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

2021 ◽  
Vol 16 (1) ◽  
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 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.

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

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.

scholarly journals Combined primary carnitine deficiency with neonatal intrahepatic cholestasis caused by citrin deficiency in a Chinese newborn

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Yiming Lin ◽  
Weihua Lin ◽  
Yanru Chen ◽  
Chunmei Lin ◽  
Zhenzhu Zheng ◽  
...  
Keyword(s):  
Intrahepatic Cholestasis ◽  
Autosomal Recessive ◽  
Metabolic Diseases ◽  
Autosomal Recessive Disorder ◽  
Carnitine Deficiency ◽  
Acid Oxidation ◽  
Dual Disorders ◽  
Expanded Newborn Screening ◽  
Primary Carnitine Deficiency ◽  
Citrin Deficiency

Abstract Background Primary carnitine deficiency (PCD) is an autosomal recessive disorder affecting the carnitine cycle and resulting in defective fatty acid oxidation. Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is an autosomal recessive disorder and one of the main causes of inherited neonatal cholestasis. Both PCD and NICCD are included in the current expanded newborn screening (NBS) targets. Case presentation Targeted exome sequencing was performed on a Chinese proband, and Sanger sequencing was utilised to validate the detected mutations. The patient who was initially suspected to have PCD based on the NBS results presented with neonatal intrahepatic cholestasis and ventricular septal defect. Further investigations not only confirmed PCD but also revealed the presence of NICCD. Four distinct mutations were detected, including c.51C > G (p.F17L) and c.760C > T (p.R254X) in SLC22A5 as well as c.615 + 5G > A and IVS16ins3kb in SLC25A13. Conclusions This is the first reported case of PCD and NICCD occurring in the same patient. The dual disorders in a newborn broaden our understanding of inherited metabolic diseases. Thus, this study highlighted the importance of further genetic testing in patients presenting with unusual metabolic screening findings.

scholarly journals Newborn Screening and Genetic Analysis Identify Six Novel Genetic Variants for Primary Carnitine Deficiency in Ningbo Area, China

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiangchun Yang ◽  
Qiong Li ◽  
Fei Wang ◽  
Lulu Yan ◽  
Danyan Zhuang ◽  
...  
Keyword(s):  
Newborn Screening ◽  
Dna Analysis ◽  
Autosomal Recessive Disorder ◽  
Carnitine Deficiency ◽  
Compound Heterozygous ◽  
Clinical Value ◽  
Birth Prevalence ◽  
Carnitine Transporter ◽  
Novel Variants ◽  
Primary Carnitine Deficiency

Primary carnitine deficiency (PCD) is an autosomal recessive disorder that could result in sudden death. It is caused by a defect in the carnitine transporter encoded by SLC22A5 (Solute Carrier Family 22 Member 5, MIM:603377). Currently, a number of variants in SLC22A5 have been identified, however, the PCD prevalence and its variants in Ningbo area are unclear. In this study, we screened 265,524 newborns by using tandem mass spectrometry. Variants in SLC22A5 were further detected by next-generation sequencing in individuals with abnormal free carnitine levels (C0). We identified 53 newborns with abnormal C0 levels and 26 with variants in SLC22A5. Among them, 16 with compound heterozygous or homozygous variants in SLC22A5 were diagnosed with PCD, suggesting the PCD birth prevalence in Ningbo city was 1/16,595. Moreover, the C0 level was significantly (P = 0.013) higher in PCD patients than in those with one variant. Besides, the c.1400C > G (p. S467C) and c.51C > G (p. F17L) variants were the most frequent and six novel variants are all predicted to be damaging. This study reports the largest PCD patients in Ningbo area by newborn screening and expands the variant spectrum of SLC22A5. Our findings demonstrate the clinical value of combining NBS program results with DNA analysis for the diagnosis of PCD.

scholarly journals Biochemical and molecular features of Chinese patients with glutaric acidemia type 1 detected through newborn screening

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Yiming Lin ◽  
Wenjun Wang ◽  
Chunmei Lin ◽  
Zhenzhu Zheng ◽  
Qingliu Fu ◽  
...  
Keyword(s):  
Newborn Screening ◽  
Organic Acid ◽  
Allelic Frequency ◽  
Carnitine Deficiency ◽  
Chinese Patients ◽  
Genetic Characteristics ◽  
Molecular Features ◽  
Panel Testing ◽  
Southern Chinese

Abstract Background Glutaric acidemia type 1 (GA1) is a treatable disorder affecting cerebral organic acid metabolism caused by a defective glutaryl-CoA dehydrogenase (GCDH) gene. GA1 diagnosis reports following newborn screening (NBS) are scarce in the Chinese population. This study aimed to assess the acylcarnitine profiles and genetic characteristics of patients with GA1 identified through NBS. Results From January 2014 to September 2020, 517,484 newborns were screened by tandem mass spectrometry, 102 newborns with elevated glutarylcarnitine (C5DC) levels were called back. Thirteen patients were diagnosed with GA1, including 11 neonatal GA1 and two maternal GA1 patients. The incidence of GA1 in the Quanzhou region was estimated at 1 in 47,044 newborns. The initial NBS results showed that all but one of the patients had moderate to markedly increased C5DC levels. Notably, one neonatal patient with low free carnitine (C0) level suggest primary carnitine deficiency (PCD) but was ultimately diagnosed as GA1. Nine neonatal GA1 patients underwent urinary organic acid analyses: eight had elevated GA and 3HGA levels, and one was reported to be within the normal range. Ten distinct GCDH variants were identified. Eight were previously reported, and two were newly identified. In silico prediction tools and protein modeling analyses suggested that the newly identified variants were potentially pathogenic. The most common variant was c.1244-2 A>C, which had an allelic frequency of 54.55% (12/22), followed by c.1261G>A (p.Ala421Thr) at 9.09% (2/22). Conclusions Neonatal GA1 patients with increased C5DC levels can be identified through NBS. Maternal GA1 patients can also be detected using NBS due to the low C0 levels in their infants. Few neonatal GA1 patients may have atypical acylcarnitine profiles that are easy to miss during NBS; therefore, multigene panel testing should be performed in newborns with low C0 levels. This study indicates that the GCDH variant spectra were heterogeneous in this southern Chinese cohort.

scholarly journals Allele frequency of variants reported to cause adenine phosphoribosyltransferase deficiency

2021 ◽  
Author(s):  
Hrafnhildur L. Runolfsdottir ◽  
John A. Sayer ◽  
Olafur S. Indridason ◽  
Vidar O. Edvardsson ◽  
Brynjar O. Jensson ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Autosomal Recessive Disorder ◽  
European Population ◽  
Adenine Phosphoribosyltransferase ◽  
Genomic Databases ◽  
Pathogenic Variants ◽  
Adenine Phosphoribosyltransferase Deficiency ◽  
Variation Database ◽  
The Uk ◽  
Aprt Deficiency

AbstractAdenine phosphoribosyltransferase deficiency is a rare, autosomal recessive disorder of purine metabolism that causes nephrolithiasis and progressive chronic kidney disease. The small number of reported cases indicates an extremely low prevalence, although it has been suggested that missed diagnoses may play a role. We assessed the prevalence of APRT deficiency based on the frequency of causally-related APRT sequence variants in a diverse set of large genomic databases. A thorough search was carried out for all APRT variants that have been confirmed as pathogenic under recessive mode of inheritance, and the frequency of the identified variants examined in six population genomic databases: the deCODE genetics database, the UK Biobank, the 100,000 Genomes Project, the Genome Aggregation Database, the Human Genetic Variation Database and the Korean Variant Archive. The estimated frequency of homozygous genotypes was calculated using the Hardy-Weinberg equation. Sixty-two pathogenic APRT variants were identified, including six novel variants. Most common were the missense variants c.407T>C (p.(Met136Thr)) in Japan and c.194A>T (p.(Asp65Val)) in Iceland, as well as the splice-site variant c.400 + 2dup (p.(Ala108Glufs*3)) in the European population. Twenty-nine variants were detected in at least one of the six genomic databases. The highest cumulative minor allele frequency (cMAF) of pathogenic variants outside of Japan and Iceland was observed in the Irish population (0.2%), though no APRT deficiency cases have been reported in Ireland. The large number of cases in Japan and Iceland is consistent with a founder effect in these populations. There is no evidence for widespread underdiagnosis based on the current analysis.

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

2009 ◽  
Vol 12 (1) ◽  
pp. 19-24 ◽  
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

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

2020 ◽  
Author(s):  
Sarah Catharina Grünert ◽  
Sara Tucci ◽  
Anke Schumann ◽  
Meike Schwendt ◽  
Gwendolyn Gramer ◽  
...  
Keyword(s):  
Pilot Study ◽  
Heart Transplantation ◽  
Newborn Screening ◽  
Cardiac Death ◽  
Clinical Symptoms ◽  
Carnitine Deficiency ◽  
Carnitine Supplementation ◽  
Expanded Newborn Screening ◽  
Patients At Risk ◽  
Primary Carnitine Deficiency

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.

scholarly journals Genetic Characteristics and Phenotype of Korean Patients with Stickler Syndrome: A Korean Multicenter Analysis Report No. 1

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1578
Author(s):  
Soon-Il Choi ◽  
Se-Joon Woo ◽  
Baek-Lok Oh ◽  
Jinu Han ◽  
Hyun-Taek Lim ◽  
...  
Keyword(s):  
Large Scale ◽  
Connective Tissue Disorder ◽  
Stickler Syndrome ◽  
Genetic Characteristics ◽  
Korean Patients ◽  
Missense Variants ◽  
Asian Patients ◽  
Pathogenic Variants ◽  
Splicing Variants ◽  
Multicenter Analysis

Stickler syndrome is an inherited connective tissue disorder of collagen. There are relatively few reports of East Asian patients, and no large-scale studies have been conducted in Korean patients yet. In this study, we retrospectively analyzed the genetic characteristics and clinical features of Korean Stickler syndrome patients. Among 37 genetically confirmed Stickler syndrome patients, 21 types of gene variants were identified, of which 12 were novel variants. A total of 30 people had variants in the COL2A1 gene and 7 had variants in the COL11A1 gene. Among the types of pathogenic variants, missense variants were found in 11, nonsense variants in 8, and splice site variants in 7. Splicing variants were frequently associated with retinal detachment (71%) followed by missense variants. This is the first large-scale study of Koreans with Stickler syndrome, which will expand the spectrum of genetic variations of Stickler syndrome.

scholarly journals Hypoketotic hypoglycemia in citrin deficiency: a case report

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Yoichi Wada ◽  
Natsuko Arai-Ichinoi ◽  
Atsuo Kikuchi ◽  
Osamu Sakamoto ◽  
Shigeo Kure
Keyword(s):  
Case Report ◽  
Fatty Acid ◽  
Large Scale ◽  
Ketone Bodies ◽  
Medium Chain Triglyceride ◽  
Severe Hypoglycemia ◽  
Acid Oxidation ◽  
Fatty Acid Oxidation Disorders ◽  
Pathogenic Variants ◽  
Citrin Deficiency

Abstract Background Citrin deficiency (CD) is a recessive metabolic disease caused by biallelic pathogenic variants in SLC25A13. Although previous studies have reported ketosis in CD, it was observed at the time of euglycemia or mild hypoglycemia. Blood ketone levels concomitant with symptomatic or severe hypoglycemia in CD have not been a topic of focus despite its importance in identifying the etiology of hypoglycemia and assessing the ability of fatty acid utilization. Herein, we describe a patient with CD who had repeated episodes of hypoglycemia with insufficient ketosis. Case presentation A 1-year-old boy with repetitive hypoglycemia was referred to us to investigate its etiology. The fasting load for 13 h led to hypoketotic hypoglycemia, indicating the possibility of partial β-oxidation dysfunction. A genetic test led to the diagnosis of CD. The hypoglycemic episodes disappeared after switching to a medium-chain triglyceride-containing formula. Conclusions This case report suggests that symptomatic or severe hypoglycemia in patients with CD could be associated with relatively low levels of ketone bodies, implying that β-oxidation in these patients might possibly be partially disrupted. When encountering a patient with hypoglycemia, clinicians should check blood ketone levels and bear in mind the possibility of CD because excessive intravenous administration of glucose can cause decompensated symptoms in patients with CD as opposed to other disorders presenting with hypoketotic hypoglycemia, such as fatty acid oxidation disorders. Further studies in a large-scale cohort are warranted to confirm our speculation.

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