A mutation creating an upstream translation initiation codon in
            <i>SLC22A5</i>
            5′UTR is a frequent cause of primary carnitine deficiency

Ferdinandusse, Sacha; Brinke, Heleen te; Ruiter, J. P. N.; Haasjes, Janet; Oostheim, W.; Lenthe, Henk van; IJlst, Lodewijk; Ebberink, Merel S.; Wanders, Ronald J. A.; Vaz, Frédéric M.; Waterham, Hans R.

doi:10.1002/humu.23839

Cited by 25 publications

(17 citation statements)

References 19 publications

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“…Therefore, genetic testing is mainly used for diagnostic confirmation. However, it is noteworthy that some disease-causing pathogenic variants can escape detection because the genetic diagnostic yield for PCD has been relatively low [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Biochemical and genetic characteristics of patients with primary carnitine deficiency identified through newborn screening

Lin¹,

Lin²,

Chen³

et al. 2021

Orphanet J Rare Dis

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Background Primary carnitine deficiency (PCD) is an autosomal recessive disorder of carnitine transportation that leads to impaired fatty acid oxidation. Large-scale studies on newborn screening (NBS) for PCD are limited. This study aimed to investigate the biochemical and genetic characteristics of patients with PCD detected through NBS. Results A total of 548 247 newborns were screened for PCD between January 2014 and June 2021; 1714 newborns with low free carnitine (C0) levels were called back and 49 patients were diagnosed with PCD. The latest incidence rate in Quanzhou, China, was estimated to be 1 in 11 189 newborns. NBS results showed that the 49 patients had varying degrees of decreased C0 levels, whereas seven patients exhibited normal C0 levels during the recall review. All patients harbored biallelic pathogenic variants of the SLC22A5 gene. Nineteen distinct SLC22A5 variants were detected in these 49 patients, and most of the detected variants were clustered in exons 1, 4, and 7. The top eight variants had an allele frequency of 86.73%. The most common variant was c.760C > T (p.R254*) with an allele frequency of 31.63%, followed by c.51C > G (p.F17L) (17.35%) and c.1400C > G (p.S467C) (16.33%). The C0 level of patients with the N/N genotype was significantly lower than that of the M/M group. The C0 levels of patients with genotypes of R254*/R254* and R254*/F17L were far lower than those of patients with the R254*/S467C genotype. Conclusions This study presented more than 500,000 NBS data with the latest incidence of 1:11 189 in the Quanzhou area. The SLC22A5 variant spectrum in the selected southern Chinese population has been updated. Patients with null variants were associated with low C0 levels. Combining NBS with genetic testing is critical to improve screening efficiency because patients with PCD may have normal C0 levels during NBS and recall review.

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Section: Introductionmentioning

confidence: 99%

Biochemical and genetic characteristics of patients with primary carnitine deficiency identified through newborn screening

Lin¹,

Lin²,

Chen³

et al. 2021

Orphanet J Rare Dis

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“…In Norway, the introduction of second-tier molecular analysis has reduced both the number of CTD FPs and the detection of maternal CTD cases. Disease-causing variants can occur outside the coding regions, such as in deep intronic variants and promoter and intergenic variants, which are not studied by conventional DNA sequencing [ 26 , 27 ], so confirmatory molecular testing, commonly restricted to exonic regions, has its limitations. Technical and bioinformatic limitations can often make it difficult to detect copy number variants and other structural variants.…”

Section: Discussionmentioning

confidence: 99%

Performance of Expanded Newborn Screening in Norway Supported by Post-Analytical Bioinformatics Tools and Rapid Second-Tier DNA Analyses

Tangeraas

Sæves

Klingenberg

et al. 2020

IJNS

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In 2012, the Norwegian newborn screening program (NBS) was expanded (eNBS) from screening for two diseases to that for 23 diseases (20 inborn errors of metabolism, IEMs) and again in 2018, to include a total of 25 conditions (21 IEMs). Between 1 March 2012 and 29 February 2020, 461,369 newborns were screened for 20 IEMs in addition to phenylketonuria (PKU). Excluding PKU, there were 75 true-positive (TP) (1:6151) and 107 (1:4311) false-positive IEM cases. Twenty-one percent of the TP cases were symptomatic at the time of the NBS results, but in two-thirds, the screening result directed the exact diagnosis. Eighty-two percent of the TP cases had good health outcomes, evaluated in 2020. The yearly positive predictive value was increased from 26% to 54% by the use of the Region 4 Stork post-analytical interpretive tool (R4S)/Collaborative Laboratory Integrated Reports 2.0 (CLIR), second-tier biochemical testing and genetic confirmation using DNA extracted from the original dried blood spots. The incidence of IEMs increased by 46% after eNBS was introduced, predominantly due to the finding of attenuated phenotypes. The next step is defining which newborns would truly benefit from screening at the milder end of the disease spectrum. This will require coordinated international collaboration, including proper case definitions and outcome studies.

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“…Diagnosis will be confirmed using fibroblast or leukocyte culture [ 37 , 38 , 39 ], where defects in the plasma membrane of the carnitine transporter can be demonstrated, and/or by a genetic study. The clinical and biochemical response to carnitine treatment is significant, restoring the serum levels of carnitine to almost normal levels, along with the formation of hepatic ketogenesis and improved clinical signs of myopathy and cardiomyopathy [ 40 ], despite not restoring carnitine levels at the muscular or cardiac level.…”

Section: Study Of Metabolites In the Diagnosis Of Fatty Acid Oxidation Defectsmentioning

confidence: 99%

Biochemical Markers for the Diagnosis of Mitochondrial Fatty Acid Oxidation Diseases

Ruíz-Sala

Quintana

2021

JCM

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Mitochondrial fatty acid β-oxidation (FAO) contributes a large proportion to the body’s energy needs in fasting and in situations of metabolic stress. Most tissues use energy from fatty acids, particularly the heart, skeletal muscle and the liver. In the brain, ketone bodies formed from FAO in the liver are used as the main source of energy. The mitochondrial fatty acid oxidation disorders (FAODs), which include the carnitine system defects, constitute a group of diseases with several types and subtypes and with variable clinical spectrum and prognosis, from paucisymptomatic cases to more severe affectations, with a 5% rate of sudden death in childhood, and with fasting hypoketotic hypoglycemia frequently occurring. The implementation of newborn screening programs has resulted in new challenges in diagnosis, with the detection of new phenotypes as well as carriers and false positive cases. In this article, a review of the biochemical markers used for the diagnosis of FAODs is presented. The analysis of acylcarnitines by MS/MS contributes to improving the biochemical diagnosis, both in affected patients and in newborn screening, but acylglycines, organic acids, and other metabolites are also reported. Moreover, this review recommends caution, and outlines the differences in the interpretation of the biomarkers depending on age, clinical situation and types of samples or techniques.

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A mutation creating an upstream translation initiation codon in SLC22A5 5′UTR is a frequent cause of primary carnitine deficiency

Cited by 25 publications

References 19 publications

Biochemical and genetic characteristics of patients with primary carnitine deficiency identified through newborn screening

Biochemical and genetic characteristics of patients with primary carnitine deficiency identified through newborn screening

Performance of Expanded Newborn Screening in Norway Supported by Post-Analytical Bioinformatics Tools and Rapid Second-Tier DNA Analyses

Biochemical Markers for the Diagnosis of Mitochondrial Fatty Acid Oxidation Diseases

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