MCID: MTH054
MIFTS: 51

Methylmalonic Aciduria and Homocystinuria, Cblc Type

Categories: Genetic diseases, Rare diseases, Metabolic diseases, Neuronal diseases, Eye 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 53 49 13
Methylmalonic Aciduria and Homocystinuria Type Cblc 12 71 14
Vitamin B12 Metabolic Defect with Combined Deficiency of Methylmalonyl-Coa Mutase and Homocysteine:methyltetrahydrofolate Methyltransferase 53 71
Combined Defect in Adenosylcobalamin and Methylcobalamin Synthesis, Type Cblc 55
Methylmalonic Aciduria and Homocystinuria, Vitamin B12-Responsive 53
Methylmalonic Aciduria and Homocystinuria Vitamin B12-Responsive 71
Methylmalonic Acidemia with Homocystinuria, Type Cblc 55
Methylmalonic Aciduria with Homocystinuria, Type Cblc 55
Methylmalonic Acidemia and Homocystinuria, Cblc Type 53
Methylmalonic Acidemia with Homocystinuria Type Cblc 49
Methylmalonic Acidemia and Homocystinuria Cblc Type 71
Methylmalonic Acidemia with Homocystinuria Cblc 28
Methylmalonic Acidemia and Homocystinuria Cblc 49
Methylmalonic Aciduria and Homocystinuria Cblc 49
Methylmalonic Acidemia with Homocystinuria 69
Cobalamin C Deficiency 12
Cobalamin C Disease 49
Cobalamin C Defect 55
Cblc Defect 55
Mmahcc 71
Mahcc 53
Cblc 49

Characteristics:

Orphanet epidemiological data:

55
methylmalonic acidemia with homocystinuria, type cblc
Inheritance: Autosomal recessive; Age of onset: All ages; Age of death: any age;

OMIM:

53
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:

31
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 : 53 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), cblF (277380), and cblJ (614857). 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 methylmalonic aciduria, cblb type, and has symptoms including fatigue, 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 Selenium Micronutrient Network. The drugs Hydroxocobalamin and Cyanocobalamin have been mentioned in the context of this disorder. Affiliated tissues include kidney, liver and bone.

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.

NIH Rare Diseases : 49 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

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

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:

53
Neurologic Central Nervous System:
seizures
lethargy
developmental delay
hypotonia
mental retardation
more
Head And Neck Head:
hydrocephalus
microcephaly

Growth Other:
failure to thrive

Hematology:
anemia
thrombocytopenia
neutropenia
megaloblastic anemia

Head And Neck Face:
long face
high forehead
flat philtrum

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

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

Head And Neck Eyes:
nystagmus
pigmentary retinopathy
decreased visual acuity

Laboratory Abnormalities:
proteinuria
hematuria
methylmalonic aciduria
uremia
cystathioninuria
more
Cardiovascular Vascular:
thromboembolism
thrombotic microangiopathy
vascular lesions

Metabolic Features:
metabolic acidosis

Abdomen Gastroin testinal:
poor feeding


Clinical features from OMIM:

277400

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

55 31 (show all 49)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 fatigue 55 31 hallmark (90%) Very frequent (99-80%) HP:0012378
2 seizures 55 31 hallmark (90%) Very frequent (99-80%) HP:0001250
3 lethargy 55 31 hallmark (90%) Very frequent (99-80%) HP:0001254
4 hydrocephalus 55 31 hallmark (90%) Very frequent (99-80%) HP:0000238
5 failure to thrive 55 31 hallmark (90%) Very frequent (99-80%) HP:0001508
6 microcephaly 55 31 hallmark (90%) Very frequent (99-80%) HP:0000252
7 retinopathy 55 31 hallmark (90%) Very frequent (99-80%) HP:0000488
8 pallor 55 31 hallmark (90%) Very frequent (99-80%) HP:0000980
9 anorexia 55 31 hallmark (90%) Very frequent (99-80%) HP:0002039
10 megaloblastic bone marrow 55 31 hallmark (90%) Very frequent (99-80%) HP:0001980
11 tremor 31 HP:0001337
12 abnormality of extrapyramidal motor function 31 HP:0002071
13 low-set ears 31 HP:0000369
14 nystagmus 31 HP:0000639
15 intellectual disability 31 HP:0001249
16 macrotia 31 HP:0000400
17 global developmental delay 31 HP:0001263
18 smooth philtrum 31 HP:0000319
19 visual impairment 31 HP:0000505
20 feeding difficulties in infancy 31 HP:0008872
21 renal insufficiency 31 HP:0000083
22 proteinuria 31 HP:0000093
23 nephropathy 31 HP:0000112
24 thromboembolism 31 HP:0001907
25 reduced visual acuity 31 HP:0007663
26 thrombocytopenia 31 HP:0001873
27 cerebral cortical atrophy 31 HP:0002120
28 hematuria 31 HP:0000790
29 dementia 31 HP:0000726
30 long face 31 HP:0000276
31 neutropenia 31 HP:0001875
32 high forehead 31 HP:0000348
33 metabolic acidosis 31 HP:0001942
34 methylmalonic aciduria 31 HP:0012120
35 confusion 31 HP:0001289
36 generalized hypotonia 31 HP:0001290
37 pigmentary retinopathy 31 HP:0000580
38 megaloblastic anemia 31 HP:0001889
39 decreased methylcobalamin 31 HP:0003223
40 cystathioninuria 31 HP:0003153
41 homocystinuria 31 HP:0002156
42 hyperhomocystinemia 31 HP:0002160
43 hypomethioninemia 31 HP:0003658
44 methylmalonic acidemia 31 HP:0002912
45 cystathioninemia 31 HP:0003286
46 hemolytic-uremic syndrome 31 HP:0005575
47 decreased methionine synthase activity 31 HP:0003524
48 decreased adenosylcobalamin 31 HP:0003145
49 decreased methylmalonyl-coa mutase activity 31 HP:0003210

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


seizures, lethargy

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

Interventional clinical trials:


# 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:

# Genetic test Affiliating Genes
1 Methylmalonic Acidemia with Homocystinuria Cblc 28

Anatomical Context for Methylmalonic Aciduria and Homocystinuria, Cblc Type

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

38
Kidney, Liver, Bone, Eye, Bone Marrow

Publications for Methylmalonic Aciduria and Homocystinuria, Cblc Type

Articles related to Methylmalonic Aciduria and Homocystinuria, Cblc Type:

# 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
Early onset methylmalonic aciduria and homocystinuria cblC type with demyelinating neuropathy. ( 20610126 )
2010
6
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
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)
# 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 rs1002571805Methylmalonic
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 rs538023671

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

6 (show all 18)
# Gene Variation Type Significance SNP ID Assembly Location
1 MMACHC NM_015506.2(MMACHC): c.609G> A (p.Trp203Ter) single nucleotide variant Pathogenic rs587776889 GRCh37 Chromosome 1, 45974647: 45974647
2 MMACHC MMACHC, 3-BP DEL, 658AAG deletion Pathogenic
3 MMACHC NM_015506.2(MMACHC): c.481C> T (p.Arg161Ter) single nucleotide variant Pathogenic rs370596113 GRCh37 Chromosome 1, 45974519: 45974519
4 MMACHC NM_015506.2(MMACHC): c.547_548delGT (p.Val183Thrfs) deletion Pathogenic rs398124293 GRCh37 Chromosome 1, 45974585: 45974586
5 MMACHC NM_015506.2(MMACHC): c.608G> A (p.Trp203Ter) single nucleotide variant Pathogenic rs398124295 GRCh37 Chromosome 1, 45974646: 45974646
6 MMACHC NM_015506.2(MMACHC): c.658_660delAAG (p.Lys220del) deletion Pathogenic rs398124296 GRCh37 Chromosome 1, 45974696: 45974698
7 MMACHC NM_015506.2(MMACHC): c.276G> T (p.Glu92Asp) single nucleotide variant Pathogenic rs556977618 GRCh37 Chromosome 1, 45973222: 45973222
8 MMACHC NM_015506.2(MMACHC): c.276G> A (p.Glu92=) single nucleotide variant Pathogenic rs556977618 GRCh37 Chromosome 1, 45973222: 45973222
9 MMACHC NM_015506.2(MMACHC): c.464G> A (p.Gly155Glu) single nucleotide variant Pathogenic rs606231425 GRCh37 Chromosome 1, 45974502: 45974502
10 MMACHC NM_015506.2(MMACHC): c.271dupA (p.Arg91Lysfs) duplication Pathogenic rs398124292 GRCh38 Chromosome 1, 45507545: 45507545
11 MMACHC NM_015506.2(MMACHC): c.347T> C (p.Leu116Pro) single nucleotide variant Pathogenic rs121918240 GRCh37 Chromosome 1, 45973954: 45973954
12 MMACHC NM_015506.2(MMACHC): c.394C> T (p.Arg132Ter) single nucleotide variant Pathogenic rs121918241 GRCh37 Chromosome 1, 45974001: 45974001
13 MMACHC NM_015506.2(MMACHC): c.331C> T (p.Arg111Ter) single nucleotide variant Pathogenic rs121918242 GRCh37 Chromosome 1, 45973938: 45973938
14 MMACHC NM_015506.2(MMACHC): c.328_331delAACC (p.Asn110Aspfs) deletion Pathogenic rs796052000 GRCh38 Chromosome 1, 45508263: 45508266
15 MMACHC NM_015506.2(MMACHC): c.440G> C (p.Gly147Ala) single nucleotide variant Pathogenic/Likely pathogenic rs140522266 GRCh37 Chromosome 1, 45974478: 45974478
16 MMACHC NM_015506.2(MMACHC): c.615C> G (p.Tyr205Ter) single nucleotide variant Pathogenic rs747527726 GRCh37 Chromosome 1, 45974653: 45974653
17 MMACHC NM_015506.2(MMACHC): c.270dupT (p.Arg91Terfs) duplication Pathogenic GRCh38 Chromosome 1, 45507544: 45507544
18 MMACHC NM_015506.2(MMACHC): c.82-11_82-8delTTCT deletion Pathogenic rs751236442 GRCh38 Chromosome 1, 45507345: 45507348

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:

# 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:

# 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
27 GO
28 GTR
29 HGMD
30 HMDB
31 HPO
32 ICD10
33 ICD10 via Orphanet
34 ICD9CM
35 IUPHAR
36 KEGG
37 LifeMap
39 MedGen
41 MeSH
42 MESH via Orphanet
43 MGI
45 NCI
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47 NDF-RT
50 NINDS
51 Novoseek
53 OMIM
54 OMIM via Orphanet
58 PubMed
60 QIAGEN
65 SNOMED-CT via HPO
66 SNOMED-CT via Orphanet
67 TGDB
68 Tocris
69 UMLS
70 UMLS via Orphanet
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