Molecular spectrum of SLC22A5 (OCTN2) gene mutations detected in 143 subjects evaluated for systemic carnitine deficiency

Li, Fangyuan; El‐Hattab, Ayman W.; Bawle, Erawati V.; Boles, Richard G.; Schmitt, Éric; Scaglia, Fernando; Wong, Lee‐Jun C.

doi:10.1002/humu.21311

Cited by 61 publications

(59 citation statements)

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“…As in other previous studies, no genotype-phenotype relationship was observed. (Garavaglia et al 1991;Lamhonwah et al 2002;Li et al 2010;Longo et al 2006;Stanley et al 1991;Wang et al 2000aWang et al , b, 2001). Even siblings with the same mutation have different ages of onset and different progressions of disease pointing to the presence of clinical heterogeneity (Table 1).…”

Section: Discussionmentioning

confidence: 99%

“…This therefore suggests that the wide variability in phenotypic expression in carnitine transporter defect is most likely related to exogenous stressors that exacerbate the carnitine deficiency. These could include decreased intake due to dietary carnitine deficiency (vegetarian diets), drugs that increase the elimination of carnitine (valproic acid, pivalic acid) or inhibitors of carnitine transport (verapamil, pyrilamine, b-lactam antibiotics), and conditions such as fasting or infection, which would increase the demands on carnitine-dependent fatty acid oxidation (Holme et al 1989;Lamhonwah et al 2002;Li et al 2010;Spiekerkoetter et al 2003;Tein et al 1993;Toh et al 2010). Lack of genotype/phenotype correlation could also be influenced by polygenic factors.…”

Section: Discussionmentioning

confidence: 99%

“…OCTN2 gene is located on chromosome 5q31 with ten exons encoding a 557-amino acid transmembrane protein consisting of 12 transmembrane domains and one ATP-binding domain and predicted molecular mass of 63 kDa (Saito et al 2002;Wu et al 1999). More than 90 mutations have been identified up to date (Amat di San Filippo C et al 2006aFilippo C et al , b, 2008Burwinkel et al 1999;Cederbaum et al 2002;Dobrowolski et al 2005;Koizumi et al 1999;Lamhonwah et al 2002;Li et al 2010;Makhseed et al 2004;Mayatepek et al 2000;Nezu et al 1999;Rahbeeni et al 2002;Spiekerkoetter et al 2003;Tang et al 1999;Vaz et al 1999;Wang et al 1999Wang et al , 2000aWang et al , b, 2001.…”

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confidence: 99%

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Identification of Mutations and Evaluation of Cardiomyopathy in Turkish Patients with Primary Carnitine Deficiency

et al. 2011

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Primary systemic carnitine deficiency (SCD) is an autosomal recessive disorder caused by defective cellular carnitine transport. Patients usually present with predominant metabolic or cardiac manifestations. SCD is caused by mutations in the organic cation/carnitine transporter OCTN2 (SLC22A5) gene. Mutation analysis of SLC22A5 gene was carried out in eight Turkish patients from six families. Six patients presented with signs and symptoms of heart failure, cardiomyopathy, and low plasma carnitine levels, five of them with concurrent anemia. A patient with dilated cardiomyopathy had also facial dysmorphia, microcephaly, and developmental delay. Tandem MS analyses in siblings of the patients revealed two more cases with low plasma carnitine levels. SCD diagnosis was confirmed in these two cases by mutation screening. These two cases were asymptomatic but echocardiography revealed left ventricular dilatation in one of them. Carnitine treatment was started before the systemic signs and symptoms developed in these patients. Mean value of serum carnitine levels of the patients was 2.63 AE 1.92 mmol/L at the time of diagnosis. After 1 year of treatment, carnitine values increased to 16.62 AE 5.11 (p < 0.001) and all responded to carnitine supplementation clinically.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Identification of Mutations and Evaluation of Cardiomyopathy in Turkish Patients with Primary Carnitine Deficiency

et al. 2011

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“…Alternatively, a point mutation identified by PCR-based DNA sequencing may appear to be homozygous when the other allele contains a deletion spanning the region containing the mutation. 17 A patient could thus be compound heterozygous for two deleterious mutations (one a point mutation and the other a deletion), consistent with affected status. The chance that a new mutation could have occurred in a patient with a recessive disorder who had already inherited an identical mutation from one of the parents, or that one parent has gonadal mosaicism, is highly unlikely, and not considered as part of our standard evaluation of apparently homozygous mutations.…”

Section: Discussionmentioning

confidence: 92%

Detection of uniparental isodisomy in autosomal recessive mitochondrial DNA depletion syndrome by high-density SNP array analysis

et al. 2011

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Mitochondrial DNA (mtDNA) depletion syndrome encompasses a heterogeneous group of disorders characterized by a reduction in the mtDNA copy number. We identified two patients with clinical presentations consistent with mtDNA depletion syndrome (MDS), who were subsequently found to have apparently homozygous point mutations in TYMP and DGUOK, two of the nine nuclear genes commonly associated with these disorders. Further sequence analyses of parents indicated that in each case only one parent; the mother of the first and the father of the second, was a heterozygous carrier of the mutation identified in the affected child. The presence of underlying deletions was ruled out by use of a custom target array comparative genomic hybridization (CGH) platform. A high-density single-nucleotide polymorphism (SNP) array analysis revealed that the first patient had a region of copy-neutral absence of heterozygosity (AOH) consistent with segmental isodisomy for an 11.3 Mb region at the long-arm terminus of chromosome 22 (including the TYMP gene), and the second patient had results consistent with complete isodisomy of chromosome 2 (where the DGUOK gene is located). The combined sequencing, array CGH and SNP array approaches have demonstrated the first cases of MDS due to uniparental isodisomy. This diagnostic scenario also demonstrates the necessity of comprehensive examination of the underlying molecular defects of an apparently homozygous mutation in order to provide patients and their families with the most accurate molecular diagnosis and genetic counseling.

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“…Poza tym w PUNK w biopsji skóry obserwuje się zmniejszenie transportu karnityny przez fibroblasty (< 10%) [31,36]. U niemowląt, u których w przesiewowych testach stwierdzono obniżony poziom karnityny mutacje w genie SLC22A5 wykrywa się u około 70% przypadków [37].…”

Section: Pierwotny Układowy Niedobór Karnitynunclassified

Primary L-carnitine deficiencies – symptoms, clinical syndromes, proceed ings

Fliciński¹,

Malendowicz-Major²,

Steinborn³

2016

Child Neurology

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StreSzczenieW artykule przedstawiono aktualny stan wiedzy na temat pierwotnych niedoborów L-karnityny. Ponadto w artykule opisano właściwości, funkcje oraz objawy niedoboru L-karnityny. L-karnityna jest zaliczana do substancji witamionopodobnych i odgrywa istotną rolę w organizmie człowieka zwłaszcza w procesie β-oksydacji kwasów tłuszczowych. Objawy niedoboru karnityny są mało specyficzne i z tego powodu są często niezdiagnozowane, szczególnie u dzieci. Wyodrębnia się trzy typy niedoboru karnityny: pierwotny układowy niedobór L-karnityn, pierwotny miopatyczny niedobór L-karnityny oraz wtórny niedobór L-karnityny. Pierwotny układowy niedobór karnityny jest jedną z najczęstszych chorób związanych z zaburzeniami metabolizmu lipidów i jest spowodowany przez mutację w genie SLC22A5, która jest dziedziczona autosomalnie recesywnie. Objawy pierwotnego mięśniowego niedoboru karnityny postę-pują powoli i zwykle rozpoczynają się w dzieciństwie, jak do tej pory nie udało się ustalić mutacji genetycznej, która odpowiadałaby za ten typ niedoboru L-karnityny. Wczesne rozpoznanie oraz włączenie L-karnityny może przyczynić się w niektórych przypadkach do uratowania życia. Słowa kluczowe: L-karnityna, zespoły niedoborowe L-karnityny, pierwotny układowy niedobór karnityny, pierwotny miopatyczny niedobór karnityny abStract The goal of this article is to present the current state of knowledge about primary L-carnitine deficiencies. Furthermore, this article describes the features, functions and symptoms of L-carnitine deficiency. L-carnitine is a vitamin and plays an important role in human body, particularly in β-oxidation of fatty acids. The symptoms of L-carnitine deficiency are non-specific and therefore are undiagnosed, especially in children. There are three types of carnitine deficiency: primary systemic carnitine deficiency, primary myopathic carnitine deficiency and secondary carnitine deficiency. Primary systemic carnitine deficiency, the most common disorder of lipid metabolism, is an autosomal recessive disease caused by mutations in the SLC22A5 gene. The symptoms of primary myopathic carnitine deficiency are progressing slowly and usually start in childhood, so far the genetic mutation which is responsible for this type of L-carnitine deficiency is unknown. Early diagnosis and supplementation of L-carnitine can contribute to save life of some patients. Key words: L-carnitine, L-carnitine deficiency syndrome, primary carnitine deficiency, primary myopathic carnitine deficiency Skróty zastosowane w artykule: BBD -dioksygeneza butyrobetainy; Co-A -koenzym A; acetylo-CoA -acetylo-koenzym A; PUNK -pierwotny układowy niedobór karnityny;, została odkryta z izolacji mięśni w 1905 roku, a nazwa tej substancji pochodzi z języka łacińskiego od słowa carnus, co oznacza -mięso [1,2]. W organizmie karnityna występuje pod postacią dwóch izomerów L i D, przy czym aktywność biologiczną wykazuje tylko L-karnityna. Zapotrzebowanie na L-karnitynę jest pokrywane w 25% przez endogenną syntezę, a pozostałe 75% dostarczane jest wraz z pokarm...

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Molecular spectrum of SLC22A5 (OCTN2) gene mutations detected in 143 subjects evaluated for systemic carnitine deficiency

Cited by 61 publications

References 16 publications

Identification of Mutations and Evaluation of Cardiomyopathy in Turkish Patients with Primary Carnitine Deficiency

Identification of Mutations and Evaluation of Cardiomyopathy in Turkish Patients with Primary Carnitine Deficiency

Detection of uniparental isodisomy in autosomal recessive mitochondrial DNA depletion syndrome by high-density SNP array analysis

Primary L-carnitine deficiencies – symptoms, clinical syndromes, proceed ings

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