Very Long-Chain Acyl-CoA Dehydrogenase Deficiency: High Incidence of Detected Patients With Expanded Newborn Screening Program

Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a rare autosomal recessive disorder of fatty acid metabolism with a variable presentation. The aim of this study was to describe five patients with VLCADD diagnosed through the pilot study and expanded newborn screening (NBS) program that started in 2018 in Slovenia. Four patients were diagnosed through the expanded NBS program with tandem mass spectrometry; one patient was previously diagnosed in a pilot study preceding the NBS implementation. Confirmatory testing consisted of acylcarnitines analysis in dried blood spots, organic acids profiling in urine, genetic analysis of ACADVL gene, and enzyme activity determination in lymphocytes or fibroblasts. Four newborns with specific elevation of acylcarnitines diagnostic for VLCADD and disease-specific acylcarnitines ratios (C14:1, C14, C14:2, C14:1/C2, C14:1/C16) were confirmed with genetic testing: all were compound heterozygotes, two of them had one previously unreported ACDVL gene variant each (NM_000018.3) c.1538C > G; (NP_000009) p.(Ala513Gly) and c.661A > G; p.(Ser221Gly), respectively. In addition, one patient diagnosed in the pilot study also had a specific elevation of acylcarnitines. Subsequent ACDVL genetic analysis confirmed compound heterozygosity. In agreement with the diagnosis, enzyme activity was reduced in five patients tested. In seven other newborns with positive screening results, only single allele variants were found in the ACDVL gene, so the diagnosis was not confirmed. Among these, two variants were novel, c.416T > C and c.1046C > A, respectively (p.Leu139Pro and p.Ala349Glu). In the first 2 years of the expanded NBS program in Slovenia altogether 30,000 newborns were screened. We diagnosed four cases of VLCADD. The estimated VLCADD incidence was 1:7,500 which was much higher than that of the medium-chain acyl-CoA dehydrogenase deficiency (MCADD) cases in the same period. Our study also provided one of the first descriptions of ACADVL variants in Central-Southeastern Europe and reported on 4 novel variants.

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Very long‐chain acyl‐CoA dehydrogenase deficiency in a Swedish cohort: Clinical symptoms, newborn screening, enzyme activity, and genetics

JIMD Reports ◽

10.1002/jmd2.12268 ◽

2022 ◽

Author(s):

David Olsson ◽

Michela Barbaro ◽

Charlotte Haglind ◽

Maria Halldin ◽

Svetlana Lajic ◽

...

Keyword(s):

Enzyme Activity ◽

Newborn Screening ◽

Dehydrogenase Deficiency ◽

Clinical Symptoms ◽

Chain Acyl ◽

Swedish Cohort ◽

Long Chain

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

International Journal of Neonatal Screening ◽

10.3390/ijns6030051 ◽

2020 ◽

Vol 6 (3) ◽

pp. 51 ◽

Cited By ~ 1

Author(s):

Trine Tangeraas ◽

Ingjerd Sæves ◽

Claus Klingenberg ◽

Jens Jørgensen ◽

Erle Kristensen ◽

...

Keyword(s):

Newborn Screening ◽

Screening Program ◽

Good Health ◽

Dried Blood Spots ◽

Case Definitions ◽

Inborn Errors ◽

Disease Spectrum ◽

Expanded Newborn Screening ◽

Second Tier ◽

Biochemical Testing

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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The natural history of elevated tetradecenoyl-L-carnitine detected by newborn screening in New Zealand: implications for very long chain acyl-CoA dehydrogenase deficiency screening and treatment

Journal of Inherited Metabolic Disease ◽

10.1007/s10545-015-9911-z ◽

2016 ◽

Vol 39 (3) ◽

pp. 409-414 ◽

Cited By ~ 8

Author(s):

Bryony Ryder ◽

Detlef Knoll ◽

Donald R. Love ◽

Phillip Shepherd ◽

Jennifer M. Love ◽

...

Keyword(s):

New Zealand ◽

Natural History ◽

Newborn Screening ◽

Dehydrogenase Deficiency ◽

Chain Acyl ◽

History Of ◽

Deficiency Screening ◽

Long Chain

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Pilot study of expanded newborn screening for 573 genes related to severe diseases in China: results from 1173 newborns

10.21203/rs.2.13332/v3 ◽

2019 ◽

Author(s):

Xiaomei Luo ◽

Yu Sun ◽

Feng Xu ◽

Jun Guo ◽

Lin Li ◽

...

Keyword(s):

Pilot Study ◽

Genetic Analysis ◽

Newborn Screening ◽

Genetic Variants ◽

Metabolic Diseases ◽

False Negative ◽

Dried Blood Spots ◽

Carnitine Deficiency ◽

Chinese Patients ◽

Inherited Metabolic Diseases

Abstract Background: Current newborn screening (NBS) in China is mainly aimed at detecting biochemical levels of metabolites in the blood, which may generate false positive/negative results. To explore whether next-generation sequencing (NGS) for dried blood spots can increase the detecting rate of genetic disorders, we carried out a pilot study using NGS in 1,173 newborns who had been tested by traditional NBS. With a focus on inherited metabolic diseases (IMDs), our team investigated the current frequencies of genes related to common inherited metabolic diseases in this cohort. Methods: We designed an NGS panel of 573 genes related to severe diseases and performed NBS in 1,173 individuals who had been screened by tandem mass spectrometry (MS/MS) as well as for phenylalanine (Phe), thyroid-stimulating hormone (TSH), 17-α-hydroxyprogesterone (17-OHP), and glucose-6-phosphate dehydrogenase (G6PD) abnormalities in a traditional biochemical NBS conducted in September 2016. We compared the biochemical results to the genetic variants and investigated the carrier frequencies of 77 genes related to disorders by MS/MS in these newborns.Results: The biochemical results showed that four newborns (all male) were positive for G6PD by enzymatic assay, while the other biochemical findings including MS/MS, Phe, TSH and 17-OHP were negative. Genetic analysis results revealed that all the four newborns with positive G6PD values harbored hemizygous G6PD mutations. The NGS results also revealed an individual (ID 84123) carrying two SLC22A5 mutations (c.760C>T/p.R254* and c.1400C>G/p.S467C) common in Chinese patients with carnitine deficiency, which were later verified to be in trans, who was biochemically negative in 2016. The MS/MS results in 2019 showed free carnitine deficiency, consistent with the genetic analysis findings. The top five genes with the highest carrier frequencies in these newborns were PAH (1.77%), ETFDH (1.24%), MMACHC (1.15%), SLC25A13 (0.98%), and GCDH (0.80%). Conclusions: Our study provided data combing biochemical results with genetic variants in 1,173 newborns and confirmed a primary carnitine deficiency patient with false-negative biochemical results. This is also the first study to report the carrier frequencies of 77 IMD-causing genes in China.

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Pilot study of expanded newborn screening for 573 genes related to severe diseases in China: results from 1173 newborns

10.21203/rs.2.13332/v2 ◽

2019 ◽

Author(s):

Xiaomei Luo ◽

Yu Sun ◽

Feng Xu ◽

Jun Guo ◽

Lin Li ◽

...

Keyword(s):

Pilot Study ◽

Genetic Analysis ◽

Newborn Screening ◽

Genetic Variants ◽

Metabolic Diseases ◽

False Negative ◽

Dried Blood Spots ◽

Carnitine Deficiency ◽

Chinese Patients ◽

Inherited Metabolic Diseases

Abstract Background: Current newborn screening (NBS) in China is mainly aimed at detecting biochemical levels of metabolites in the blood, which may generate false positive/negative results. To explore whether next-generation sequencing (NGS) for dried blood spots can increase the detecting rate, we carried out a pilot study using NGS in 1,173 newborns who had been tested by traditional NBS. With a focus on inherited metabolic diseases (IMDs), our team investigated the current frequencies of genes related to common inherited metabolic diseases in this cohort. Methods: We designed an NGS panel of 573 genes related to severe diseases and performed NBS in 1,173 individuals who had been screened by tandem mass spectrometry (MS/MS) as well as for phenylalanine (Phe), thyroid-stimulating hormone (TSH), 17-α-hydroxyprogesterone (17-OHP), and glucose-6-phosphate dehydrogenase (G6PD) abnormalities in a traditional biochemical NBS conducted in September 2016. We compared the biochemical results to the genetic variants and investigated the carrier frequencies of 77 genes related to disorders by MS/MS in these newborns.Results: The biochemical results showed that four newborns (all male) were positive for G6PD by enzymatic assay, while the other biochemical findings including MS/MS, Phe, TSH and 17-OHP were negative. Genetic analysis results revealed that all the four newborns with positive G6PD values harbored hemizygous G6PD mutations. The NGS results also revealed an individual (ID 84123) carrying two SLC22A5 mutations (c.760C>T/p.R254* and c.1400C>G/p.S467C) common in Chinese patients with carnitine deficiency, which were later verified to be in trans, who was biochemically negative in 2016. The MS/MS results in 2019 showed free carnitine deficiency, consistent with the genetic analysis findings. The top five genes with the highest carrier frequencies in these newborns were PAH (1.77%), ETFDH (1.24%), MMACHC (1.15%), SLC25A13 (0.98%), and GCDH (0.80%). Conclusions: Our study provided data combing biochemical results with genetic variants in 1,173 newborns and confirmed a primary carnitine deficiency patient with false-negative biochemical results. This is also the first study to report the carrier frequencies of 77 IMD-causing genes in China.

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