowledge-sharing on this critical subject to improve the care for newborns identified with 5q SMA.

Integrating Genetic Services in the Philippine Public Health Delivery System: The Value of Networks.

The delivery of genetic services in developing countries is faced with significant challenges, despite medical and technological advances globally. The Philippines, being an archipelago, faces even more challenges, with significant disparities in access to healthcare, and tertiary medical centers and specialists being concentrated in the major cities. The utilization of different networks for the integration of genetic services in the existing public health delivery system has been valuable. Using the well-established network of the national newborn screening program, genetic services have been successfully integrated into the delivery of healthcare, even at the grassroot level. Equitable access to healthcare, including genetic services, was highlighted and supported by the enactment of the Rare Disease Law in 2016. The support of the academe to assure the sustainability of services was evident in the establishment of a genetic counseling program to augment the work of a handful of clinical geneticists. Professional societies and support groups have been instrumental in identifying genetic conditions to be prioritized and lobbying for increased public awareness, leading to national programs and policies. This paper primarily discusses the value of networks in the delivery of genetic services, specifically newborn screening, programs for rare diseases, birth defects, and genetic counseling.

Diagnosis and Treatment of Newborns Referred to the Metabolism Department From the National Newborn Screening Program in Türkiye: A 5-Year Single-Center Experience

Objective: The aims of this study were to investigate biochemical and genetic tests and treatment plans of newborns referred to our center with inherited metabolic disorders screened in Türkiye National Newborn Screening Program (NNSP). Material and Methods: The medical records of babies referred by the NNSP between January 2019 and November 2023 were scanned retrospectively. Plasma biotinidase activity and the biotinidase gene (BTD) analysis results for suspected biotinidase deficiency (BD), the plasma phenylalanine and phenylalanine hydroxylase gene (PAH) analysis for a suspicion of phenylketonuria (PKU) were documented with treatment information. Results: A total of 143 babies, 78 (54.5%) with suspected BD and 65 (45.5%) with suspected PKU were included. A PAH gene analysis was performed on 23 (35.4%) of those had high plasma phenylalanine levels, among which 86.9% were identified with the biallelic variant. Five patients were started on sapropterin-diet combined therapy, three on diet therapy and one on sapropterin therapy. In the first serum biotinidase activity measurement of babies referred with suspected BD, a heterozygous deficiency was detected in 48.7%, partial deficiency in 39.7% and profound deficiency in 10.3%. A BTD gene analysis was performed on 79.5% of those with suspected BD, and biallelic variants were detected in 50%. Forty-six patients (59.0%) underwent biotin treatment. Conclusion: In our study, approximately one-third of the babies referred from NNSP over the five-year course of the study had biallelic variants of the relevant disease. Our research is one of the few studies on NNSP in our country and presents the diagnosis and treatment process of PKU and BD.

High frequency of transient congenital hypothyroidism among infants referred for suspected congenital hypothyroidism from the Turkish National screening program: thyroxine dose may guide the prediction of transients.

We aimed to determine the frequency of transient congenital hypothyroidism (TCH) in 17 participating centers inTürkiye, evaluate the etiological distribution in permanent congenital hypothyroidism (PCH) cases, and investigate the role of laboratory and clinical findings in predicting TCH. This retrospective observational multicenter study included patients from 17 pediatric endocrinology centers identified by "National Newborn Screening Program" (NNSP) who were born in 2015 and followed for 6years. Demographic, clinical, and laboratory information of the cases were compiled through the database http://cedd.saglik-network.org (CEDD-NET). Of the 239 cases initially treated for CH, 128 (53.6%) were determined as transient in whom a trial of levothyroxine (LT4) withdrawal was performed at a median age of 36 (34-38) months. Among the patients with PCH (n = 111), thyroid dysgenesis was diagnosed in 39.6% (n = 44). The predictive factors for TCH were: LT4 dose at the withdrawal of treatment, and initial newborn blood screening (NBS)-TSH level. Based on the receiver operating characteristic (ROC) curve analysis to predict optimal cut-offs for TCH predictors, LT4 dose < 2.0µg/kg/day at treatment discontinuation was predictive for TCH and was associated with 94.5% specificity and 55.7% sensitivity, with an area under the curve (AUC) of 0.802. The initial NBS-TSH level value <45µIU/mL was predictive for TCH with 93.1% specificity and 45.5% sensitivity, with an AUC of 0.641. In patients with eutopic thyroid gland only LT4 dose < 1.1µg/kg/day at withdrawal time was predictive for TCH with 84.7% sensitivity and 40.4% specificity, with an AUC of 0.750. According to our national follow-up data, the frequency of TCH was 53.6%. We determined the LT4 dose < 2.0µg/kg/day at discontinuation of treatment and the initial NBS-TSH level < 45µIU/mL as the best cut-off limits to predict TCH.

Incorporating a new disease in the newborn screening programs in Europe: the spinal muscular atrophy case study

Patient advocacy organizations have a forefront role in ensuring that patients’ voices and needs are embedded as a constitutive basis in drug development, diagnosis, and policy recommendations in the healthcare ecosystem. Their sustained involvement in accelerating the policy changes for inclusion of additional diseases in the newborn screening (NBS) programs, supporting harmonization in terms of number of screened diseases across the European Union, constitutes a driving force for advancing the quality of care and the management of rare diseases by aligning NBS policies and practices internationally. In the current European landscape, NBS varies significantly across regions and countries. Patient advocacy organizations are acting to alert healthcare authorities of the existing inequity in NBS and recommending that additional diseases be added to the national NBS programs. Here, we describe the state of play for Spinal Muscular Atrophy (SMA) as a model for advancing NBS for rare diseases where a treatment regime is available. Ultimately, a broad understanding of NBS for SMA will additionally serve as a means to understand the financial impact of early therapeutic intervention for a rare disease.

Evaluation of newborn hearing screening results of infants with phenylketonuria

ObjectiveThe purpose of this study is comparing the newborn hearing screening failure rate between phenylketonuria (PKU) infants and matched healthy control infants. Patients and methodsBetween April 2021 and April 2023, data obtained from the national newborn hearing screening program were examined for patients who presented to the pediatric metabolism clinic of Konya City Hospital with a clinical and genetic diagnosis of PKU. A healthy control group, matched for age and gender, was established. The newborn hearing screening test results, demographic information, and pregnancy data of infants with PKU and the control group were compared to assess risk factors. ResultsIn the initial screening test, 23 out of 73 PKU infants (31.5%) and 12 out of 73 infants in the control group (16.4%) failed the test (p = 0.033). Among the 23 PKU infants who did not pass the first test, 9 (35%) also failed the second test and were referred. In contrast, all 12 infants in the control group who did not pass the first test passed the second test. The failure rate in the second test was significantly higher in PKU infants compared to the control group (p = 0.003). It was observed that the maternal age of PKU infants who underwent the second test was significantly higher than that of the control group (p < 0.029). Diagnostic hearing test results were found to be normal in all nine PKU patients who failed the secondary screening test and were referred to a tertiary center. ConclusionIn our study, it was determined that infants with phenylketonuria (PKU) who did not have any risk factors for hearing loss failed the hearing screening test significantly more than healthy infants.

Newborn screening program and advanced therapies as a chance for the youngest patients – based on spinal muscular atrophy (SMA)

Abstract Introduction. Newborn screening programs, commonly conducted, are prophylactic procedures with the aim to detect serious, often lethal diseases in their presymptomatic stage. It should be emphasized that the costs of the program are lower than medical care and treatment costs for sick citizens without diagnosis of these disorders. Every step, starting from receiving the parental consent, taking a dried blood spot sample by the nurses and finally testing was fully prepared and is under the supervision of the Institute of Mother and Child in Warsaw. In March 2022 screening for spinal muscular atrophy (SMA) among all newborns was introduced. This disorder leads to progressive deterioration of motor skills and sometimes even to death. The breakthrough of the SMA therapy was Zolgensma, called the most expensive drug in the world. Currently, this treatment is fully funded for some patients under the national drug program. Aim. The aim is to present issues related to the newborn screening program and advanced SMA therapies. Material and methods. Analysis of scientific studies in the PubMed database and national newborn screening programs. Conclusions. Early implementation of the appropriate treatment gives the chance to improve the quality of life, especially if the earliest detection is provided by newborn screening program.

Difficult Diagnosis in a Patient with Phenylketonuria (PKU) and Metachromatic Leukodystrophy (MLD)

Abstract Introduction Since phenylalanine level was included in the national newborn screening program in Egypt, patients with phenylketonuria (PKU) were early diagnosed and management and have better outcome with nearly normal motor and mental development. Neuro-regression or poor cognition is never recognized in compliant patients. Case presentation Herein we present an Egyptian child who was diagnosed by neonatal screening as PKU who was compliant on dietary treatment and normal development. After the age of 18 months, he started to loose previously acquired developmental milestones. Because of his average phenylalanine levels all through, a second neurodegenerative disease was suspected. Several investigations were done and the diagnosis of metachromatic leukodystrophy was suspected and was later confirmed by molecular testing showing homozygous frame shift mutation in ARSA gene c.583del, p. (Trp 195Glyfs*5) in addition to homozygous Missense mutation in PAH gene c.842C&amp;gt;T, p. (Pro281 Leu). Conclusion The presence of two genetic diseases in the same family should be suspected in consanguineous communities like ours especially if the clinical data of the primary disease does not fit.

Which stimulus should be used for auditory brainstem response in newborns; CE-Chirp® level specific versus Click stimulus.

Auditory Brainstem Response (ABR), the electrical responses in the neuronal pathways extending from the inner ear to the auditory cortex, are evaluated with auditory stimuli. ABR analysis evaluates waves I, III and V's absolute-latencies, amplitude values, interpeak-latencies, interaural-latency differences, and morphologies. This study aims to reveal the advantages of CE-Chirp® LS stimulus and its clinical uses to increase by comparing the amplitude, latency, and interpeak-latency differences of waves I, III, and V at 80dB nHL and wave V at 60, 40, 20dB nHL by using click and CE-Chirp® LS stimuli. 100 (54 boys, 46 girls) infants with normal hearing were included in the National Newborn Hearing Screening Program. With the click and CE-Chirp® LS ABR, the absolute latency and amplitude values of wave V at 20, 40, and 60dB nHL, and the absolute-latency, interpeak-latency, and amplitude values of waves I, III, and V at 80dB nHL are determined between stimuli and right-left ear. When the wave V latency and amplitudes obtained at 80, 60, 40, and 20dB nHL levels were examined between genders, and according to the risk factor, no significant difference was found between click and CE-Chirp® LS stimuli (p>0.05). Waves I, III, and V absolute-latency, amplitudes were compared at 80dB nHL and wave V absolute-latency, amplitudes at 60, 40, and 20dB nHL; the amplitudes measured with CE-Chirp® LS were significantly higher than the click stimulus (p<0.05). When two stimuli were compared for I-III and III-V interpeak-latency values at 80dB nHL level, no significant difference was found between the two stimuli (p>0.05). However, the I-V interpeak-latency value was statistically significantly decreased for two stimuli, regardless of the ear (p<0.05). It is suggested to increase the use of CE-Chirp® LS stimulus with better morphology and amplitude in clinics, believing that it facilitates clinicians' interpretation.

Incidence of congenital hypothyroidism in Lithuania: data from the National New-born screening program, 2002-2019

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Evaluation of 700 patients referred with a preliminary diagnosis of biotinidase deficiency by the national newborn metabolic screening program: a single-center experience.

This study aimed to investigate the clinical, demographic and laboratory characteristics of the patients referred with a preliminary diagnosis of biotinidase deficiency through the national newborn metabolic screening program. We also attempted to determine the cut-off level of the fluorometric method used for screening biotinidase deficiency by the Ministry of Health. A total of 700 subjects who were referred to the Pediatric Metabolism Outpatient Clinic with a preliminary diagnosis of biotinidase deficiency through the national newborn metabolic screening program were retrospectively evaluated. Patients detected by family screening were excluded. Biotinidase enzyme activity was assessed and BTD gene analysis was performed in all patients. Of 700 subjects who were referred by the screening program, 284 (40.5 %) had biotinidase deficiency (BD). Theenzyme activity was 0-10, 10-30 and >30 % in 39 (5.5 %), 245 (35 %) and 416 (59.5 %) patients, respectively. The BD was partial in majority of patients (86.2 %). The cut-off level was 59.5 MRU for partial BD and 50.5 MRU for profound BD. The most common mutation detected was p.Arg157His (c.470G>A) among patients with profound BD, and p.D444H (c.1330G>C) among patients with partial BD. Treatment should be initiated promptly in patients who are referred by the newborn screening program. Any mean activity under 59.5 MRU should be considered partial BD, while less than 50.5 MRU should be considered profound BD. It should be kept in mind that clinical manifestations may develop both in profound and partial BD.

Need and Challenges in Establishing Newborn Screening Programs for Inherited Metabolic Disorders in Developing Countries.

Even in this post genomic era, no national level newborn screening (NBS) programs for inborn errors of metabolism (IEMs) are yet available in several developing countries including Pakistan. Through NBS, various IEMs can be screened using minute quantities of biofluids. Targeted metabolomics and genomic techniques are the main approaches used for NBS. However, lack of technical expertise and such high-end "omics" based analytical facilities, and meager funding for healthcare in developing countries are the major reasons for unavailability of NBS programs. As it is reflected by only a handful reports about IEMs from Pakistan with population of ≈220 million and consanguinity rate of about 70%, which suggests an unmet need for an NBS program owing to reasonably high prevalence of inherited diseases. Around 200 IEMs are potentially treatable if diagnosed at an earlier stage through biochemical marker and genetic screening, so such patients can get benefit from the NBS program. This overview will help to persuade the stakeholdersto setup NBS programs in developing countries including Pakistan, due to multitude of benefits for IEMs; timely diagnosis and early treatment can help the patients to live a nearly healthy life, reduced suffering of the family and minimal burden on society or national healthcare system.

5613004 NEWBORN SCREENING FOR SICKLE CELL DISEASE IN GERMANY - THE FIRST YEAR

Newborn screening is the first and most important step in secondary prevention in children with sickle cell disease. Serious complications and deaths can be almost completely prevented by ensuring the necessary preventive measures against infection (vaccinations and penicillin prophylaxis) and with the help of training measures that enable parents to recognize the symptoms of acute anemia/hemolysis in good time. In 2017, as part of a consensus conference with over 50 participants from 13 nations, the requirements that a newborn screening program for sickle cell disease should meet were defined. In Germany, we have consistently implemented these requirements. In addition, a total of five pilot studies involving almost 220,000 participants were carried out. These studies have shown that if sickle cell disease were part of newborn screening, it would probably be one of the most prevalent target diseases. On the basis of the consensus document and the epidemiological data collected for the first time, the relevant institutions and authorities could ultimately be convinced of the usefulness of the screening. The amendment to the law required for the introduction of screening came into force on September 30, 2021. Since then, all children born in Germany have also been screened for sickle cell disease as part of the national newborn screening program. Due to the federal organization of the German state, there is still no official evaluation of the screening results. However, we conducted a survey among the eleven German screening laboratories and the 47 pediatric haematology centers that will take on the long-term care of the sick children. The data indicate that in the first year, approximately 120-150 of 800,000 newborns have sickle cell disease. The German authorities have approved HPLC, capillary electrophoresis and tandem mass spectrometry as measurement methods in screening. Deviating from this, some laboratories use molecular genetic methods to screen for the HbS mutation. In the laboratories participating in our survey, 13 false-positive findings were recorded during the survey period. 4 children had thalassemia major, which is not formally a target disease but is of course definitely worth reporting. Four children were HbS heterozygous. Three children had very rare hemoglobin variants and in three children we have no feedback on the false positive finding. We assume that the heterozygotes and the rare variants were reported out of uncertainty and fall under the “starting difficulties” category. These false positives all occurred within the first few weeks of the program and could be eliminated by retraining the laboratory staff. Conclusion: Not only, but also thanks to the constant support of our European colleagues, especially in the form of the 2017 consensus paper, we have succeeded in introducing newborn screening for sickle cell disease. The first preliminary data show that sickle cell disease, with a prevalence of 1:5000 - 1:6000, will be one of the top diagnoses in screening even in Germany.

Addressing the Visible and Invisible Gaps and Challenges in the Diagnosis and Management of Intellectual Disability

Intellectual disability (ID) can be caused by various environmental and genetic factors and can lead to significant disability. There are numerous challenges in the field in terms of diagnosis and management. In this article, we have reviewed the literature in this field. A dependable estimate of the prevalence in India still remains to be made. Preventive measures and screening play an important role. The country could greatly benefit from a national newborn screening program, presence of more trained professionals, and public awareness measures. Drug treatments spanning beyond the usual drug classes have not yet found a breakthrough. Persons with ID face many challenges in the field of education, disability certification, access to government schemes, job placements, and living arrangements. We must take cognizance of these challenges at the earliest and work toward rectifying them.

Prevalence of congenital hypothyroidism in North Macedonia: data from a newborn screening program conducted for twenty years.

Congenital hypothyroidism (CH) is a common endocrine disorder that can be treated if timely detected by newborn screening, optimizing the developmental outcome in affected children. In the present study, we analyze the data of the national newborn thyroid screening program in North Macedonia collected over twenty years, including the CH prevalence as well as its geographical and ethnic variations. The thyroid-stimulating hormone (TSH) was measured on a filter paper blood spot sample using the DELFIA fluoroimmunometric assay. A TSH value of 15 mIU/L whole blood was used as the cutoff point until 2010 and 10 mIU/L thereafter. Out of 377,508 screened live births, a total of 226 newborns with primary CH were detected, providing an overall prevalence of 6.0 per 10,000. Lowering the TSH cutoff led to an apparently increased prevalence of the transient CH, from 0.2 to 2.4 per 10,000 live births (p < 0.0001) with an impact on the overall prevalence of primary CH (from 4.0 to 7.1 per 10,000, p=0.0001). Taking ethnicity into account, the significantly highest primary CH prevalence of 11.3 per 10,000 live births was observed among the Roma neonates, with a predominance of permanent CH (75.5%). There were also regional differences in the prevalence of primary CH. The highest primary CH prevalence of 11.7 per 10,000 live births was observed in the Vardar region, together with the highest regional prevalence of the transient CH (3.2 per 10,000). The highest prevalence of permanent CH was observed in the Pelagonia region (6.6 per 10,000) where the largest percentage of the Roma population lives. The overall CH prevalence is high in North Macedonia, with substantial ethnic and geographical variations. Further analysis to elucidate the causes for the significant variations in the CH prevalence including environmental factors is warranted.

Phenotypic and molecular features of Thai patients with primary carnitine deficiency.

Primary carnitine deficiency (PCD) is screened by expanded newborn screening (NBS) using tandem mass spectrometry (MS/MS) that can detect both affected neonates and mothers. This study aimed to delineate the clinical, biochemical, and molecular findings of Thai PCD patients. Expanded NBS using MS/MS was implemented in Bangkok and 146,757 neonates were screened between 2014 and 2018. PCD was screened by low free carnitine (C0) levels in dried blood spots. Plasma C0 levels and C0 clearance values were measured in neonates and their mothers with positive screening results. Clinically diagnosed cases were described. The coding regions and intron-exon boundaries of the SLC22A5 gene were sequenced in all cases with low plasma C0 levels. There were 14 cases with confirmed PCD: two clinically diagnosed cases, and 12 cases identified through NBS including five newborns, six mothers, and one older sibling. Thus, the incidence of PCD in neonates was 1:29,351. All affected neonates and mothers were asymptomatic except one mother with dilated cardiomyopathy. SLC22A5 gene sequencing identified biallelic causative variants in all cases, comprising 10 different variants of which four were novel. c.51C > G (p.Phe17Leu) and c.760C > T (p.Arg254Ter) were the most prevalent variants in this study. Cases with significant clinical features tended to have higher C0 clearance values. Primary carnitine deficiency is a common inherited metabolic disorder (IMD) in Thailand. Our findings broaden the spectrum of SLC22A5 variants. The future national NBS program will shed more light on PCD and other IMDs in Thailand.

Addition of galactose-1-phosphate measurement enhances newborn screening for classical galactosemia.

Galactosemia is an inborn disorder of carbohydrate metabolism of which early detection can prevent severe illness. Although the assay for galactose-1-phosphate uridyltransferase (GALT) enzyme activity has been available since the 1960s, many issues prevented it from becoming universal. In order to develop the Israeli newborn screening pilot algorithm for galactosemia, flow injection analysis tandem mass spectrometry measurement of galactose-1-phosphate in archived dried blood spots from newborns with classical galactosemia, galactosemia variants, epimerase deficiency, and normal controls, was conducted. Out of 431 330 newborns screened during the pilot study (30 months), two with classical galactosemia and four with epimerase deficiency were identified and confirmed. Five false positives and no false negatives were recorded. Following this pilot study, the Israeli final and routine newborn screening algorithm, as recommended by the Advisory Committee to the National Newborn Screening Program, now consists of galactose-1-phosphate measurement integrated into the routine tandem mass spectrometry panel as the first-tier screening test, and GALT enzyme activity as the second-tier performed to identify only newborns suspected to be at risk for classical galactosemia. The GALT enzyme activity cut-off used in the final algorithm was lowered in order to avoid false positives.