Primary carnitine deficiency – diagnosis after heart transplantation: Better late than never!

Abstract Background Primary carnitine deficiency due to mutations in the OCTN2 gene is a rare but well-treatable metabolic disorder that puts patients at risk for metabolic decompensations, skeletal and cardiac myopathy and sudden cardiac death. Results We report on a 7-year-old boy diagnosed with primary carnitine deficiency 2 years after successful heart transplantation thanks his younger sister’s having been identified via expanded newborn screening during a pilot study evaluating an extension of the German newborn screening panel. Conclusion As L-carnitine supplementation can prevent and mostly reverse clinical symptoms of primary carnitine deficiency, all patients with cardiomyopathy should be investigated for primary carnitine deficiency even if newborn screening results were unremarkable.

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Expanded newborn screening identifies maternal primary carnitine deficiency

Molecular Genetics and Metabolism ◽

10.1016/j.ymgme.2006.10.003 ◽

2007 ◽

Vol 90 (4) ◽

pp. 441-445 ◽

Cited By ~ 62

Author(s):

Lisa A. Schimmenti ◽

Eric A. Crombez ◽

Bernd C. Schwahn ◽

Bryce A. Heese ◽

Timothy C. Wood ◽

...

Keyword(s):

Newborn Screening ◽

Carnitine Deficiency ◽

Expanded Newborn Screening ◽

Primary Carnitine Deficiency

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Primary Carnitine Deficiency and Newborn Screening for Disorders of the Carnitine Cycle

Annals of Nutrition and Metabolism ◽

10.1159/000448321 ◽

2016 ◽

Vol 68 (Suppl. 3) ◽

pp. 5-9 ◽

Cited By ~ 25

Author(s):

Nicola Longo

Keyword(s):

Newborn Screening ◽

Carnitine Deficiency ◽

The Body ◽

Molecular Testing ◽

Inner Mitochondrial Membrane ◽

Inborn Errors ◽

Irreversible Damage ◽

Carnitine Transport ◽

Patients At Risk ◽

Primary Carnitine Deficiency

Carnitine is needed for transfer of long-chain fatty acids across the inner mitochondrial membrane for subsequent β-oxidation. Carnitine can be synthesized by the body and is also obtained in the diet through consumption of meat and dairy products. Defects in carnitine transport such as those caused by defective activity of the OCTN2 transporter encoded by the SLC22A5 gene result in primary carnitine deficiency, and newborn screening programmes can identify patients at risk for this condition before irreversible damage. Initial biochemical diagnosis can be confirmed through molecular testing, although direct study of carnitine transport in fibroblasts is very useful to confirm or exclude primary carnitine deficiency in individuals with genetic variations of unknown clinical significance or who continue to have low levels of carnitine despite negative molecular analyses. Genetic defects in carnitine biosynthesis do not generally result in low plasma levels of carnitine. However, deletion of the trimethyllysine hydroxylase gene, a key gene in carnitine biosynthesis, has been associated with non-dysmorphic autism. Thus, new roles for carnitine are emerging that are unrelated to classic inborn errors of metabolism.

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The first territory-wide expanded newborn screening for inborn errors of metabolism in Hong Kong: a pilot study

Pathology ◽

10.1016/j.pathol.2016.12.280 ◽

2017 ◽

Vol 49 ◽

pp. S98 ◽

Cited By ~ 1

Author(s):

Ching-wan Lam ◽

Chun-yiu Law ◽

Chloe Miu Mak ◽

Wai-kwan Siu ◽

Hencher Han-Chih Lee ◽

...

Keyword(s):

Hong Kong ◽

Pilot Study ◽

Newborn Screening ◽

Inborn Errors Of Metabolism ◽

Inborn Errors ◽

Expanded Newborn Screening

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Maternal systemic primary carnitine deficiency uncovered by newborn screening: Clinical, biochemical, and molecular aspects

Genetics in Medicine ◽

10.1097/gim.0b013e3181c5e6f7 ◽

2009 ◽

Vol 12 (1) ◽

pp. 19-24 ◽

Cited By ~ 62

Author(s):

Ayman W El-Hattab ◽

Fang-Yuan Li ◽

Joseph Shen ◽

Berkley R Powell ◽

Erawati V Bawle ◽

...

Keyword(s):

Newborn Screening ◽

Carnitine Deficiency ◽

Primary Carnitine Deficiency ◽

Molecular Aspects

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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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Biochemical And Genetic Characteristics of Patients With Primary Carnitine Deficiency Identified Through Newborn Screening

10.21203/rs.3.rs-948430/v1 ◽

2021 ◽

Author(s):

Yiming Lin ◽

Bangbang Lin ◽

Yanru Chen ◽

Zhenzhu Zheng ◽

Qingliu Fu ◽

...

Keyword(s):

Newborn Screening ◽

Allele Frequency ◽

Large Scale ◽

Autosomal Recessive Disorder ◽

Carnitine Deficiency ◽

Acid Oxidation ◽

Genetic Characteristics ◽

Pathogenic Variants ◽

Southern Chinese ◽

Primary Carnitine Deficiency

Abstract Background: Primary carnitine deficiency (PCD) is an autosomal recessive disorder of the 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 by NBS.Results: A total of 548,247 newborns were screened for PCD between January 2014 and June 2021, 1714 newborns had low free carnitine (C0) levels were called back and forty-nine 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 all patients had varying degrees of decreased C0 levels, while seven patients exhibited normal C0 levels during recall review. All patients harbored biallelic pathogenic variants in the SLC22A5 gene. Nineteen distinct SLC22A5 variants were detected in the 49 patients, most of the detected variants were clustered in exons 1, 4, and 7. The top eight variants together 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 N/N genotype was significantly lower than that of M/M group. The C0 level of patients with genotypes of R254*/R254* and R254*/F17L were far lower than patients with genotype of R254*/S467C.Conclusions: This study presented more than 500,000 NBS data with the latest incidence of 1:11,189 in Quanzhou area. The SLC22A5 variant spectrum in the selected southern Chinese population was updated. Patients with null variants were associated with low C0 levels. It is necessary to combine genetic testing to improve screening efficiency due to PCD patients may have normal C0 levels during NBS and recall review.

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The first pilot study of expanded newborn screening for inborn errors of metabolism and survey of related knowledge and opinions of health care professionals in Hong Kong

Hong Kong Medical Journal ◽

10.12809/hkmj176939 ◽

2018 ◽

pp. 226-237 ◽

Cited By ~ 1

Author(s):

Chloe M Mak ◽

◽

Eric CY Law ◽

Hencher HC Lee ◽

WK Siu ◽

...

Keyword(s):

Health Care ◽

Hong Kong ◽

Pilot Study ◽

Newborn Screening ◽

Health Care Professionals ◽

Inborn Errors Of Metabolism ◽

Inborn Errors ◽

Expanded Newborn Screening

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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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