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Methylmalonic acidemia (MMA), also called methylmalonic aciduria, is an autosomal recessive^[1] metabolic disorder.^[2] It is a classical type of organic acidemia.^[3]

Methylmalonic acidemia stems from several genotypes,^[4] all forms of the disorder usually diagnosed in the early neonatal period, presenting progressive encephalopathy, and secondary hyperammonemia. The disorder can result in death if undiagnosed or left untreated.

Causes

Genetic

Methylmalonic acidemia has an autosomal recessive pattern of inheritance.

Methylmalonic acidemia is caused by a defect in the vitamin B₁₂-dependent enzyme methylmalonyl CoA mutase.

The inherited forms of methylmalonic acidemia cause defects in the metabolic pathway where methylmalonyl-coenzyme A (CoA) is converted into succinyl-CoA by the enzyme methylmalonyl-CoA mutase.^[5]

Vitamin B₁₂ is also needed for the conversion of methylmalonyl-CoA to Succinyl-CoA. Mutations leading to defects in vitamin B₁₂ metabolism or in its transport frequently result in the development of methylmalonic acidemia.

This disorder has an autosomal recessive inheritance pattern, which means the defective gene is located on an autosome, and two copies of the gene—one from each parent—must be inherited to be affected by the disorder. The parents of a child with an autosomal recessive disorder are carriers of one copy of the defective gene, but are usually not affected by the disorder.

Nutritional

A severe nutritional deficiency of vitamin B₁₂ can also result in methylmalonic acidemia.^[6] Methylmalonyl CoA requires vitamin B₁₂ to form succinyl-CoA. When the amount of B₁₂ is insufficient for the conversion of cofactor methylmalonyl-CoA into succinyl-CoA, the buildup of unused methylmalonyl-CoA eventually leads to methylmalonic acidemia. This diagnosis is often used as an indicator of vitamin B₁₂ deficiency in serum.^[7]

Pathogenesis

Methylmalonic acidemia has varying diagnoses, treatment requirements and prognoses, which are determined by the specific genetic mutation causing the inherited form of the disorder.^[4] The following are the known genotypes responsible for methylmalonic acidemia:

OMIM	Name	Gene
251100	cblA type	MMAA
251110	cblB type	MMAB
277400	cblC type	MMACHC
277410	cblD type	MMADHC^[8]
277380	cblF type	LMBRD1^[9]
251000	mut type	MUT

References

^ Radmanesh, A; Zaman, T; Ghanaati, H; Molaei, S; Robertson, Rl; Zamani, Aa (July 2008). "Methylmalonic acidemia: brain imaging findings in 52 children and a review of the literature". Pediatric radiology 38 (10): 1054–61. doi:10.1007/s00247-008-0940-8. PMID 18636250.
^ http://www.genome.gov/19016901
^ Dionisi-Vici C, Deodato F, Raschinger W, Rhead W, Wilcken B (2006). "Classical organic acidurias, propionic aciduria, methylmalonic aciduria, and isovaleric aciduria: long-term outcome and effects of expanded newborn screening using tandem mass spectrometry". J Inherit Metab Dis. 29 (2-3): 383–389. doi:10.1007/s10545-006-0278-z. PMID 16763906.
^ ^a ^b Matsui, Sm; Mahoney, Mj; Rosenberg, Le (April 1983). "The natural history of the inherited methylmalonic acidemias" (Free full text). The New England Journal of Medicine 308 (15): 857–61. doi:10.1056/NEJM198304143081501. ISSN 0028-4793. PMID 6132336.
^ Sakomoto O, Ohura T, Matsubara Y, Takayanagi M, Tsuchiya S (2007). "Mutation and haplotype analyses of the MUT gene in Japanese patients with methylmalonic acidemia". Journal of Human Genetics 52 (1): 48–55. doi:10.1007/s10038-006-0077-2. PMID 17075691.
^ Higginbottom MC, Sweetman L, Nyhan WL (1978). "A syndrome of methylmalonic aciduria, homocystinuria, megaloblastic anemia and neurological abnormalities in a vitamin B₁₂-deficient breast-fed infant of a strict vegetarian". N Engl J Med. 299 (7): 317–323. doi:10.1056/NEJM197808172990701. PMID 683264.
^ http://www.biology.arizona.edu/biochemistry/problem_sets/b12/04t.html
Vitamin B₁₂ deficiency - The methylmalonic aciduria connection
^ Gene identification for the cblD defect of vitamin B₁₂ metabolism. Coelho D, Suormala T, Stucki M, Lerner-Ellis JP, Rosenblatt DS, Newbold RF, Baumgartner MR, Fowler B. N Engl J Med. 2008 Apr 3;358(14):1454-64. PMID 18385497
^ Rutsch F, Gailus S, Miousse IR, Suormala T, Sagné C, Toliat MR, Nürnberg G, Wittkampf T, Buers I, Sharifi A, Stucki M, Becker C, Baumgartner M, Robenek H, Marquardt T, Höhne W, Gasnier B, Rosenblatt DS, Fowler B, Nürnberg P (Feb 2009). "Identification of a putative lysosomal cobalamin exporter altered in the cblF defect of vitamin B₁₂ metabolism". Nat Genet 41 (2): 234–9. doi:10.1038/ng.294. PMID 19136951.

External links

Organic Acidemia Association
Methylmalonic acidemia at NLM Genetics Home Reference
Washington Health Center
GeneReviews article on Methylmalonic Acidemia
GeneReviews article on Disorders of Intracellular Cobalamin Metabolism
[1]

UpToDate Contents

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1. 有機酸血症 organic acidemias
2. 後天性TTPおよびその他の原発性血栓性微小血管障害症（TMA）の病態生理 pathophysiology of acquired ttp and other primary thrombotic microangiopathies tmas
3. 先天性代謝異常：疫学、病因、および臨床的特徴 inborn errors of metabolism epidemiology pathogenesis and clinical features
4. 先天性代謝異常：分類 inborn errors of metabolism classification
5. ビタミンB12および葉酸欠乏症の診断および治療 diagnosis and treatment of vitamin b12 and folate deficiency

English Journal

Brain damage in methylmalonic aciduria: 2-methylcitrate induces cerebral ammonium accumulation and apoptosis in 3D organotypic brain cell cultures.

Jafari P, Braissant O, Zavadakova P, Henry H, Bonafé L, Ballhausen D.AbstractABSTRACT: BACKGROUND: Methylmalonic aciduria is an inborn error of metabolism characterized by accumulation of methylmalonate (MMA), propionate and 2-methylcitrate (2-MCA) in body fluids. Early diagnosis and current treatment strategies aimed at limiting the production of these metabolites are only partially effective in preventing neurological damage.
Orphanet journal of rare diseases.Orphanet J Rare Dis.2013 Jan 8;8(1):4. [Epub ahead of print]
ABSTRACT: BACKGROUND: Methylmalonic aciduria is an inborn error of metabolism characterized by accumulation of methylmalonate (MMA), propionate and 2-methylcitrate (2-MCA) in body fluids. Early diagnosis and current treatment strategies aimed at limiting the production of these metabolites are only
PMID 23298464

Oxidative stress and apoptosis in homocystinuria patients with genetic remethylation defects.

Richard E, Desviat LR, Ugarte M, Pérez B.SourceCentro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular Severo Ochoa CSIC-UAM, Departamento de Biología Molecular. Universidad Autónoma de Madrid, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), IdiPAZ, Madrid, Spain. erichard@cbm.uam.es
Journal of cellular biochemistry.J Cell Biochem.2013 Jan;114(1):183-91. doi: 10.1002/jcb.24316.
Oxidative stress has been described as a putative disease mechanism in pathologies associated with an elevation of homocysteine. An increased reactive oxygen species (ROS) production and apoptosis rate have been associated with several disorders of cobalamin metabolism, particularly with methylmalon
PMID 22887477

Subcellular location of MMACHC and MMADHC, two human proteins central to intracellular vitamin B(12) metabolism.

Mah W, Deme JC, Watkins D, Fung S, Janer A, Shoubridge EA, Rosenblatt DS, Coulton JW.SourceDepartment of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada; Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
Molecular genetics and metabolism.Mol Genet Metab.2012 Dec 7. pii: S1096-7192(12)00713-5. doi: 10.1016/j.ymgme.2012.11.284. [Epub ahead of print]
MMACHC and MMADHC are the genes responsible for cblC and cblD defects of vitamin B(12) metabolism, respectively. Patients with cblC and cblD defects present with various combinations of methylmalonic aciduria (MMA) and homocystinuria (HC). Those with cblC mutations have both MMA and HC whereas cblD
PMID 23270877

Japanese Journal

ホモシスチン尿症をともなったメチルマロン酸尿症の1例

臨床神経学 55(1), 23-28, 2015
NAID 130004921292

Methylmalonic acidemia and hyperglycemia : An unusual association

Brain & development 34(2), 113-114, 2012-02-01
NAID 10031049756

Mutation spectrum of MMACHC in Chinese patients with combined methylmalonic aciduria and homocystinuria

Journal of human genetics 55(9), 621-626, 2010-09-01
NAID 10030736837

「プロピオン酸」

Methylmalonic acidemia
	Methylmalonic acid
Classification and external resources
Specialty	endocrinology
ICD-10	E71.1
ICD-9-CM	270.3
OMIM	251000 251100 251110 277380 277400 277410 606169
DiseasesDB	29509 29510
MedlinePlus	001162
eMedicine	neuro/576

　　[★]

英: propionic acid
同: プロパン酸、プロパン
関: カルボン酸

http://ja.wikipedia.org/wiki/%E3%83%97%E3%83%AD%E3%83%94%E3%82%AA%E3%83%B3%E9%85%B8
C3H6O2
CH3-CH2-COOH

プロピオン酸（プロピオンさん、propionic acid）は示性式CH₃CH₂COOH、分子量74.08のカルボン酸。IUPAC命名法ではプロパン酸 (propanoic acid) となる。CAS登録番号は79-09-4。

物性

単体は融点−21℃、沸点141℃の無色の液体で、不快な臭気を有する。水、エタノール、クロロホルム、エーテルなどに溶けやすい。1-プロパノール、プロピオンアルデヒドの酸化によって得られる。

反芻動物におけるプロピオン酸

反芻胃で食物の中のセルロースやヘミセルロースを嫌気発酵して、プロピオン酸などの短鎖脂肪酸を生成している。

ヒト(非反芻動物を含む)におけるプロピオン酸

奇数脂肪酸のβ酸化、イソロイシンとコレステロール側鎖の酸化によって得られる。(HBC.169)

代謝

HBC. 169

プロピオン酸　＋　CoA-SH　＋　ATP　－－(acyl-CoA synthetase + Mg2+)－→　AMP　＋　PPi　＋　プロピオニルCoA
プロピオニルCoA　＋　CO2　＋　H2O　＋　ATP　－－(propionyl-CoA carboxylase+ビオチン)－→　D-メチルマロニルCoA　＋　ADP　＋　Pi

→プロピオン酸血症

D-メチルマロニルCoA　－－(methylmalonyl-CoA racemase)－→　L-メチルマロニルCoA
L-メチルマロニルCoA　－－(methylmalonyl-CoA isomerase/methylmalonyl-CoA mutase+ビタミンB12)－→　サクシニルCoA

→メチルマロン酸尿症

誘導体

イブプロフェン、ナプロキセン、ロキソプロフェンナトリウムなど、Α炭素に芳香族部位が置換した非ステロイド性抗炎症薬 (NSAIDs) が知られ、「プロピオン酸系」と称される。

臨床関連

「尿」

　　[★]

英: urine
ラ: urina
関: 尿浸透圧、尿量

臨床関連

尿中への代謝物質の異常排出

尿の色

決定する要素：ウロビリノゲン、ヘモグロビン、ミオグロビンなど

褐色　：ビリルビン(閉塞性黄疸など)
赤褐色

「メチルマロン酸尿症」

　　[★]

英: methylmalonic aciduria
関: ビタミンB12欠乏症

「methylmalonic acidurias」

　　[★] メチルマロン酸尿症

「methylmalonic」

　　[★]

adj.

メチルマロン酸の

関: methylmalonic acid

[1] Radmanesh, A; Zaman, T; Ghanaati, H; Molaei, S; Robertson, Rl; Zamani, Aa (July 2008). "Methylmalonic acidemia: brain imaging findings in 52 children and a review of the literature". Pediatric radiology 38 (10): 1054–61. doi:10.1007/s00247-008-0940-8. PMID 18636250.

[2] ttp://www.genome.gov/19016901

[3] Dionisi-Vici C, Deodato F, Raschinger W, Rhead W, Wilcken B (2006). "Classical organic acidurias, propionic aciduria, methylmalonic aciduria, and isovaleric aciduria: long-term outcome and effects of expanded newborn screening using tandem mass spectrometry". J Inherit Metab Dis. 29 (2-3): 383–389. doi:10.1007/s10545-006-0278-z. PMID 16763906.

[geno-4] Matsui, Sm; Mahoney, Mj; Rosenberg, Le (April 1983). "The natural history of the inherited methylmalonic acidemias" (Free full text). The New England Journal of Medicine 308 (15): 857–61. doi:10.1056/NEJM198304143081501. ISSN 0028-4793. PMID 6132336.

[5] Sakomoto O, Ohura T, Matsubara Y, Takayanagi M, Tsuchiya S (2007). "Mutation and haplotype analyses of the MUT gene in Japanese patients with methylmalonic acidemia". Journal of Human Genetics 52 (1): 48–55. doi:10.1007/s10038-006-0077-2. PMID 17075691.

[6] Higginbottom MC, Sweetman L, Nyhan WL (1978). "A syndrome of methylmalonic aciduria, homocystinuria, megaloblastic anemia and neurological abnormalities in a vitamin B₁₂-deficient breast-fed infant of a strict vegetarian". N Engl J Med. 299 (7): 317–323. doi:10.1056/NEJM197808172990701. PMID 683264.

[7] ttp://www.biology.arizona.edu/biochemistry/problem_sets/b12/04t.html
Vitamin B₁₂ deficiency - The methylmalonic aciduria connection

[8] Gene identification for the cblD defect of vitamin B₁₂ metabolism. Coelho D, Suormala T, Stucki M, Lerner-Ellis JP, Rosenblatt DS, Newbold RF, Baumgartner MR, Fowler B. N Engl J Med. 2008 Apr 3;358(14):1454-64. PMID 18385497

[9] Rutsch F, Gailus S, Miousse IR, Suormala T, Sagné C, Toliat MR, Nürnberg G, Wittkampf T, Buers I, Sharifi A, Stucki M, Becker C, Baumgartner M, Robenek H, Marquardt T, Höhne W, Gasnier B, Rosenblatt DS, Fowler B, Nürnberg P (Feb 2009). "Identification of a putative lysosomal cobalamin exporter altered in the cblF defect of vitamin B₁₂ metabolism". Nat Genet 41 (2): 234–9. doi:10.1038/ng.294. PMID 19136951.

リンク元	「プロピオン酸」「尿」「メチルマロン酸尿症」
拡張検索	「methylmalonic acidurias」
関連記事	「methylmalonic」

匿名

検索

案内

案内

methylmalonic aciduria

Wikipedia preview

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Contents

Causes

Genetic

Nutritional

Pathogenesis

See also

References

External links

UpToDate Contents

English Journal

Japanese Journal

Related Links

★リンクテーブル★

「プロピオン酸」

物性

反芻動物におけるプロピオン酸

ヒト(非反芻動物を含む)におけるプロピオン酸

代謝

誘導体

臨床関連

「尿」

臨床関連

尿中への代謝物質の異常排出

尿の色

「メチルマロン酸尿症」

「methylmalonic acidurias」

「methylmalonic」