Newborn screening for primary carnitine deficiency in Quanzhou, China

Lin, Weihua; Wang, Kunyi; Zheng, Zhiyong; Chen, Yanru; Fu, Caifeng; Lin, Yiming; Chen, Dongmei

doi:10.1016/j.cca.2020.11.005

Cited by 9 publications

(6 citation statements)

References 29 publications

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“…Of the symptomatic maternal cases (17/102; 16.7%), nine experienced exclusively pregnancy‐related/nonspecific symptoms (see Table 2) and eight patients developed the following symptoms: VF and hypotonia ( N = 1; 1.0%), sus‐VT ( N = 1; 1.0%), cardiomyopathy with cardiac dilation ( N = 1; 1.0%), hepatic steatosis with hypoglycemia ( N = 1; 1.0%), muscle weakness ( N = 3; 3.9%), and fasting intolerance ( N = 1; 1.0%). The signs and symptoms in NBS patients (25/249; 10.0%) were, respectively: nonspecific ( N = 11), cardiac involvement ( N = 4; atrial/ventricular septal defect and/or mitral valve insufficiency), metabolic signs ( N = 1; metabolic decompensation), metabolic signs and neurological symptoms ( N = 3; hypoglycemia and coma/convulsions), hepatic symptoms ( N = 1; elevated alanine aminotransferase (ALAT)), muscle symptoms ( N = 2; mild muscle weakness, elevated creatine kinase), and death ( N = 3) 6,27‐32 . In patients identified through high‐risk screening, the majority of individuals did not experience any (PCD‐related) symptoms (30.3% asymptomatic and 44.0% only nonspecific symptoms).…”

Section: Resultsmentioning

confidence: 99%

“…The signs and symptoms in NBS patients (25/249; 10.0%) were, respectively: nonspecific ( N = 11), cardiac involvement ( N = 4; atrial/ventricular septal defect and/or mitral valve insufficiency), metabolic signs ( N = 1; metabolic decompensation), metabolic signs and neurological symptoms ( N = 3; hypoglycemia and coma/convulsions), hepatic symptoms ( N = 1; elevated alanine aminotransferase (ALAT)), muscle symptoms ( N = 2; mild muscle weakness, elevated creatine kinase), and death ( N = 3). 6 , 27 , 28 , 29 , 30 , 31 , 32 In patients identified through high‐risk screening, the majority of individuals did not experience any (PCD‐related) symptoms (30.3% asymptomatic and 44.0% only nonspecific symptoms). But the prevalence of severe symptoms (cardiomyopathy, cardiac events, and sudden death) was higher in this group than in patients identified through newborn screening (NBS and maternal cases).…”

Section: Resultsmentioning

confidence: 99%

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Clinical characteristics of primary carnitine deficiency: A structured review using a case‐by‐case approach

Crefcoeur

Visser

Ferdinandusse

et al. 2022

J of Inher Metab Disea

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A broad spectrum of signs and symptoms has been attributed to primary carnitine deficiency (PCD) since its first description in 1973. Advances in diagnostic procedures have improved diagnostic accuracy and the introduction of PCD in newborn screening (NBS) programs has led to the identification of an increasing number of PCD patients, including mothers of screened newborns, who may show a different phenotype compared to clinically diagnosed patients. To elucidate the spectrum of signs and symptoms in PCD patients, we performed a structured literature review. Using a case‐by‐case approach, clinical characteristics, diagnostic data, and mode of patient identification were recorded. Signs and symptoms were categorized by organ involvement. In total, 166 articles were included, reporting data on 757 individual patients. In almost 20% (N = 136) of the cases, the diagnosis was based solely on low carnitine concentration which we considered an uncertain diagnosis of PCD. The remaining 621 cases had a diagnosis based on genetic and/or functional (ie, carnitine transporter activity) test results. In these 621 cases, cardiac symptoms (predominantly cardiomyopathy) were the most prevalent (23.8%). Neurological (7.1%), hepatic (8.4%), and metabolic (9.2%) symptoms occurred mainly in early childhood. Adult onset of symptoms occurred in 16 of 194 adult patients, of whom 6 (3.1%) patients suffered a severe event without any preceding symptom (five cardiac events and one coma). In conclusion, symptoms in PCD predominantly develop in early childhood. Most newborns and mothers of newborns detected through NBS remain asymptomatic. However, though rarely, severe complications do occur in both groups.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Clinical characteristics of primary carnitine deficiency: A structured review using a case‐by‐case approach

Crefcoeur

Visser

Ferdinandusse

et al. 2022

J of Inher Metab Disea

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“…Thirteen distinct SLC22A5 variants were identified, seven of which were included in the designed panel, one previously reported mutation, c.845G > A, was not included in the designed panel, and the remaining five were newly identified pathogenic variants that were recently reported by our team [20].The most common mutation was c.760C > T, with an allelic frequency of 32% (16/50), followed by c.1400C > G (7/50, 14%), and c.51C > G (7/50, 14%). Four other mutations, c.695C > T, c.1139C > T, c.338G > A, and c.797C > T were also relatively common mutations.…”

Section: Newborn Genetic Screening and Diagnosismentioning

confidence: 99%

Increased detection of primary carnitine deficiency through second-tier newborn genetic screening

Lin¹,

Zhang²,

Huang³

et al. 2021

Orphanet J Rare Dis

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Background Newborn screening for primary carnitine deficiency (NBS) is commonly implemented worldwide; however, it has poor sensitivity. This study aimed to evaluate the feasibility of improving screening by including a second-tier genetic assay. Results An Agena iPLEX assay was developed to identify 17 common SLC22A5 mutations in Chinese populations and was applied in NBS as a second-tier screening. From January 2017 to December 2018, 204,777 newborns were screened for PCD using tandem mass spectrometry. A total of 316 (0.15%) residual NBS-positive specimens with low free carnitine (C0) levels were subjected to this second-tier screening. The screening identified 20 screen-positive newborns who harboured biallelic mutations in theSLC22A5 gene, 99 carriers with one mutation, and 197 screen-negative newborns with no mutations. Among the 99 carriers, four newborns were found to have a second disease-causing SLC22A5mutation by further genetic analysis. Among the 197 screen-negatives were four newborns with persistently low C0 levels, and further genetic analysis revealed that one newborn had two novel SLC22A5 pathogenic variants. In total, 25 newborns were diagnosed with PCD, for a positive predictive value of 7.91% (25/316). Based on these data, we estimate the incidence of PCD in Quanzhou is estimated to be 1:8191.Thirteen distinct SLC22A5 variants were identified, and the most common was c.760C > T, with an allelic frequency of 32% (16/50), followed by c.1400C > G (7/50, 14%), and c.51C > G (7/50, 14%). Conclusion Data from this study revealed that 24% (6/25) of PCD cases would have been missed by conventional NBS. This high-throughput iPLEX assay is a powerful tool for PCD genotyping. The addition of this second-tier genetic screening to the current NBS program could identify missed PCD cases, thereby increasing PCD detection. However, further studies are needed to optimise the workflow of the new screening algorithm and to evaluate the cost-effectiveness of this screening approach.

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“…Therefore, during the study period the incidence of PCD in selected population was estimated at 1:8191. Thirteen distinct SLC22A5 mutations were identi ed, seven of which were included in the designed panel, one previously reported mutation c.845G > A was not included in the designed panel, the remaining ve were newly identi ed pathogenic variants and were recently reported by our team [25].The most common mutation was c.760C > T with an allelic frequency of 32% (16/50), followed by c.1400C > G (7/50, 14%) and c.51C > G (7/50, 14%). Besides, c.695C > T, c.1139C > T, c.338G > A, and c.797C > T were also relatively common mutations.…”

Section: Newborn Genetic Screening and Diagnosismentioning

confidence: 99%

Increased primary carnitine deficiency detection through second-tier newborn genetic screening

Lin

Zhang

Huang

et al. 2021

Preprint

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Background Newborn screening for (NBS) for primary carnitine deficiency (PCD) is widely implemented worldwide, however, with poor sensitivity. This study aimed to evaluate the feasibility of improving the screening using second-tier genetic assay. Methods An Agena iPLEX assay was developed to identify 17 SLC22A5 mutations in the Chinese populations, then this assay was applied in NBS for second-tier mutation screening of newborns with low free carnitine (C0) levels. Results The Agena iPLEX assay was successfully established and performed in second-tier genetic screening. A total of316 (0.15%) residual NBS-positive specimens were subjected to second-tier genetic screening. Twenty screen-positive newborns harbored biallelic mutations in SLC22A5 gene, 99 screen-carriers with one mutation, and 197 screen-negative newborns with no mutation identified. Among 99 carriers, four newborns were found with a second disease-causing SLC22A5mutation by further genetic analysis. Four newborns were found with persistently low C0 levels among 197 screen-negatives, further genetic analysis revealed that one newborn with two novel SLC22A5 pathogenic variants. In total, 25 newborns were diagnosed with PCD, for a positive predictive value of 7.91% (25/316). The incidence of PCD in Quanzhou was estimated at 1:8191. Conclusion Data from this study revealed that 24% (6/25) of PCD cases would have been missed by conventional NBS. The high throughput iPLEX assay is a powerful tool for PCD genotyping. The incorporation of second-tier genetic screening into NBS program could increase PCD detection, however, further studies are needed to optimize the workflow of new screening algorithm.

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Newborn screening for primary carnitine deficiency in Quanzhou, China

Cited by 9 publications

References 29 publications

Clinical characteristics of primary carnitine deficiency: A structured review using a case‐by‐case approach

Clinical characteristics of primary carnitine deficiency: A structured review using a case‐by‐case approach

Increased detection of primary carnitine deficiency through second-tier newborn genetic screening

Increased primary carnitine deficiency detection through second-tier newborn genetic screening

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