CMAMMA
MCID: CMB011
MIFTS: 41

Combined Malonic and Methylmalonic Aciduria (CMAMMA)

Categories: Blood diseases, Genetic diseases, Metabolic diseases, Nephrological diseases, Neuronal diseases, Rare diseases

Aliases & Classifications for Combined Malonic and Methylmalonic Aciduria

MalaCards integrated aliases for Combined Malonic and Methylmalonic Aciduria:

Name: Combined Malonic and Methylmalonic Aciduria 56 12 52 25 58 73 36 29 13 6 43 71
Cmamma 56 12 52 25 58 73
Combined Malonic and Methylmalonic Acidemia 12 52 58 15
Aciduria, Combined Malonic and Methylmalonic 39

Characteristics:

Orphanet epidemiological data:

58
combined malonic and methylmalonic acidemia
Inheritance: Autosomal dominant,Autosomal recessive; Age of onset: All ages;

HPO:

31
combined malonic and methylmalonic aciduria:
Inheritance autosomal recessive inheritance


Classifications:

Orphanet: 58  
Inborn errors of metabolism


Summaries for Combined Malonic and Methylmalonic Aciduria

Genetics Home Reference : 25 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 sugar (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.

MalaCards based summary : Combined Malonic and Methylmalonic Aciduria, also known as cmamma, is related to isolated methylmalonic acidemia and methylmalonic acidemia. An important gene associated with Combined Malonic and Methylmalonic Aciduria is ACSF3 (Acyl-CoA Synthetase Family Member 3), and among its related pathways/superpathways are Valine, leucine and isoleucine degradation and Fatty acid biosynthesis. Affiliated tissues include brain, and related phenotypes are methylmalonic aciduria and methylmalonic acidemia

Disease Ontology : 12 An organic acidemia characterized by elevated levels of methylmalonic acid and malonic acid in body fluids typically resulting in developmental delay and failure to thrive in children and neurological symptoms in adults that has material basis in homozygous or compound heterozygous mutation in ACSF3 on 16q24.3.

NIH Rare Diseases : 52 Combined malonic and methylmalonic aciduria (CMAMMA) is an inherited condition in which certain chemicals accumulate in the blood and urine of affected individuals. People with CMAMMA can have a wide variety of symptoms. Children with CMAMMA can suffer from developmental delays and a failure to gain weight and grow (failure to thrive ). In those who were identified as adults, symptoms may include psychiatric features and neurological problems that can mimic Alzheimer's disease and multiple sclerosis . Recently, researchers have found that mutations in the ACSF3 gene cause CMAMMA.

KEGG : 36 Combined malonic and methylmalonic aciduria (CMAMMA) is a rare recessive inborn error of metabolism characterised by elevations of urine malonic acid and methylmalonic acid. Unlike classic phenotype of methylmalonic acidemia, malonyl-CoA decarboxylase activity is normal. Mutations in ACSF3 have been identified as a cause of CMAMMA. ACSF3 encodes an enzyme that catalyzes the initial reaction in intramitochondrial fatty acid synthesis.

UniProtKB/Swiss-Prot : 73 Combined malonic and methylmalonic aciduria: A metabolic disease characterized by malonic and methylmalonic aciduria, with urinary excretion of much larger amounts of methylmalonic acid than malonic acid, in the presence of normal malonyl-CoA decarboxylase activity. Clinical features include coma, ketoacidosis, hypoglycemia, failure to thrive, microcephaly, dystonia, axial hypotonia and/or developmental delay, and neurologic manifestations including seizures, psychiatric disease and/or cognitive decline.

More information from OMIM: 614265

Related Diseases for Combined Malonic and Methylmalonic Aciduria

Graphical network of the top 20 diseases related to Combined Malonic and Methylmalonic Aciduria:



Diseases related to Combined Malonic and Methylmalonic Aciduria

Symptoms & Phenotypes for Combined Malonic and Methylmalonic Aciduria

Human phenotypes related to Combined Malonic and Methylmalonic Aciduria:

58 31 (show all 28)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 methylmalonic aciduria 58 31 hallmark (90%) Very frequent (99-80%) HP:0012120
2 methylmalonic acidemia 58 31 hallmark (90%) Very frequent (99-80%) HP:0002912
3 dicarboxylic acidemia 58 31 hallmark (90%) Very frequent (99-80%) HP:0040145
4 global developmental delay 58 31 occasional (7.5%) Occasional (29-5%) HP:0001263
5 behavioral abnormality 58 31 occasional (7.5%) Occasional (29-5%) HP:0000708
6 delayed speech and language development 58 31 occasional (7.5%) Occasional (29-5%) HP:0000750
7 microcephaly 58 31 occasional (7.5%) Occasional (29-5%) HP:0000252
8 failure to thrive 58 31 occasional (7.5%) Occasional (29-5%) HP:0001508
9 dehydration 58 31 occasional (7.5%) Occasional (29-5%) HP:0001944
10 vomiting 58 31 occasional (7.5%) Occasional (29-5%) HP:0002013
11 hypoglycemia 58 31 occasional (7.5%) Occasional (29-5%) HP:0001943
12 memory impairment 58 31 occasional (7.5%) Occasional (29-5%) HP:0002354
13 elevated hepatic transaminase 58 31 occasional (7.5%) Occasional (29-5%) HP:0002910
14 dystonia 58 31 occasional (7.5%) Occasional (29-5%) HP:0001332
15 migraine 58 31 occasional (7.5%) Occasional (29-5%) HP:0002076
16 encephalopathy 58 31 occasional (7.5%) Occasional (29-5%) HP:0001298
17 focal impaired awareness seizure 58 31 occasional (7.5%) Occasional (29-5%) HP:0002384
18 intermittent diarrhea 58 31 occasional (7.5%) Occasional (29-5%) HP:0002254
19 muscular hypotonia of the trunk 58 31 occasional (7.5%) Occasional (29-5%) HP:0008936
20 ketoacidosis 58 31 occasional (7.5%) Occasional (29-5%) HP:0001993
21 impaired continence 58 31 occasional (7.5%) Occasional (29-5%) HP:0031064
22 nasogastric tube feeding 58 31 occasional (7.5%) Occasional (29-5%) HP:0040288
23 generalized clonic seizure 31 occasional (7.5%) HP:0011169
24 seizures 58 Frequent (79-30%)
25 diarrhea 31 HP:0002014
26 acidosis 58 Occasional (29-5%)
27 dicarboxylic aciduria 58 Very frequent (99-80%)
28 generalized clonic seizures 58 Occasional (29-5%)

Clinical features from OMIM:

614265

Drugs & Therapeutics for Combined Malonic and Methylmalonic Aciduria

Interventional clinical trials:


# Name Status NCT ID Phase Drugs
1 Combined Malonic and Methylmalonic Aciduria (CMAMMA): Gene Identification and Outcome Study Unknown status NCT01289158

Search NIH Clinical Center for Combined Malonic and Methylmalonic Aciduria

Cochrane evidence based reviews: combined malonic and methylmalonic aciduria

Genetic Tests for Combined Malonic and Methylmalonic Aciduria

Genetic tests related to Combined Malonic and Methylmalonic Aciduria:

# Genetic test Affiliating Genes
1 Combined Malonic and Methylmalonic Aciduria 29 ACSF3

Anatomical Context for Combined Malonic and Methylmalonic Aciduria

MalaCards organs/tissues related to Combined Malonic and Methylmalonic Aciduria:

40
Brain

Publications for Combined Malonic and Methylmalonic Aciduria

Articles related to Combined Malonic and Methylmalonic Aciduria:

# Title Authors PMID Year
1
Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria. 6 56 61
21841779 2011
2
Combined malonic and methylmalonic aciduria with normal malonyl-coenzyme A decarboxylase activity: a case supporting multiple aetiologies. 61 56
9700595 1998
3
Methylmalonic and malonic aciduria in a dog with progressive encephalomyelopathy. 56
8869944 1996
4
Malonic aciduria. 56
7537025 1994
5
Brain metabolism and neurological symptoms in combined malonic and methylmalonic aciduria. 61
31969167 2020
6
The emerging role of the mitochondrial fatty-acid synthase (mtFASII) in the regulation of energy metabolism. 61
31376476 2019
7
Combined malonic and methylmalonic aciduria due to ACSF3 mutations: Benign clinical course in an unselected cohort. 61
30740739 2019
8
A New Approach for Fast Metabolic Diagnostics in CMAMMA. 61
26915364 2016
9
Combined malonic and methylmalonic aciduria: exome sequencing reveals mutations in the ACSF3 gene in patients with a non-classic phenotype. 61
21785126 2011

Variations for Combined Malonic and Methylmalonic Aciduria

ClinVar genetic disease variations for Combined Malonic and Methylmalonic Aciduria:

6 (show top 50) (show all 104) ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎
# Gene Name Type Significance ClinVarId dbSNP ID GRCh37 Pos GRCh38 Pos
1 ACSF3 NM_001243279.3(ACSF3):c.305del (p.Cys102fs)deletion Pathogenic 657796 16:89167394-89167394 16:89100986-89100986
2 ACSF3 NM_001243279.3(ACSF3):c.451G>T (p.Glu151Ter)SNV Pathogenic 642668 16:89167540-89167540 16:89101132-89101132
3 ACSF3 NM_001243279.3(ACSF3):c.675del (p.Leu226fs)deletion Pathogenic 653700 16:89169018-89169018 16:89102610-89102610
4 ACSF3 NM_001243279.3(ACSF3):c.689G>A (p.Trp230Ter)SNV Pathogenic 642486 16:89169034-89169034 16:89102626-89102626
5 ACSF3 NM_001243279.3(ACSF3):c.828G>A (p.Trp276Ter)SNV Pathogenic 646673 16:89178505-89178505 16:89112097-89112097
6 ACSF3 NM_001243279.3(ACSF3):c.1300C>T (p.Arg434Ter)SNV Pathogenic 639703 16:89199604-89199604 16:89133196-89133196
7 ACSF3 NM_001243279.3(ACSF3):c.246del (p.Cys83fs)deletion Pathogenic 855742 16:89167335-89167335 16:89100927-89100927
8 ACSF3 NM_001243279.3(ACSF3):c.286G>T (p.Glu96Ter)SNV Pathogenic 842479 16:89167375-89167375 16:89100967-89100967
9 ACSF3 NM_001243279.3(ACSF3):c.424C>T (p.Gln142Ter)SNV Pathogenic 839825 16:89167513-89167513 16:89101105-89101105
10 ACSF3 NM_001243279.3(ACSF3):c.803del (p.Pro268fs)deletion Pathogenic 851516 16:89169147-89169147 16:89102739-89102739
11 ACSF3 NM_001243279.3(ACSF3):c.1310G>A (p.Trp437Ter)SNV Pathogenic 844844 16:89199614-89199614 16:89133206-89133206
12 ACSF3 NM_001243279.3(ACSF3):c.1535G>A (p.Trp512Ter)SNV Pathogenic 843811 16:89212379-89212379 16:89145971-89145971
13 ACSF3 NM_001243279.3(ACSF3):c.1412G>A (p.Arg471Gln)SNV Pathogenic 31138 rs387907119 16:89211720-89211720 16:89145312-89145312
14 ACSF3 NM_001243279.3(ACSF3):c.1073C>T (p.Thr358Ile)SNV Pathogenic 31139 rs387907120 16:89180842-89180842 16:89114434-89114434
15 ACSF3 NM_001243279.3(ACSF3):c.728C>T (p.Pro243Leu)SNV Pathogenic 31140 rs140986055 16:89169073-89169073 16:89102665-89102665
16 ACSF3 NM_001243279.3(ACSF3):c.593T>G (p.Met198Arg)SNV Pathogenic 31141 rs387907121 16:89167682-89167682 16:89101274-89101274
17 ACSF3 ACSF3, LYS462THR AND GLY465_GLY470 DELdeletion Pathogenic 31142
18 ACSF3 NM_001243279.3(ACSF3):c.1602dup (p.Glu535fs)duplication Pathogenic 840232 16:89212443-89212444 16:89146035-89146036
19 ACSF3 NM_001243279.3(ACSF3):c.1567C>T (p.Arg523Ter)SNV Pathogenic 31135 rs387907118 16:89212411-89212411 16:89146003-89146003
20 ACSF3 NM_001243279.3(ACSF3):c.1672C>T (p.Arg558Trp)SNV Pathogenic/Likely pathogenic 31134 rs141090143 16:89220556-89220556 16:89154148-89154148
21 ACSF3 NM_001243279.3(ACSF3):c.1608G>A (p.Trp536Ter)SNV Pathogenic/Likely pathogenic 379920 rs201954387 16:89212452-89212452 16:89146044-89146044
22 ACSF3 NM_001243279.3(ACSF3):c.1502-2A>GSNV Pathogenic/Likely pathogenic 598729 rs1188774860 16:89212344-89212344 16:89145936-89145936
23 ACSF3 NM_001243279.3(ACSF3):c.1405C>T (p.Arg469Ter)SNV Pathogenic/Likely pathogenic 569646 rs748382994 16:89211713-89211713 16:89145305-89145305
24 ACSF3 NM_001243279.3(ACSF3):c.1573G>T (p.Gly525Ter)SNV Likely pathogenic 852537 16:89212417-89212417 16:89146009-89146009
25 ACSF3 NM_001243279.3(ACSF3):c.1607G>A (p.Trp536Ter)SNV Likely pathogenic 837811 16:89212451-89212451 16:89146043-89146043
26 ACSF3 NC_000016.10:g.89100703_89111915deldeletion Likely pathogenic 836367
27 ACSF3 NM_001243279.3(ACSF3):c.1075G>A (p.Glu359Lys)SNV Conflicting interpretations of pathogenicity 31136 rs150487794 16:89180844-89180844 16:89114436-89114436
28 ACSF3 NM_001243279.3(ACSF3):c.1406G>A (p.Arg469Gln)SNV Conflicting interpretations of pathogenicity 203601 rs144681140 16:89211714-89211714 16:89145306-89145306
29 ACSF3 NM_001243279.3(ACSF3):c.1081G>A (p.Gly361Ser)SNV Conflicting interpretations of pathogenicity 539847 rs145285434 16:89180850-89180850 16:89114442-89114442
30 ACSF3 NM_001243279.3(ACSF3):c.122A>T (p.Asp41Val)SNV Uncertain significance 565935 rs545886514 16:89167211-89167211 16:89100803-89100803
31 ACSF3 NM_001243279.3(ACSF3):c.358G>A (p.Gly120Ser)SNV Uncertain significance 574883 rs200703917 16:89167447-89167447 16:89101039-89101039
32 ACSF3 NM_001243279.3(ACSF3):c.541G>A (p.Glu181Lys)SNV Uncertain significance 573161 rs1567685421 16:89167630-89167630 16:89101222-89101222
33 ACSF3 NM_001243279.3(ACSF3):c.313G>A (p.Asp105Asn)SNV Uncertain significance 658792 16:89167402-89167402 16:89100994-89100994
34 ACSF3 NM_001243279.3(ACSF3):c.431C>T (p.Ser144Phe)SNV Uncertain significance 651756 16:89167520-89167520 16:89101112-89101112
35 ACSF3 NM_001243279.3(ACSF3):c.682C>G (p.His228Asp)SNV Uncertain significance 640535 16:89169027-89169027 16:89102619-89102619
36 ACSF3 NM_001243279.3(ACSF3):c.506C>T (p.Pro169Leu)SNV Uncertain significance 646427 16:89167595-89167595 16:89101187-89101187
37 ACSF3 NC_000016.10:g.(?_89100662)_(89154227_?)dupduplication Uncertain significance 832685 16:89167070-89220635
38 ACSF3 NM_001243279.3(ACSF3):c.1411C>T (p.Arg471Trp)SNV Uncertain significance 31137 rs138680796 16:89211719-89211719 16:89145311-89145311
39 ACSF3 NM_001243279.3(ACSF3):c.1614-6C>TSNV Likely benign 391424 rs368789945 16:89220492-89220492 16:89154084-89154084
40 ACSF3 NM_001243279.3(ACSF3):c.1629G>A (p.Pro543=)SNV Likely benign 381844 rs146779456 16:89220513-89220513 16:89154105-89154105
41 ACSF3 NM_001243279.3(ACSF3):c.756C>T (p.Asn252=)SNV Likely benign 388888 rs147718091 16:89169101-89169101 16:89102693-89102693
42 ACSF3 NM_001243279.3(ACSF3):c.978-7C>TSNV Likely benign 388630 rs190927208 16:89180740-89180740 16:89114332-89114332
43 ACSF3 NM_001243279.3(ACSF3):c.1614-10G>CSNV Likely benign 381840 rs370941606 16:89220488-89220488 16:89154080-89154080
44 ACSF3 NM_001243279.3(ACSF3):c.978-6G>ASNV Likely benign 390065 rs377217672 16:89180741-89180741 16:89114333-89114333
45 ACSF3 NM_001243279.3(ACSF3):c.390C>T (p.Pro130=)SNV Likely benign 787086 16:89167479-89167479 16:89101071-89101071
46 ACSF3 NM_001243279.3(ACSF3):c.1704G>A (p.Ala568=)SNV Likely benign 755958 16:89220588-89220588 16:89154180-89154180
47 ACSF3 NM_001243279.3(ACSF3):c.823-5C>TSNV Likely benign 764436 16:89178495-89178495 16:89112087-89112087
48 ACSF3 NM_001243279.3(ACSF3):c.666+9C>TSNV Likely benign 764155 16:89167764-89167764 16:89101356-89101356
49 ACSF3 NM_001243279.3(ACSF3):c.438C>T (p.Val146=)SNV Likely benign 798111 16:89167527-89167527 16:89101119-89101119
50 ACSF3 NM_001243279.3(ACSF3):c.723G>A (p.Val241=)SNV Likely benign 794747 16:89169068-89169068 16:89102660-89102660

UniProtKB/Swiss-Prot genetic disease variations for Combined Malonic and Methylmalonic Aciduria:

73
# Symbol AA change Variation ID SNP ID
1 ACSF3 p.Met198Arg VAR_066504 rs387907121
2 ACSF3 p.Pro243Leu VAR_066505 rs140986055
3 ACSF3 p.Thr358Ile VAR_066506 rs387907120
4 ACSF3 p.Glu359Lys VAR_066507 rs150487794
5 ACSF3 p.Lys462Thr VAR_066508 rs136250421
6 ACSF3 p.Arg471Gln VAR_066510 rs387907119
7 ACSF3 p.Arg471Trp VAR_066511 rs138680796
8 ACSF3 p.Gly480Ser VAR_066512
9 ACSF3 p.Arg558Trp VAR_066513 rs141090143

Expression for Combined Malonic and Methylmalonic Aciduria

Search GEO for disease gene expression data for Combined Malonic and Methylmalonic Aciduria.

Pathways for Combined Malonic and Methylmalonic Aciduria

Pathways related to Combined Malonic and Methylmalonic Aciduria according to KEGG:

36
# Name Kegg Source Accession
1 Valine, leucine and isoleucine degradation hsa00280
2 Fatty acid biosynthesis hsa00061

Pathways related to Combined Malonic and Methylmalonic Aciduria according to GeneCards Suite gene sharing:

# Super pathways Score Top Affiliating Genes
1
Show member pathways
11.74 MMADHC MMAB MMAA
2
Show member pathways
11.12 MMADHC MMAA
3 10.12 MMADHC MMAB MMAA

GO Terms for Combined Malonic and Methylmalonic Aciduria

Cellular components related to Combined Malonic and Methylmalonic Aciduria according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 mitochondrion GO:0005739 9.35 MMADHC MMAB MMAA MLYCD ACSF3
2 mitochondrial matrix GO:0005759 8.92 MMAB MMAA MLYCD ACSF3

Biological processes related to Combined Malonic and Methylmalonic Aciduria according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 fatty acid metabolic process GO:0006631 9.16 MLYCD ACSF3
2 fatty acid biosynthetic process GO:0006633 8.96 MLYCD ACSF3
3 cobalamin metabolic process GO:0009235 8.8 MMADHC MMAB MMAA

Sources for Combined Malonic and Methylmalonic Aciduria

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 ExPASy
19 FMA
28 GO
29 GTR
30 HMDB
31 HPO
32 ICD10
33 ICD10 via Orphanet
34 ICD9CM
35 IUPHAR
36 KEGG
37 LifeMap
39 LOVD
41 MedGen
43 MeSH
44 MESH via Orphanet
45 MGI
48 NCI
49 NCIt
50 NDF-RT
53 NINDS
54 Novoseek
56 OMIM
57 OMIM via Orphanet
61 PubMed
63 QIAGEN
68 SNOMED-CT via HPO
69 TGDB
70 Tocris
71 UMLS
72 UMLS via Orphanet
Content
Loading form....