Next Article in Journal
Comment on Jones et al. Application of a Novel Algorithm for Expanding Newborn Screening for Inherited Metabolic Disorders across Europe. Int. J. Neonatal Screen. 2022, 8, 20
Previous Article in Journal
Acknowledgment to the Reviewers of International Journal of Neonatal Screening in 2022
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Newborn Screening of Primary Carnitine Deficiency: An Overview of Worldwide Practices and Pitfalls to Define an Algorithm before Expansion of Newborn Screening in France

Rennes University Hospital Center, 35033 Rennes, France
Reference Center of Inherited Metabolic Disorders, Clocheville Hospital, 37000 Tours, France
Reference Center for Inborn Error of Metabolism, Department of Pediatrics, Necker-Enfants Malades Hospital, APHP, 75015 Paris, France
Metabolism and Rare Disease Unit, Department of Biochemistry and Molecular Biology, Center of Biology and Pathology, Lille University Hospital Center, 59000 Lille, France
Center for Inherited Metabolic Disorders and Neonatal Screening, East Biology and Pathology Department, Groupement Hospitalier Est (GHE), Hospices Civils de Lyon, 69500 Bron, France
Author to whom correspondence should be addressed.
Int. J. Neonatal Screen. 2023, 9(1), 6;
Received: 1 January 2023 / Revised: 24 January 2023 / Accepted: 28 January 2023 / Published: 1 February 2023


Primary Carnitine Deficiency (PCD) is a fatty acid oxidation disorder that will be included in the expansion of the French newborn screening (NBS) program at the beginning of 2023. This disease is of high complexity to screen, due to its pathophysiology and wide clinical spectrum. To date, few countries screen newborns for PCD and struggle with high false positive rates. Some have even removed PCD from their screening programs. To understand the risks and pitfalls of implementing PCD to the newborn screening program, we reviewed and analyzed the literature to identify hurdles and benefits from the experiences of countries already screening this inborn error of metabolism. In this study, we therefore, present the main pitfalls encountered and a worldwide overview of current practices in PCD newborn screening. In addition, we address the optimized screening algorithm that has been determined in France for the implementation of this new condition.

1. Introduction

Primary Carnitine Deficiency (PCD) (OMIM #212140)—also referred to as systemic primary carnitine deficiency (CDSP), carnitine transporter defect (CTD), or carnitine uptake deficiency (CUD)—is an autosomal recessive inborn error of metabolism involving a disorder of the carnitine cycle. It is a part of fatty acid oxidation (FAO) disorders and is caused by a partial or complete loss of function of the membrane transporter organic cation/carnitine transporter novel 2 (OCTN2). This solute carrier is coded by the SLC22A5 gene, comprising 10 exons, located approximately on a 26 kb region on chromosome 5q31.1 (chr5:132,369,710–132,395,612) [1,2]. This sodium-dependent carnitine symporter is the main carnitine (3-hydroxy-4-(trimethylazaniumyl)butanoate) transporter in mammals, displaying a high affinity for carnitine (KM = 4.3 µmol·L−1) [3]. OCTN2 is ubiquitous, with expression predominantly in kidney and intestinal cells, to ensure absorption and reabsorption of L-carnitine, and in skeletal muscles, to allow the shuttling of long chain fatty acids across inner mitochondrial membranes toward the fatty acid oxidation process [4]. Carnitine is almost exclusively intracellular (>99% of the total pool), with high tissue concentrations [5]. Carnitine homeostasis is balanced by dietary intake, endogenous biosynthesis, and especially by renal reabsorption. There are compensatory mechanisms, thus even a poor carnitine diet or a defect in carnitine biosynthesis does not affect FAO [6,7]. However, when OCTN2 function is impaired, a major urinary leak of free carnitine leads to a progressively significant decrease in both intracellular and circulating carnitine concentrations, resulting in PCD. Clinical characteristics of PCD encompass a broad clinical spectrum and have been widely assessed in high quality reviews [8,9,10,11]. In absence of newborn screening (NBS), patients usually present in their infancy: acute metabolic decompensation with hypoketotic hypoglycemia; dilated cardiomyopathy; and hepatic cytolysis. Without L-carnitine treatment, death can occur due to heart failure. Fortunately, PCD has an excellent prognosis upon L-carnitine supplementation and almost all patients remain asymptomatic [11]. Incidence of primary carnitine deficiency was quite variable depending on the studied population, ranging from 1:300 in the Faroe Islands [12] where there was a founding mutation, to 1:30-142,000 in Japan, Australia, or USA [13,14,15]. Regarding the incidence, the knowledge of this disease’s natural history, and the availability of a safe and efficient treatment, PCD follows consolidated principles for newborn screening [16], especially as free carnitine (C0) represents an easily measurable biomarker on dried blood spot (DBS) [17]. New South Wales (Australia) was the first state to evaluate PCD newborn screening in the late 1990s [18], and this was usually conducted by expanded newborn screening programs deployed since then [19,20,21]. Nevertheless, screening of primary carnitine deficiency is not simple, due to various secondary carnitine deficiencies that may generate false-positives (e.g., maternal carnitine deficiency, organic acidurias, pivalic acid-based antibiotherapy, pre-term birth, etc.) which represent pitfalls for the diagnosis and management of newborn PCD. Consequently, several algorithms for screening have been proposed, which include: different thresholds for C0 and other biomarkers; molecular sequencing of SLC22A5; and functional confirmation by carnitine uptake assay on skin fibroblasts. In this study, we aimed to review the situation of PCD newborn screening worldwide before the expansion of newborn screening in France at the beginning of 2023 [22], by gathering epidemiological, biological, and molecular data, to set an appropriate screening algorithm.

2. Worldwide Overview of Primary Carnitine Deficiency Newborn Screening

2.1. Countries/Regions Screening PCD

To evaluate the extent of PCD NBS worldwide, we have screened national NBS programs and the literature for countries/regions that have implemented this condition. Actual NBS programs including PCD and excluding PCD are represented in Figure 1.

2.1.1. Australia and New Zealand

Australia was the first country to include PCD in NBS [18], in 1998. The cut-off for low free carnitine to trigger a retest during screening was set to 10 µmol·L−1. A confirmed level of C0 < 5 µmol·L−1 generated a second sample, and PCD diagnosis was confirmed through OCTN2 activity on fibroblasts. To date, PCD NBS is performed nationwide [23].
New Zealand implemented PCD to ENBS in 2006, with a screen-positive level of C0 of 5 µmol·L−1 and molecular confirmation [24]. However, due to the low incidence (two cases in ten years; 1:300,000 births); the prevalence of asymptomatic patients; and the impact of diagnosing more mothers with PCD than newborns, PCD screening was considered unsuitable for NBS and was therefore discontinued [25].

2.1.2. North America

North America has almost a full coverage of PCD screening. Newborn screening has been nationally organized since mid-1980s under the aegis of the Council of Regional Networks for Genetic Services (CORN) [26]. In 2006, the American College of Medical Genetics (ACMG) provided guidelines to promote a standardized and uniform newborn screening program [27]. These guidelines had a substantial impact on perinatal healthcare through early identification and treatment of inborn errors of metabolism, including PCD, reducing morbidity and mortality [20,28,29]. Consequently, the USA has a solid nationwide background on NBS, its follow-up and outcomes [30], enhanced by standardization tools and programs [31].
English-speaking Canadian regions follow the ACMG’s guidelines [32,33,34], whereas French-Canadian provinces do not screen DBS for PCD even though they provide an interesting urinary NBS for organic acidurias, urea cycle disorders, cystinuria, homocystinuria, and creatine synthesis and transport disorders [34].

2.1.3. Central and South America

Mexico and South America started NBS in mid-1970s with PKU and struggled to achieve a whole coverage of population since then, with the exception of Cuba, Costa Rica, Chile, and Uruguay, where around 100% coverage was reached [35,36]. Difficulties encountered were mostly due to the lack of financial resources and fundings for free national NBS programs (especially regarding the high cost of tandem MS equipment), and the high prevalence of major, priority health issues, such as malnutrition and infectious diseases. As a result, most Central and South American countries have NBS programs, but to date, none of them include PCD, and only Costa Rica and Uruguay have set up a tandem MS NBS program [37]. It is to be noted that French Guyana and French Polynesia follow French guidelines for NBS.

2.1.4. Europe

PCD NBS in Europe is heterogeneous. Germany was the first country to include PCD to their program in a pilot study between 1998 and 2001 [38]. Biomarkers used for the screening were C0 < 10 µmol·L−1 and total acylcarnitines (C3 to C18) of <10 µmol·L−1. Confirmation was biochemically deduced by determining OCTN2 activity on fibroblasts. In 2007, only Austria, Belgium, Denmark, and Poland had PCD on their ENBS panel [19]. NBS for Greenland and Faroe Islands are managed by Denmark. In Faroese population, there was a high incidence (~1:300) of PCD caused by a founder pathogenic variant on SLC22A5: c.95A>G, p.(Asn32Ser) [39]. Consequently, to minimize false negatives on NBS and to ensure diagnosis of all PCD patients, a nationwide second screening performed at two months of age had been introduced [40]. In addition, all Scandinavian countries have included PCD to NBS, and few other countries have conducted pilot studies or have already began to screen PCD, such as Portugal or Italy [21,41]. It is to be noted that the UK does not screen PCD, to date, even though in 2009, England had conducted a pilot study of amino acid and acylcarnitines analysis on cord blood samples to identify inborn errors of metabolism [42]. The Netherlands have listed PCD, along with seven other diseases, in the upcoming schedule of NBS expansion [43], and France will be including PCD to NBS at the beginning of 2023.

2.1.5. Africa

Middle East and North Africa (MENA) is a large region consisting of 21 countries; from Morocco in northwestern Africa, to Iran in southwestern Asia. Genetic disorders are relatively common in this area due to the high rate of consanguinity [44]. Efforts have allowed NBS programs to emerge, resulting from pilot programs and successful studies [45,46,47]. However, to date, only Qatar and Saudi Arabia have included PCD in their programs [48,49,50].
Regarding Sub-Saharan Africa, NBS implementation is still at its beginning. However, much efforts are being made by a Pan-African Workshop on Newborn Screening [51]. Sickle Cell Disease (SCD) is the disease with the highest prevalence in this region and is, therefore, of priority and collaborations will be needed to expand NBS toward a larger panel in the future.

2.1.6. Asia

Teams in Asia were the first to elude that pathogenic variations in the SLC22A5 gene was the molecular basis of primary carnitine deficiency [14,52,53]. Incidence of PCD appears to be more frequent in Asian populations than in those from western countries, even being one of the most prevalent inherited metabolic diseases in the Chinese population [54]. However, the first pilot study of ESI-MS/MS-based NBS in Japan, led by Schigematsu et al., did not report any cases of PCD. First Asian studies and experience on PCD NBS started in late 2000s in China (province-based program), Taiwan, South Korea, and Japan. More recently, Thailand and Philippines included PCD to the ENBS program as well [41,55,56]. To our knowledge, India still struggles to initiate a nationwide NBS program, and other Asian Pacific or Central Asia countries have not included PCD to their program to date [57]. The high incidence of PCD in Asian populations, along with the development of Next Generation Sequencing, have led to the emergence of a systematic study of the SLC22A5 gene as a second-tier testing after phenotypic screening [58,59,60].

2.1.7. Russia

As it is part of both Europe and Asia, Russia is addressed as a separate entity. To date, the nationwide NBS program in Russia includes: phenylketonuria, congenital hypothyroidism, congenital adrenal hyperplasia, galactosemia, and cystic fibrosis. However, Primorsky and Moscow regions are currently performing tandem MS ENBS to identify 39 and 11 diseases, respectively, and the national expansion of NBS is being discussed [61].

3. Reports of NBS for PCD Worldwide

We screened the literature for regional or nationwide studies on either focused PCD newborn screening or, failing this, a general report on NBS. We found over fifty-five suitable publications and gathered the following data, upon availability: country/region; period of the study; number of newborns screened; free carnitine (C0) cut-off for screening; second tier screening if performed; the number of patients diagnosed and their subsequent incidence of PCD; the number of mothers with PCD identified by their infant’s NBS; and the number of false positive patients and positive predictive value (PPV%). Data are presented by region rather than chronologically to ease comprehension in Table 1.
From these data, we calculated regional incidences of 1:348,333 for Australia and New-Zealand (6:2,090,000 births); 1:121,609 for North America (306:37,212,366); 1:127,912 for Europe, excluding Denmark, Greenland, and Faroe Islands (59:7,546,812); and 1:50,386 for Asia (544:27,409,799). Incidences were compared to each other using a chi-square test of equal frequencies. Incidence was significantly higher in Asia compared to all other regions (p < 0.0001). Incidence in Europe did not differ from that in North America (p = 0.72), whereas Australia displayed a lower incidence compared with Europe (p = 0.015) and North America (p = 0.001). Among these studies, only a few countries used a secondary batch of biomarkers in order to reduce false positive rates. For example, Tang et al. and Huang et al. [97,105] showed that using the sum of propionylcarnitine and palmitoylcarnitine on DBS (C3 + C16) < 2 µmol·L−1 cut-off, in addition to a C0 cut-off of 10 µmol·L−1, allowed sensitivity which was as effective as using a sole C0 < 8.5 µmol·L−1 cut-off, while reducing false positives samples from 314 to 165. The positive predictive value (PPV%) increased from 8.7 to 15.3%. It is noteworthy that some countries, such as China, Norway, or Slovenia, have decided to use a next-generation sequencing research of common pathogenic variants on DBS as a second-tier screening. The main argument to this is the need to identify heterozygous newborns, and thus excluding false positive children born from PCD mothers. This leads to an increase in PPV%, which is generally low for PCD. However, the use of second tier biomarkers or molecular tests raise PPV% to almost 20%.

4. Molecular Findings

From the above-mentioned studies, we gathered individual molecular data that were available [58,64,72,73,78,80,83,86,89,92,96,98,101,103,104,107,110]. Genotype data were described for 175 newborns and C0 levels on screening were mentioned for 132 of the newborns. Seventy-five unique variants were identified: 49 missense, 10 nonsense, 10 frameshift, 10 intronic, and 1 in frame. The most prevalent variants were c.1400C>G, p.(Ser467Cys), representing 79 alleles (22.6%) out of 350, followed by c.760C>T p.(Arg254*), 56 alleles (16.0%); and c.51C>G p.(Phe17Leu), 49 alleles (14%). Unfortunately, most of the data came from Asian studies because of the limited molecular reports from other areas, which does not allow a global overview. In addition, databases on population allele frequency (GnomAD) confirmed that these variants were prevalent in East-Asian population, but not in other populations. Interestingly, in the study by Martín-Rivada et al., p.(Ser467Cys) and p.(Arg254*) were only present once out of 22 alleles and both in the same patient, who originated from China, whereas other described variants were not present in Asian studies, in accordance with a region-dependent polymorphism. Therefore, we cannot postulate on a global genotype-phenotype correlation between the pathogenic variants found in PCD patients who were identified through newborn screening. Nevertheless, it is interesting to note that in these data, C0 values for homozygous or composite heterozygous missense variants displayed milder decreased free carnitine levels (mean C0 ± Sd = 5.92 ± 1.76 µmol·L−1), which is consistent with the literature on its effect on residual OCTN2 activity [111]. On the contrary, truncating genotypes were more deleterious, with a mean C0 level below 3 µmol·L−1 at the homozygous state. Hence, in order to increase the positive predictive value and sensitivity of NBS, it is desirable to know the molecular distribution within a population to set an appropriate cut-off for the biomarker of interest.

5. Pitfalls of Newborn Screening for PCD

Including primary carnitine deficiency to NBS is not as simple as it is for other inborn errors of metabolism. Indeed, PCD is eligible based on the Wilson and Jungner criteria, as it is an easily treatable and very serious condition. Nonetheless, there are substantial obstacles. It is one of the rare diseases for which the screening biomarker is not expected to be detectable above a cut-off value, but below. This is a major problem as there are common causes of decreased free carnitine levels in a newborn, such as: preterm birth [50], maternal PCD, inborn errors of metabolism or vegetarian/vegan diet [112,113], and pivalic acid-based therapeutics in the mother (e.g., pivmecillinam, cephalosporin antibiotics, sivelestat, etc.) [114,115]. These situations are causes of false positive screening test results.
In addition, preanalytical issues can impact the DBS test. For example, the extraction method, using derivatization or not, will lead to different levels of C0, which are higher with derivatized methods [95]. Therefore, there is a need for standardization, at least for screening centers within the same country. The timing of blood collection is crucial as well, as C0 seems to decrease during the first 48 h of life before increasing until 120 h after [116,117]. Ethnicity can be a variating factor as well, as Asian populations seem to have higher C0 levels [118].
Particularly, the high incidence of identification of asymptomatic mothers with PCD from their child’s NBS, raises the question of the limit of the screening approach. Associated with the low sensitivity and positive predictive value of PCD NBS, it would lead to the diagnosis of more mothers than children. For this reason, and the possible side effects of a long term supplementation with L-carnitine, such as trimethyl-N-oxide (TMAO) accumulation and repression of compensation mechanisms observed in PCD, New-Zealand decided to discontinue PCD from their NBS program [25].
In summary, newborn screening for PCD is undoubtedly useful, but only if the following requirements are fulfilled: an algorithm to reduce false positive results, and to increase the positive predictive value by utilizing 1st, 2nd, and even 3rd tier analyses comprising C0 test and retest, along with 2nd tier biomarkers, and molecular and/or functional studies.

6. Discussion of a Suitable Screening Algorithm

The experience reported in the literature on PCD NBS confirmed its complexity. In order to propose a suitable algorithm for France, with an optimal PPV%, some lines of thought were identified such as:
Using supplemental biomarkers in addition to C0.
Coupling SLC22A5 molecular testing on initial DBS.
Performing a retest on a second DBS sample to prevent the impact of the maternal status.
A national working group proposed to use C0 as a first-tier biomarker, and total acylcarnitines as a second-step confirmation analysis (including acylcarnitines measured in other screened conditions: propionylcarnitine C3, isovalerylcarnitine C5, octanoylcarnitine C8, glutarylcarnitine C5DC, decanoyl C10, and 3-OH palmitoylcarnitine C16OH). A novel C0 analysis on a new DBS sample at day 21 of life was selected as a third-tier analysis to limit false positives due to maternal PCD, prematurity, or other inborn errors of metabolism. As illustrated in Figure 2:
A C0 higher (>) than cut-off 1 (8 µmol·L−1) means a negative screening, and the patient is ruled-out.
If C0 is lower or equal (≤) to cut-off 1, a duplicate retest on the birth DBS is performed.
If mean C0 of this retest is >cut-off 2 (6 µmol·L−1), the patient is ruled-out.
If mean C0 is ≤cut-off 3 (4 µmol·L−1), the screening is positive and the patient is reported to the PCD referent pediatrician.
If C0 is between cut-offs 2 and 3, the sum of supplemental acylcarnitines is calculated.
If supplemental acylcarnitines are >cut-off 4 (1 µmol·L−1), the patient is ruled-out.
If supplemental acylcarnitines are ≤cut-off 4, another DBS is sampled at day 21 of life.
If C0 on the 2nd DBS sample is >cut-off 5 (6 µmol·L−1), the patient is ruled-out.
If C0 is ≤cut-off 5, the screening is positive and the patient is reported to the PCD referent pediatrician.
It is to be noted that our algorithm was designed for full-term babies. Pre-term babies are known to have lower C0 levels and there is a physiological decrease from birth until 48 h after birth [116]. Thus, there is a risk of false positives in this population. Ramaswamy et al. showed that secondary carnitine deficiency due to carnitine depletion in pre-term babies did not exceed 10%, which is reassuring [50]. In addition, the third step with a new sample at day 21 after birth, will help to rule out these newborns and avoid entering the diagnosis process. On the other hand, total parenteral nutrition (TPN) can be a confounding factor too, as it can lead to false negatives if the preparation is supplemented with carnitine. In France, TPN are not carnitine enriched, therefore, it is likely that the risk of false negatives is very low.

7. Conclusions

Primary carnitine deficiency is a complex inborn error of metabolism. Firstly, this is because it involves a membrane transporter, which is polyspecific of a large panel of substrates, as opposed to enzymatic deficiencies mainly concerning only a single substrate. This implies that in addition to the hereditary defect due to deleterious biallelic variants in SLC22A5, several secondary etiologies can jeopardize a screening approach. Moreover, this disease displays variable expressivity. Indeed, almost half of the patients with PCD remain asymptomatic. Nonetheless, PCD is a permanent threat with a risk of sudden death in the event of decompensation. Furthermore, there is an efficient, cost-effective, and safe treatment through L-carnitine supplementation. If started at the pre-symptomatic phase, it can even prevent any onset of PCD symptoms. Finally, there are sensitive and specific screening and diagnosis tools with appropriate algorithms. For these reasons, a nationwide newborn screening program for this disease seems legitimate. Through this literature review, we provide a worldwide overview on current practices of PCD newborn screening and emphasize the pitfalls of this particular disease. We also present the algorithm that working groups for French newborn screening program have deemed the most appropriate.

Author Contributions

Conceptualization, C.R.L., F.L., D.D., J.-B.A., A.-F.D., M.T., D.C. and C.A.-B.; methodology, C.R.L., F.L., D.C. and C.A.-B.; software, C.R.L.; validation, D.C. and C.A.-B.; formal analysis, C.R.L.; investigation, C.R.L.; resources, C.R.L., D.D., M.F. and F.L.; data curation, C.R.L.; writing—original draft preparation, C.R.L.; writing—review and editing, all authors; visualization, M.F, P.R., C.M. and C.B.; supervision, D.C., C.A.-B., C.M., L.D. and F.L.; project administration, D.C., C.A.-B. and F.L.; funding acquisition, not applicable. All authors have read and agreed to the published version of the manuscript.


This project was supported by financial allowance from the Research and Innovation Department of Rennes University Hospital Centre, 2 rue Henri Le Guilloux, 35000 Rennes, France.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Wu, X.; Prasad, P.D.; Leibach, F.H.; Ganapathy, V. CDNA Sequence, Transport Function, and Genomic Organization of Human OCTN2, a New Member of the Organic Cation Transporter Family. Biochem. Biophys. Res. Commun. 1998, 246, 589–595. [Google Scholar] [CrossRef] [PubMed]
  2. Nezu, J.; Tamai, I.; Oku, A.; Ohashi, R.; Yabuuchi, H.; Hashimoto, N.; Nikaido, H.; Sai, Y.; Koizumi, A.; Shoji, Y.; et al. Primary Systemic Carnitine Deficiency Is Caused by Mutations in a Gene Encoding Sodium Ion-Dependent Carnitine Transporter. Nat. Genet. 1999, 21, 91–94. [Google Scholar] [CrossRef] [PubMed]
  3. Juraszek, B.; Nałęcz, K.A. SLC22A5 (OCTN2) Carnitine Transporter—Indispensable for Cell Metabolism, a Jekyll and Hyde of Human Cancer. Molecules 2020, 25, 14. [Google Scholar] [CrossRef]
  4. Tamai, I.; Ohashi, R.; Nezu, J.; Yabuuchi, H.; Oku, A.; Shimane, M.; Sai, Y.; Tsuji, A. Molecular and Functional Identification of Sodium Ion-Dependent, High Affinity Human Carnitine Transporter OCTN2*. J. Biol. Chem. 1998, 273, 20378–20382. [Google Scholar] [CrossRef] [PubMed]
  5. Stanley, C.A. Carnitine Deficiency Disorders in Children. Ann. N. Y. Acad. Sci. 2004, 1033, 42–51. [Google Scholar] [CrossRef]
  6. Longo, N. Primary Carnitine Deficiency and Newborn Screening for Disorders of the Carnitine Cycle. Ann. Nutr. Metab. 2016, 68, 5–9. [Google Scholar] [CrossRef]
  7. Longo, N.; Frigeni, M.; Pasquali, M. Carnitine Transport and Fatty Acid Oxidation. Biochim. Biophys. Acta BBA-Mol. Cell Res. 2016, 1863, 2422–2435. [Google Scholar] [CrossRef]
  8. Stanley, C.A.; DeLeeuw, S.; Coates, P.M.; Vianey-Liaud, C.; Divry, P.; Bonnefont, J.P.; Saudubray, J.M.; Haymond, M.; Trefz, F.K.; Breningstall, G.N. Chronic Cardiomyopathy and Weakness or Acute Coma in Children with a Defect in Carnitine Uptake. Ann. Neurol. 1991, 30, 709–716. [Google Scholar] [CrossRef]
  9. El-Hattab, A.W.; Scaglia, F. Disorders of Carnitine Biosynthesis and Transport. Mol. Genet. Metab. 2015, 116, 107–112. [Google Scholar] [CrossRef]
  10. El-Hattab, A.W. Systemic Primary Carnitine Deficiency. In GeneReviews®; Adam, M.P., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., Bean, L.J., Gripp, K.W., Amemiya, A., Eds.; University of Washington: Seattle, DC, USA, 1993. [Google Scholar]
  11. Crefcoeur, L.L.; Visser, G.; Ferdinandusse, S.; Wijburg, F.A.; Langeveld, M.; Sjouke, B. Clinical Characteristics of Primary Carnitine Deficiency—A Structured Review Using a Case by Case Approach. J. Inherit. Metab. Dis. 2022, 45, 386–405. [Google Scholar] [CrossRef]
  12. Rasmussen, J.; Nielsen, O.W.; Janzen, N.; Duno, M.; Køber, L.; Steuerwald, U.; Lund, A.M. Carnitine Levels in 26,462 Individuals from the Nationwide Screening Program for Primary Carnitine Deficiency in the Faroe Islands. J. Inherit. Metab. Dis. 2014, 37, 215–222. [Google Scholar] [CrossRef] [PubMed]
  13. Rose, E.C.; di San Filippo, C.A.; Ndukwe Erlingsson, U.C.; Ardon, O.; Pasquali, M.; Longo, N. Genotype-Phenotype Correlation in Primary Carnitine Deficiency. Hum. Mutat. 2012, 33, 118–123. [Google Scholar] [CrossRef] [PubMed]
  14. Koizumi, A.; Nozaki, J.; Ohura, T.; Kayo, T.; Wada, Y.; Nezu, J.; Ohashi, R.; Tamai, I.; Shoji, Y.; Takada, G.; et al. Genetic Epidemiology of the Carnitine Transporter OCTN2 Gene in a Japanese Population and Phenotypic Characterization in Japanese Pedigrees with Primary Systemic Carnitine Deficiency. Hum. Mol. Genet. 1999, 8, 2247–2254. [Google Scholar] [CrossRef] [PubMed]
  15. Wilcken, B.; ChB, M. Disorders of the Carnitine Cycle and Detection by Newborn Screening. Ann. Acad. Med. Singap. 2008, 37, 3. [Google Scholar]
  16. Dobrow, M.J.; Hagens, V.; Chafe, R.; Sullivan, T.; Rabeneck, L. Consolidated Principles for Screening Based on a Systematic Review and Consensus Process. CMAJ Can. Med. Assoc. J. 2018, 190, E422–E429. [Google Scholar] [CrossRef]
  17. Barns, R.J.; Bowling, F.G.; Brown, G.; Clague, A.E.; Thompson, A. Carnitine in Dried Blood Spots: A Method Suitable for Neonatal Screening. Clin. Chim. Acta 1991, 197, 27–33. [Google Scholar] [CrossRef]
  18. Wilcken, B.; Wiley, V.; Sim, K.G.; Carpenter, K. Carnitine Transporter Defect Diagnosed by Newborn Screening with Electrospray Tandem Mass Spectrometry. J. Pediatr. 2001, 138, 581–584. [Google Scholar] [CrossRef]
  19. Bodamer, O.A.; Hoffmann, G.F.; Lindner, M. Expanded Newborn Screening in Europe 2007. J. Inherit. Metab. Dis. 2007, 30, 439–444. [Google Scholar] [CrossRef]
  20. Sontag, M.K.; Yusuf, C.; Grosse, S.D.; Edelman, S.; Miller, J.I.; McKasson, S.; Kellar-Guenther, Y.; Gaffney, M.; Hinton, C.F.; Cuthbert, C.; et al. Infants with Congenital Disorders Identified Through Newborn Screening—United States, 2015–2017. MMWR Morb. Mortal. Wkly. Rep. 2020, 69, 1265–1268. [Google Scholar] [CrossRef]
  21. Koracin, V.; Mlinaric, M.; Baric, I.; Brincat, I.; Djordjevic, M.; Drole Torkar, A.; Fumic, K.; Kocova, M.; Milenkovic, T.; Moldovanu, F.; et al. Current Status of Newborn Screening in Southeastern Europe. Front. Pediatr. 2021, 9, 648939. [Google Scholar] [CrossRef]
  22. Haute Autorité de Santé: Évaluation a priori de l’extension du dépistage néonatal à une ou plusieurs erreurs innées du métabolisme par spectrométrie de masse en tandem en population générale en France. Available online: (accessed on 21 July 2022).
  23. Care, A.G.D. List of Conditions Screened by Jurisdiction—September 2022. Available online: (accessed on 30 July 2022).
  24. Wilson, C.; Kerruish, N.J.; Wilcken, B.; Wiltshire, E.; Webster, D. Diagnosis of Disorders of Intermediary Metabolism in New Zealand before and after Expanded Newborn Screening: 2004–2009. N. Z. Med. J. 2012, 125, 42–50. [Google Scholar] [PubMed]
  25. Wilson, C.; Knoll, D.; de Hora, M.; Kyle, C.; Glamuzina, E.; Webster, D. The Decision to Discontinue Screening for Carnitine Uptake Disorder in New Zealand. J. Inherit. Metab. Dis. 2019, 42, 86–92. [Google Scholar] [CrossRef]
  26. Therrell, B.L.; Hannon, W.H. National Evaluation of US Newborn Screening System Components. Ment. Retard. Dev. Disabil. Res. Rev. 2006, 12, 236–245. [Google Scholar] [CrossRef] [PubMed]
  27. Watson, M.S.; Mann, M.Y.; Lloyd-Puryear, M.A.; Rinaldo, P.; Howell, R.R. American College of Medical Genetics Newborn Screening Expert Group Newborn Screening: Toward a Uniform Screening Panel and System—Executive Summary. Pediatrics 2006, 117, S296–S307. [Google Scholar] [CrossRef] [PubMed]
  28. Centers for Disease Control and Prevention (CDC) Impact of Expanded Newborn Screening--United States, 2006. MMWR Morb. Mortal. Wkly. Rep. 2008, 57, 1012–1015.
  29. Centers for Disease Control and Prevention (CDC) CDC Grand Rounds: Newborn Screening and Improved Outcomes. MMWR Morb. Mortal. Wkly. Rep. 2012, 61, 390–393.
  30. Magoulas, P.L.; El-Hattab, A.W. Systemic Primary Carnitine Deficiency: An Overview of Clinical Manifestations, Diagnosis, and Management. Orphanet J. Rare Dis. 2012, 7, 68. [Google Scholar] [CrossRef]
  31. Ojodu, J.; Singh, S.; Kellar-Guenther, Y.; Yusuf, C.; Jones, E.; Wood, T.; Baker, M.; Sontag, M. NewSTEPs: The Establishment of a National Newborn Screening Technical Assistance Resource Center. Int. J. Neonatal Screen. 2017, 4, 1. [Google Scholar] [CrossRef]
  32. Hanley, W.B. Newborn Screening in Canada—Are We out of Step? Paediatr. Child Health 2005, 10, 203–207. [Google Scholar] [CrossRef]
  33. Dyack, S. Expanded Newborn Screening: Lessons Learned from MCAD Deficiency. Paediatr. Child Health 2004, 9, 241–243. [Google Scholar] [CrossRef]
  34. Auray-Blais, C.; Boutin, M.; Lavoie, P.; Maranda, B. Neonatal Urine Screening Program in the Province of Quebec: Technological Upgrade from Thin Layer Chromatography to Tandem Mass Spectrometry. Int. J. Neonatal Screen. 2021, 7, 18. [Google Scholar] [CrossRef] [PubMed]
  35. Borrajo, G.J.C. Newborn Screening in Latin America at the Beginning of the 21st Century. J. Inherit. Metab. Dis. 2007, 30, 466–481. [Google Scholar] [CrossRef] [PubMed]
  36. Cabello, J.F.; Novoa, F.; Huff, H.V.; Colombo, M. Expanded Newborn Screening and Genomic Sequencing in Latin America and the Resulting Social Justice and Ethical Considerations. Int. J. Neonatal Screen. 2021, 7, 6. [Google Scholar] [CrossRef] [PubMed]
  37. Borrajo, G.J.C. Newborn Screening in Latin America: A Brief Overview of the State of the Art. Am. J. Med. Genet. C Semin. Med. Genet. 2021, 187, 322–328. [Google Scholar] [CrossRef]
  38. Schulze, A.; Lindner, M.; Kohlmüller, D.; Olgemöller, K.; Mayatepek, E.; Hoffmann, G.F. Expanded Newborn Screening for Inborn Errors of Metabolism by Electrospray Ionization-Tandem Mass Spectrometry: Results, Outcome, and Implications. Pediatrics 2003, 111, 1399–1406. [Google Scholar] [CrossRef]
  39. Lund, A.M.; Joensen, F.; Hougaard, D.M.; Jensen, L.K.; Christensen, E.; Christensen, M.; Nørgaard-Petersen, B.; Schwartz, M.; Skovby, F. Carnitine Transporter and Holocarboxylase Synthetase Deficiencies in The Faroe Islands. J. Inherit. Metab. Dis. 2007, 30, 341–349. [Google Scholar] [CrossRef] [PubMed]
  40. Steuerwald, U.; Lund, A.M.; Rasmussen, J.; Janzen, N.; Hougaard, D.M.; Longo, N. Neonatal Screening for Primary Carnitine Deficiency: Lessons Learned from the Faroe Islands. Int. J. Neonatal Screen. 2017, 3, 1. [Google Scholar] [CrossRef]
  41. Loeber, J.G.; Platis, D.; Zetterström, R.H.; Almashanu, S.; Boemer, F.; Bonham, J.R.; Borde, P.; Brincat, I.; Cheillan, D.; Dekkers, E.; et al. Neonatal Screening in Europe Revisited: An ISNS Perspective on the Current State and Developments Since 2010. Int. J. Neonatal Screen. 2021, 7, 15. [Google Scholar] [CrossRef]
  42. Walter, J.H.; Patterson, A.; Till, J.; Besley, G.T.N.; Fleming, G.; Henderson, M.J. Bloodspot Acylcarnitine and Amino Acid Analysis in Cord Blood Samples: Efficacy and Reference Data from a Large Cohort Study. J. Inherit. Metab. Dis. 2009, 32, 95–101. [Google Scholar] [CrossRef]
  43. Jansen, M.E.; Klein, A.W.; Buitenhuis, E.C.; Rodenburg, W.; Cornel, M.C. Expanded Neonatal Bloodspot Screening Programmes: An Evaluation Framework to Discuss New Conditions With Stakeholders. Front. Pediatr. 2021, 9, 635353. [Google Scholar] [CrossRef] [PubMed]
  44. Therrell, B.L.; Padilla, C.D.; Loeber, J.G.; Kneisser, I.; Saadallah, A.; Borrajo, G.J.C.; Adams, J. Current Status of Newborn Screening Worldwide: 2015. Semin. Perinatol. 2015, 39, 171–187. [Google Scholar] [CrossRef] [PubMed]
  45. Al Hosani, H.; Salah, M.; Osman, H.M.; Farag, H.M.; El Assiouty, L.; Saade, D.; Hertecant, J. Expanding the Comprehensive National Neonatal Screening Programme in the United Arab Emirates from 1995 to 2011. East. Mediterr. Health J. 2014, 20, 17–23. [Google Scholar] [CrossRef] [PubMed]
  46. Golbahar, J.; Al-Jishi, E.A.; Altayab, D.D.; Carreon, E.; Bakhiet, M.; Alkhayyat, H. Selective Newborn Screening of Inborn Errors of Amino Acids, Organic Acids and Fatty Acids Metabolism in the Kingdom of Bahrain. Mol. Genet. Metab. 2013, 110, 98–101. [Google Scholar] [CrossRef] [PubMed]
  47. Hassan, F.A.; El-Mougy, F.; Sharaf, S.A.; Mandour, I.; Morgan, M.F.; Selim, L.A.; Hassan, S.A.; Salem, F.; Oraby, A.; Girgis, M.Y.; et al. Inborn Errors of Metabolism Detectable by Tandem Mass Spectrometry in Egypt: The First Newborn Screening Pilot Study. J. Med. Screen. 2016, 23, 124–129. [Google Scholar] [CrossRef]
  48. Mohamed, S.; Elsheikh, W.; Al-Aqeel, A.I.; Alhashem, A.M.; Alodaib, A.; Alahaideb, L.; Almashary, M.; Alharbi, F.; AlMalawi, H.; Ammari, A.; et al. Incidence of Newborn Screening Disorders among 56632 Infants in Central Saudi Arabia: A 6-Year Study. Saudi Med. J. 2020, 41, 703–708. [Google Scholar] [CrossRef]
  49. Lindner, M.; Abdoh, G.; Fang-Hoffmann, J.; Shabeck, N.; Al Sayrafi, M.; Al Janahi, M.; Ho, S.; Abdelrahman, M.O.; Ben-Omran, T.; Bener, A.; 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, 522–529. [Google Scholar] [CrossRef]
  50. Ramaswamy, M.; Anthony Skrinska, V.; Fayez Mitri, R.; Abdoh, G. Diagnosis of Carnitine Deficiency in Extremely Preterm Neonates Related to Parenteral Nutrition: Two Step Newborn Screening Approach. Int. J. Neonatal Screen. 2019, 5, 29. [Google Scholar] [CrossRef]
  51. Therrell, B.L.; Lloyd-Puryear, M.A.; Ohene-Frempong, K.; Ware, R.E.; Padilla, C.D.; Ambrose, E.E.; Barkat, A.; Ghazal, H.; Kiyaga, C.; Mvalo, T.; et al. Empowering Newborn Screening Programs in African Countries through Establishment of an International Collaborative Effort. J. Community Genet. 2020, 11, 253–268. [Google Scholar] [CrossRef]
  52. Lamhonwah, A.M.; Tein, I. Carnitine Uptake Defect: Frameshift Mutations in the Human Plasmalemmal Carnitine Transporter Gene. Biochem. Biophys. Res. Commun. 1998, 252, 396–401. [Google Scholar] [CrossRef]
  53. Tang, N.L.S.; Hwu, W.L.; Chan, R.T.; Law, L.K.; Fung, L.M.; Zhang, W.M. A Founder Mutation (R254X) of SLC22A5 (OCTN2) in Chinese Primary Carnitine Deficiency Patients. Hum. Mutat. 2002, 20, 232. [Google Scholar] [CrossRef]
  54. Tang, N.; Hui, J. 20 Years After Discovery of the Causative Gene of Primary Carnitine Deficiency, How Much More Have We Known About the Disease? HK J Paediatr New Ser. 2020, 25, 23–29. [Google Scholar]
  55. Liammongkolkul, S.; Sanomcham, K.; Vatanavicharn, N.; Sathienkijkanchai, A.; Ranieri, E.; Wasant, P. AB133. Expanded Newborn Screening Program in Thailand. Ann. Transl. Med. 2017, 5, AB133. [Google Scholar] [CrossRef]
  56. Padilla, C.D.; Therrell, B.L.; Alcausin, M.M.L.B.; Chiong, M.A.D.; Abacan, M.A.R.; Reyes, M.E.L.; Jomento, C.M.; Dizon-Escoreal, M.T.T.; Canlas, M.A.E.; Abadingo, M.E.; et al. Successful Implementation of Expanded Newborn Screening in the Philippines Using Tandem Mass Spectrometry. Int. J. Neonatal Screen. 2022, 8, 8. [Google Scholar] [CrossRef] [PubMed]
  57. Mookken, T. Universal Implementation of Newborn Screening in India. Int. J. Neonatal Screen. 2020, 6, 24. [Google Scholar] [CrossRef] [PubMed][Green Version]
  58. Wang, L.-Y.; Chen, N.-I.; Chen, P.-W.; Chiang, S.-C.; Hwu, W.-L.; Lee, N.-C.; Chien, Y.-H. Newborn Screening for Citrin Deficiency and Carnitine Uptake Defect Using Second-Tier Molecular Tests. BMC Med. Genet. 2013, 14, 24. [Google Scholar] [CrossRef]
  59. Huang, X.; Wu, D.; Zhu, L.; Wang, W.; Yang, R.; Yang, J.; He, Q.; Zhu, B.; You, Y.; Xiao, R.; et al. Application of a Next-Generation Sequencing (NGS) Panel in Newborn Screening Efficiently Identifies Inborn Disorders of Neonates. Orphanet J. Rare Dis. 2022, 17, 66. [Google Scholar] [CrossRef] [PubMed]
  60. Lin, Y.; Zhang, W.; Huang, C.; Lin, C.; Lin, W.; Peng, W.; Fu, Q.; Chen, D. Increased Detection of Primary Carnitine Deficiency through Second-Tier Newborn Genetic Screening. Orphanet J. Rare Dis. 2021, 16, 149. [Google Scholar] [CrossRef]
  61. Volgina, S.Y.; Sokolov, A.A. An Analysis of Medical Care Services for Children With Rare Diseases in the Russian Federation. Front. Pharmacol. 2021, 12, 754073. [Google Scholar] [CrossRef]
  62. Frazier, D.M.; Millington, D.S.; McCandless, S.E.; Koeberl, D.D.; Weavil, S.D.; Chaing, S.H.; Muenzer, J. The Tandem Mass Spectrometry Newborn Screening Experience in North Carolina: 1997–2005. J. Inherit. Metab. Dis. 2006, 29, 76–85. [Google Scholar] [CrossRef]
  63. Therrell, B.L.; Lloyd-Puryear, M.A.; Camp, K.M.; Mann, M.Y. Inborn Errors of Metabolism Identified via Newborn Screening: Ten-Year Incidence Data and Costs of Nutritional Interventions for Research Agenda Planning. Mol. Genet. Metab. 2014, 113, 14–26. [Google Scholar] [CrossRef]
  64. Gallant, N.M.; Leydiker, K.; Wilnai, Y.; Lee, C.; Lorey, F.; Feuchtbaum, L.; Tang, H.; Carter, J.; Enns, G.M.; Packman, S.; et al. Biochemical Characteristics of Newborns with Carnitine Transporter Defect Identified by Newborn Screening in California. Mol. Genet. Metab. 2017, 122, 76–84. [Google Scholar] [CrossRef] [PubMed]
  65. La Marca, G.; Malvagia, S.; Casetta, B.; Pasquini, E.; Donati, M.A.; Zammarchi, E. Progress in Expanded Newborn Screening for Metabolic Conditions by LC-MS/MS in Tuscany: Update on Methods to Reduce False Tests. J. Inherit. Metab. Dis. 2008, 31, 395–404. [Google Scholar] [CrossRef] [PubMed]
  66. Vilarinho, L.; Rocha, H.; Sousa, C.; Marcão, A.; Fonseca, H.; Bogas, M.; Osório, R.V. Four Years of Expanded Newborn Screening in Portugal with Tandem Mass Spectrometry. J. Inherit. Metab. Dis. 2010, 33, 133–138. [Google Scholar] [CrossRef] [PubMed]
  67. Lund, A.M.; Hougaard, D.M.; Simonsen, H.; Andresen, B.S.; Christensen, M.; Dunø, M.; Skogstrand, K.; Olsen, R.K.J.; Jensen, U.G.; Cohen, A.; et al. Biochemical Screening of 504,049 Newborns in Denmark, the Faroe Islands and Greenland—Experience and Development of a Routine Program for Expanded Newborn Screening. Mol. Genet. Metab. 2012, 107, 281–293. [Google Scholar] [CrossRef] [PubMed]
  68. Kasper, D.C.; Ratschmann, R.; Metz, T.F.; Mechtler, T.P.; Möslinger, D.; Konstantopoulou, V.; Item, C.B.; Pollak, A.; Herkner, K.R. The National Austrian Newborn Screening Program–Eight Years Experience with Mass Spectrometry. Past, Present, and Future Goals. Wien. Klin. Wochenschr. 2010, 122, 607–613. [Google Scholar] [CrossRef] [PubMed]
  69. Loukas, Y.L.; Soumelas, G.-S.; Dotsikas, Y.; Georgiou, V.; Molou, E.; Thodi, G.; Boutsini, M.; Biti, S.; Papadopoulos, K. Expanded Newborn Screening in Greece: 30 Months of Experience. J. Inherit. Metab. Dis. 2010, 33, 341–348. [Google Scholar] [CrossRef]
  70. Lindner, M.; Gramer, G.; Haege, G.; Fang-Hoffmann, J.; Schwab, K.O.; Tacke, U.; Trefz, F.K.; Mengel, E.; Wendel, U.; Leichsenring, M.; et al. Efficacy and Outcome of Expanded Newborn Screening for Metabolic Diseases-Report of 10 Years from South-West Germany *. Orphanet J. Rare Dis. 2011, 6, 44. [Google Scholar] [CrossRef]
  71. Couce, M.L.; Castiñeiras, D.E.; Bóveda, M.D.; Baña, A.; Cocho, J.A.; Iglesias, A.J.; Colón, C.; Alonso-Fernández, J.R.; Fraga, J.M. Evaluation and Long-Term Follow-up of Infants with Inborn Errors of Metabolism Identified in an Expanded Screening Programme. Mol. Genet. Metab. 2011, 104, 470–475. [Google Scholar] [CrossRef]
  72. Smon, A.; Repic Lampret, B.; Groselj, U.; Zerjav Tansek, M.; Kovac, J.; Perko, D.; Bertok, S.; Battelino, T.; Trebusak Podkrajsek, K. Next Generation Sequencing as a Follow-up Test in an Expanded Newborn Screening Programme. Clin. Biochem. 2018, 52, 48–55. [Google Scholar] [CrossRef]
  73. Tangeraas, T.; Sæves, I.; Klingenberg, C.; Jørgensen, J.; Kristensen, E.; Gunnarsdottir, G.; Hansen, E.V.; Strand, J.; Lundman, E.; Ferdinandusse, S.; et al. Performance of Expanded Newborn Screening in Norway Supported by Post-Analytical Bioinformatics Tools and Rapid Second-Tier DNA Analyses. Int. J. Neonatal Screen. 2020, 6, 51. [Google Scholar] [CrossRef]
  74. Maguolo, A.; Rodella, G.; Dianin, A.; Nurti, R.; Monge, I.; Rigotti, E.; Cantalupo, G.; Salviati, L.; Tucci, S.; Pellegrini, F.; et al. Diagnosis, Genetic Characterization and Clinical Follow up of Mitochondrial Fatty Acid Oxidation Disorders in the New Era of Expanded Newborn Screening: A Single Centre Experience. Mol. Genet. Metab. Rep. 2020, 24, 100632. [Google Scholar] [CrossRef]
  75. Lund, A.; Wibrand, F.; Skogstrand, K.; Cohen, A.; Christensen, M.; Jäpelt, R.B.; Dunø, M.; Skovby, F.; Nørgaard-Pedersen, B.; Gregersen, N.; et al. Danish Expanded Newborn Screening Is a Successful Preventive Public Health Programme. Dan. Med. J. 2020, 67, A06190341. [Google Scholar]
  76. Messina, M.; Meli, C.; Raudino, F.; Pittalá, A.; Arena, A.; Barone, R.; Giuffrida, F.; Iacobacci, R.; Muccilli, V.; Sorge, G.; et al. Expanded Newborn Screening Using Tandem Mass Spectrometry: Seven Years of Experience in Eastern Sicily. Int. J. Neonatal Screen. 2018, 4, 12. [Google Scholar] [CrossRef] [PubMed]
  77. Sörensen, L.; von Döbeln, U.; Åhlman, H.; Ohlsson, A.; Engvall, M.; Naess, K.; Backman-Johansson, C.; Nordqvist, Y.; Wedell, A.; Zetterström, R.H. Expanded Screening of One Million Swedish Babies with R4S and CLIR for Post-Analytical Evaluation of Data. Int. J. Neonatal Screen. 2020, 6, 42. [Google Scholar] [CrossRef]
  78. Martín-Rivada, Á.; Palomino Pérez, L.; Ruiz-Sala, P.; Navarrete, R.; Cambra Conejero, A.; Quijada Fraile, P.; Moráis López, A.; Belanger-Quintana, A.; Martín-Hernández, E.; Bellusci, M.; et al. Diagnosis of Inborn Errors of Metabolism within the Expanded Newborn Screening in the Madrid Region. JIMD Rep. 2022, 63, 146–161. [Google Scholar] [CrossRef] [PubMed]
  79. Conejero, A.C.; Figueras, L.M.; Temprado, A.O.; Soto, P.B.; Martín, Á.; Pérez, L.P.; Villarroya, E.C.; Giner, C.P.; Fraile, P.Q.; Martín-Hernández, E.; et al. Análisis de Casos positivos de cribado neonatal de errores congénitos del metabolismo en la comunidad de madrid. Rev. Esp. Salud. Pública 2020, 94, 15. [Google Scholar]
  80. Schiergens, K.A.; Weiss, K.J.; Röschinger, W.; Lotz-Havla, A.S.; Schmitt, J.; Dalla Pozza, R.; Ulrich, S.; Odenwald, B.; Kreuder, J.; Maier, E.M. Newborn Screening for Carnitine Transporter Defect in Bavaria and the Long-Term Follow-up of the Identified Newborns and Mothers: Assessing the Benefit and Possible Harm Based on 19 ½ Years of Experience. Mol. Genet. Metab. Rep. 2021, 28, 100776. [Google Scholar] [CrossRef] [PubMed]
  81. Ruoppolo, M.; Malvagia, S.; Boenzi, S.; Carducci, C.; Dionisi-Vici, C.; Teofoli, F.; Burlina, A.; Angeloni, A.; Aronica, T.; Bordugo, A.; et al. Expanded Newborn Screening in Italy Using Tandem Mass Spectrometry: Two Years of National Experience. Int. J. Neonatal Screen. 2022, 8, 47. [Google Scholar] [CrossRef] [PubMed]
  82. Niu, D.-M.; Chien, Y.-H.; Chiang, C.-C.; Ho, H.-C.; Hwu, W.-L.; Kao, S.-M.; Chiang, S.-H.; Kao, C.-H.; Liu, T.-T.; Chiang, H.; et al. Nationwide Survey of Extended Newborn Screening by Tandem Mass Spectrometry in Taiwan. J. Inherit. Metab. Dis. 2010, 33, 295–305. [Google Scholar] [CrossRef]
  83. Lee, N.-C.; Tang, N.L.-S.; Chien, Y.-H.; Chen, C.-A.; Lin, S.-J.; Chiu, P.-C.; Huang, A.-C.; Hwu, W.-L. Diagnoses of Newborns and Mothers with Carnitine Uptake Defects through Newborn Screening. Mol. Genet. Metab. 2010, 100, 46–50. [Google Scholar] [CrossRef]
  84. Chien, Y.-H.; Lee, N.-C.; Chao, M.-C.; Chen, L.-C.; Chen, L.-H.; Chien, C.-C.; Ho, H.-C.; Suen, J.-H.; Hwu, W.-L. Fatty Acid Oxidation Disorders in a Chinese Population in Taiwan. In JIMD Reports-Volume 11; Zschocke, J., Gibson, K.M., Brown, G., Morava, E., Peters, V., Eds.; JIMD Reports; Springer: Berlin/Heidelberg, Germany, 2013; Volume 11, pp. 165–172. ISBN 978-3-642-37327-5. [Google Scholar]
  85. Lim, J.S.; Tan, E.S.; John, C.M.; Poh, S.; Yeo, S.J.; Ang, J.S.M.; Adakalaisamy, P.; Rozalli, R.A.; Hart, C.; Tan, E.T.H.; et al. Inborn Error of Metabolism (IEM) Screening in Singapore by Electrospray Ionization-Tandem Mass Spectrometry (ESI/MS/MS): An 8year Journey from Pilot to Current Program. Mol. Genet. Metab. 2014, 113, 53–61. [Google Scholar] [CrossRef] [PubMed]
  86. Sun, Y.; Wang, Y.-Y.; Jiang, T. Clinical Features and Genotyping of Patients with Primary Carnitine Deficiency Identified by Newborn Screening. J. Pediatr. Endocrinol. Metab. JPEM 2017, 30, 879–883. [Google Scholar] [CrossRef] [PubMed]
  87. Chong, S.C.; Law, L.K.; Hui, J.; Lai, C.Y.; Leung, T.Y.; Yuen, Y.P. Expanded Newborn Metabolic Screening Programme in Hong Kong: A Three-Year Journey. Hong Kong Med. J. 2017, 23, 489–496. [Google Scholar] [CrossRef] [PubMed]
  88. Zheng, J.; Zhang, Y.; Hong, F.; Yang, J.; Tong, F.; Mao, H.; Huang, X.; Zhou, X.; Yang, R.; Zhao, Z.; et al. Screening for fatty acid oxidation disorders of newborns in Zhejiang province:prevalence, outcome and follow-up. Zhejiang Xue Xue Bao Yi Xue Ban 2017, 46, 248–255. [Google Scholar]
  89. Guo, K.; Zhou, X.; Chen, X.; Wu, Y.; Liu, C.; Kong, Q. Expanded Newborn Screening for Inborn Errors of Metabolism and Genetic Characteristics in a Chinese Population. Front. Genet. 2018, 9, 122. [Google Scholar] [CrossRef] [PubMed]
  90. Shibata, N.; Hasegawa, Y.; Yamada, K.; Kobayashi, H.; Purevsuren, J.; Yang, Y.; Dung, V.C.; Khanh, N.N.; Verma, I.C.; Bijarnia-Mahay, S.; et al. Diversity in the Incidence and Spectrum of Organic Acidemias, Fatty Acid Oxidation Disorders, and Amino Acid Disorders in Asian Countries: Selective Screening vs. Expanded Newborn Screening. Mol. Genet. Metab. Rep. 2018, 16, 5–10. [Google Scholar] [CrossRef]
  91. Kang, E.; Kim, Y.-M.; Kang, M.; Heo, S.-H.; Kim, G.-H.; Choi, I.-H.; Choi, J.-H.; Yoo, H.-W.; Lee, B.H. Clinical and Genetic Characteristics of Patients with Fatty Acid Oxidation Disorders Identified by Newborn Screening. BMC Pediatr. 2018, 18, 103. [Google Scholar] [CrossRef][Green Version]
  92. Zhou, W.; Li, H.; Huang, T.; Zhang, Y.; Wang, C.; Gu, M. Biochemical, Molecular, and Clinical Characterization of Patients With Primary Carnitine Deficiency via Large-Scale Newborn Screening in Xuzhou Area. Front. Pediatr. 2019, 7, 50. [Google Scholar] [CrossRef]
  93. Wang, T.; Ma, J.; Zhang, Q.; Gao, A.; Wang, Q.; Li, H.; Xiang, J.; Wang, B. Expanded Newborn Screening for Inborn Errors of Metabolism by Tandem Mass Spectrometry in Suzhou, China: Disease Spectrum, Prevalence, Genetic Characteristics in a Chinese Population. Front. Genet. 2019, 10, 1052. [Google Scholar] [CrossRef]
  94. Yang, N.; Gong, L.-F.; Zhao, J.-Q.; Yang, H.-H.; Ma, Z.-J.; Liu, W.; Wan, Z.-H.; Kong, Y.-Y. Inborn Errors of Metabolism Detectable by Tandem Mass Spectrometry in Beijing. J. Pediatr. Endocrinol. Metab. JPEM 2020, 33, 639–645. [Google Scholar] [CrossRef]
  95. Lin, Y.; Xu, H.; Zhou, D.; Hu, Z.; Zhang, C.; Hu, L.; Zhang, Y.; Zhu, L.; Lu, B.; Zhang, T.; et al. Screening 3.4 Million Newborns for Primary Carnitine Deficiency in Zhejiang Province, China. Clin. Chim. Acta Int. J. Clin. Chem. 2020, 507, 199–204. [Google Scholar] [CrossRef]
  96. Wang, S.; Leng, J.; Diao, C.; Wang, Y.; Zheng, R. Genetic Characteristics and Follow-up of Patients with Fatty Acid β-Oxidation Disorders through Expanded Newborn Screening in a Northern Chinese Population. J. Pediatr. Endocrinol. Metab. JPEM 2020, 33, 683–690. [Google Scholar] [CrossRef] [PubMed]
  97. Huang, Y.L.; Tang, C.F.; Liu, S.C.; Sheng, H.Y.; Tang, F.; Jiang, X.; Zheng, R.D.; Mei, H.F.; Liu, L. Newborn screening for primary carnitine deficiency and variant spectrum of SLC22A5 gene in Guangzhou. Zhonghua Er Ke Za Zhi 2020, 58, 476–481. [Google Scholar] [CrossRef] [PubMed]
  98. Chen, Y.; Lin, Q.; Zeng, Y.; Qiu, X.; Liu, G.; Zhu, W. Gene Spectrum and Clinical Traits of 10 Patients with Primary Carnitine Deficiency. Mol. Genet. Genomic Med. 2021, 9, e1583. [Google Scholar] [CrossRef]
  99. Lin, Y.; Zheng, Q.; Zheng, T.; Zheng, Z.; Lin, W.; Fu, Q. Expanded Newborn Screening for Inherited Metabolic Disorders and Genetic Characteristics in a Southern Chinese Population. Clin. Chim. Acta Int. J. Clin. Chem. 2019, 494, 106–111. [Google Scholar] [CrossRef] [PubMed]
  100. Lin, W.; Wang, K.; Zheng, Z.; Chen, Y.; Fu, C.; Lin, Y.; Chen, D. Newborn Screening for Primary Carnitine Deficiency in Quanzhou, China. Clin. Chim. Acta Int. J. Clin. Chem. 2021, 512, 166–171. [Google Scholar] [CrossRef]
  101. Lin, Y.; Lin, B.; Chen, Y.; Zheng, Z.; Fu, Q.; Lin, W.; Zhang, W. Biochemical and Genetic Characteristics of Patients with Primary Carnitine Deficiency Identified through Newborn Screening. Orphanet J. Rare Dis. 2021, 16, 503. [Google Scholar] [CrossRef]
  102. Yang, X.; Li, Q.; Wang, F.; Yan, L.; Zhuang, D.; Qiu, H.; Li, H.; Chen, L. Newborn Screening and Genetic Analysis Identify Six Novel Genetic Variants for Primary Carnitine Deficiency in Ningbo Area, China. Front. Genet. 2021, 12, 686137. [Google Scholar] [CrossRef]
  103. Tan, J.; Chen, D.; Chang, R.; Pan, L.; Yang, J.; Yuan, D.; Huang, L.; Yan, T.; Ning, H.; Wei, J.; et al. Tandem Mass Spectrometry Screening for Inborn Errors of Metabolism in Newborns and High-Risk Infants in Southern China: Disease Spectrum and Genetic Characteristics in a Chinese Population. Front. Genet. 2021, 12, 631688. [Google Scholar] [CrossRef]
  104. Yang, C.; Shi, C.; Zhou, C.; Wan, Q.; Zhou, Y.; Chen, X.; Jin, X.; Huang, C.; Xu, P. Screening and Follow-up Results of Fatty Acid Oxidative Metabolism Disorders in 608 818 Newborns in Jining, Shandong Province. Zhejiang Xue Xue Bao Yi Xue Ban 2021, 50, 472–480. [Google Scholar] [CrossRef]
  105. Tang, C.; Tan, M.; Xie, T.; Tang, F.; Liu, S.; Wei, Q.; Liu, J.; Huang, Y. Screening for Neonatal Inherited Metabolic Disorders by Tandem Mass Spectrometry in Guangzhou. Zhejiang Xue Xue Bao Yi Xue Ban 2021, 50, 463–471. [Google Scholar] [CrossRef]
  106. Geng, G.; Yang, Q.; Fan, X.; Lin, C.; Wu, L.; Chen, S.; Luo, J. Analysis of metabolic profile and genetic variants for newborns with primary carnitine deficiency from Guangxi. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2021, 38, 1051–1054. [Google Scholar] [CrossRef] [PubMed]
  107. Li, X.; He, J.; He, L.; Zeng, Y.; Huang, X.; Luo, Y.; Li, Y. Spectrum Analysis of Inherited Metabolic Disorders for Expanded Newborn Screening in a Central Chinese Population. Front. Genet. 2021, 12, 763222. [Google Scholar] [CrossRef] [PubMed]
  108. Zhang, R.; Qiang, R.; Song, C.; Ma, X.; Zhang, Y.; Li, F.; Wang, R.; Yu, W.; Feng, M.; Yang, L.; et al. Spectrum Analysis of Inborn Errors of Metabolism for Expanded Newborn Screening in a Northwestern Chinese Population. Sci. Rep. 2021, 11, 2699. [Google Scholar] [CrossRef] [PubMed]
  109. Zhou, M.; Deng, L.; Huang, Y.; Xiao, Y.; Wen, J.; Liu, N.; Zeng, Y.; Zhang, H. Application of the Artificial Intelligence Algorithm Model for Screening of Inborn Errors of Metabolism. Front. Pediatr. 2022, 10, 855943. [Google Scholar] [CrossRef]
  110. Luo, X.; Sun, Y.; Xu, F.; Guo, J.; Li, L.; Lin, Z.; Ye, J.; Gu, X.; Yu, Y. A Pilot Study of Expanded Newborn Screening for 573 Genes Related to Severe Inherited Disorders in China: Results from 1,127 Newborns. Ann. Transl. Med. 2020, 8, 1058. [Google Scholar] [CrossRef]
  111. Frigeni, M.; Balakrishnan, B.; Yin, X.; Calderon, F.R.O.; Mao, R.; Pasquali, M.; Longo, N. Functional and Molecular Studies in Primary Carnitine Deficiency. Hum. Mutat. 2017, 38, 1684–1699. [Google Scholar] [CrossRef]
  112. El-Hattab, A.W.; Li, F.-Y.; Shen, J.; Powell, B.R.; Bawle, E.V.; Adams, D.J.; Wahl, E.; Kobori, J.A.; Graham, B.; Scaglia, F.; et al. Maternal Systemic Primary Carnitine Deficiency Uncovered by Newborn Screening: Clinical, Biochemical, and Molecular Aspects. Genet. Med. 2010, 12, 19–24. [Google Scholar] [CrossRef]
  113. Lin, H.J.; Neidich, J.A.; Salazar, D.; Thomas-Johnson, E.; Ferreira, B.F.; Kwong, A.M.; Lin, A.M.; Jonas, A.J.; Levine, S.; Lorey, F.; et al. Asymptomatic Maternal Combined Homocystinuria and Methylmalonic Aciduria (CblC) Detected through Low Carnitine Levels on Newborn Screening. J. Pediatr. 2009, 155, 924–927. [Google Scholar] [CrossRef]
  114. Holme, E.; Jodal, U.; Linstedt, S.; Nordin, I. Effects of Pivalic Acid-Containing Prodrugs on Carnitine Homeostasis and on Response to Fasting in Children. Scand. J. Clin. Lab. Investig. 1992, 52, 361–372. [Google Scholar] [CrossRef]
  115. Yamada, K.; Kobayashi, H.; Bo, R.; Takahashi, T.; Hasegawa, Y.; Nakamura, M.; Ishige, N.; Yamaguchi, S. Elevation of Pivaloylcarnitine by Sivelestat Sodium in Two Children. Mol. Genet. Metab. 2015, 116, 192–194. [Google Scholar] [CrossRef]
  116. Peng, G.; Tang, Y.; Cowan, T.M.; Zhao, H.; Scharfe, C. Timing of Newborn Blood Collection Alters Metabolic Disease Screening Performance. Front. Pediatr. 2020, 8, 623184. [Google Scholar] [CrossRef] [PubMed]
  117. He, F.; Yang, R.; Huang, X.; Tian, Y.; Pei, X.; Bohn, M.K.; Zou, L.; Wang, Y.; Li, H.; Wang, T.; et al. Reference Standards for Newborn Screening of Metabolic Disorders by Tandem Mass Spectrometry: A Nationwide Study on Millions of Chinese Neonatal Populations. Front. Mol. Biosci. 2021, 8, 719866. [Google Scholar] [CrossRef] [PubMed]
  118. Peng, G.; Tang, Y.; Gandotra, N.; Enns, G.M.; Cowan, T.M.; Zhao, H.; Scharfe, C. Ethnic Variability in Newborn Metabolic Screening Markers Associated with False-positive Outcomes. J. Inherit. Metab. Dis. 2020, 43, 934–943. [Google Scholar] [CrossRef] [PubMed][Green Version]
Figure 1. A world map of primary carnitine deficiency newborn screening programs, according to national NBS societies and the literature (created on, accessed on 27 October 2022).
Figure 1. A world map of primary carnitine deficiency newborn screening programs, according to national NBS societies and the literature (created on, accessed on 27 October 2022).
Ijns 09 00006 g001
Figure 2. The three-step screening algorithm for PCD as proposed by the CNCDN and G2M working group. Cut-offs are set for the method using underivatized-based sample preparation.
Figure 2. The three-step screening algorithm for PCD as proposed by the CNCDN and G2M working group. Cut-offs are set for the method using underivatized-based sample preparation.
Ijns 09 00006 g002
Table 1. Retrospective studies on PCD screening experience.
Table 1. Retrospective studies on PCD screening experience.
Survey Duration
Newborns ScreenedFirst Tier Test
C0 Threshold (µmol·L−1)
Number of Patients Diagnosed
Number of Maternal PCD IdentifiedFalse Positive Tests
Australia and New-Zealand
[18]New South Wales (Australia)1998–20001,490,000<10 (<5 *) 4
ND1017 (0.4%)
[24,25]New Zealand2006–2016~600,000<5/5 2 (1:300,000)973 (2.7%)
North America
[62]North Carolina (USA)1997–2005944,078<13 0 (<1:944,078) ND0
[63]USA 2001–201120,908,664ND 147 (1:142,236)
[64]California (USA)2005–20123,608,768<12 (derivatized) 48 screened (1:75,000)
21 confirmed (1:172,000)
61030 (4.7%)
<7 (underivatized)
[20]USA2015–201711,750,856ND 138 (1:85,151)
[65]Tuscany (Italy)2002–2004160,000<8 1
11 (50%)
[42]England2.5 years24,983<2
(Cord blood)
0 (<1:24,983)22
[38]Germany1998–2001250,000<10Sum of (C3–C18) < 5 µmol·L−11
ND86 (1.2%)
[66]Portugal4 years316,243<7 4
Faroe Islands
2002–2011504,049<5.7C5 < 0.43 µmol·L−1
AC/Cit < 3.0
5 (1:100,809)828 (15%)
[68]Austria2002–2009622,489ND 2 (1:311,245)NDND
[69]Greece2007–200945,000<6.25 0 (<1:45,000)NDND
[70]Germany1999–20091,084,195<10 3 (1:361,398)NDND
[71]Galicia (Spain)2000–2015210,165<9.5 1 (1:210,165)NDND
[72]Slovenia2013–201410,048<7.7AC/Cit < 1.90 (<1:10,048)NDND
[73]Norway2012–2020461,369<6C3 + C16 > 2 µmol·L−13 (1:153,790)222 (12%)
[74]Verona (Italy)2014–201986,320ND 3 (1:28,773)NDND
Faroe Islands
2002–2018967,780C0 < 5.7C5 < 0.43 µmol·L−1
Ac/Cit < 3.0
40 (1:24,195)
32 TP + 8 FN
19114 (21.9%)
[76]Sicilia2011–201760,408ND 0 (1:60,408)NDND
[77]Sweden2011–20191,000,000ND 13 (1:76,923)694 (12%)
[78,79]Madrid (Spain)2011–2019592,822C0 < ND
AC/Cit < ND
12 (1:49,402)ND73 (14%)
1999–20181,816,000<9 6 (1:302,667)12151 (3.8%)
[81]Italy2017–2020806,770NDTotal AC10 (1:80,677)20ND
(<2 *)Recall DBS5 confirmed
+2 unconfirmed
0111 (4.3%)
Recall DBS4 (1:67,000) 612 (25%)
[84]Taiwan2003–2012790,569<6.44 22 (1:35,934)12ND
[58]Taiwan6 months30,237<12 (<6.0 *) 1 (1:30,237)0209 (0.48%)
[85]Singapore2006–2014117,267<8C2 < 7 µmol·L−15 (1:35,453)520 (20%)
[86]Nanjing (China)2013–201662,568<10 7 (1:8,938)NDND
[87]Hong Kong2013–201630,448<6.4 0 (<1:30448)117
[88]Zhejiang (China)2009–20161,861,262ND 78 (1:23,350)NDND
[55]Thailand2014–201799,234ND 5 (1: 372,252)6ND
201548,287ND 5 (1:9,657)NDND
[90]Japan1997–20153,360,000ND 17 (1:199,000)NDND
Taiwan2001–20141,390,000 20 (1:70,000)
South Korea2000–20153,440,000 10 (1:345,000)
Germany2002–20157,510,000 30 (1:250,000)
(South Korea)
2002–2016ND<12 1 (ND)NDND
2015–2017236,368<9.63 (<5 *) 10 (1:23,637)6176 (5.4%)
2014–2018401,660<9.5 15 (1:26,777)NDND
2014–201958,651<10 1 (1:58,651)NDND
2009–20193,410,600<14 (derivatized) 113 (1:30,182)63ND
<10.28 (underivatized)
10 (1:22,044)NDND
[97]Guangzhou (China)2015–2019200,180<10C0 < 8.5 µmol·L−1
C0 [8.5–10] And
C3 + C16 < 2 µmol·L−1
15 (1:13,345)22239 (5.9%)
2015–202094,453<8.8 9 (1:10,495) 1ND
2014–2021548,247<8.5 49 (1:11,189)61665 (2.9%)
2014–2018265,524<9.5 16 (1:16,595)3 confirmed + 7 unconfirmed1669 (0.96%)
2012–2020111,986<9 12 (1:9,332) 2452 (0.49%)
2014–2019608,818<10 16 (1:38,051)NDND
2015–2020272,117<10(1) C0 < 8.5 µmol·L−1
(2) C0 [8.5–10] And
C3 + C16 < 2 µmol·L−1
21 (1:12,958)30(1) 314 (8.7%)
(2) 165 (15.3%)
2014–2018400,575ND 22 (1:18,208)9ND
2016–2020300,849<8.5 22 (13,675)NDND
2014–2019146,152<8.5 3 (1:48,717)2ND
[56]Philippines2005–2011111,127ND 0 (<1:111,127)NDND
[109]Shaoyang (Chine)2016–202094,648ND 5 (1:18,930)ND474 (1%)
*: Second threshold at retest in case of positivity (i.e., action cut-off); PPV%: Positive predictive value (%); ND: Not determined; ‡: Calculated by authors based on changes in protocol; p/sAC: plasma/serum acylcarnitines profile; AC/Cit: Acylcarnitines/Citrulline ratio; TP: True positive; FN: False negative; uC0: urinary free carnitine.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Lefèvre, C.R.; Labarthe, F.; Dufour, D.; Moreau, C.; Faoucher, M.; Rollier, P.; Arnoux, J.-B.; Tardieu, M.; Damaj, L.; Bendavid, C.; et al. Newborn Screening of Primary Carnitine Deficiency: An Overview of Worldwide Practices and Pitfalls to Define an Algorithm before Expansion of Newborn Screening in France. Int. J. Neonatal Screen. 2023, 9, 6.

AMA Style

Lefèvre CR, Labarthe F, Dufour D, Moreau C, Faoucher M, Rollier P, Arnoux J-B, Tardieu M, Damaj L, Bendavid C, et al. Newborn Screening of Primary Carnitine Deficiency: An Overview of Worldwide Practices and Pitfalls to Define an Algorithm before Expansion of Newborn Screening in France. International Journal of Neonatal Screening. 2023; 9(1):6.

Chicago/Turabian Style

Lefèvre, Charles R., François Labarthe, Diane Dufour, Caroline Moreau, Marie Faoucher, Paul Rollier, Jean-Baptiste Arnoux, Marine Tardieu, Léna Damaj, Claude Bendavid, and et al. 2023. "Newborn Screening of Primary Carnitine Deficiency: An Overview of Worldwide Practices and Pitfalls to Define an Algorithm before Expansion of Newborn Screening in France" International Journal of Neonatal Screening 9, no. 1: 6.

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop