MCID: MTH054
MIFTS: 48

Methylmalonic Aciduria and Homocystinuria, Cblc Type

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

Aliases & Classifications for Methylmalonic Aciduria and Homocystinuria, Cblc Type

MalaCards integrated aliases for Methylmalonic Aciduria and Homocystinuria, Cblc Type:

Name: Methylmalonic Aciduria and Homocystinuria, Cblc Type 54 50 24 13
Methylmalonic Aciduria and Homocystinuria Type Cblc 12 71 14
Cblc 50 24
Vitamin B12 Metabolic Defect with Combined Deficiency of Methylmalonyl-Coa Mutase and Homocysteine:methyltetrahydrofolate Methyltransferase 71
Combined Defect in Adenosylcobalamin and Methylcobalamin Synthesis, Type Cblc 56
Methylmalonic Aciduria and Homocystinuria Vitamin B12-Responsive 71
Methylmalonic Acidemia with Homocystinuria, Type Cblc 56
Methylmalonic Aciduria with Homocystinuria, Type Cblc 56
Methylmalonic Acidemia with Homocystinuria Type Cblc 50
Methylmalonic Acidemia and Homocystinuria, Cblc Type 24
Methylmalonic Acidemia and Homocystinuria Cblc Type 71
Methylmalonic Acidemia with Homocystinuria Cblc 29
Methylmalonic Acidemia and Homocystinuria Cblc 50
Methylmalonic Aciduria and Homocystinuria Cblc 50
Methylmalonic Acidemia with Homocystinuria 69
Cobalamin C Deficiency 12
Cobalamin C Disease 50
Cobalamin C Defect 56
Cblc Defect 56
Mmahcc 71

Characteristics:

Orphanet epidemiological data:

56
methylmalonic acidemia with homocystinuria, type cblc
Inheritance: Autosomal recessive; Age of onset: All ages; Age of death: any age;

OMIM:

54
Inheritance:
autosomal recessive

Miscellaneous:
onset usually in first year of life
early-onset associated with more severe course and early death
adolescent or adult onset associated with neuropsychiatric symptoms
patients with later onset do not have dysmorphic features
variable response to vitamin b12 therapy
see also cbld


HPO:

32
methylmalonic aciduria and homocystinuria, cblc type:
Onset and clinical course infantile onset
Inheritance autosomal recessive inheritance


Classifications:



Summaries for Methylmalonic Aciduria and Homocystinuria, Cblc Type

OMIM : 54
Combined methylmalonic aciduria (MMA) and homocystinuria is a genetically heterogeneous disorder of cobalamin (cbl; vitamin B12) metabolism. The defect causes decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), which results in decreased activity of the respective enzymes methylmalonyl-CoA mutase (MUT; 609058) and methyltetrahydrofolate:homocysteine methyltransferase, also known as methionine synthase (MTR; 156570). Different forms of the disorder have been classified according to complementation groups of cells in vitro: cblC, cblD (277410), and cblF (277380). Isolated methylmalonic acidurias have also been classified by complementation groups: MMA 'mut' (251000) is caused by mutation in the MUT gene on chromosome 6p21; MMA cblA (251100) is caused by mutation in the MMAA gene (607481) on 4q31; and MMA cblB (251110) is caused by mutation in the MMAB gene (607568) on 12q24. Methylmalonic aciduria and homocystinuria, cblC type, is the most common inborn error of vitamin B12 (cobalamin) metabolism, with about 250 known cases (Lerner-Ellis et al., 2006). Affected individuals may have developmental, hematologic, neurologic, metabolic, ophthalmologic, and dermatologic clinical findings. Although considered a disease of infancy or childhood, some individuals develop symptoms in adulthood (Rosenblatt et al., 1997). (277400)

MalaCards based summary : Methylmalonic Aciduria and Homocystinuria, Cblc Type, also known as methylmalonic aciduria and homocystinuria type cblc, is related to homocystinuria and mental retardation, x-linked 3, and has symptoms including failure to thrive, seizures and lethargy. An important gene associated with Methylmalonic Aciduria and Homocystinuria, Cblc Type is MMACHC (Methylmalonic Aciduria (Cobalamin Deficiency) CblC Type, With Homocystinuria), and among its related pathways/superpathways are One carbon pool by folate and Cobalamin (Cbl, vitamin B12) transport and metabolism. The drugs Hydroxocobalamin and Folic Acid have been mentioned in the context of this disorder. Affiliated tissues include liver, bone and kidney.

NIH Rare Diseases : 50 methylmalonic academia with homocystinuria (mma+hcu) cblc is a genetic disorder that prevents the body from breaking down certain amino acids found in protein (i.e., isoleucine, valine, methionine, and threonine). as a result, homocystine, methylmalonic acid, and other harmful substances build-up in the body. treatment should begin as soon as possible. in general, treatment may involve a low-protein diet, medical formula/drink, regular meals, careful monitoring, and vitamin b12 shots. most us states now offer newborn screening for mma+hcu, allowing for early detection and treatment. however even with early treatment, most children with mma+hcu experience some symptoms affecting vision, growth, and learning. mma+hcu cblc type is caused by changes in the mmachc gene. it is inherited in an autosomal recessive fashion. last updated: 6/11/2014

UniProtKB/Swiss-Prot : 71 Methylmalonic aciduria and homocystinuria type cblC: A disorder of cobalamin metabolism characterized by decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). Affected individuals may have developmental, hematologic, neurologic, metabolic, ophthalmologic, and dermatologic clinical findings. Although considered a disease of infancy or childhood, some individuals develop symptoms in adulthood.

Disease Ontology : 12 A methylmalonic acidemia that has material basis in deficiency in synthesis of both AdoCbl and MeCbl (cblC) and is characterized by decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), which results in decreased activity of the respective enzymes methylmalonyl-CoA mutase.

Related Diseases for Methylmalonic Aciduria and Homocystinuria, Cblc Type

Diseases related to Methylmalonic Aciduria and Homocystinuria, Cblc Type via text searches within MalaCards or GeneCards Suite gene sharing:

(show all 28)
id Related Disease Score Top Affiliating Genes
1 homocystinuria 29.9 CBS MMACHC MMD MTR SLC22A5
2 mental retardation, x-linked 3 10.9
3 methylmalonic aciduria and homocystinuria, cbld type 10.7
4 methylmalonic aciduria, vitamin b12-responsive 10.7
5 methylmalonic aciduria, mut(0) type 10.7
6 methylmalonic aciduria and homocystinuria, cblf type 10.7
7 methylmalonic aciduria, vitamin b12-responsive, due to defect in synthesis of adenosylcobalamin, cblb complementation type 10.7
8 methylmalonic acidemia with homocystinuria 10.7
9 vitamin b12-responsive methylmalonic acidemia 10.7
10 homocystinuria due to mthfr deficiency 10.5 CBS MTR
11 ectopic pregnancy 10.4 CBS MTR
12 calcaneonavicular coalition 10.4 MMACHC MTR
13 agammaglobulinemia 2 10.2 MMD MTR
14 homologous wasting disease 10.2 CBS MMACHC MTR
15 neuropathy 10.2
16 primary cerebellar degeneration 10.2 CBS MMACHC MTR
17 hyperhomocysteinemia 10.1 MMD PLG
18 homocarnosinosis 10.1 MMD PLG
19 ovarian clear cell malignant adenofibroma 10.1 CBS MMD
20 neural tube defects, folate-sensitive 10.0 MTHFD1 MTR
21 priapism 9.9 CBS MTR
22 chronic progressive external ophthalmoplegia 9.8 CD46 DGKE
23 nephrotic syndrome 9.7
24 hemolytic-uremic syndrome 9.7
25 methylmalonic acidemia 9.7
26 hydrops fetalis 9.7
27 ehlers-danlos syndrome, type viic 9.7 MTHFD1 MTR
28 neural tube defects 9.5 CBS MTHFD1 MTR

Graphical network of the top 20 diseases related to Methylmalonic Aciduria and Homocystinuria, Cblc Type:



Diseases related to Methylmalonic Aciduria and Homocystinuria, Cblc Type

Symptoms & Phenotypes for Methylmalonic Aciduria and Homocystinuria, Cblc Type

Symptoms via clinical synopsis from OMIM:

54

Growth- Other:
failure to thrive

Head And Neck- Eyes:
nystagmus
pigmentary retinopathy
decreased visual acuity

Head And Neck- Face:
high forehead
long face
flat philtrum

Head And Neck- Ears:
low-set ears
large, floppy ears

Abdomen- Gastroin testinal:
poor feeding

Metabolic Features:
metabolic acidosis

Neurologic- Central Nervous System:
hypotonia
mental retardation
developmental delay
seizures
lethargy
more
Hematology:
neutropenia
megaloblastic anemia
thrombocytopenia
anemia

Head And Neck- Head:
microcephaly
hydrocephalus

Cardiovascular- Vascular:
vascular lesions
thrombotic microangiopathy
thromboembolism

Genitourinary- Kidneys:
renal failure
hemolytic-uremic syndrome
thrombotic microangiopathic nephropathy

Laboratory- Abnormalities:
homocystinuria
homocysteinemia
methylmalonic aciduria
methylmalonic acidemia
decreased serum methionine
more

Clinical features from OMIM:

277400

Human phenotypes related to Methylmalonic Aciduria and Homocystinuria, Cblc Type:

56 32 (show all 49)
id Description HPO Frequency Orphanet Frequency HPO Source Accession
1 failure to thrive 56 32 hallmark (90%) Very frequent (99-80%) HP:0001508
2 seizures 56 32 hallmark (90%) Very frequent (99-80%) HP:0001250
3 lethargy 56 32 hallmark (90%) Very frequent (99-80%) HP:0001254
4 microcephaly 56 32 hallmark (90%) Very frequent (99-80%) HP:0000252
5 hydrocephalus 56 32 hallmark (90%) Very frequent (99-80%) HP:0000238
6 fatigue 56 32 hallmark (90%) Very frequent (99-80%) HP:0012378
7 retinopathy 56 32 hallmark (90%) Very frequent (99-80%) HP:0000488
8 pallor 56 32 hallmark (90%) Very frequent (99-80%) HP:0000980
9 anorexia 56 32 hallmark (90%) Very frequent (99-80%) HP:0002039
10 megaloblastic bone marrow 56 32 hallmark (90%) Very frequent (99-80%) HP:0001980
11 visual impairment 32 HP:0000505
12 nystagmus 32 HP:0000639
13 neutropenia 32 HP:0001875
14 tremor 32 HP:0001337
15 high forehead 32 HP:0000348
16 long face 32 HP:0000276
17 low-set ears 32 HP:0000369
18 pigmentary retinopathy 32 HP:0000580
19 thromboembolism 32 HP:0001907
20 hemolytic-uremic syndrome 32 HP:0005575
21 metabolic acidosis 32 HP:0001942
22 megaloblastic anemia 32 HP:0001889
23 thrombocytopenia 32 HP:0001873
24 homocystinuria 32 HP:0002156
25 methylmalonic aciduria 32 HP:0012120
26 methylmalonic acidemia 32 HP:0002912
27 cystathioninemia 32 HP:0003286
28 cystathioninuria 32 HP:0003153
29 hematuria 32 HP:0000790
30 proteinuria 32 HP:0000093
31 reduced visual acuity 32 HP:0007663
32 global developmental delay 32 HP:0001263
33 renal insufficiency 32 HP:0000083
34 intellectual disability 32 HP:0001249
35 cerebral cortical atrophy 32 HP:0002120
36 confusion 32 HP:0001289
37 dementia 32 HP:0000726
38 smooth philtrum 32 HP:0000319
39 hyperhomocystinemia 32 HP:0002160
40 hypomethioninemia 32 HP:0003658
41 muscular hypotonia 32 HP:0001252
42 feeding difficulties in infancy 32 HP:0008872
43 nephropathy 32 HP:0000112
44 macrotia 32 HP:0000400
45 abnormality of extrapyramidal motor function 32 HP:0002071
46 decreased methylcobalamin 32 HP:0003223
47 decreased methionine synthase activity 32 HP:0003524
48 decreased adenosylcobalamin 32 HP:0003145
49 decreased methylmalonyl-coa mutase activity 32 HP:0003210

UMLS symptoms related to Methylmalonic Aciduria and Homocystinuria, Cblc Type:


lethargy, seizures

Drugs & Therapeutics for Methylmalonic Aciduria and Homocystinuria, Cblc Type

Drugs for Methylmalonic Aciduria and Homocystinuria, Cblc Type (from DrugBank, HMDB, Dgidb, PharmGKB, IUPHAR, NovoSeek, BitterDB):

(show all 16)
id Name Status Phase Clinical Trials Cas Number PubChem Id
1
Hydroxocobalamin Approved Phase 2 13422-51-0 11953898 5460373 44475014
2
Folic Acid Approved, Nutraceutical, Vet_approved Phase 2 59-30-3 6037
3
Cyanocobalamin Approved, Nutraceutical Phase 2 68-19-9 44176380
4 Ubiquinone Phase 2
5 Micronutrients Phase 2
6 Hematinics Phase 2
7 Trace Elements Phase 2
8 Vitamin B 12 Phase 2
9 Vitamin B Complex Phase 2
10 Vitamins Phase 2
11 Antioxidants Phase 2
12 Folate Nutraceutical Phase 2
13 Vitamin B12 Nutraceutical Phase 2
14
Cobalamin Nutraceutical Phase 2 13408-78-1 6438156
15
Methylcobalamin Experimental, Nutraceutical Phase 2 13422-55-4
16 Vitamin B9 Nutraceutical Phase 2

Interventional clinical trials:


id Name Status NCT ID Phase Drugs
1 EPI-743 in Cobalamin C Defect: Effects on Visual and Neurological Impairment Completed NCT01793090 Phase 2 Epi-743

Search NIH Clinical Center for Methylmalonic Aciduria and Homocystinuria, Cblc Type

Genetic Tests for Methylmalonic Aciduria and Homocystinuria, Cblc Type

Genetic tests related to Methylmalonic Aciduria and Homocystinuria, Cblc Type:

id Genetic test Affiliating Genes
1 Methylmalonic Acidemia with Homocystinuria Cblc 29
2 Cblc 24 MMACHC

Anatomical Context for Methylmalonic Aciduria and Homocystinuria, Cblc Type

MalaCards organs/tissues related to Methylmalonic Aciduria and Homocystinuria, Cblc Type:

39
Liver, Bone, Kidney, Bone Marrow, Eye

Publications for Methylmalonic Aciduria and Homocystinuria, Cblc Type

Articles related to Methylmalonic Aciduria and Homocystinuria, Cblc Type:

id Title Authors Year
1
Genetic analysis of four cases of methylmalonic aciduria and homocystinuria, cblC type(.). ( 26464686 )
2015
2
First Chinese case of successful pregnancy with combined methylmalonic aciduria and homocystinuria, cblC type. ( 24974159 )
2014
3
A clinical and gene analysis of late-onset combined methylmalonic aciduria and homocystinuria, cblC type, in China. ( 22560872 )
2012
4
Combined methylmalonic aciduria and homocystinuria cblC type of a Taiwanese infant with c.609G>A and C.567dupT mutations in the MMACHC gene. ( 21835369 )
2011
5
Newborn screening and early biochemical follow-up in combined methylmalonic aciduria and homocystinuria, cblC type, and utility of methionine as a secondary screening analyte. ( 19836982 )
2010
6
Early onset methylmalonic aciduria and homocystinuria cblC type with demyelinating neuropathy. ( 20610126 )
2010
7
Spectrum of MMACHC mutations in Italian and Portuguese patients with combined methylmalonic aciduria and homocystinuria, cblC type. ( 18164228 )
2008
8
DNA-based diagnosis of methylmalonic aciduria and homocystinuria, cblC type in a Chinese patient presenting with mild developmental delay. ( 16963011 )
2007
9
Marfanoid features in a child with combined methylmalonic aciduria and homocystinuria (CblC type). ( 17768669 )
2007
10
Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type. ( 16311595 )
2006

Variations for Methylmalonic Aciduria and Homocystinuria, Cblc Type

UniProtKB/Swiss-Prot genetic disease variations for Methylmalonic Aciduria and Homocystinuria, Cblc Type:

71 (show all 14)
id Symbol AA change Variation ID SNP ID
1 MMACHC p.Gln27Arg VAR_024770 rs546099787
2 MMACHC p.Leu116Pro VAR_024771 rs121918240
3 MMACHC p.His122Arg VAR_024772
4 MMACHC p.Tyr130His VAR_024773 rs372670428
5 MMACHC p.Gly147Ala VAR_024774 rs140522266
6 MMACHC p.Gly147Asp VAR_024775 rs140522266
7 MMACHC p.Gly156Asp VAR_024776
8 MMACHC p.Trp157Cys VAR_024777
9 MMACHC p.Arg161Gly VAR_024778
10 MMACHC p.Arg161Gln VAR_024779 rs121918243
11 MMACHC p.Arg189Ser VAR_024780 rs200895671
12 MMACHC p.Leu193Pro VAR_024781
13 MMACHC p.Arg206Pro VAR_024782
14 MMACHC p.Arg206Trp VAR_024783

ClinVar genetic disease variations for Methylmalonic Aciduria and Homocystinuria, Cblc Type:

6 (show all 15)
id Gene Variation Type Significance SNP ID Assembly Location
1 MMACHC NM_015506.2(MMACHC): c.271dupA (p.Arg91Lysfs) duplication Pathogenic rs398124292 GRCh38 Chromosome 1, 45507545: 45507545
2 MMACHC NM_015506.2(MMACHC): c.347T> C (p.Leu116Pro) single nucleotide variant Pathogenic rs121918240 GRCh37 Chromosome 1, 45973954: 45973954
3 MMACHC NM_015506.2(MMACHC): c.394C> T (p.Arg132Ter) single nucleotide variant Pathogenic rs121918241 GRCh37 Chromosome 1, 45974001: 45974001
4 MMACHC NM_015506.2(MMACHC): c.331C> T (p.Arg111Ter) single nucleotide variant Pathogenic rs121918242 GRCh37 Chromosome 1, 45973938: 45973938
5 MMACHC NM_015506.2(MMACHC): c.609G> A (p.Trp203Ter) single nucleotide variant Pathogenic rs587776889 GRCh37 Chromosome 1, 45974647: 45974647
6 MMACHC MMACHC, 3-BP DEL, 658AAG deletion Pathogenic
7 MMACHC NM_015506.2(MMACHC): c.481C> T (p.Arg161Ter) single nucleotide variant Pathogenic rs370596113 GRCh37 Chromosome 1, 45974519: 45974519
8 MMACHC NM_015506.2(MMACHC): c.547_548delGT (p.Val183Thrfs) deletion Pathogenic rs398124293 GRCh37 Chromosome 1, 45974585: 45974586
9 MMACHC NM_015506.2(MMACHC): c.608G> A (p.Trp203Ter) single nucleotide variant Pathogenic rs398124295 GRCh37 Chromosome 1, 45974646: 45974646
10 MMACHC NM_015506.2(MMACHC): c.658_660delAAG (p.Lys220del) deletion Pathogenic rs398124296 GRCh37 Chromosome 1, 45974696: 45974698
11 MMACHC NM_015506.2(MMACHC): c.276G> T (p.Glu92Asp) single nucleotide variant Pathogenic rs556977618 GRCh37 Chromosome 1, 45973222: 45973222
12 MMACHC NM_015506.2(MMACHC): c.276G> A (p.Glu92=) single nucleotide variant Pathogenic rs556977618 GRCh37 Chromosome 1, 45973222: 45973222
13 MMACHC NM_015506.2(MMACHC): c.464G> A (p.Gly155Glu) single nucleotide variant Pathogenic rs606231425 GRCh37 Chromosome 1, 45974502: 45974502
14 MMACHC NM_015506.2(MMACHC): c.615C> G (p.Tyr205Ter) single nucleotide variant Pathogenic rs747527726 GRCh37 Chromosome 1, 45974653: 45974653
15 MMACHC NM_015506.2(MMACHC): c.270dupT (p.Arg91Terfs) duplication Pathogenic GRCh38 Chromosome 1, 45507544: 45507544

Expression for Methylmalonic Aciduria and Homocystinuria, Cblc Type

Search GEO for disease gene expression data for Methylmalonic Aciduria and Homocystinuria, Cblc Type.

Pathways for Methylmalonic Aciduria and Homocystinuria, Cblc Type

GO Terms for Methylmalonic Aciduria and Homocystinuria, Cblc Type

Biological processes related to Methylmalonic Aciduria and Homocystinuria, Cblc Type according to GeneCards Suite gene sharing:

id Name GO ID Score Top Affiliating Genes
1 cobalamin metabolic process GO:0009235 9.26 MMACHC MTR
2 methionine biosynthetic process GO:0009086 9.16 MTHFD1 MTR
3 transsulfuration GO:0019346 8.96 CBS MTHFD1
4 cellular amino acid biosynthetic process GO:0008652 8.8 CBS MTHFD1 MTR

Molecular functions related to Methylmalonic Aciduria and Homocystinuria, Cblc Type according to GeneCards Suite gene sharing:

id Name GO ID Score Top Affiliating Genes
1 cobalamin binding GO:0031419 8.62 MMACHC MTR

Sources for Methylmalonic Aciduria and Homocystinuria, Cblc Type

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
16 ExPASy
18 FMA
28 GO
29 GTR
30 HGMD
31 HMDB
32 HPO
33 ICD10
34 ICD10 via Orphanet
35 ICD9CM
36 IUPHAR
37 KEGG
38 LifeMap
40 MedGen
42 MeSH
43 MESH via Orphanet
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46 NCI
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48 NDF-RT
51 NINDS
52 Novoseek
54 OMIM
55 OMIM via Orphanet
59 PubMed
60 QIAGEN
65 SNOMED-CT via HPO
66 SNOMED-CT via Orphanet
67 TGDB
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70 UMLS via Orphanet
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