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Carnitine transporter deficiency
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
The inborn errors of fatty acid oxidation, including carnitine transporter deficiency (CTD) [1, 2], represent a relatively recently recognized area of human disease. The rate of discovery of distinct disorders has increased rapidly since the discovery of medium-chain acyl CoA dehydrogenase (MCAD) deficiency in 1982 (Chapter 39). Deficiency of carnitine is common in these disorders in which fatty acyl CoA compounds accumulate which then form esters with carnitine and are preferentially excreted in the urine. Carnitine deficiency may also be profound in organic acidemias, such as propionic acidemia, for the same reason. The transport of carnitine into fibroblasts is inhibited by long- and medium-chain acylcarnitines [3], and this may be an additional factor in carnitine deficiency in disorders of fatty acid oxidation. Primary carnitine deficiency resulting from an abnormality in the synthesis of carnitine from protein-bound lysine has not yet been observed. Many of the patients reported early as primary carnitine deficiency have turned out to have MCAD deficiency. Deficiency of carnitine as a result of abnormality in the transporter (Figure 35.1) that facilitates its entry into certain cells has been referred to as primary carnitine deficiency [1]. The carnitine transporter is an organic cation transporter (OCTN2) in the solute carrier family. The gene SLC22A5 has been cloned, and increasing numbers of mutations are being found [4–6].
Liver Diseases
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
Carnitine is synthesized in the liver and enters the tissues via the circulation. Tissue levels greatly exceed serum levels, which implies that tissue uptake is dependent on an active transport mechanism. Thus, carnitine deficiency might be caused by an impaired hepatic biosynthesis or a defective active transport.146,270 Some cases of carnitine deficiency are due to a transport defect since hepatic synthesis is intact and the serum levels are within normal limits. In other cases, hepatic biosynthesis is faulty, and serum, muscle, and liver carnitine levels are below normal. Carnitine concentration is highest in skeletal and cardiac muscle, while the brain and liver have the lowest.
Cardiac and cardiovascular disorders
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
Endocardial fibroelastosis may be secondary to acquired myocarditis or may accompany other congenital heart defects; idiopathic fibroelastosis should be accepted as the diagnosis only with autopsy or biopsy evidence. Some cases may result from systemic carnitine deficiency. A thorough study from Toronto found a recurrence risk of 3.8% in sibs, rather higher than expected from the incidence of the disorder. It is possible that a small subgroup follows autosomal recessive inheritance but, if it exists, it cannot at present be distinguished from the majority and may represent an underlying metabolic disorder. Remember that the cardiac phenotype of the X-linked Barth syndrome can manifest as endocardial fibroelastosis, not always as a simple (i.e. typical) cardiomyopathy.
Kinetics of carnitine concentration after switching from oral administration to intravenous injection in hemodialysis patients
Published in Renal Failure, 2018
Anna Suzuki, Yukinao Sakai, Kazumasa Hashimoto, Hirokazu Osawa, Shuichi Tsuruoka
l-carnitine is a water-soluble amine (molecular weight 162) present in the mitochondria of the tissues of cardiac muscle, skeletal muscle, brain, and liver, among others, as free-carnitine (FC) or acyl-carnitine (AC) [1]. Carnitine has high dialyzability and is often deficient in dialysis patients, because these patients are undernourished due to inflammation. Energy may be produced by beta-oxidation or through the tricarboxylic acid (TCA) cycle by conveying long-chain fatty acids through the inner mitochondrial membrane to carnitine. In addition, carnitine bound to acyl-coenzyme A (CoA) inhibited ATP transfer and carbohydrate metabolism, returned them to CoA and AC, and assisted in energy production by transferring them to the outside of the mitochondria [2]. Carnitine is present as FC or AC in the blood. As CoA and free CoA ratio balance is preserved, the blood AC/FC ratio shows carnitine metabolism. Carnitine deficiency causes systemic disorders such as heart failure, anemia, and muscle symptoms. As carnitine is eliminated by hemodialysis (HD), dialysis patients are particularly susceptible to carnitine deficiency and, consequently, to hypotension [3] and erythropoietin low-responsiveness anemia [4,5].
Diagnostic challenges in metabolic myopathies
Published in Expert Review of Neurotherapeutics, 2020
Corrado Angelini, Roberta Marozzo, Valentina Pegoraro, Sabrina Sacconi
CPT-II deficiency [23] and Carnitine deficiency syndrome [24]were identified on biochemical grounds. In systemic primary carnitine deficiency syndrome, the pathogenetic recessive mutation are located in the SLC22A5 gene in chromosome 5, which encodes Organic Cation/Carnitine Transporter 2 (OCTN2). Molecular defects impairing OCTN2 functions were identified in the patient described by Chapoy, and in various cases [25,26] resulting in low concentration of intracellular, plasma, and urine total carnitine. The carnitine deficiency syndrome causes defective fatty acid oxidation and is characterized by fluctuating weakness and hypotonia with cardiomyopathy.
Emerging therapeutic targets in the short QT syndrome
Published in Expert Opinion on Therapeutic Targets, 2018
Jules C Hancox, Dominic G Whittaker, Chunyun Du, A. Graham Stuart, Henggui Zhang
The existence, at the time of writing, of eight distinct SQTS genotypes firmly establishes the SQTS as a primary genetic syndrome. The relatively low proportion (approximately 1 in 4 tested [124]) of successfully genotyped cases makes it important to differentiate clearly congenital from acquired causes of the syndrome and that any potential acquired causes (including hypercalcaemia, cardiac glycoside, anabolic steroid use [11–17]) are eliminated from the picture (and treated, where necessary) during diagnosis. SQTS as a consequence of carnitine deficiency has been associated with mutations to the SLC22A5 gene that encodes the OCTN2 carnitine transporter [17] and so, arguably, SQTS could be considered to be secondary to SLC22A5 mutations in such cases. Mice with induced carnitine deficiency showed both structural remodeling and abbreviated ventricular repolarization, substantiating a causal link [17]. Where carnitine deficiency-associated SQTS is observed dietary carnitine supplementation may be beneficial [17]. The poor rate adaptation of the QT interval in congenital SQTS patients makes cases likely to be more apparent on ECGs at low/resting heart rates [124] and the presence of mixed Brugada-SQTS phenotypes in some SQT variants, together with evidence for a high prevalence (~65%) of early-repolarization in SQTS patients [125], means that in some instances SQTS may exist as an ‘overlap’ syndrome. Given the potential for differences in calculated QTc interval to arise dependent on the rate correction method used [21], and as highlighted by the authors of [21], to mitigate such issues it is important that ECG measurements are repeated in individuals with suspected SQTS at rates as close to 60 beats min−1 as possible.