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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].
Laboratory techniques to study the cellular and molecular processes of disorders
Published in Louis-Philippe Boulet, Applied Respiratory Pathophysiology, 2017
Gene sequencing with high throughput PCR platforms also facilitates the study of methylation in disease pathogenesis. Methylation is one of the epigenetic mechanisms that alters the transcription process of a gene without changing the gene sequence. While hypermethylation is generally associated with transcriptional repression, hypomethylation is with transcriptional activation [35]. Epigenetic mechanisms are, in most cases, essential for cell development and cell activities during the life of an individual. Importantly, these alterations are reversible. Hence, the ability to measure epigenetics such as DNA methylation is invaluable. DNA methylation in humans occurs on a cytosine residue that is followed by a guanine residue, denoted as CpG where p stands for phosphate. These CpGs are uniformly distributed in the human genome and are enriched in the promoter regions. One of the most commonly used techniques to measure DNA methylation is bisulfite pyrosequencing [36]. Briefly, isolated DNA first undergoes a bisulfite treatment to convert all cytosine residues into uracil residues (Figure 3.8). For a methylated cytosine residue (i.e., methylcytosine), no conversion occurs. Each amplified product undergoes pyrosequencing to determine its sequence. Pyrosequencing is a PCR-based platform with the Taq polymerase presented with the four nucleotides, one at a time. The incorporation of the correct nucleotide releases a pyrophosphate molecule and subsequently generates a light output. By detecting which nucleotide gives off the light output the identity of the incorporated nucleotide at that location is known. However, the decoded sequence needs to distinguish a TG dinucleotide from a “true” TG or a CG dinucleotide (which converted to UG then TG during the bisulfite treatment). By identifying genomic locations where there are mixed base (T:C) signals, the extent of methylation can be estimated. The various high throughput pyrosequencing platforms used for measuring methylation levels of an entire genome have been compressively reviewed elsewhere [37]. Using bisulfite pyrosequencing methylation assays, polymorphisms at the promoter regions of interleukin 1 receptor type II (IIL1R2), solute carrier family 22 (organic 3 cation/camitine transporter) member 5 (SLC22A5), zona pellucida binding protein 2 (ZPBP2), and gasdermin A (GSDMA) were found to influence the methylation level at its gene's promoter region [38]. The data also suggested interactions between the methylation level of ZPBP2, GSDMA and asthma in female asthmatic subjects and SLC22A5 in male asthmatic subjects [38]. The study illustrated the intricate relationship between genotypes, methylation levels, and disease status.
Recent advances in drug delivery via the organic cation/carnitine transporter 2 (OCTN2/SLC22A5)
Published in Expert Opinion on Therapeutic Targets, 2018
Longfa Kou, Rui Sun, Vadivel Ganapathy, Qing Yao, Ruijie Chen
L-Carnitine (β-hydroxy-γ-trimethylaminobutyrate), also named as vitamin Bt, is a highly polar zwitterionic molecule. It plays an essential role in the transfer of long-chain fatty acids from the cytoplasm into the mitochondrial matrix across the inner mitochondrial membrane for β-oxidation [1], and the transport of peroxisomal β-oxidation metabolites into mitochondria for completion of oxidation via tricarboxylic acid (TCA) cycle [2,3]. L-Carnitine also functions as an effective scavenger of reactive oxygen species (ROS) to prevent oxidant injury [3,4]. The deficiency of L-carnitine in body could result in lipid metabolism disorders, hypoglycemia, skeletal weakness, cardiac hypertrophy, hyperammonemia, and even death [5,6]. L-Carnitine is synthesized de novo to a significant extent in the liver, kidney and brain using lysine as a carbon backbone and methionine as a donor of methyl groups; it is also available in the diet with efficient absorption in the intestinal tract, which is the major contributor to L-carnitine in the body. Intestinal absorption, distribution in systemic tissues, and reabsorption in the kidney of L-carnitine rely principally on the carnitine/organic cation transporter OCTN2, also known as SLC22A5, which shows high affinity for this important metabolite/nutrient with the Michaelis constant in the low micromolar range. There are other transporters that also show ability to transport L-carnitine; these are OCTN1 (SLC22A4), CT2 (SLC22A16), and ATB°,+ (SLC6A14), but the affinity of these transporters for L-carnitine is much lower than that for OCTN2 and also their tissue distribution is different from that of OCTN2 (Table 1) [7].
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.
Whole-exome sequencing in three children with sporadic Blau syndrome, one of them co-presenting with recurrent polyserositis
Published in Autoimmunity, 2020
Carlos Córdova-Fletes, Martha M. Rangel-Sosa, Lizeth A. Martínez-Jacobo, Luis Eduardo Becerra-Solano, Carmen Araceli Arellano-Valdés, José Alberto Tlacuilo-Parra, Kame Alberto Galán-Huerta, Ana María Rivas-Estilla, Angélica Alejandra Hernandez-Orozco, José Elías García-Ortiz
Regarding patient 3, mutations in exon 10 of MEFV have been associated to FMF (also known as recurrent polyserositis), an autosomal recessive autoinflammatory disorder mainly characterised by fever, serositis or synovitis, and skin eruption [23], clinical picture that along with uveitis/panuveitis, initially suggested BS. Actually, BS is itself a differential diagnosis of FMF. FMF affects primarily to Mediterranean populations [24,25]. Interestingly, individuals who do not have the pathogenic variant p.Met694Val (in exon 10) are expected to be only mildly affected (i.e. those with infrequent inflammatory attacks) [23]. However, this patient exhibited a severe form (including arthritis) of FMF. The more plausible explanation for this discrepancy is the presence of the NOD2 variant that could act synergistically with the abovementioned MEFV variant causing an “atypical FMF” or an FMF-BS compound phenotype. Of note, very recently, Yildiz et al. [26] reported the (clinical) co-existence of several inflammatory diseases with FMF, including idiopathic uveitis but not BS (there was not analysis of NOD2). The immediate closeness of the patient’s MEFV variant (i.e. Lys695Arg) to that of more affected FMF patients (i.e. p.Met694Val), may also suggest a novel, highly harmful variant out of changes at Met694. Thus, alike a few mutations (including p.Met694Val), this SNV could be a dominant one. This patient also presents a mutation in SLC22A5, which encodes the OCTN2 transporter involved in organic cation transport and sodium-dependent high affinity carnitine transport. Mutations in this gene have been associated with Crohn’s disease [27]. The absence of said disorder in this patient seems to be consistent with the notion that that is a multifactorial entity [12,28].