原发性肉碱转移酶缺乏症基因突变研究SLC22A5
Drug Metab.Pharmacokinet.25(1):112–119(2010).SNP CommunicationGenetic Variations of the SLC22A5Gene in the Chinese andIndian Populations of SingaporeDorothy Su Lin T OH1,2,Jie Yin Y EE1,Seok Hwee K OO1,Michael M URRAY2and Edmund Jon Deoon L EE1,*1Department of Pharmacology,Yong Loo Lin School of Medicine,National University of Singapore,Singapore2Faculty of Pharmacy,the University of Sydney,Sydney,NSW,AustraliaFull text of this paper is available at http://www.jstage.jst.go.jp/browse/dmpkSummary:Novel organic cation transporter2(OCTN2)is a multispecific,bidirectional,pH-dependent or-ganic cation transporter.It can function as a carnitine co-transporter with higher affinity for carnitine than OCTN1but also functions as a uniporter for other cations.Drugs such as verapamil,pyrilamine and b-lactam antibiotics have been characterized as substrates of OCTN2and/or inhibitors of carnitine transport.This study identified variants of the SLC22A5gene in two distinct ethnic groups of the Singaporean population(n＝192)by DNA sequencing.Twenty-eight genetic variants of SLC22A5,including13that were novel,were found:14were located in the coding exons,10in the introns,1in the promoter region,2in the5?-untransla-ted region and1in the3?-untranslated region.Among the novel nonsynonymous variants,Asp122Tyr was predicted to be functionally significant.Functional nonsynonymous variants detected include Ser467Cys and Arg254X;the latter resulted in a premature stop codon and is predicted to result in a truncated protein that is less than half the molecular mass of wild-type OCTN2.These data constitute fundamental information of value for future pharmacogenetic studies in Asian populations on drugs that are substrates of OCTN2.Keywords:SLC22transporters;OCTN2;pharmacogenetics;human genetics;single nucleotide poly-morphism;clinical pharmacologyIntroductionNovel organic cation transporter2(OCTN2)is a mul-tispecific,bidirectional,pH-dependent transporter of or-ganic cations such as carnitine and tetraethylammonium (TEA).Whereas OCTN2-mediated transport of the proto-typical substrate,L-carnitine,is sodium-dependent,1,2) other organic cations,such as xenobiotic TEA,are trans-ported in a pH-dependent and Na-independent manner.3) OCTN2has also been shown to transport drugs such as verapamil,pyrilamine and b-lactam antibiotics.4)These a-gents may inhibit carnitine transport.SLC22A5,the gene encoding OCTN2,consists of10exons and is located on chromosome5q31.5)OCTN2is a557-amino-acid protein with12putative transmembrane domains and a predict-ed molecular mass of63kDa.2)OCTN2is expressed in numerous tissues,including kidney,skeletal muscle,placenta,heart,prostate,thyroid,pancreas,liver,lung, brain,intestine,lymphocytes,spinal cord,uterus, trachea,thymus and adrenal gland.6,7)Within the human gastrointestinal tract,OCTN2mRNA was detected in duodenum and ileum,and at higher levels in the colon.8,9) The physiological role of OCTN2expression in the kidney is primarily in L-carnitine reabsorption,as body carnitine stores are tightly regulated by the kidney.1,2)Ex-pression in muscle cells also facilitates L-carnitine uptake in tissues.2)L-Carnitine is a highly polar,naturally occur-ring amino acid derivative that is synthesized primarily in the liver and,to a lesser extent,in the kidney and brain.10) The cardiac and skeletal muscles are not capable of syn-thesizing it.10)L-Carnitine is essential not only for the transfer of long-chain fatty acids to the mitochondrion for b-oxidation,which is required for energy generation, but also for the elimination of short-and medium-chain112113 Population Genetic Variations of SLC22A5Genefatty acids from the cell.6)Tissue carnitine concentrations are typically20–50times higher than those in serum;11) thus,uptake is dependent on OCTN2carrier-mediated active uptake of L-carnitine from the bloodstream.11)L-Carnitine is not bound to plasma proteins and is exten-sively filtered at the glomerulus;thus,renal OCTN2plays a critical role in the tubular reabsorption of L-carnitine.10) OCTN2is located at the apical membrane of the placen-tal syncytiotrophoblast and mediates L-carnitine uptake from the maternal circulation to the fetus.Carnitine is pivotal for the fetal organism because it is an important stimulator of the mitochondrial respiratory chain and production of surfactant.12,13)Primary systemic carnitine deficiency(PSCD)is caused by defects in OCTN2function as a result of mutations in the SLC22A5gene.11)In PSCD,renal L-carnitine reabsorp-tion and entry of long-chain fatty acids into the mitochondrion are decreased,which depletes body carni-tine stores and impairs cellular energy production.14) PSCD is an early-onset disorder with clinical presentation of cardiomyopathy,skeletal myopathy,hypoketotic coma,hypoglycemia,encephalopathy,hyperammonemia and acute liver failure.15,16)In a Japanese study,the inci-dence of PSCD was estimated as1per40,000births.17) SLC22A5polymorphisms in patients with PSCD include both missense and nonsense mutations,as well as inser-tions/deletions and frameshift mutations.15,16)Estimates of the overall carrier frequency have ranged from1:100in a Japanese population17)to1:150–1:480in an Australian population.18)Apart from complete loss-of-function mu-tations,heterozygosity for SLC22A5mutations has also been shown to produce an intermediate carnitine deficiency phenotype,suggesting that even a partial loss of OCTN2function may be detrimental.17)A number of SNPs in the SLC22A5gene have been as-sociated with altered carnitine transport in vitro.In par-ticular,the Trp132X and Pro478Leu19)variants did not support carnitine transport,while the function of the Phe17Leu,Tyr449Asp and the rare Val481Phe variants was significantly decreased compared to the wild-type transporter.20,21)Additional variants that markedly decrease transporter function or that only minimally af-fect function have also been studied in transfected cells.17,19–23)Information on the incidence of polymorphisms in the SLC22A5gene in populations is limited.The aim of the present study was to assess the extent of genetic variation in the SLC22A5gene in Chinese and Indian ethnic groups within the Singaporean population.To our knowledge, this is the first comprehensive analysis of the SLC22A5 gene in Chinese and Indian populations.The establish-ment of the pattern of genetic variability in various racial groups will assist future pharmacogenetic studies in Asi-ans on drugs that are substrates for OCTN2.The present findings may also aid the understanding of differential disease susceptibility in specific population groups.Materials and MethodsHuman genomic DNA samples:Genetic materi-als used in this study were randomly selected from a previously developed cell repository from healthy volun-teers of Chinese and Indian descent.The fully anonymized white cell lines obtained from192individ-uals within the two major ethnic groups of the Sin-gaporean population(Chinese and Indian;n＝96each) were screened in this study.All donors had been recruit-ed previously in accordance with requirements of the ethical review board of the National University Hospital, Singapore,and had provided written informed consent. The mean age was23±4.3years(range20–43)and24±6.3years(range18–46)for Chinese and Indians, respectively.The male:female gender ratio was54:39for Chinese and61:32for Indians.Ethnicity was defined by self-declaration of similar ethnicity over three genera-tions.Genomic DNA was extracted from the immortal-ized lymphocytes by standard methods.PCR and sequence analysis:The exonic frag-ments of the SLC22A5gene were generated using the primer sequences shown in Table1.The amplifications were performed in a total volume of30m l containing 1×Master Mix(Promega,Madison,WI,USA),0.4m M of each primer(Sigma Proligo,Singapore)and60ng of DNA.PCR conditions were pre-denaturation at959C for 5min,followed by35cycles of denaturation at959C for 1min,annealing at609C for1min and extension at 729C for1min;and then a final extension at729C for 10min.PCR products were sequenced using the Big-Dye Ter-minator v3.1Cycle Sequencing Kit and run on the auto-mated ABI Prism Model3100Avant Genetic Analyzer (Applied Biosystems,Foster City,CA,USA).The se-quences were analyzed with Mutation Surveyor TM v3.24 (Softgenetics,State College,PA,USA)and Chromas (Techelysium software).Bidirectional sequencing was performed on novel variants to rule out PCR-associated mutations and sequencing artifacts.Linkage disequilibrium(LD)analysis:All SNPs were tested for Hardy-Weinberg equilibrium and LD be-tween all SNPs was assessed using Haploview software version4.1.24)Pairwise LD coefficients(r2)between the variations were calculated.Results and DiscussionSequence analysis of the SLC22A5gene in DNA from 192Asian subjects resulted in the identification of28 genetic variations,including13that were novel(Table 2).Of these,14were located in the coding exons(9non-synonymous and5synonymous variants),10in the in-trons,1in the promoter region,2in the5?-untranslated region and1in the3?-untranslated region.Six of the9114Dorothy Su Lin T OH,et al.nonsynonymous variants were novel:Glu109Gln, Asp122Tyr,Val175Met,Lys191Asn,Ala214Val and Lys302Glu.Three of the five synonymous variants were novel,resulting in conservation of the codons:Phe23Phe, Leu186Leu and Asn375Asn.These variants were found in individuals of both Chinese and Indian ethnicity.The locations of the nine nonsynonymous variants in the predicted secondary structure of OCTN2are shown in Figure1.The secondary structure shown in Figure1 was based on that provided by Urban et al.20) Using the PolyPhen program(/pph/),the potential functional effects of the novel amino acid substitutions were evaluated.The Asp122Tyr substitution was predicted to have the poten-tial to disrupt function based on the position-specific in-dependent count score differences derived from multiple alignments.In Asp122Tyr-OCTN2,the polar hydrophilic asparagine residue is replaced by a nonpolar hydrophobic tyrosine.The location of the Val175Met residue in the functionally important TMD3may alter the substrate selectivity or specificity of the variant OCTN2transport-er.However,because the amino acid change in Val175Met-OCTN2is conservative,its effect on function may not be pronounced.It is important to note, however,that such predictions based on computational modeling are tentative and require experimental cor-roboration.The SLC22A5gene displays extensive sequence varia-tion,including a large number of nonsynonymous SNPs, as well as SNPs within introns and the5?-and3?-untranslated regions.Most information has emerged from genetic analysis of SLC22A5in individuals with PSCD.However,these studies typically comprised a small number of individuals with a limited subset of OCTN2mutations.The study of Koizumi et al.was large,17)consisting of793Japanese patients,including14 with PSCD.OCTN2mutations were identified in9sub-jects with the Trp132X,Ser467Cys,Trp283Cys and Met179Leu variants detected in3,4,1and1subjects, respectively.It is of interest that the Ser467Cys variant of OCTN2,which is functionally important and has been detected in an individual with partial carnitine deficien-cy,was also detected in our Chinese population.Previ-ously,this variant had only been identified in individuals from Japan.In vitro functional analysis of the missense mutation Ser467Cys also showed that there was a sig-nificant reduction of L-carnitine uptake.17)Other publica-tions have shown that heterozygotes who carry missense or truncated mutations had a consistently low serum free-carnitine phenotype.19,25)The Trp132X variant was also detected in a Chinese subject by Tang et al.,19)whereas Vaz et al.26)and Burwin-kle et al.27)detected another truncating mutation, Arg282X,in patients from Germany and North Africa. Tang et al.detected Arg254X in a Chinese subject with PSCD and in two heterozygous carriers in the control population without PSCD.28)In accord with the latter finding,the Arg254X mutation,which encodes a protein product that is approximately half that of the reference OCTN2,was also observed in our Singaporean Chinese population.There is no information about the carnitine status of the sampled individuals as this was a healthy volunteer cohort and the subjects were not tested for their carnitine levels.Hence it is not possible to deter-mine if individuals with the functional variants such as Ser467Cys and Arg254X had low carnitine transport ac-tivity.In addition to the nonsense variants,there are numerous missense variants of OCTN2.The available in-formation in this regard has been summarized recently by Amat di San Filippo et al.22)Although mutations are found throughout the transporter structure,many are concentrated around the intracellular loop between TMD10and11that is encoded by exon8of SLC22A5; alternate mutations were identified within other TMDs. In the present study,novel missense variants were detect-ed(with their location in the transporter indicated): Glu109Gln and Asp122Tyr(extracellular loop between TMD1and TMD2),Val175Met(TMD3),Lys191Asn (extracellular loop2),Ala214Val(intracellular loop be-tween TMD4and TMD5)and Lys302Glu(intracellular loop between TMD6and TMD7).To our knowledge, this is the first study to report a rare nonsynonymous variant in an Indian population,Asp122Tyr,that may be associated with decreased transport function.The impact of missense mutations on OCTN2func-tion has not been investigated in all studies.Thus,infer-ences on the functional impact of the present SLC22A5 variants on transport are difficult to make.However, Koizumi et al.,found that the activity of Met179Leu-OCTN2was quite well conserved,17)which suggests that the function of Val175Met may also be retained.In con-trast,Wang et al.found that Ala301Asp-OCTN2was es-sentially devoid of transport activity;23)thus,the function of Lys302Glu-OCTN2observed in the present study may also be impaired.Amat di San Filippo et al.reported that the activity of Arg488His-OCTN2,which was also de-tected in the present study,was conserved.21)Most stu-dies of genetic variation in SLC22A5have been under-taken in patients with the PSCD phenotype,and informa-tion on mutation incidence is sparse.In the present study,all novel variants exhibited allele frequencies low-er than0.05and so might not be expected to greatly in-fluence the transport of carnitine and other drug sub-strates of OCTN2in many individuals from Chinese and Indian populations.Further information on SNP incidence appears in another study20)that included four population subsets: African Americans,European Americans,Asian Ameri-cans(which included Chinese Americans and Japanese115Population Genetic Variations of SLC22A5Gene Japanese and Caucasians were submitted to PharmGKB 29)and are summarized in Table 2.Six variants were com-mon to these populations:Leu95Leu,IVS1＋17,Leu269Leu,IVS4＋13,IVS8–34and IVS10＋47.IVS4＋38was present only in our Chinese rma-tion on the frequencies of three additional variants was obtained in PharmGKB:－234C ÀG (white Caucasians:0),－207C ÀG (white Caucasians:0.5)and Ser467Cys (Asian Japanese:0.12).From the International HapMap project,30)the fre-quencies of the variants Leu269Leu and IVS4＋13in both Japanese and Utah residents of northern and western European ancestry were similar to those report-ed by Urban et al.,whereas for IVS4＋38,the frequency in Tokyo Japanese was 0.01.The Arg488His variant,which was also observed in the present study,exhibited a frequency of 0.01in the HapMap database for Italians from the Tuscany region near Florence.Linkage disequilibrium (LD)was assessed across the SNPs in the SLC22A431)and SLC22A5genes in the ethnic groups studied in the present report.Pairwise LD coefficients (r 2)are shown in Figures 2and 3for both the Indian and Chinese subsets,respectively.All SNPs were in Hardy-Weinberg equilibrium (p À0.001,which is the default setting in Haploview)except for two vari-ants in the Chinese subset (IVS2－6T ÀA,IVS4＋37T ÀC in SLC22A4)and one variant in the Indian subset (Met258Ile in SLC22A4).This may have been due to the relatively limited number of subjects that were available analysis.In the Indian subset,absolute LD (r 2＝1)was ob-served for the following SNP combinations in SLC22A5:IVS1－78and IVS1－77,and Leu269Leu and IVS4＋13.Strong LD was observed for the following commonly de-tected SNPs:Thr394Thr in SLC22A4and Leu95Leu,Leu269Leu and IVS4＋13in SLC22A5.A similar pattern of LD was seen in the Chinese subset,which also had three additional SNPs,IVS1＋17,IVS8－34and IVS10－38in SLC22A5,that were in complete LD (r 2＝1).Of note is that the LD of the haplotype associated with sus-ceptibility to Crohn's disease (L503F in OCTN1and G-207C in SLC22A5)has an r 2value of 0.36in our Indian cohort which,as expected,was lower than in patients with Crohn's disease.32)In conclusion,a total of 28genetic variants in the SLC22A5gene were identified in the present study,in-cluding 13that were novel.Among the novel nonsynony-mous variations detected,Asp122Tyr was predicted to significantly modify function.Other nonsynonymous variants that may alter function detected include Ser467Cys and Arg254X,the latter being a truncating mutation and is predicted to result in a truncated protein that is less than half the molecular mass of wild-type OCTN2.The findings from the present study provide fundamental information for pharmacogenetic studies that could be used to investigate the associations of the transporter variations with interindividual differences in the disposition of substrate drugs,especially in Asian populations.116Dorothy Su Lin T OH,et al.Fig.1.Location of nonsynonymous variants in the predicted secondary structure of OCTN2Novel amino-acid substitutions are shown as red circles and bold font.Previously reported amino-acid substitutions that were also found in our population are shown in green circles and in italics.The transmembrane topology diagram was rendered using TOPO2[SJ Johns (UCSF,San Francisco,USA)and RC Speth (Washington State University,Pullman,USA)],transmembrane protein display software available at the UCSF Sequence Analysis Consulting Group website:/TOPO/topo.html).Fig.2.Pattern of linkage disequilibrium (LD)between the SNPs detected in SLC22A4and SLC22A5in Indian subsetPairwise LD is shown for the SNPs analyzed.Values in the cells show the coefficient r 2(×100).Black cells denote r 2＝1,indicating absolute LD,and white cells indicate no LD.117Population Genetic Variations of SLC22A5GeneFig.3.Pattern of linkage disequilibrium between the SNPs detected in SLC22A4and SLC22A5in Chinese subsetPairwise LD is shown for the SNPs analyzed.Values in the cells show the coefficient r2(×100).Black cells denote r2＝1,indicating absolute LD,and white cells indicate no LD.118Dorothy Su Lin T OH,et al.Acknowledgments:We 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原发性肉碱缺乏症临床和基因突变特点及1例产前诊断研究
原发性肉碱缺乏症临床和基因突变特点及1例产前诊断研究崔冬;胡宇慧;唐根;温鹏强;沈丹;廖建湘;陈淑丽【摘要】目的探讨原发性肉碱缺乏症的临床特点、基因突变及产前基因诊断.方法回顾分析8例原发性肉碱缺乏症患儿的临床资料、基因突变分析结果,以及1例患儿母亲再次妊娠羊水细胞产前基因诊断结果.结果 6例男性、2例女性患儿,发病年龄5个月～3岁,以呕吐、腹泻、抽搐、意识障碍等就诊.血浆游离肉碱均降低(0.67～4.184μmol/L),血红蛋白均偏低(67～110 g/L).6例患儿存在不同程度肝功能和心肌酶异常,6例血氨升高,2例血糖降低.心脏彩超示心肌病4例.心电图异常2例.SLC22A5基因共检出6种突变,分别为c.760C>T(p.Arg254X)、c.1400C>G(p.Ser467Cys)c.844dupC(p.R282PfsX10)、IVS2+1G>T、c.3G>T(p.Met1Ile)、c.338G>A(p.Cys113Tyr).1例患儿染色体微阵列分析显示5q23.3q31.3区域存在大片段杂合性缺失.1例患儿母亲再次妊娠18周时的羊水细胞检出c.760C>T杂合突变,提示胎儿为携带者,出生后外周血SLC22A5基因存在一个c.760C>T杂合突变位点,血浆游离肉碱浓度无异常.除1例患儿猝死外,其余7例经左卡尼汀治疗有效,随访中.结论原发性肉碱缺乏症患儿起病急,心肌、肝脏损伤尤为突出,左卡尼汀治疗效果肯定.SLC22A5基因分析可作为确诊和产前诊断的依据.【期刊名称】《临床儿科杂志》【年(卷),期】2019(037)006【总页数】5页(P449-453)【关键词】原发性肉碱缺乏症;心肌病;游离肉碱;SLC22A5基因;左卡尼汀【作者】崔冬;胡宇慧;唐根;温鹏强;沈丹;廖建湘;陈淑丽【作者单位】汕头大学医学院附属深圳市儿童医院儿科研究所广东深圳 518038;汕头大学医学院附属深圳市儿童医院遗传代谢专科广东深圳 518038;汕头大学医学院附属深圳市儿童医院儿科研究所广东深圳 518038;汕头大学医学院附属深圳市儿童医院儿科研究所广东深圳 518038;汕头大学医学院附属深圳市儿童医院检验科广东深圳 518038;汕头大学医学院附属深圳市儿童医院遗传代谢专科广东深圳 518038;汕头大学医学院附属深圳市儿童医院检验科广东深圳 518038【正文语种】中文原发性肉碱缺乏症（primary carnitine deficiency，PCD，MIM212140）是一种线粒体β氧化障碍性疾病，属常染色体隐性遗传，是SLC22A5基因突变所致肉碱转运蛋白OCTN2功能缺陷。
肉碱转运障碍(原发性肉碱缺乏、肉碱摄取障碍)
三、临床表现
• 此症主要造成心肌、中枢神经系统及肌肉骨骼三方面的症状；在疾病 初期，患者易发生低酮体性低血糖的脑神经病变，而出现昏睡、意识 混乱，甚至是昏迷的情形发生。若未能及时的给予肉毒碱补充，而出 现反覆性的脑神经病变，可能导致患童出现发展迟缓及中枢神经功能 失常的情形。此外，长期低酮体性低血糖的症状，易进而造成肝肿大、 肝脏脂肪变性(Steatosis)、肝功能指数上升及高血氨症。在心脏方面， 较大的患童可能出现心脏肥大等心肌病变，并易进展成心衰竭。在肌 肉方面，常出现虚弱、肌肉低张力及肌肉无力的情形。此外，肉碱缺 乏也会造成肠胃蠕动不良，造成反覆性的腹痛与腹泻。贫血及反覆性 感染也是常见症状。虽然在出生后个案的肉碱代谢即发生异常，但由 于疾病的初期症状较不易察觉，因此若未及早诊断，此症患者的第一 次发病就可能会导致猝死。
四、诊断
• 在实验室检验项目上，可检验患者血液及尿液中的肉碱浓度、血氨、 血糖、尿酮、肝功能、电解质、尿酸、CK（肌肝酸）值、乳酸及凝 血功能等数值。
• 可经心脏超音波、X光等影像学检查，以了解是否发生心脏肥大的情 形。
• 在疾病确诊上，为经皮肤切片，以检测细胞中的酵素活性，或抽血经 分子生物技术进行缺陷基因的检测。目前国内将Tandem Mass串联 质谱仪的技术应用于新生儿筛检上，将可能因此可以早期检测出患者， 以于早期提供治疗，预防脑部及心脏等器官发生病变。
五、治疗
• 在治疗上，平时可口服补充肉碱，并避免饥饿及禁食的情形发生，以 防症状的恶化。当急性发作，而出现低酮性低血糖的脑神经病变时， 则应先给予患者葡萄糖静脉输液；若已确认为此症患者，则可经由静 脉补充肉碱，以提升组织内的肉碱含量，将有利于粒线体内的脂肪酸 运输及代谢。长期治疗的患者，可以口服的方式补充肉碱。
原发性肉碱缺乏症(总结)
原发性肉碱缺乏症一、发病机理机体内，肉碱通过细胞膜上肉碱转运蛋白的转运进入细胞内，肉碱转运蛋白存在于心肌、骨骼肌、小肠、肾小管、皮肤成纤维细胞及胎盘等组织细胞膜上，其编码基因SLC22A5突变导致肉碱转运蛋白无法定植于细胞膜上或功能区不同程度受损，肉碱不能被转运至细胞内，通过肠道吸收的肉碱减少，体液中游离肉碱相应减少。
同时肾小管肉碱重吸收障碍致尿液肉碱排泄增加、血浆肉碱水平降低，细胞内肉碱更加缺乏。
肉碱的主要功能是协助长链脂肪酸转运进入线粒体内参与β氧化，肉碱缺乏导致长链脂肪酸不能进入线粒体而在细胞质中蓄积，同时脂肪酸氧化代谢途径能量生成减少，并间接影响葡萄糖有氧氧化、糖异生、酮体生成等其他代谢途径，进而出现一系列生化异常及脏器损害，尤其当需要脂肪酸作为主要能量来源时，组织不能得到足够能量，而脂质等有毒物质大量蓄积，导致脏器损害。
1、心脏损伤机制患儿常见的心肌损害有心室扩大、心肌肥厚、心功能下降甚至衰竭、心律失常等。
发病机制主要与能量缺乏和脂肪酸等的毒性作用有关。
正常心肌能量供应的60%～90%来自脂肪代谢，肉碱缺乏导致细胞能量不足，引起心肌收缩力降低，促进心肌重构，而脂肪酸的堆积加速了心肌不可逆的损伤过程。
且游离脂肪酸可改变心肌细胞电活动导致心律失常。
心肌脂肪酸代谢障碍导致主要能量来源由脂肪酸向葡萄糖转变，尤其在心肌细胞缺血缺氧时，能量代谢以无氧酵解为主，心肌细胞内ATP和磷酸肌酸生成更少，H+增多，加重心肌细胞结构和功能损害。
2、骨骼肌损伤机制骨骼肌受累的患儿常表现为肌无力、肌张力减退、运动不耐受或肌痛等，血中肌肉型肌酸激酶升高，肌肉活检显示肌纤维内大量脂滴沉积。
损害机制与供能不足及脂质沉积有关。
对于持续时间较长的低到中等强度的运动，长链脂肪酸是能量的主要来源。
骨骼肌细胞内肉碱缺乏导致线粒体脂肪酸氧化障碍，不能提供机体运动所需的能量，导致运动强度和耐力下降，抗疲劳能力减退。
而肌痛可能与脂肪酸及代谢中间产物蓄积有关。
原发性肉碱缺乏症
诊断
确诊原发性肉碱缺乏症需要依赖血清或组织肉碱谱检测，患者游离肉碱显著降低， 酯酰肉碱正常或降低。通过基因分析或皮肤成纤维细胞肉碱转运功能检测，可进一步 确定诊断。利用串联质谱技术分析血清酯酰肉碱谱有助于观察患者脂肪酸氧化状况， 国内外已应用于新生儿筛査。
治疗
患儿平时应注意预防低血糖、避免饥饿、多餐饮食、避免长时间运动，一般 无特殊饮食要求。对于病情危重的患儿,还应积极对症支持治疗。患儿对左旋肉 碱治疗敏感，尤其在不可逆病变（如中枢神经系统损伤）发生之前应用，预后较 好。经左旋肉碱治疗后,患儿症状显著缓解，心功能迅速改善.心脏大小及心室壁 厚度缩小，肌力及肌张力逐渐恢复，肝功能好转，肝脏缩小，智力、运动及生长 发育正常。
实验室检查
除低血糖、低血酮外，代谢性酸中毒、高血氨较常见，部分患儿有肝功能异 常、肌酸激酶轻度升高。腹部超声提示肝大、脂肪肝。胸片可提示心影增大，心 电图示各种心律失常、左心室肥厚、QT间期延长、T波增高等，超声心动图常发 现心脏扩大、室壁肥厚、射血分数降低、心肌收缩力减弱、继发性二尖瓣关闭不 全等。肌肉活检提示脂质沉积性肌病，见大量脂质沉积于I型纤维，而II型纤维 出现萎缩。
原发性肉碱缺乏症
基本介绍
原发性肉碱缺乏症又称肉碱转运蛋白缺陷，由于编码肉碱转运蛋白的基因突 变引起，属于常染色体隐性遗传病。肉碱缺乏导致长链脂肪酸不能进入线粒体参 与氧化，当机体需要脂肪动员供能时，组织不能得到足够能量，且细胞内脂质蓄 积，继而出现一系列生化异常及脏器损害，如低酮性低血糖、扩张型心肌病、肝 大、肌无力等。
临床表现
临床表现个体差异大，既可表现为急性能量代谢障碍危象，甚至猝死，也可 表现为心肌、骨骼肌、肝脏等组织的慢性进行性损害，表现肌无力、肌张力减退、 肌痛、不能耐受运动,心功能不全，反复腹痛、腹泻、食欲下降、呕吐、胃食管反 流等胃肠道症状。另外、贫血、发育迟缓、反复感染、癫痫等也有报道。近几年. 随着新生儿疾病筛检的开展，也发现了一些发育良好、无症状的患儿。感染、饥 饿等应激状态可诱发患儿出现急性能量代谢障碍危象，表现为低酮型低血糖症。
经基因分析确诊的原发性肉碱缺乏症1例并文献复习
2019 年4月第6卷/第10期V ol.6, No.10 Apr. 2019全科口腔医学电子杂志Electronic Journal Of General Stomatology119·病例报告·经基因分析确诊的原发性肉碱缺乏症1例并文献复习李妍涵（中国医学科学院血液病医院（血液学研究所）实验动物中心，天津 300020）【摘要】目的 分析1例经基因分析确诊的原发性肉碱缺乏症患儿的临床及遗传学特点。
方法 回顾性分析1例原发性肉碱缺乏症患儿的临床经过，采用桑格尔测序进行致病基因分析，并进行文献复习。
结果 女性患儿，于3个月出现反应差、呕吐及嗜睡，经血糖、血液氨基酸、酯酰肉碱谱分析及影像学检查考虑原发性肉碱缺乏症可能性大。
SLC22A5基因分析发现c.1400C＞G（p.S467C）纯合突变。
结论 患儿存在低酮症性低血糖、肝肿大、心肌病及高脂血症时，要考虑原发性肉碱缺乏症的可能，SLC22A5基因析有助于确诊。
【关键词】原发性肉碱缺乏症；SLC22A5基因；脂肪酸氧化障碍；遗传代谢病【中图分类号】R446 【文献标识码】A 【文章编号】ISSN.2095-8803.2019.10.119.02原发性肉碱缺乏症（primary carnitine deficiency，PCD，MIM#212140），是一种罕见的常染色体隐性遗传病，影响脂肪酸代谢，以低酮性低血糖、心肌病、肝肿大、高脂血症等为主要特征。
该病若不经及时治疗，可导致猝死[1]。
我国研究中，该病上海发病率约为1/45 000[2]，浙江为1/22 384[3]，南京为1/22 384[4]。
本文就一例经基因诊断明确的中国原发性肉碱缺乏症患儿的诊疗经过、基因突变特点进行研究，并结合文献进行分析。
1 资料与方法1.1 一般资料患儿，女，为第1胎，足月顺产，出生体重4000 g，Apgar评分1分钟10分，5分钟10分。
患儿为母乳喂养，于3个月出现反应差及呕吐，呕吐物为胃内容物，呕吐约一天2-3次，为非喷射性，和进食无关，并出现嗜睡。
肉碱-酰基肉碱移位酶缺乏症研究进展
肉碱-酰基肉碱移位酶缺乏症研究进展发表时间：2018-09-03T14:00:26.850Z 来源：《医药前沿》2018年8月第24期作者：范歆张强[导读] 肉碱-酰基肉碱移位酶缺乏症是一种罕见的脂肪酸代谢障碍疾病，病情进展快，死亡率高。
（广西壮族自治区妇幼保健院遗传代谢中心实验室广西南宁 530000）【摘要】肉碱-酰基肉碱移位酶缺乏症是一种罕见的脂肪酸代谢障碍疾病，病情进展快，死亡率高。
通过临床特点及血酰基肉碱谱分析及尿有机酸分析，进一步通过基因诊断、酶活性分析可确诊。
治疗原则避免空腹时间过长，高碳水化合物、低脂饮食，补充甘油三酯等。
【关键词】脂肪酸代谢；肉碱酰基肉碱移位酶【中图分类号】R596 【文献标识码】A 【文章编号】2095-1752（2018）24-0015-03 肉碱-酰基肉碱移位酶缺乏症（Carnitine-acylcarnitine Translocase Deficiency, CACT Deficiency, OMIM 212138）是由于肉碱-酰基肉碱移位酶缺陷，导致长链酰基肉碱不能进入线粒体内膜参与β氧化导致的一系列能量代谢障碍，累及心脏、肝脏、骨骼肌等重要器官[1]。
随着串联质谱遗传代谢病筛查技术的发展，对该病的筛查和诊断提供有力的支持。
本文将该病的发病机制、临床表现、实验室检查、分子病因以及治疗等方面作一综述。
1.CACT的概述CACT缺乏症为罕见的常染色体隐性遗传，该病最早在1992年被报道，相关致病基因在1997年被确认[2-3]。
文献报道国外发病率在0.2～1.8/10万，我国的发病率不详[4]，浙江省对180万新生儿筛查的数据总结中，未确诊本病患者[5]；湖南省约15万新生儿筛查资料中，确诊2例，发病率约为1/76895[6]；香港发病率约为1/60000[7]。
绝大部分已报道的病例预后不良，约82%的患者于新生儿期发病，该病主要累及大脑、心脏、骨骼肌等，主要表现为抽搐、昏迷、心率失常和肌无力等，病情进展快，死亡率高。
菏泽市新生儿原发性肉碱缺乏症串联质谱筛查分析
菏泽市新生儿原发性肉碱缺乏症串联质谱筛查分析作者：***来源：《中国现代医生》2022年第07期[摘要] 目的了解原發性肉碱缺乏症（PCD）在菏泽市新生儿中的发病率，并对基因突变特点、治疗及预后进行分析。
方法利用串联质谱技术对2016年1月至2020年12月258 682例新生儿进行血酰基肉碱谱检测，对初筛游离肉碱（C0）低于9 μmol/L伴有多个酰基肉碱下降的新生儿及母亲进行串联质谱、二代测序基因检测。
结果共确诊游离肉碱缺乏症21例，其中9例原发性肉碱缺乏症，11例母源性肉碱缺乏症，1例父源性肉碱缺乏症。
8例进行基因检测，其中7例检测到2个等位基因（孩子5例、母亲1例、父亲1例）、杂合1例。
SLC22A5基因共发现10种基因突变位点：c.1400C>G、c.51C>G、c.95A>G、c.865C>T、c.680G>A、c.761G>A、c.760C>T、c.952-21C>G、c.572A>G、c.1229G>A。
其中c.952-21C>G、c.572A>G 以及c.1229G>A，均为新发突变位点。
结论利用串联质谱技术筛查结合二代测序技术可早期检出原发性或母源性肉碱缺乏症。
经左卡尼汀治疗的患儿预后良好，可有效预防猝死。
菏泽市新生儿原发性肉碱缺乏症患病率约为1/28 743，与国内已报道的发病率接近。
基因检测发现10种SLC22A5基因突变位点，其中c.1400C>G位点在菏泽市出现频率较高，3个新发突变位点，新突变的位点丰富了SLC22A5基因的突变图谱。
[关键词] 原发性肉碱缺乏症;串联质谱;SLC22A5基因;新生儿[中图分类号] R722.11;R363.25 [文献标识码] B [文章编号] 1673-9701（2022）07-0154-04Screening analysis of neonatal primary carnitine deficiency by tandem mass spectrometry in HezeWANG YufengNeonatal Disease Screening Center，Heze Maternal and Child Health and Family Planning Service Center， Heze 274000， China[Abstract] Objective To investigate the incidence of primary carnitine deficiency（PCD） in newborns in Heze， and to analyze the characteristics， treatment and prognosis of gene mutation. Methods The blood acylcarnitine carnitine profiles of 258 682 neonates from January 2016 to December 2020 were detected by tandem mass spectrometry， and the primary screened neonates and mothers with free carnitine （C0） less than 9 umol/L and multiple acyl carnitine decreases were subjected to tandem mass spectrometry and second-generation sequencing gene detection. Results A total of 21 cases of free carnitine deficiency were diagnosed， including 9 cases of primary carnitine deficiency， 11 cases of maternal carnitine deficiency and 1 case of paternal carnitine deficiency. Gene detection was performed in 8 cases， of which 2 alleles （5 children， 1 mother， 1 father）and 1 heterozygosity were detected in 7 cases. Ten mutation sites of SLC22A5 gene were found：c.1400C > G， c.51C > G， c.95A > G， c.865C > T， c.680G > A， c.761G > A， c.760C > T，c.952-21C > G， c.572A > G， c.1229G > A. Among them， c. 952-21C > G， c. 572A > G and c. 1229G > A were all new mutation sites. Conclusion The screening by tandem mass spectrometry combined with second-generation sequencing can detect primary or maternal carnitine deficiency in the early stage. Children treated with levocarnitine have a good prognosis， which can effectively prevent sudden death. The prevalence rate of PCD in newborns in Heze is about 1/28743， which is close to the incidence reported in China. Ten kinds of mutation sites of SLC22A5 gene were found by gene detection， among which c. 1400C > G site appeared more frequently in Heze， and there were 3 new mutation sites. The new mutation sites enriched the mutation map of SLC22A5 gene.[Key words] Primary carnitine deficiency; Tandem mass spectrometry; SLC22A5 gene; Newborn原发性肉碱缺乏症（primary carnitine deficiency，PCD）是由于细胞膜肉碱转运蛋白的编码基因SLC22A5突变致脂肪酸β氧化障碍而引发的遗传方式为常染色体隐性遗传的疾病[1]。
原发性肉碱缺乏症汇报ppt课件
根据临床表现和基因突变类型，原发性肉碱缺乏症可分为经典型、新生儿型和晚发型三种类型。经典型患者在新 生儿期即出现症状，病情较重；新生儿型患者在出生后数天内出现症状，病情相对较轻；晚发型患者则在儿童期 或成年期出现症状。
诊断标准与鉴别诊断
诊断标准
原发性肉碱缺乏症的诊断主要依据临床表现、生化检查和基因检测结果。临床表现包括 低血糖、高血氨、肝性脑病等；生化检查可发现血氨升高、血糖降低、乳酸升高等异常
对症治疗
02
针对患者可能出现的并发症，如低血糖、酮症酸中毒等，医生
应制定相应的对症治疗方案。
避免使用干扰脂肪代谢的药物
03
某些药物可能干扰脂肪代谢，加重肉碱缺乏症状。因此，在治
疗过程中应避免使用这些药物。
患者教育及心理支持
疾病知识教育
向患者及其家属详细解释原发性肉碱缺乏症的病因、症状 、治疗及预后等知识，提高他们对疾病的认识和理解。
06
家庭护理及康复训练指导
家庭护理要点
饮食调整
提供高蛋白、低脂肪的饮食，避免长时间空 腹，以防止低血糖和酮症的发生。
规律作息
注意家居安全，避免患者受到外伤，同时防 止自伤行为。
安全防护
建立规律的作息习惯，保证充足的睡眠和休 息，避免过度劳累。
病情监测
定期监测患者的生化指标、营养状况及病情 变化，及时调整治疗方案。
康复训练计划制定
01
运动训练
根据患者的年龄和身体状况， 制定个性化的运动训练计划， 如力量训练、耐力训练等，以 提高身体素质和减少并发症。
02
语言训练
针对患者的语言障碍，进行语 言训练，包括发音、词汇、语 法等方面的练习，提高语言表 达能力。
03
原发性肉碱缺乏症
损伤) 发生之前应用，预后较好。
[16]Jalil MA，Horiuchi M，Wakamatsu M，et al. Attenuation of cardi-ac hypertrophy in carnitine-deficient juvenile visceral steatosis (JVS) mice achieved by lowering dietary lipid [J]. J Biochem, 2006，139(2)：263-270.
6.治疗
●PCD患者需终身服用左旋肉碱，突然停药可使血浆肉碱浓度迅速下降，
出现反复Reye综合征样发作、甚至猝死[18]
●对于无症状的PCD患者，补充左旋肉碱，可有效预防发病及猝死
●应用左旋肉碱治疗PCD杂合子还没有共识，但有研究发现心功能不全
的杂合子补充肉碱后心脏情况得到改善[19]
[18]Hwu WL，Chien YH，Tang NL，et al. Deficiency of the carni-tine transporter (OCTN2) with partial N-acetylglutamate synthase (NAGS) deficiency [J]. J Inherit Metab Dis，2007，30(5)：816. [19]Sarafoglou K，Tridgell AH，Bentler K，et al. Cardiac conduction improvement in two heterozygotes for primary carnitine deficiency on L-carnitine supplementation [J]. Clin Genet， 2010，78(2)： 191-194.
原发性肉碱缺乏症发病机制及基因突变研究进展
原发性肉碱缺乏症发病机制及基因突变研究进展陈锦国（东莞市妇幼保健院，广东 东莞 523002）【摘要】随着现代医疗水平的不断提升，对各种疾病的干预与治疗均有显著突破，但在进行疾病研究与治疗之前，需要充分了解疾病的发病机制，对其形成过程详细了解，并定位诱发因素，锁定研究目标，从而逐步探索疾病治疗工作。
本文主要针对原发性肉碱缺乏症的发病机制及基因突变相关因素的研究进行如下综述。
【关键词】原发性肉碱缺乏症；发病机制；基因突变；研究进展【中图分类号】R725.9…【文献标识码】A…【文章编号】2096-5249（2023）24-0195-04原发性肉碱属于肉碱转运体功能缺陷类疾病，该病可对机体多个器官的正常运行造成影响，同时也可诱发患者出现不同的临床症状；我国针对该病近些年展开诸多研究，并在疾病早期诊断筛查与治疗中均出现突破性进展；下文重点讲述肉碱对机体运行的重要性以及其相关疾病形成过程。
1 肉碱概述肉碱是一种类氨基酸，属于季铵阳离子复合物，也属于一种小分子水溶性化合物，该物质广泛存在动物源食物之中，植物源性食物中也存在，但含量相对较少；肉碱可通过生物合成的方法从赖氨酸及蛋氨酸中合成；肉碱存在两种立体异构，分别为左旋肉碱、右旋肉碱，其中左旋肉碱最早在作为黄粉虫的生长因子被发现，随着医学研究的不断深入，发现很多生物细胞中存在左旋肉碱，该成分在脂肪新陈代谢过程中，是脂肪酸从胞质溶胶运送到线粒体内重要成分，同时该过程也是代谢脂肪重要物质之一，可有效减少脂肪酸在细胞内的不断积聚。
2 原发性肉碱缺乏症2.1 原发性肉碱缺乏症概述原发性肉碱缺乏症是一种肉碱转运体功能缺陷类疾病，该病属于脂肪酸氧化代谢疾病，为常染色体隐性进遗传病。
在相关研究报道中显示原发性肉碱缺乏症可导致患者CoA生成减少，并继发其机体出现一些生化指标异常，直接损害脏器，可诱发的疾病类型包括肌无力、肝肿大、扩张型心肌病、低酮型低血糖等；随着串联质谱技术的应用，对新生儿筛查及临床高危疾病诊断率明显提升，同时也相对增加原发性肉碱缺乏症病例数量[1]。