Silent and symptomatic primary carnitine deficiency within the same family due toidentical mutations in the organic cation/carnitine transporter OCTN2

Spiekerkoetter, Ute; Huener, G.; Baykal, T.; Demirkol, Mübeccel; Durán, Marinus; Wanders, Ronald J. A.; Nezu, Jun-ichi; Mayatepek, Ertan

doi:10.1023/a:1025968502527

Cited by 45 publications

(19 citation statements)

References 6 publications

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“…Other children, diagnosed because of an affected sibling, had only mild developmental delays or were asymptomatic [3, 103, 104]. …”

Section: Disorders Of Fatty Acid Oxidationmentioning

confidence: 99%

“…These mothers, as other adults with primary carnitine deficiency, are at high risk for cardiac arrhythmia and sudden death even if asymptomatic [87, 109, 113, 117–119]. Therefore, low carnitine levels in infants might unmask primary carnitine deficiency in the mother [104, 109–113, 120, 121]. Additional maternal conditions that can cause low carnitine levels in newborns include maternal glutaric acidemia type I [122], medium chain acyl-CoA dehydrogenase deficiency [123], and 3-methyl-crotonyl-CoA carboxylase deficiency [124].…”

Section: Disorders Of Fatty Acid Oxidationmentioning

confidence: 99%

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Carnitine transport and fatty acid oxidation

Longo

Frigeni

Pasquali

2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

639

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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“…Other children, diagnosed because of an affected sibling, had only mild developmental delays or were asymptomatic [3, 103, 104]. …”

Section: Disorders Of Fatty Acid Oxidationmentioning

confidence: 99%

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

639

506

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“…Adults with CDSP have been reported with no symptoms or mild symptoms including decreased stamina or easy fatigability [1,6-9]. Some women with CDSP have been ascertained after newborn screening identified low carnitine levels in their infants.…”

Section: Clinical Descriptionmentioning

confidence: 99%

Systemic primary carnitine deficiency: an overview of clinical manifestations, diagnosis, and management

Magoulas

El‐Hattab

2012

Orphanet J Rare Dis

193

170

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Systemic primary carnitine deficiency (CDSP) is an autosomal recessive disorder of carnitine transportation. The clinical manifestations of CDSP can vary widely with respect to age of onset, organ involvement, and severity of symptoms, but are typically characterized by episodes of hypoketotic hypoglycemia, hepatomegaly, elevated transaminases, and hyperammonemia in infants; skeletal myopathy, elevated creatine kinase (CK), and cardiomyopathy in childhood; or cardiomyopathy, arrhythmias, or fatigability in adulthood. The diagnosis can be suspected on newborn screening, but is established by demonstration of low plasma free carnitine concentration (<5 μM, normal 25-50 μM), reduced fibroblast carnitine transport (<10% of controls), and molecular testing of the SLC22A5 gene. The incidence of CDSP varies depending on ethnicity; however the frequency in the United States is estimated to be approximately 1 in 50,000 individuals based on newborn screening data. CDSP is caused by recessive mutations in the SLC22A5 gene. This gene encodes organic cation transporter type 2 (OCTN2) which transport carnitine across cell membranes. Over 100 mutations have been reported in this gene with the c.136C > T (p.P46S) mutation being the most frequent mutation identified. CDSP should be differentiated from secondary causes of carnitine deficiency such as various organic acidemias and fatty acid oxidation defects. CDSP is an autosomal recessive condition; therefore the recurrence risk in each pregnancy is 25%. Carrier screening for at-risk individuals and family members should be obtained by performing targeted mutation analysis of the SLC22A5 gene since plasma carnitine analysis is not a sufficient methodology for determining carrier status. Antenatal diagnosis for pregnancies at increased risk of CDSP is possible by molecular genetic testing of extracted DNA from chorionic villus sampling or amniocentesis if both mutations in SLC22A5 gene are known. Once the diagnosis of CDSP is established in an individual, an echocardiogram, electrocardiogram, CK concentration, liver transaminanses measurement, and pre-prandial blood sugar levels, should be performed for baseline assessment. Primary treatment involves supplementation of oral levocarnitine (L-carnitine) at a dose of 50–400 mg/kg/day divided into three doses. No formal surveillance guidelines for individuals with CDSP have been established to date, however the following screening recommendations are suggested: annual echocardiogram and electrocardiogram, frequent plasma carnitine levels, and CK and liver transaminases measurement can be considered during acute illness. Adult women with CDSP who are planning to or are pregnant should meet with a metabolic or genetic specialist ideally before conception to discuss management of carnitine levels during pregnancy since carnitine levels are typically lower during pregnancy. The prognosis for individuals with CDSP depends on the age, presentation, and severity of symptoms at the time of diagnosis; however the long-term prognosis is favorab...

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“…Patients with identical mutations can have different ages of onset and different types of clinical presentations 41). Even siblings with the same mutation have different ages of onset and different progressions of disease pointing to the presence of clinical heterogeneity 21).…”

Section: Genotype-phenotype Relationshipmentioning

confidence: 99%

Primary Carnitine Deficiency and Cardiomyopathy

Huang

Chen

2013

Korean Circ J

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Carnitine is essential for the transfer of long-chain fatty acids from the cytosol into mitochondria for subsequent β-oxidation. A lack of carnitine results in impaired energy production from long-chain fatty acids, especially during periods of fasting or stress. Primary carnitine deficiency (PCD) is an autosomal recessive disorder of mitochondrial β-oxidation resulting from defective carnitine transport and is one of the rare treatable etiologies of metabolic cardiomyopathies. Patients affected with the disease may present with acute metabolic decompensation during infancy or with severe cardiomyopathy in childhood. Early recognition of the disease and treatment with L-carnitine may be life-saving. In this review article, the pathophysiology, clinical presentation, diagnosis, treatment and prognosis of PCD are discussed, with a focus on cardiac involvements.

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Silent and symptomatic primary carnitine deficiency within the same family due toidentical mutations in the organic cation/carnitine transporter OCTN2

Cited by 45 publications

References 6 publications

Carnitine transport and fatty acid oxidation

Carnitine transport and fatty acid oxidation

Systemic primary carnitine deficiency: an overview of clinical manifestations, diagnosis, and management

Primary Carnitine Deficiency and Cardiomyopathy

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