Primary Carnitine Deficiency: Is Foetal Development Affected and Can Newborn Screening Be Improved?

Rasmussen, Jan; Hougaard, David M.; Sandhu, Noreen; Fjællegaard, Katrine; Petersen, Poula R; Steuerwald, Ulrike; Lund, Allan M.

doi:10.1007/8904_2016_30

Cited by 11 publications

(10 citation statements)

References 25 publications

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“…Likewise, babies with CUD, if sampled in the first few days of life, may not yet have developed sufficiently low levels of C0 to test positive . The older the baby is when screened, the greater the sensitivity and specificity of NBS for CUD . NBS has detected relatively few cases of CUD (; https://www.clir-r4s.org/msCard.aspx), suggesting that it is either one of the rarer disorders of fatty acid oxidation or the current NBS is not a particularly sensitive test.…”

Section: Resultsmentioning

confidence: 99%

The decision to discontinue screening for carnitine uptake disorder in New Zealand

Wilson

Knoll

Hora

et al. 2019

J of Inher Metab Disea

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When screening for carnitine uptake disorder (CUD), the New Zealand (NZ) newborn screening (NBS) service identified infants as screen-positive if they had initial and repeat free carnitine (C0) levels of less than 5.0 μmol/L. Since 2006, the NBS service has identified two infants with biochemical and genetic features consistent with neonatal CUD and nine mothers with features consistent with maternal CUD. A review of the literature suggests that these nine women reflect less than half the true prevalence and that CUD is relatively common. However, the NZ results (two infants) suggest a very low sensitivity and positive predictive value of NBS.While patients presenting with significant disease due to CUD are well described, the majority of adults with CUD are asymptomatic. Nonetheless, treatment with highdose oral L-carnitine is recommended. Compliance with oral L-carnitine is likely to be poor long term. This may represent a specific risk as treatment could repress the usual compensatory mechanisms seen in CUD, such that a sudden discontinuation of treatment may be dangerous. L-carnitine is metabolized to trimethylamine-N-oxide (TMAO) and treated patients have extremely high plasma TMAO levels. TMAO is an independent risk factor for atherosclerosis and, thus, caution should be exercised regarding long-term treatment with high-dose carnitine of asymptomatic patients who may have a biochemical profile without disease. Due to these concerns, the NZ Newborn Metabolic Screening Programme (NMSP) initiated a review via a series of advisory and governance committees and decided to discontinue screening for CUD.

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Section: Resultsmentioning

confidence: 99%

The decision to discontinue screening for carnitine uptake disorder in New Zealand

Wilson

Knoll

Hora

et al. 2019

J of Inher Metab Disea

View full text Add to dashboard Cite

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“…Traditionally, serum C 0 levels have been assessed (23, 24) based on quantifiable biochemical manifestations and DNA analysis. Sixteen patients showed a lower C 0 level (<9.63 μmol/L) at the primary screening; with a mean value of 6.48 μmol/L, emphasizing the utility of MS/MS neonatal screening for PCD diagnosis.…”

Section: Discussionmentioning

confidence: 99%

Biochemical, Molecular, and Clinical Characterization of Patients With Primary Carnitine Deficiency via Large-Scale Newborn Screening in Xuzhou Area

Zhou

Huang

et al. 2019

Front. Pediatr.

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Background: Primary carnitine deficiency (PCD) is attributed to a variation in the SLC22A5 (OCTN2) gene which encodes the key protein of the carnitine cycle, the OCTN2 carnitine transporter. PCD is typically identified in childhood by either hypoketotic hypoglycemia, or skeletal and cardiac myopathy. The aim of this study was to the clinical, biochemical, and molecular characteristics of PCD patients via newborn screening with tandem mass spectrometry (MS/MS). Methods: MS/MS was performed to screen newborns for inherited metabolic diseases. SLC22A5 gene mutations were detected in the individual and/or their family member by DNA mass array and next-generation sequencing (NGS). Results: Among the 236,368 newborns tested, ten exhibited PCD, and six others were diagnosed with low carnitine levels caused by their mothers, who had asymptomatic PCD. The incidence of PCD in the Xuzhou area is ~1:23,637. The mean initial free carnitine (C 0 ) concentration of patients was 6.41 ± 2.01 μmol/L, and the follow-up screening concentration was 5.80 ± 1.29 μmol/L. After treatment, the concentration increased to 22.8 ± 4.13 μmol/L. Conclusion: This study demonstrates the important clinical value of combining MS/MS and NGS for the diagnosis of PCD and provides new insight into the diagnosis of PCD and maternal patients with PCD using C 0 concentration and SLC22A5 mutations.

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“…This frequency is significantly higher than the one reported by newborn screening, indicating that some affected individuals might be missed by the current neonatal screening protocols. We do not know whether this is due to specific mutations (Chen et al., ) and/or to problems related to the timing of collection of the newborn screening sample, in which the blood samples are collected at 1–3 days of age and carnitine levels might reflect those of the mother (Pasquali & Longo, ; Rasmussen et al., ; Schimmenti et al., ). Carnitine is transferred from the mother to the child via the placenta, and immediately after birth levels of free carnitine (C0) are usually lower in infants of mothers with primary carnitine deficiency as compared to infants with the disease themselves (Pasquali & Longo, ).…”

Section: Discussionmentioning

confidence: 99%

Functional and molecular studies in primary carnitine deficiency

et al. 2017

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Primary carnitine deficiency is caused by a defect in the OCTN2 carnitine transporter encoded by the SLC22A5 gene. It can cause hypoketotic hypoglycemia or cardiomyopathy in children, and sudden death in children and adults. Fibroblasts from affected patients have reduced carnitine transport. We evaluated carnitine transport in fibroblasts from 358 subjects referred for possible carnitine deficiency. Carnitine transport was reduced to 20% or less of normal in fibroblasts of 140/358 subjects. Sequencing of the 10 exons and flanking regions of the SLC22A5 gene in 95/140 subjects identified causative variants in 84% of the alleles. The missense variants identified in our patients and others previously reported (n=92) were expressed in CHO cells. Carnitine transport was impaired by 73/92 variants expressed. Prediction algorithms (Polyphen-2, SIFT) correctly predicted the functional effects of expressed variants in about 80% of cases. These results indicate that mutations in the coding region of the SLC22A5 gene cannot be identified in about 16% of the alleles causing primary carnitine deficiency. Prediction algorithms failed to determine the functional effects of amino acid substitutions in this transmembrane proteins in about 20% of cases. Therefore, functional studies in fibroblasts remain the best strategy to confirm or exclude a diagnosis of primary carnitine deficiency.

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Primary Carnitine Deficiency: Is Foetal Development Affected and Can Newborn Screening Be Improved?

Cited by 11 publications

References 25 publications

The decision to discontinue screening for carnitine uptake disorder in New Zealand

The decision to discontinue screening for carnitine uptake disorder in New Zealand

Biochemical, Molecular, and Clinical Characterization of Patients With Primary Carnitine Deficiency via Large-Scale Newborn Screening in Xuzhou Area

Functional and molecular studies in primary carnitine deficiency

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