因预防接种诱发急性脑病的甲基丙二酸尿症cblA型一例

目的 报道1例因预防接种诱发急性脑病的中国甲基丙二酸尿症的cblA型病例.方法 就病例临床、血液酯酰肉碱谱、尿有机酸、甲基丙二酸尿症相关基因等特点进行分析.结果 患儿男,1岁3个月时因“间断呕吐、酸中毒、发育落后8个月”就诊.患儿生后7个月内发育正常,7个月时接种乙肝疫苗后lh出现呕吐、昏迷.临床诊断“中度脱水,电解质紊乱,代谢性酸中毒”,经补液等治疗后好转.此后,患儿发育落后,间断呕吐.1岁3个月时接种百白破疫苗,接种3h后再次出现呕吐,嗜睡,静脉补液后未见好转,7d后喘憋、呼吸困难、昏迷.患儿血液丙酰肉碱16.3μmol/L(参考值1.0 ～ 5.0μmol/L)、丙酰肉碱/游离肉碱0.27(参考值0.03 ～0.25)增高,尿甲基丙二酸(388.21 mmol/mol肌酐,参考值0.2～3.6 mmol/mol肌酐)及其代谢产物浓度显著增高,血浆总同型半胱氨酸浓度正常,符合单纯型甲基丙二酸血症,MMAA基因存在c.650 T＞A(p.L217X)和c.742 C＞T(p.Q248X)复合杂合突变,确诊为cblA型.经羟钴铵肌内注射、左卡尼汀、低蛋白饮食及特殊配方奶粉治疗后,患儿病情逐渐好转.患儿现2岁7个月,智力运动正常.结论 报道我国首例因预防接种诱发急性脑病的cblA型甲基丙二酸尿症.对疑似遗传代谢病患儿,预防接种前的代谢筛查是减少意外的关键.     

上呼吸道感染患儿口服尼美舒利后发生瑞氏综合征及猝死样症状

患儿，男，6岁3个月，2个月前因上呼吸道感染、发热，父母参照说明书予以尼美舒利口服，半小时后抽搐，呼吸心跳骤停，急诊检查发现低酮性低血糖，代谢性酸中毒，血清转氨酶及肌酶显著升高，肾功能受损。经积极复苏治疗后患儿意识及生命体征恢复，但是智力、运动严重倒退。患儿血液游离肉碱降低，中长链酯酰肉碱增高，尿液戊二酸、3-羟基戊二酸、异戊酰甘氨酸、乙基丙二酸等增高，提示多种酯酰辅酶A脱氢酶缺乏症。经维生素B₂、左卡尼汀、苯扎贝特等治疗后患儿病情逐渐好转，3个月后复查生化指标恢复正常。患儿ETFDH基因存在复合杂合突变，c.341G > A（p.R114H）为已知突变（来自母亲），c.1484C > G（p.P495R）为未报道的新突变（来自父亲）。患儿最终确诊为多种酰基辅酶A脱氢酶缺乏症，因发热服用尼美舒利诱发急性代谢危象，导致瑞氏综合征、猝死样发作。遗传代谢病是导致瑞氏综合征、猝死的一组主要病因，生化及基因分析是识别潜在疾病的关键。     

遗传性代谢病致儿童脑发育落后的治疗与预后

目的探讨遗传性代谢疾病致儿童脑发育落后中治疗及影响预后的相关因素。方法用串联质谱仪对278例原因不明的脑发育落后患儿进行血氨基酸谱和酰基肉碱谱筛查,对疑似代谢性疾病患儿进行尿气相色谱/质谱（GC/MS）及相关酶活性检测,对检出的遗传性代谢病患儿的临床资料进行综合分析。结果17/278例（6.15%）确诊为遗传性代谢病,其中甲基丙二酸血症4例,甲基丙二酸血症伴同型胱氨酸尿症4例,丙酸血症3例,鸟氨酸氨甲酰转移酶缺乏症、枫糖尿病、Ⅰ型戊二酸血症、异染色性白质脑病、苯丙酮尿症、生物素酶缺乏症各1例。临床表现为智能及运动发育落后或倒退、惊厥、昏迷、呕吐、肌张力降低、营养不良、嗜睡、反复感染等。实验室检查显示代谢性酸中毒、血氨及血乳酸增高、贫血等。MRI表现为脑萎缩、双侧脑白质T2w高信号或伴T1w低信号、多发性脑软化或囊样变等。起病早、伴严重酸中毒及昏迷的维生素B12无效型甲基丙二酸血症预后极差。患儿经特殊奶方、低蛋白饮食、肉碱、维生素B12及生物素等治疗后,好转11例,死亡5例,未愈1例。结论对原因不明的脑发育落后患儿应予遗传代谢性病筛查;早期、合理治疗有助于改善预后。     

迟发型3-羟基-3-甲基戊二酸尿症导致脑白质病

3-羟基-3-甲基戊二酸尿症是一种罕见的有机酸代谢病,病因为常染色体隐性遗传所导致的3-羟基-3-甲基戊二酰辅酶A裂解酶缺陷。患者通常在新生儿期至婴幼儿期发病。本研究报告1例晚发型3-羟基3-甲基戊二酸尿症导致的脑白质病。患儿为7岁男孩,急性起病,表现为头痛、困倦、呕吐, 进行性加重,一般化验发现肝损害、酮症、白细胞减少,脑磁共振扫描示双侧脑白质对称弥漫性病变。血液羟异戊酰肉碱、乙酰肉碱显著增高。尿液3-羟基-3-甲基戊二酸显著增高,3-甲基戊烯二酸、3-羟基戊二酸、甲基巴豆酰甘氨酸增高。经静脉滴注葡萄糖和左旋肉碱症状缓解。维持治疗半年后复诊,尿3-羟基3-甲基戊二酸降低,全身情况良好。     

先天性遗传代谢病的早期诊断

目的提高儿科医生对新生儿期遗传代谢病的认识,做到早期诊断、早期治疗.方法自2003年9月至2004年9月,根据临床表现确定18名遗传代谢病高危患儿,用"滤纸片代"将采集的尿标本外寄进行气相色谱-质谱(GC/MS)分析,筛查遗传代谢病.结果 18例高危儿中确诊为遗传代谢病5例,分别为戊二酸尿症Ⅱ型1例(46h,男),鸟氨酸氨甲酰转移酶缺陷1例(66h,男),枫糖尿病1例(8 d,男),甲基丙二酸血症1例(13 d,男),丙酸血症1例(21 d,女),并对其临床特点进行归纳总结.结论掌握新生儿遗传代谢病临床特点,对高危儿早期进行尿GC/MS分析,可以早期诊断遗传代谢病,有利于优生优育.     

丙酮酸脱氢酶复合物缺陷Leigh 综合征2 例临床及PDHA1基因分析

目的探讨PDHA1基因突变所致丙酮酸脱氢酶复合物E1α亚单位缺陷Leigh综合征的临床特点及诊断和治疗。方法回顾分析2例因发育落后就诊,磁共振扫描提示Leigh综合征,并经生化代谢及基因检测确诊患儿的临床资料。结果 2例男性患儿分别于1岁1个月、4个月就诊,发育落后,肌张力障碍,肌力低下;头颅磁共振检查发现双侧基底节区对称性损害;血清丙酮酸、乳酸明显增高,血氨基酸及酯酰肉碱谱无异常。基因分析发现2例患儿X染色体PDHA1基因分别存在c.615CG、c.605AG错义突变,均为未报道的新突变,证实为丙酮酸脱氢酶复合物E1α亚单位缺陷所致Leigh综合征。结论 PDHA1基因突变患儿临床表现复杂多样,对于不明原因的发育落后儿童,应注意线粒体病的可能,基因检测有助于诊断、治疗及遗传咨询。     

气相-色谱质谱法尿有机酸检测诊断遗传代谢病患儿的疾病谱

目的了解气相色谱-质谱技术检测尿有机酸水平诊断的遗传代谢病患儿的氨基酸、有机酸、脂肪酸氧化代谢病疾病谱。方法回顾性分析2005年1月至2021年12月上海交通大学医学院附属新华医院诊断为遗传代谢病的2 461例患儿的疾病谱, 患儿均通过气相色谱-质谱尿有机酸谱检测, 并结合血串联质谱氨基酸及酰基肉碱检测结果及基因变异检测结果诊断。结果 2 461例患儿中男1 446例, 女1 051例, 共有32种遗传代谢病, 其中氨基酸代谢病10种662例(26.9%), 常见的前6种疾病为高苯丙氨酸血症、希特林蛋白缺乏症、鸟氨酸氨甲酰转移酶缺乏症、枫糖尿病、尿黑酸尿症及酪氨酸血症-Ⅰ型;有机酸血症17种1 683例(68.4%), 常见的前6种疾病为甲基丙二酸血症、丙酸血症、戊二酸血症-Ⅰ型、异戊酸血症、3-甲基巴豆酰辅酶A羧化酶缺乏症及多种羧化酶缺乏症;脂肪酸β氧化代谢病5种116例(4.7%), 常见的前2种疾病为多种酰基辅酶A脱氢酶缺乏症和短链酰基辅酶A脱氢酶缺乏症。结论气相色谱-质谱技术尿有机酸谱检测诊断的疾病中有机酸血症最常见, 然后为氨基酸代谢病及脂肪酸氧化代谢病。     

尿素酶预处理-气相色谱-质谱法选择性筛查遗传代谢病高危患儿327例初步研究

目的　通过对遗传代谢病高危患儿尿液成分进行生化分析 ,筛查遗传代谢病 ,为临床诊断和治疗提供实验依据。方法　收集遗传代谢病高危患儿尿液标本 ,经去尿素、加内标、除蛋白、真空干燥、三甲基硅烷基衍生等处理后 ,应用气相色谱 -质谱联用仪分析尿液中有机酸、氨基酸、糖类、多醇、嘌呤、嘧啶等成分。这一流程在国际上被称为尿素酶预处理 气相色谱 质谱法。结果　对来自中国大陆 6省、区和直辖市的 3 2 7例遗传代谢病高危患儿的尿液标本进行检测 ,共筛查出遗传代谢病 16种 2 7例 ,阳性率为 8.2 6% ,其中高苯丙氨酸血症、甘油尿症和Leigh综合征各 3例 ,丙酸血症、甲基丙二酸尿症、vonGierke病、果糖 1,6 二磷酸酶缺陷病、果糖尿症各 2例 ,多种羧化酶缺陷病、戊二酸血症Ⅰ型、枫糖尿病、高甘氨酸血症、3 氨基异丁酸尿症、半乳糖血症、瓜氨酸血症Ⅱ型及Fanconi综合征各 1例。经临床干预虽然仍有部分患儿预后不良 ,但多种羧化酶缺陷病、甲基丙二酸尿症、半乳糖血症等患儿获得较好的治疗效果。其余患儿的病情有待追踪观察。结论　应用尿素酶预处理 气相色谱 质谱法分析尿液成分 ,是筛查某些遗传代谢病的有效方法 ,检测结果可为患儿的诊断和治疗提供有效指导。     

新生儿全血细胞减少伴代谢异常

患儿,男,9d,急性起病,表现为咳嗽、气促、喂养困难、嗜睡、昏迷。辅助检查提示肺部感染、严重代谢性酸中毒、高血糖、高血氨、血象三系减少。为查明病因,进行了血液酯酰肉碱谱及尿液有机酸分析及基因诊断。结果发现：血异戊酰肉碱及尿异戊酰甘氨酸和3-羟基异戊酸显著升高,游离肉碱降低,提示异戊酸血症 （IVA）;基因检测提示第12号外显子纯合突变c.1208A > G （p.Tyr403Cys）,父母为杂合突变携带者。经低亮氨酸饮食、左卡尼汀等治疗后症状稍改善,但1周后患儿死亡。新生儿肺炎是新生儿常见感染,但可能是遗传代谢病患儿的诱发因素,因此对于肺炎起病的伴有难以解释的代谢异常患儿,应进行遗传代谢性疾病筛查。     

以急性脑干脑炎及脊髓炎起病的单纯型甲基丙二酸尿症1例

MUT 基因突变引起的甲基丙二酰辅酶A 变位酶缺陷是我国单纯型甲基丙二酸尿症的主要病因。该文报道我国首例以急性脑干脑炎和脊髓炎样形式起病的MUT 型患者,探讨甲基丙二酸尿症的复杂临床表型。患儿,女,3 岁2 个月时因发热伴肢体进行性无力3 d,呼吸困难伴意识障碍1 d 就诊。头颅MRI 扫描提示双侧苍白球及脑干背侧对称片状高信号,脊髓MRI 扫描提示急性脊髓炎样改变。临床诊断为"病毒性脑炎、中枢型呼吸衰竭?",血液丙酰肉碱(6.83 μmol/L,参考值1.0~5.0 μmol/L)增高,尿甲基丙二酸(133.2 mmol/mol肌酐,参考值 0.2~3.6 mmol/mol 肌酐)显著增高,血清总同型半胱氨酸正常。MUT 基因存在c.1663C>T 和c.1630_1631GG>TA 突变,其中c.1663C>T(p.A555T)为新突变,确诊为MUT 型甲基丙二酸尿症。经特殊饮食、维生素B12、左卡尼汀治疗后,患儿病情逐渐好转。甲基丙二酸尿症临床表现复杂,早期的代谢筛查及基因诊断是鉴别病型、指导治疗的关键技术。     

Nail matrix arrest in the course of hand, foot and mouth disease

Onychomadesis describes complete nail shedding from the proximal portion; it is consecutive to a nail matrix arrest and can affect both fingernails and toenails. It is a rare disorder in children. Except for serious generalised diseases or inherited forms, most cases are considered to be idiopathic. Few reports in literature concern common triggering phenomena. We present four patients in whom the same benign viral condition in childhood appeared as a stressful event preceding onychomadesis. In each case, spontaneous complete healing of the nails was achieved within a few weeks. CONCLUSION: Onychomadesis and/or onycholysis is a newly recognised complication in the course of viral infections presenting clinically as hand, foot and mouth disease, and because of mild forms, is probably underestimated.     

维生素B2治疗有效的晚发型戊二酸尿症Ⅱ型

目的 探讨戊二酸尿症Ⅱ型(glutaric aciduria typeⅡ,GAⅡ)的诊断和治疗。方法 应用气相色谱-质谱分析技术(GC-MS)对2例肌无力患儿的尿滤纸片标本进行有机酸分析。确诊为GAⅡ型后,在低蛋白、低脂肪、高碳水化合物饮食控制的基础上,应用VitB2进行治疗,并观察治疗前后临床、生化及尿有机酸分析等方面的变化。结果 (1)两患儿尿滤纸片标本有机酸分析检出大量戊二酸、异戊酰甘氨酸、乙基丙二酸及己二酸、辛二酸、癸二酸等二羧酸,提示为戊二酸尿症Ⅱ型;(2)经饮食控制和VitB2治疗后,2例患儿的肌无力症状明显好转,肌力明显增强,四肢肌张力恢复正常,尿有机酸分析显示上述有机酸的排出量逐步降低、甚至消失,血清谷-草转氨酶、肌酸激酶以及乳酸脱氢酶水平均较治疗前显著降低。血氨基本降至正常水平。结论 戊二酸尿症是一种严重的先天代谢障碍性疾病。部分本症患儿在低蛋白、低脂肪、高碳水化合物饮食控制的基础上,应用VitB2进行治疗,可取得较好的临床效果。     

Macrocephaly and dystonic cerebral palsy in a child with type I glutaric aciduria

In a male infant with macrocephaly and dystonic cerebral palsy glutaric aciduria type I was detected by analysis of urine for organic acids. Glutaric aciduria type I is an inherited metabolic disorder of organic acids due to a defect of glutaryl-CoA-dehydrogenase in the intermediate metabolic step of lysine and tryptophan degradation. In the urine glutaric acid is usually accompanied by 3-hydroxy-glutaric acid in abnormal quantities. The enzyme defect in our patient was proved in cultured fibroblasts. In the cerebral computer tomography marked atrophy of bilateral frontotemporal regions could be demonstrated. The amount of urinary glutarat excretion decreased after protein but especially after lysine and tryptophan restriction in the diet. The administration of carnitine improved carnitine levels in blood and urine. Although the progression of neurological impairment could be stopped, dystonia and dyskinesis remained nearly unaltered. In spite of severe motor retardation, recognition and vocalisation were established. In the two year old patient mental retardation is relatively mild comparing with motor retardation. The administration of 100 or 200 mg Riboflavin/day was stopped, as it did not alter clinical symptoms or excretion of glutarat. Baclofen, an analogue of gamma-amino-butyric acid, was orally given (2 mg/kg/day) and improved dystonia, but did not influence organic aciduria. The neurological manifestations may be due in part to inhibition of neuronal glutamat decarboxylase by glutaric acid with decreased gamma-amino-butyric acid biosynthesis. The characteristic clinical symptoms with macrocephaly and dystonia and the very typical pattern of organic acids in urine are a challenge for rapid diagnosis and therapy.     

Outbreak of enterovirus 71 infection in Victoria, Australia, with a high incidence of neurologic involvement

An outbreak of infections caused by enterovirus 71 occurred in southeastern Australia during the winter of 1986. Infection was confirmed by virus isolation or serology in 114 patients, 65 of whom were admitted to hospital. Fifty-one percent of inpatients were infants younger than 12 months old and 85% were younger than 5 years old. Many cases of hand, foot and mouth disease occurred in the community during the epidemic, but 51% (33 of 65) of patients admitted to hospital had central nervous system involvement, often associated with severe symptoms. Six patients had encephalitis and one had a poliomyelitis-like paralytic illness. Various skin manifestations other than hand, foot and mouth disease occurred, especially in young children, and 25 patients had significant respiratory disease including at least 7 with pneumonia. Enterovirus 71 is one of very few viruses that cause hand, foot and mouth disease as well as a variety of other clinical manifestations. The most important of these is meningoencephalitis, which causes significant morbidity, especially in infants and young children.     

尿滤纸片法气相色谱-质谱分析技术在遗传性代谢病高危筛查诊断中的应用

目的 建立一种适合我国国情的有机酸尿症及其他遗传性代谢病的高危筛查诊断方法。方法 应用滤纸片收集尿标本,建立尿有机酸及氨基酸代谢产物的萃取、衍化和气相色谱-质谱分析方法;成立遗传代谢性疾病高危筛查诊断协作网络并开展工作。结果 352例样本中共检出阳性病例34例(9．66％),病种包括甲基丙二酸血症6例,α—酮戊二酸尿症5例,酪氨酸血症I型4例,二羧酸尿症4例,多种羧化酶缺乏症3例,苯丙酮尿症3例,高乳酸血症3例,丙酸血症2例,鸟氨酸氨甲酰基转移酶缺乏症1例,乙基丙二酸-己二酸尿症1例,戊二酸尿症Ⅱ型1例和3—甲基巴豆酰羧化酶缺乏症1例。常见的临床症状和体征包括智能发育落后、惊厥、肌张力异常和黄疸。常规实验室检查多见代谢性酸中毒、低血糖和高血氨等异常。结论 尿有机酸气相色谱—质谱分析为遗传性代谢病高危筛查诊断的重要技术。应用滤纸片收集尿标本后在遗传代谢病诊断中心进行检测为实用而有效的方法。建立协作网络是成功开展遗传性代谢病高危筛查诊断工作的关键。     

Octenylsuccinic aciduria in children fed protein-hydrolysate formulas containing modified cornstarch.

The excretion of 2-(2'-octenyl)succinic acid (OSA) and several metabolites of OSA was studied by gas chromatography/mass spectrometry in 17 infants and children fed one of three proprietary elemental or protein-hydrolysate formulas that use OSA-modified cornstarch as an emulsifying agent. Variable but often large amounts (up to 2500 mg/g creatinine) of the fatty acid-like OSA and its metabolites were found in the urine of these children, and levels of OSA in their blood ranged from 9.5 to 57.9 mumol/L. Apparently secondary abnormalities, such as increased urinary levels of glutaric acid and 2-ketoglutaric acid, were also found in more than half of the urine specimens. The molecular weight and mass fragmentation patterns of the nine compounds associated with the excretion of OSA are consistent with the proposal that OSA is metabolized in human infants and children by a combination of omega-, omega-1-, and beta-oxidation steps, similar to the metabolism of another branched-chain fatty acid, valproic acid. The urinary organic acid pattern of children fed elemental formulas containing OSA-modified starch often was dominated by OSA and its metabolites, and in several children the OSA-related changes were mistaken for a primary metabolic disease. Physicians and laboratories evaluating children for suspected metabolic diseases should be aware of the possibility of abnormal organic acid studies associated with OSA-containing formulas.     

Glutaric aciduria. 1 new case]

A 4 year old girl with mild mental retardation presented with convulsions, coma and hepatomegaly. She died rapidly. The main biochemical findings were hypoglycaemia, metabolic acidosis, generalised aminoaciduria, elevation of the plasma and urine alpha-amino adipic acid, massive urine excretion of glutaric and glutaconic acids with traces of alpha-hydroxyglutaric acid. The diagnosis of glutaric aciduria was confirmed by the low activity of glutaryl CoA dehydrogenase in liver tissue. This diagnosis should be considered in children with progressive neurological disorders (dystonia, choreoathetosis) and in children with an illness similar to Reye's syndrome.     

Screening newborns for multiple organic acidurias in dried filter paper urine samples: method development

Screening urine for inherited and acquired organic acidurias in newborns has the potential of preventing severe disease, mental retardation, and death. A method for screening dried urine filter paper samples for acidic markers of at least 20 different metabolic conditions has been developed. These conditions include, among others, maple syrup urine disease; methylmalonic, propionic, isovaleric, glutaric, and hydroxymethylglutaric acidurias; methylcrotonylglycinuria; medium-chain acyl-CoA dehydrogenase deficiency; inherited vitamin responsive disorders B12, biotin, B2), and acquired deficiencies of these vitamins. The preparation of the urine extract is identical to the method we use to screen infants for neuroblastoma. Screening is based on a highly sensitive and specific determination of eight organic acid markers by an automated computerized gas chromatography mass spectrometry system using selected ion monitoring. The markers used for screening are methylmalonic acid, 2-hydroxyisocaproic acid, glutaric acid, propionylglycine, isovalerylglycine, 3-methylcrotonylglycine, hexanoylglycine, and 3-phenylpropionylglycine. The extraction efficiencies of these acids from dried filter paper were similar to extraction from water, ranging from about 40% to 80%, except for propionylglycine which showed a low extraction efficiency of 11-13%. The stability of these acids on filter paper exposed to room air and temperature over a period of 15 d was adequate for the use of this collection method for organic aciduria screening. Normal levels, adjusted to urinary creatinine, were established for these acids in 519 urine filter paper samples obtained from 3-wk-old newborns. This screening method was tested on samples obtained from 12 patients with known organic acidurias including stored urine filter paper collected at 3-wk of age from two infants later found to have organic acidurias.     

手足口病患儿外周血血管活性肠肽的表达

目的 初步探讨手足口病患儿外周血血管活性肠肽的表达水平和意义。方法 根据病情将86例手足口病患儿分为1期组 （19例）和2期组 （67例）。采用ELISA法检测外周血血浆中血管活性肠肽、γ-干扰素 （IFN-γ）和白细胞介素-4 （IL-4）浓度。流式细胞术检测CD3+T、CD4+T、CD8+T淋巴细胞亚群。RTPCR法定性检测大便肠道病毒71型 （EV71）-RNA。结果 2期组EV71-RNA阳性率明显高于1期组 （P < 0.05）;2期组血清IgG、IgA、IgM、补体C3水平高于1期组 （P < 0.05）;2期组外周血CD3+T、CD4+T、CD8+T淋巴细胞亚群比例低于1期组 （P < 0.05）;2期组外周血B细胞比例高于1期组 （P < 0.05）;2期组CD4+/CD8+比值低于1期组 （P < 0.05）;2期组外周血血管活性肠肽浓度低于1期组 （P < 0.05）。86例手足口病患儿外周血血管活性肠肽浓度与CD4+T淋巴细胞亚群比例以及CD4+/CD8+比值呈正相关 （分别r=0.533、0.532,P < 0.05）。结论 血管活性肠肽可能是反映手足口病严重程度的重要标记物。