Surprising causes of C5-carnitine false positive results in newborn screening

Boemer, François; Schoos, Roland; Halleux, Virginie de; Kalenga, Masendu; Debray, François-Guillaume

doi:10.1016/j.ymgme.2013.11.005

Cited by 27 publications

(21 citation statements)

References 10 publications

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“…Others show only selected abnormal metabolites, but not a full diagnostic pattern. Some therapeutic interventions like MCT oil, valproic acid or particular antibiotics (pivalic acid) can also mimic at least parts of the biochemical profile [[37],[38]]. Finally, due to common polymorphic alleles in the ACADS gene about 14% of the population will excrete ethylmalonic acid or will have elevated C4-acylcarnitine species in plasma [[39]].…”

Section: Discussionmentioning

confidence: 99%

Clinical and genetical heterogeneity of late-onset multiple acyl-coenzyme A dehydrogenase deficiency

Grünert

2014

Orphanet J Rare Dis

157

156

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BackgroundMultiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder caused by deficiency of electron transfer flavoprotein or electron transfer flavoprotein dehydrogenase. The clinical picture of late-onset forms is highly variable with symptoms ranging from acute metabolic decompensations to chronic, mainly muscular problems or even asymptomatic cases.MethodsAll 350 cases of late-onset MADD reported in the literature to date have been analyzed and evaluated with respect to age at presentation, diagnostic delay, biochemical features and diagnostic parameters as well as response to treatment.ResultsMean age at onset was 19.2 years. The mean delay between onset of symptoms and diagnosis was 3.9 years. Chronic muscular symptoms were more than twice as common as acute metabolic decompensations (85% versus 33% of patients, respectively). 20% had both acute and chronic symptoms. 5% of patients had died at a mean age of 5.8 years, while 3% of patients have remained asymptomatic until a maximum age of 14 years. Diagnosis may be difficult as a relevant number of patients do not display typical biochemical patterns of urine organic acids and blood acylcarnitines during times of wellbeing. The vast majority of patients carry mutations in the ETFDH gene (93%), while mutations in the ETFA (5%) and ETFB (2%) genes are the exceptions. Almost all patients with late-onset MADD (98%) are clearly responsive to riboflavin.ConclusionsLate-onset MADD is probably an underdiagnosed disease and should be considered in all patients with acute or chronic muscular symptoms or acute metabolic decompensation with hypoglycemia, acidosis, encephalopathy and hepatopathy. This may not only prevent patients from invasive diagnostic procedures such as muscle biopsies, but also help to avoid fatal metabolic decompensations.

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Section: Discussionmentioning

confidence: 99%

Clinical and genetical heterogeneity of late-onset multiple acyl-coenzyme A dehydrogenase deficiency

Grünert

2014

Orphanet J Rare Dis

157

156

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“…Antibiotics conjugated with pivalic acid to increase absorption are especially dangerous apart from their antibiotic action because pivalic acid forms pivaloylcarnitine, which is excreted by the kidney depleting carnitine . Pivalic acid is also found in nipple‐fissure unguent and can cause metabolic changes in breast feeding infants .…”

Section: What Might Be the Role Of Drugs?mentioning

confidence: 99%

Brain carnitine deficiency causes nonsyndromic autism with an extreme male bias: A hypothesis

Beaudet

2017

BioEssays

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Could 10–20% of autism be prevented? We hypothesize that nonsyndromic or “essential” autism involves extreme male bias in infants who are genetically normal, but they develop deficiency of carnitine and perhaps other nutrients in the brain causing autism that may be amenable to early reversal and prevention. That brain carnitine deficiency might cause autism is suggested by reports of severe carnitine deficiency in autism and by evidence that TMLHE deficiency – a defect in carnitine biosynthesis – is a risk factor for autism. A gene on the X chromosome (SLC6A14) likely escapes random X-inactivation (a mixed epigenetic and genetic regulation) and could limit carnitine transport across the blood-brain barrier in boys compared to girls. A mixed, common gene variant-environment hypothesis is proposed with diet, minor illnesses, microbiome, and drugs as possible risk modifiers. The hypothesis can be tested using animal models and by a trial of carnitine supplementation in siblings of probands. Perhaps the lack of any Recommended Dietary Allowance for carnitine in infants should be reviewed.

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“…In 2014, Boemer at al. [4] reported 50 FP IVA results detected in Belgium during an 18-month period, which were subsequently investigated and found to be due to the use of a nipple fissure unguent containing pivalic acid derivatives. Similarly, following the introduction of screening for IVA in 2012 in the UK, between 2012-2016, 24 FP and 16 true positive (TP) cases were reported, with 16 out of 24 of these FP cases attributable to pivaloyl carnitine in the blood spot sample (this report; see also [5]).…”

Section: Introductionmentioning

confidence: 99%

Raising Awareness of False Positive Newborn Screening Results Arising from Pivalate-Containing Creams and Antibiotics in Europe When Screening for Isovaleric Acidaemia

Bonham

Carling

Franzson

et al. 2018

IJNS

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While the early and asymptomatic recognition of treatable conditions offered by newborn screening confers clear health benefits for the affected child, the clinical referral of patients with screen positive results can cause significant harm for some families. The use of pivalate-containing antibiotics and more recently the inclusion of neopentanoate as a component within moisturising creams used as nipple balms by nursing mothers can result in a significant number of false positive results when screening for isovaleric acidaemia (IVA) by measuring C5 acylcarnitine. A recent survey conducted within centres from nine countries indicated that this form of contamination had been or was a significant confounding factor in the detection of IVA in seven of the nine who responded. In three of these seven the prominent cause was believed to derive from the use of moisturising creams and in another three from antibiotics containing pivalate; one country reported that the cause was mixed. As a result, four of these seven centres routinely perform second tier testing to resolve C5 isobars when an initial C5 result is elevated, and a fifth is considering making this change within their national programme. The use of creams containing neopentanoate by nursing mothers and evolving patterns in the prescription of pivalate-containing antibiotics during pregnancy require those involved in the design and operation of newborn screening programmes used to detect IVA and the doctors who receive clinical referrals from these programmes to maintain an awareness of the potential impact of this form of interference on patient results.

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Surprising causes of C5-carnitine false positive results in newborn screening

Cited by 27 publications

References 10 publications

Clinical and genetical heterogeneity of late-onset multiple acyl-coenzyme A dehydrogenase deficiency

Clinical and genetical heterogeneity of late-onset multiple acyl-coenzyme A dehydrogenase deficiency

Brain carnitine deficiency causes nonsyndromic autism with an extreme male bias: A hypothesis

Raising Awareness of False Positive Newborn Screening Results Arising from Pivalate-Containing Creams and Antibiotics in Europe When Screening for Isovaleric Acidaemia

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