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Combined malonic and methylmalonic acidemia(CMAMMA)

MedGen UID:
481944
Concept ID:
C3280314
Disease or Syndrome
Synonym: Combined malonic and methylmalonic aciduria
SNOMED CT: CMAMMA - combined malonic and methylmalonic aciduria (702365002); Combined malonic and methylmalonic aciduria (702365002)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): ACSF3 (16q24.3)
 
Monarch Initiative: MONDO:0013661
OMIM®: 614265
Orphanet: ORPHA289504

Definition

Combined malonic and methylmalonic aciduria (CMAMMA) is a rare recessive inborn error of metabolism characterized by elevations of urine malonic acid (MA) and methylmalonic acid (MMA). MMA excretion is higher than MA in CMAMMA patients, unlike patients with malonyl-CoA decarboxylase deficiency (248360) in whom the biochemical abnormalities include elevated MA alone or combined elevations of MA and MMA with MA mainly being higher than MMA. The clinical significance of CMAMMA is controversial. Initially, CMAMMA patients were ascertained during investigation of children with symptoms suggestive of a metabolic disorder or adults with neurologic manifestations (Sloan et al., 2011). Levtova et al. (2019) described CMAMMA patients identified by neonatal screening who had a favorable clinical course. [from OMIM]

Additional description

From MedlinePlus Genetics
Combined malonic and methylmalonic aciduria (CMAMMA) is a condition characterized by high levels of certain chemicals, known as malonic acid and methylmalonic acid, in the body. A distinguishing feature of this condition is higher levels of methylmalonic acid than malonic acid in the urine, although both are elevated.

The signs and symptoms of CMAMMA can begin in childhood. In some children, the buildup of acids causes the blood to become too acidic (ketoacidosis), which can damage the body's tissues and organs. Other signs and symptoms may include involuntary muscle tensing (dystonia), weak muscle tone (hypotonia), developmental delay, an inability to grow and gain weight at the expected rate (failure to thrive), low blood glucose (hypoglycemia), and coma. Some affected children have an unusually small head size (microcephaly).

Other people with CMAMMA do not develop signs and symptoms until adulthood. These individuals usually have neurological problems, such as seizures, loss of memory, a decline in thinking ability, or psychiatric diseases.  https://medlineplus.gov/genetics/condition/combined-malonic-and-methylmalonic-aciduria

Clinical features

From HPO
Methylmalonic aciduria
MedGen UID:
343266
Concept ID:
C1855119
Disease or Syndrome
Increased concentration of methylmalonic acid in the urine.
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Diarrhea
MedGen UID:
8360
Concept ID:
C0011991
Sign or Symptom
Abnormally increased frequency (usually defined as three or more) loose or watery bowel movements a day.
Vomiting
MedGen UID:
12124
Concept ID:
C0042963
Sign or Symptom
Forceful ejection of the contents of the stomach through the mouth by means of a series of involuntary spasmic contractions.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Generalized clonic seizure
MedGen UID:
869081
Concept ID:
C4023499
Disease or Syndrome
Generalized clonic seizure is a type of generalized motor seizure characterized by sustained bilateral jerking, either symmetric or asymmetric, that is regularly repetitive and involves the same muscle groups.
Dehydration
MedGen UID:
8273
Concept ID:
C0011175
Disease or Syndrome
A condition resulting from the excessive loss of water from the body. It is usually caused by severe diarrhea, vomiting or diaphoresis.
Ketoacidosis
MedGen UID:
67434
Concept ID:
C0220982
Disease or Syndrome
Acidosis resulting from accumulation of ketone bodies.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVCombined malonic and methylmalonic acidemia
Follow this link to review classifications for Combined malonic and methylmalonic acidemia in Orphanet.

Professional guidelines

PubMed

Schnabel E, Kölker S, Gleich F, Feyh P, Hörster F, Haas D, Fang-Hoffmann J, Morath M, Gramer G, Röschinger W, Garbade SF, Hoffmann GF, Okun JG, Mütze U
Nutrients 2023 Jul 28;15(15) doi: 10.3390/nu15153355. PMID: 37571294Free PMC Article
Venturoni LE, Venditti CP
J Inherit Metab Dis 2022 Sep;45(5):872-888. Epub 2022 Jul 21 doi: 10.1002/jimd.12534. PMID: 35766386
Carrillo-Carrasco N, Chandler RJ, Venditti CP
J Inherit Metab Dis 2012 Jan;35(1):91-102. Epub 2011 Jul 12 doi: 10.1007/s10545-011-9364-y. PMID: 21748409Free PMC Article

Curated

American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated C3 Acylcarnitine, Propionic Acidemia (PA) and Methylmalonic Acidemia (MMA), 2022

American College of Medical Genetics and Genomics, Algorithm, Propionic and Methylmalonic Acidemia: C3 Elevated, 2022

Recent clinical studies

Etiology

Schnabel E, Kölker S, Gleich F, Feyh P, Hörster F, Haas D, Fang-Hoffmann J, Morath M, Gramer G, Röschinger W, Garbade SF, Hoffmann GF, Okun JG, Mütze U
Nutrients 2023 Jul 28;15(15) doi: 10.3390/nu15153355. PMID: 37571294Free PMC Article
Manoli I, Gebremariam A, McCoy S, Pass AR, Gagné J, Hall C, Ferry S, Van Ryzin C, Sloan JL, Sacchetti E, Catesini G, Rizzo C, Martinelli D, Spada M, Dionisi-Vici C, Venditti CP
J Inherit Metab Dis 2023 Jul;46(4):554-572. Epub 2023 Jun 6 doi: 10.1002/jimd.12636. PMID: 37243446Free PMC Article
Chakrapani A, Stojanovic J, Vara R, De Nictolis F, Spada M, Dionisi-Vici C
J Inherit Metab Dis 2023 May;46(3):466-481. Epub 2023 Apr 24 doi: 10.1002/jimd.12613. PMID: 37067856
Venturoni LE, Venditti CP
J Inherit Metab Dis 2022 Sep;45(5):872-888. Epub 2022 Jul 21 doi: 10.1002/jimd.12534. PMID: 35766386
Jin L, Han X, He F, Zhang C
J Matern Fetal Neonatal Med 2022 Dec;35(25):8952-8967. Epub 2021 Nov 30 doi: 10.1080/14767058.2021.2008351. PMID: 34847798

Diagnosis

Arhip L, Brox-Torrecilla N, Romero I, Motilla M, Serrano-Moreno C, Miguélez M, Cuerda C
Orphanet J Rare Dis 2024 Jan 20;19(1):20. doi: 10.1186/s13023-024-03021-3. PMID: 38245797Free PMC Article
Schnabel E, Kölker S, Gleich F, Feyh P, Hörster F, Haas D, Fang-Hoffmann J, Morath M, Gramer G, Röschinger W, Garbade SF, Hoffmann GF, Okun JG, Mütze U
Nutrients 2023 Jul 28;15(15) doi: 10.3390/nu15153355. PMID: 37571294Free PMC Article
Manoli I, Gebremariam A, McCoy S, Pass AR, Gagné J, Hall C, Ferry S, Van Ryzin C, Sloan JL, Sacchetti E, Catesini G, Rizzo C, Martinelli D, Spada M, Dionisi-Vici C, Venditti CP
J Inherit Metab Dis 2023 Jul;46(4):554-572. Epub 2023 Jun 6 doi: 10.1002/jimd.12636. PMID: 37243446Free PMC Article
Chakrapani A, Stojanovic J, Vara R, De Nictolis F, Spada M, Dionisi-Vici C
J Inherit Metab Dis 2023 May;46(3):466-481. Epub 2023 Apr 24 doi: 10.1002/jimd.12613. PMID: 37067856
Carrillo-Carrasco N, Chandler RJ, Venditti CP
J Inherit Metab Dis 2012 Jan;35(1):91-102. Epub 2011 Jul 12 doi: 10.1007/s10545-011-9364-y. PMID: 21748409Free PMC Article

Therapy

Manoli I, Gebremariam A, McCoy S, Pass AR, Gagné J, Hall C, Ferry S, Van Ryzin C, Sloan JL, Sacchetti E, Catesini G, Rizzo C, Martinelli D, Spada M, Dionisi-Vici C, Venditti CP
J Inherit Metab Dis 2023 Jul;46(4):554-572. Epub 2023 Jun 6 doi: 10.1002/jimd.12636. PMID: 37243446Free PMC Article
Chakrapani A, Stojanovic J, Vara R, De Nictolis F, Spada M, Dionisi-Vici C
J Inherit Metab Dis 2023 May;46(3):466-481. Epub 2023 Apr 24 doi: 10.1002/jimd.12613. PMID: 37067856
Song D, Lv Y, Wang H, Ge J, Li T, Chen Y
Clin Lab 2022 Mar 1;68(3) doi: 10.7754/Clin.Lab.2021.210541. PMID: 35254044
Jin L, Han X, He F, Zhang C
J Matern Fetal Neonatal Med 2022 Dec;35(25):8952-8967. Epub 2021 Nov 30 doi: 10.1080/14767058.2021.2008351. PMID: 34847798
Andersson HC, Marble M, Shapira E
Genet Med 1999 May-Jun;1(4):146-50. doi: 10.1097/00125817-199905000-00006. PMID: 11258350

Prognosis

Lee JK, Oh A
J Korean Med Sci 2023 Nov 20;38(45):e387. doi: 10.3346/jkms.2023.38.e387. PMID: 37987109Free PMC Article
Schnabel E, Kölker S, Gleich F, Feyh P, Hörster F, Haas D, Fang-Hoffmann J, Morath M, Gramer G, Röschinger W, Garbade SF, Hoffmann GF, Okun JG, Mütze U
Nutrients 2023 Jul 28;15(15) doi: 10.3390/nu15153355. PMID: 37571294Free PMC Article
Manoli I, Gebremariam A, McCoy S, Pass AR, Gagné J, Hall C, Ferry S, Van Ryzin C, Sloan JL, Sacchetti E, Catesini G, Rizzo C, Martinelli D, Spada M, Dionisi-Vici C, Venditti CP
J Inherit Metab Dis 2023 Jul;46(4):554-572. Epub 2023 Jun 6 doi: 10.1002/jimd.12636. PMID: 37243446Free PMC Article
Ramon C, Traversi F, Bürer C, Froese DS, Stelling J
J Inherit Metab Dis 2023 May;46(3):421-435. Epub 2022 Nov 23 doi: 10.1002/jimd.12575. PMID: 36371683
Wang F, Liang L, Ling S, Yu Y, Chen T, Xu F, Gong Z, Han L
Zhejiang Da Xue Xue Bao Yi Xue Ban 2022 Jun 25;51(3):298-305. doi: 10.3724/zdxbyxb-2022-0194. PMID: 36207831Free PMC Article

Clinical prediction guides

Schnabel E, Kölker S, Gleich F, Feyh P, Hörster F, Haas D, Fang-Hoffmann J, Morath M, Gramer G, Röschinger W, Garbade SF, Hoffmann GF, Okun JG, Mütze U
Nutrients 2023 Jul 28;15(15) doi: 10.3390/nu15153355. PMID: 37571294Free PMC Article
Manoli I, Gebremariam A, McCoy S, Pass AR, Gagné J, Hall C, Ferry S, Van Ryzin C, Sloan JL, Sacchetti E, Catesini G, Rizzo C, Martinelli D, Spada M, Dionisi-Vici C, Venditti CP
J Inherit Metab Dis 2023 Jul;46(4):554-572. Epub 2023 Jun 6 doi: 10.1002/jimd.12636. PMID: 37243446Free PMC Article
Martinelli D, Catesini G, Greco B, Guarnera A, Parrillo C, Maines E, Longo D, Napolitano A, De Nictolis F, Cairoli S, Liccardo D, Caviglia S, Sidorina A, Olivieri G, Siri B, Bianchi R, Spagnoletti G, Dello Strologo L, Spada M, Dionisi-Vici C
J Inherit Metab Dis 2023 May;46(3):450-465. Epub 2023 Mar 15 doi: 10.1002/jimd.12599. PMID: 36861405
Dello Strologo L, Spada M, Vici CD, Atti MCD, Rheault M, Bjerre AK, Boyer O, Calvo PL, D'Antiga L, Harshman LA, Hörster F, Kölker S, Jahnukainen T, Knops N, Krug P, Krupka K, Lee A, Levtchenko E, Marks SD, Stojanovic J, Martelli L, Mazariegos G, Montini G, Shenoy M, Sidhu S, Spada M, Tangeras T, Testa S, Vijay S, Wac K, Wennberg L, Concepcion W, Garbade SF, Tönshoff B
Mol Genet Metab 2022 Nov;137(3):265-272. Epub 2022 Oct 3 doi: 10.1016/j.ymgme.2022.09.010. PMID: 36240580
Wang F, Liang L, Ling S, Yu Y, Chen T, Xu F, Gong Z, Han L
Zhejiang Da Xue Xue Bao Yi Xue Ban 2022 Jun 25;51(3):298-305. doi: 10.3724/zdxbyxb-2022-0194. PMID: 36207831Free PMC Article

Recent systematic reviews

Arhip L, Brox-Torrecilla N, Romero I, Motilla M, Serrano-Moreno C, Miguélez M, Cuerda C
Orphanet J Rare Dis 2024 Jan 20;19(1):20. doi: 10.1186/s13023-024-03021-3. PMID: 38245797Free PMC Article

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Curated

    • ACMG ACT, 2022
      American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated C3 Acylcarnitine, Propionic Acidemia (PA) and Methylmalonic Acidemia (MMA), 2022
    • ACMG Algorithm, 2022
      American College of Medical Genetics and Genomics, Algorithm, Propionic and Methylmalonic Acidemia: C3 Elevated, 2022

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