Residual OCTN2 transporter activity, carnitine levels and symptoms correlate in patients with primary carnitine deficiency

Rasmussen, Jan; Lund, Allan M.; Risom, Lotte; Wibrand, Flemming; Gislason, Hannes; Nielsen, Olav Wendelboe; Køber, Lars; Dunø, Morten

doi:10.1016/j.ymgmr.2014.04.008

Cited by 21 publications

(35 citation statements)

References 27 publications

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“…In addition to the prevalent p.N32S mutation, there is what we initially named the risk haplotype (RH); today we know that the haplotype segregates with a c.-149C>A mutation that likely affects transcription (100/336 mutant alleles) ( Analysis of carnitine transport indicated that fibroblasts from individuals homozygous for the c.95A>G (p.N32S) retained about 4% of normal transport activity (consistent with the expression studies in CHO cells reported above), compared to 18% for fibroblasts compound heterozygous for c.95A>G (p.N32S) and the risk haplotype and 29% for homozygotes for the risk haplotype [37].…”

Section: Molecular Bases Of Primary Carnitine Deficiency In the Faroesupporting

confidence: 59%

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Neonatal Screening for Primary Carnitine Deficiency: Lessons Learned from the Faroe Islands

Steuerwald

Lund

Rasmussen

et al. 2017

IJNS

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Primary carnitine deficiency is caused by the defective OCTN2 carnitine transporter encoded by the SLC22A5 gene. A lack of carnitine impairs fatty acid oxidation resulting in hypoketotic hypoglycemia, hepatic encephalopathy, skeletal and cardiac myopathy, and arrhythmia. This condition can be detected by finding low levels of free carnitine (C0) in neonatal screening. Mothers with primary carnitine deficiency can also be identified by low carnitine levels in their infant by newborn screening. Primary carnitine deficiency is rare (1:40,000-1:140,000 newborns) except in the Faroe Islands (1:300) due to a founder effect. A specific mutation (c.95A>G, p.N32S) is prevalent, but not unique, with three additional mutations (c.131C>T/p.A44V, a splice mutation c.825-52G>A, and a risk-haplotype) recently identified in the Faroese population. In the Faroe Islands, several adult patients suffered sudden death from primary carnitine deficiency leading to the implementation of a nationwide population screening (performed after 2 months of age) in addition to universal neonatal screening. While most affected infants can be identified at birth, some patients with primary carnitine deficiency might be missed by the current neonatal screening and could be better identified with a repeated test performed after 2 months of age.

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Section: Molecular Bases Of Primary Carnitine Deficiency In the Faroesupporting

confidence: 59%

“…Primary carnitine deficiency in the Faroe Islands is due to specific mutations in the SLC22A5 gene encoding the OCTN2 carnitine transporter [37]. The predominant mutation is c.95A>G (p.N32S) which is found on 211 of the 336 alleles of the 168 PCD-cases.…”

Section: Molecular Bases Of Primary Carnitine Deficiency In the Faroementioning

confidence: 99%

Neonatal Screening for Primary Carnitine Deficiency: Lessons Learned from the Faroe Islands

Steuerwald

Lund

Rasmussen

et al. 2017

IJNS

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“…She had a normal acylcarnitine profile (including C6, C8, and C10:1), and the urinary excretion of organic acids was normal, thereby excluding secondary depletion of carnitine. None of the frequent Faroese SLC22A5 mutations known to segregate in the Danish population (c.95A>G, c.825-52G>A) nor the risk haplotype (Rasmussen et al 2014) was identified. In parallel with the analyses in the infant, the mother (aged 36 years) was evaluated and turned out to have a normal free carnitine in plasma (30 mmol/L, ref.…”

Section: Case Reportmentioning

confidence: 91%

Abnormal Newborn Screening in a Healthy Infant of a Mother with Undiagnosed Medium-Chain Acyl-CoA Dehydrogenase Deficiency

et al. 2015

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A neonate with low blood free carnitine level on newborn tandem mass spectrometry screening was evaluated for possible carnitine transporter defect (CTD). The plasma concentration of free carnitine was marginally reduced, and the concentrations of acylcarnitines (including C6, C8, and C10:1) were normal on confirmatory tests. Organic acids in urine were normal. In addition, none of the frequent Faroese SLC22A5 mutations (p.N32S, c.825-52G>A) which are common in the Danish population were identified. Evaluation of the mother showed low-normal free carnitine, but highly elevated medium-chain acylcarnitines (C6, C8, and C10:1) consistent with medium-chain acyl-CoA dehydrogenase deficiency (MCADD). The diagnosis was confirmed by the finding of homozygous presence of the c.985A>G mutation in ACADM.

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“…Founder mutations have been reported in specific geographic areas, such as p.W132X and p.S467C in Japan [83], p.R254X in the Chinese population [136], and p.N32S in the Faroe Islands [88]. In the Faroe Islands, patients with primary carnitine deficiency are either homozygous or compound heterozygous for four different mutations (c.95A>G, p.N32S; c.136C>T, p.P46S; c.131C>T, p.A44V; c.825-52G>A) and a risk-haplotype, with p.N32S being the most prevalent [142]. Patients homozygous for p.N32S had lower mean plasma carnitine levels, the lowest mean residual OCTN2 carnitine transport activity in their fibroblasts, and had a high risk of having symptoms (hypoglycemia or cardiomyopathy in children, sudden death or fatigue in adults) [142], with plasma and tissue carnitine levels dropping rapidly after discontinuation of oral carnitine supplements [143].…”

Section: Disorders Of Fatty Acid Oxidationmentioning

confidence: 99%

Carnitine transport and fatty acid oxidation

Longo

Frigeni

Pasquali

2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

659

506

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Carnitine is essential for the transfer of long-chain fatty acids across the inner mitochondrial membrane for subsequent β-oxidation. It can be synthesized by the body or assumed with the diet from meat and dairy products. Defects in carnitine biosynthesis do not routinely result in low plasma carnitine levels. Carnitine is accumulated by the cells and retained by kidneys using OCTN2, a high affinity organic cation transporter specific for carnitine. Defects in the OCTN2 carnitine transporter results in autosomal recessive primary carnitine deficiency characterized by decreased intracellular carnitine accumulation, increased losses of carnitine in the urine, and low serum carnitine levels. Patients can present early in life with hypoketotic hypoglycemia and hepatic encephalopathy, or later in life with skeletal and cardiac myopathy or sudden death from cardiac arrhythmia, usually triggered by fasting or catabolic state. This disease responds to oral carnitine that, in pharmacological doses, enters cells using the amino acid transporter B0,+. Primary carnitine deficiency can be suspected from the clinical presentation or identified by low levels of free carnitine (C0) in the newborn screening. Some adult patients have been diagnosed following the birth of an unaffected child with very low carnitine levels in the newborn screening. The diagnosis is confirmed by measuring low carnitine uptake in the patients’ fibroblasts or by DNA sequencing of the SLC22A5 gene encoding the OCTN2 carnitine transporter. Some mutations are specific for certain ethnic backgrounds, but the majority are private and identified only in individual families. Although the genotype usually does not correlate with metabolic or cardiac involvement in primary carnitine deficiency, patients presenting as adults tend to have at least one missense mutation retaining residual activity.

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Residual OCTN2 transporter activity, carnitine levels and symptoms correlate in patients with primary carnitine deficiency

Cited by 21 publications

References 27 publications

Neonatal Screening for Primary Carnitine Deficiency: Lessons Learned from the Faroe Islands

Neonatal Screening for Primary Carnitine Deficiency: Lessons Learned from the Faroe Islands

Abnormal Newborn Screening in a Healthy Infant of a Mother with Undiagnosed Medium-Chain Acyl-CoA Dehydrogenase Deficiency

Carnitine transport and fatty acid oxidation

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