孤立Methylmalonic酸血症

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Manoli我斯隆JL Venditti CP

孤立Methylmalonic酸血症

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PubMed ID

20301409 (在PubMed

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文摘

孤立methylmalonic酸血症/酸尿,这GeneReview的主题,是由完全或部分缺乏这种酶methylmalonyl-CoA变位酶(mut0酶亚型或傻瓜——酶的亚型,分别),一个缺陷在运输或辅助因子的合成,adenosyl-cobalamin (cblA cblB,或cblD-MMA),或缺乏酶methylmalonyl-CoA差向异构酶。发病的表现孤立methylmalonic酸血症/酸尿范围从新生儿期到成年。所有表型特点是相对健康的时期和间歇代谢代谢失调,通常与并发感染和压力有关。在新生儿期疾病可以表现为嗜睡、呕吐、肌张力减退、低体温、呼吸困难,严重酮症酸中毒,hyperammonemia,中性粒细胞减少、血小板减少会导致生命的前4周内死亡。在小儿/ non-B12-responsive表型,婴儿出生时是正常的,但开发嗜睡、呕吐、脱水,未能茁壮成长,肝肿大,张力减退,脑病在几星期到几个月。一个中间B12-responsive表型偶尔可以观察到新生儿,但通常是在生命的最初几个月或几年观察;影响儿童表现出厌食,未能茁壮成长,肌张力减退、厌恶和发育迟缓,有时有蛋白质和/或蛋白质摄入后呕吐,嗜睡。非典型和“良性”/成人methylmalonic酸血症表型与增加,虽然轻微,methylmalonate尿排泄。主要次要并发症methylmalonic酸血症包括:智力障碍(变量);tubulointerstitial肾炎进行性肾功能衰竭; "metabolic stroke" (acute and chronic basal ganglia injury) causing a disabling movement disorder with choreoathetosis, dystonia, and para/quadriparesis; pancreatitis; growth failure; functional immune impairment; and optic nerve atrophy. Diagnosis of isolated methylmalonic acidemia relies on analysis of organic acids in plasma and/or urine by gas-liquid chromatography and mass spectrometry. Establishing the specific subtype of methylmalonic acidemia requires cellular biochemical studies (including 14C propionate incorporation and B12 responsiveness, complementation analysis, and cobalamin distribution assays) and molecular genetic testing. The finding of biallelic pathogenic variants in one of the five genes (MUT, MMAA, MMAB, MCEE, and MMADHC) associated with isolated methylmalonic acidemia - with confirmation of carrier status in the parents - can establish the diagnosis. Treatment of manifestations: Critically ill individuals are stabilized by restoring volume status and acid-base balance; reducing or eliminating protein intake; providing increased calories via high glucose-containing fluids and insulin to arrest catabolism; and monitoring serum electrolytes and ammonia, venous or arterial blood gases, and urine output. Management includes a high-calorie diet low in propiogenic amino acid precursors; hydroxocobalamin intramuscular injections; carnitine supplementation; antibiotics such as neomycin or metronidazole to reduce propionate production from gut flora; gastrostomy tube placement as needed; and aggressive treatment of infections. Other therapies used in a limited number of patients include N-carbamylglutamate for the treatment of acute hyperammonemic episodes; liver, kidney, or combined liver and kidney transplantation; and antioxidants for the treatment of optic nerve atrophy. Prevention of primary manifestations: In some cases, newborn screening allows for presymptomatic detection of affected newborns and early treatment. Agents/circumstances to avoid: Fasting and increased dietary protein. Other: Medic Alert(R) bracelets and up-to-date, easily accessed, detailed emergency treatment protocols facilitate care. Isolated methylmalonic acidemia is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible using molecular genetic techniques if the pathogenic variants in the family are known. In some circumstances, prenatal diagnosis for pregnancies at increased risk is possible by enzyme analysis and metabolite measurements on cultured fetal cells (obtained by chorionic villus sampling or amniocentesis).

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药物靶点

药物	目标	类	生物	药理作用	行动
羟钴胺素	Methylmalonic酸尿蛋白类型,线粒体	蛋白质	人类	未知的	其他/未知	细节