MAHCD
MCID: MTH055
MIFTS: 38

Methylmalonic Aciduria and Homocystinuria, Cbld Type (MAHCD)

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

Aliases & Classifications for Methylmalonic Aciduria and Homocystinuria, Cbld Type

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

Name: Methylmalonic Aciduria and Homocystinuria, Cbld Type 57 72
Homocystinuria, Cbld Type, Variant 1 57 29 13 6
Methylmalonic Aciduria, Cbld Type, Variant 2 57 29 6
Combined Defect in Adenosylcobalamin and Methylcobalamin Synthesis, Type Cbld 20 58
Methylmalonic Acidemia with Homocystinuria, Type Cbld 20 58
Methylmalonic Aciduria with Homocystinuria, Type Cbld 20 58
Methylmalonic Acidemia and Homocystinuria, Cbld Type 57 20
Methylmalonic Aciduria and Homocystinuria Type Cbld 12 15
Methylmalonic Acidemia with Homocystinuria Cbld 29 6
Methylmalonic Aciduria, Cblh Type, Formerly 57 20
Methylmalonic Acidemia, Cblh Type, Formerly 57 20
Cobalamin D Defect 20 58
Cbld Defect 20 58
Mahcd 57 72
Vitamin B12-Responsive Methylmalonic Acidemia, Type Cbldv2 58
Vitamin B12-Responsive Methylmalonic Aciduria, Type Cbldv2 58
Methylmalonic Aciduria and Homocystinuria Cbld-Combined 72
Methylmalonic Aciduria and Homocystinuria Cbld Original 72
Methylmalonic Aciduria, Cbld Type, Variant 2, Included 20
Aciduria, Methylmalonic, and Homocystinuria, Cbld Type 39
Functional Methionine Synthase Deficiency Type Cbldv1 58
Methylmalonic Acidemia with Homocystinuria Type Cbld 20
Methylmalonic Aciduria with Homocystinuria Cbld Type 6
Methylmalonic Acidemia and Homocystinuria Cbld Type 72
Mehtylmalonic Acidemia with Homocystinuria Cbi D 20
Homocystinuria, Cbld Type, Variant 1, Included 20
Methylcobalamin Deficiency Type Cbldv1 58
Methylmalonic Aciduria Cbld Variant 2 72
Homocystinuria Cbld Variant 1 72
Cobalamin D Deficiency 12

Characteristics:

Orphanet epidemiological data:

58
methylmalonic acidemia with homocystinuria, type cbld
Inheritance: Autosomal recessive; Prevalence: <1/1000000 (Worldwide); Age of onset: All ages;

OMIM®:

57 (Updated 05-Apr-2021)
Inheritance:
autosomal recessive

Miscellaneous:
onset in infancy
good response to vitamin b12 therapy 'variant 1' has isolated homocystinuria and decreased mecbl
'variant 2' has isolated methylmalonicaciduria and decreased adocbl


HPO:

31
methylmalonic aciduria and homocystinuria, cbld type:
Inheritance autosomal recessive inheritance
Onset and clinical course infantile onset


Classifications:

Orphanet: 58  
Rare neurological diseases
Rare renal diseases
Inborn errors of metabolism
Rare haematological diseases


Summaries for Methylmalonic Aciduria and Homocystinuria, Cbld Type

OMIM® : 57 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 (MAHCC; 277400), cblD, cblF (MAHCF; 277380), and cblJ (MAHCJ; 614857). Isolated methylmalonic acidurias have also been classified by complementation groups: MMA 'mut' (251000), caused by mutation in the MUT gene on chromosome 6p21; MMA cblA (251100), caused by mutation in the MMAA gene (607481) on 4q31; and MMA cblB (251110), caused by mutation in the MMAB gene (607568) on 12q24. Another form of isolated MMA (613646) can be caused by defect in the transcobalamin receptor (CD320; 606475). (277410) (Updated 05-Apr-2021)

MalaCards based summary : Methylmalonic Aciduria and Homocystinuria, Cbld Type, also known as homocystinuria, cbld type, variant 1, is related to methylmalonic acidemia and megaloblastic anemia. An important gene associated with Methylmalonic Aciduria and Homocystinuria, Cbld Type is MMADHC (Metabolism Of Cobalamin Associated D). Affiliated tissues include bone marrow and bone, and related phenotypes are intellectual disability and failure to thrive

Disease Ontology : 12 A methylmalonic aciduria that is characterized by combined homocystinuria and methylmalonic aciduria and deficiency of MCM and MS activities.

UniProtKB/Swiss-Prot : 72 Methylmalonic aciduria and homocystinuria, cblD type: An autosomal recessive disorder of cobalamin metabolism characterized by decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). Clinical features include developmental delay, hyotonia, mental retardation, seizures, megaloblastic anemia. Some patients manifest combined methylmalonic aciduria and homocystinuria (referred to as cblD original), some have only isolated homocystinuria (cblD variant 1), and others have only methylmalonic aciduria (cblD variant 2).

Related Diseases for Methylmalonic Aciduria and Homocystinuria, Cbld Type

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



Diseases related to Methylmalonic Aciduria and Homocystinuria, Cbld Type

Symptoms & Phenotypes for Methylmalonic Aciduria and Homocystinuria, Cbld Type

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

58 31 (show all 30)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 intellectual disability 58 31 hallmark (90%) Very frequent (99-80%) HP:0001249
2 failure to thrive 58 31 hallmark (90%) Very frequent (99-80%) HP:0001508
3 gait disturbance 58 31 hallmark (90%) Very frequent (99-80%) HP:0001288
4 global developmental delay 58 31 hallmark (90%) Very frequent (99-80%) HP:0001263
5 behavioral abnormality 58 31 hallmark (90%) Very frequent (99-80%) HP:0000708
6 fatigue 58 31 hallmark (90%) Very frequent (99-80%) HP:0012378
7 pallor 58 31 hallmark (90%) Very frequent (99-80%) HP:0000980
8 anorexia 58 31 hallmark (90%) Very frequent (99-80%) HP:0002039
9 lethargy 58 31 hallmark (90%) Very frequent (99-80%) HP:0001254
10 megaloblastic bone marrow 58 31 hallmark (90%) Very frequent (99-80%) HP:0001980
11 seizure 31 hallmark (90%) HP:0001250
12 seizures 58 Very frequent (99-80%)
13 nystagmus 31 HP:0000639
14 abnormality of movement 58 Very frequent (99-80%)
15 cerebral cortical atrophy 31 HP:0002120
16 dystonia 31 HP:0001332
17 methylmalonic aciduria 31 HP:0012120
18 generalized hypotonia 31 HP:0001290
19 spastic ataxia 31 HP:0002497
20 methylmalonic acidemia 31 HP:0002912
21 megaloblastic anemia 31 HP:0001889
22 increased mean corpuscular volume 31 HP:0005518
23 hyperhomocystinemia 31 HP:0002160
24 hypomethioninemia 31 HP:0003658
25 homocystinuria 31 HP:0002156
26 decreased adenosylcobalamin 31 HP:0003145
27 decreased methylcobalamin 31 HP:0003223
28 hypotonia 31 HP:0001252
29 decreased methionine synthase activity 31 HP:0003524
30 decreased methylmalonyl-coa mutase activity 31 HP:0003210

Symptoms via clinical synopsis from OMIM®:

57 (Updated 05-Apr-2021)
Neurologic Central Nervous System:
seizures
dystonia
lethargy
spastic ataxia
hypotonia
more
Laboratory Abnormalities:
methylmalonic aciduria
methylmalonic acidemia
homocystinuria
homocystinemia
decreased adenosylcobalamin (adocbl)
more
Head And Neck Eyes:
nystagmus

Hematology:
megaloblastic anemia
increased mean corpuscular volume

Clinical features from OMIM®:

277410 (Updated 05-Apr-2021)

Drugs & Therapeutics for Methylmalonic Aciduria and Homocystinuria, Cbld Type

Search Clinical Trials , NIH Clinical Center for Methylmalonic Aciduria and Homocystinuria, Cbld Type

Genetic Tests for Methylmalonic Aciduria and Homocystinuria, Cbld Type

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

# Genetic test Affiliating Genes
1 Homocystinuria, Cbld Type, Variant 1 29
2 Methylmalonic Acidemia with Homocystinuria Cbld 29 MMADHC
3 Methylmalonic Aciduria, Cbld Type, Variant 2 29

Anatomical Context for Methylmalonic Aciduria and Homocystinuria, Cbld Type

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

40
Bone Marrow, Bone

Publications for Methylmalonic Aciduria and Homocystinuria, Cbld Type

Articles related to Methylmalonic Aciduria and Homocystinuria, Cbld Type:

(show all 14)
# Title Authors PMID Year
1
Molecular mechanisms leading to three different phenotypes in the cblD defect of intracellular cobalamin metabolism. 6 57
22156578 2012
2
Gene identification for the cblD defect of vitamin B12 metabolism. 6 57
18385497 2008
3
The cblD defect causes either isolated or combined deficiency of methylcobalamin and adenosylcobalamin synthesis. 57 6
15292234 2004
4
Homocystinuria with methylmalonic aciduria: two cases in a sibship. 57 6
5524089 1970
5
Mutation of the MMADHC gene in adult-onset cobalamin D deficiency: A report of 2 potentially treatable cases. 6
28939051 2019
6
Neutropenia and Increased Mean Corpuscular Volume (MCV) With Abnormal Neurologic Findings: A Case of Cobalamin D Deficiency. 6
29620684 2019
7
Molecular picture of cobalamin C/D defects before and after newborn screening era. 6
27252276 2017
8
Complementation studies in the cblA class of inborn error of cobalamin metabolism: evidence for interallelic complementation and for a new complementation class (cblH). 57
10882753 2000
9
Methylmalonic aciduria due to a new defect in adenosylcobalamin accumulation by cells. 57
2339678 1990
10
Congenital methylmalonic aciduria--homocystinuria with megaloblastic anemia: observations on response to hydroxocobalamin and on the effect of homocysteine and methionine on the deoxyuridine suppression test. 57
7357085 1980
11
Cobalamin binding and cobalamin-dependent enzyme activity in normal and mutant human fibroblasts. 57
30783 1978
12
Genetic and biochemical analysis of human cobalamin mutants in cell culture. 57
371525 1978
13
Genetic complementation among inherited deficiencies of methylmalonyl-CoA mutase activity: evidence for a new class of human cobalamin mutant. 57
23678 1978
14
Phenotype, treatment practice and outcome in the cobalamin-dependent remethylation disorders and MTHFR deficiency: Data from the E-HOD registry. 61
30773687 2019

Variations for Methylmalonic Aciduria and Homocystinuria, Cbld Type

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

6 (show top 50) (show all 97)
# Gene Name Type Significance ClinVarId dbSNP ID Position
1 MMADHC NM_015702.3(MMADHC):c.776T>C (p.Leu259Pro) SNV Pathogenic 761 rs118204044 GRCh37: 2:150426603-150426603
GRCh38: 2:149570089-149570089
2 MMADHC NM_015702.3(MMADHC):c.545C>A (p.Thr182Asn) SNV Pathogenic 762 rs118204045 GRCh37: 2:150432289-150432289
GRCh38: 2:149575775-149575775
3 MMADHC NM_015702.3(MMADHC):c.746A>G (p.Tyr249Cys) SNV Pathogenic 763 rs118204046 GRCh37: 2:150426633-150426633
GRCh38: 2:149570119-149570119
4 MMADHC NM_015702.3(MMADHC):c.748C>T (p.Arg250Ter) SNV Pathogenic 767 rs118204048 GRCh37: 2:150426631-150426631
GRCh38: 2:149570117-149570117
5 MMADHC NM_015702.3(MMADHC):c.419dup (p.Tyr140Ter) Duplication Pathogenic 768 rs397509363 GRCh37: 2:150433009-150433010
GRCh38: 2:149576495-149576496
6 MMADHC NM_015702.3(MMADHC):c.696+3_696+6del Deletion Pathogenic 769 rs397509364 GRCh37: 2:150427593-150427596
GRCh38: 2:149571079-149571082
7 MMADHC NM_015702.3(MMADHC):c.228dup (p.Asn77fs) Duplication Pathogenic 219000 rs864309741 GRCh37: 2:150436088-150436089
GRCh38: 2:149579574-149579575
8 MMADHC NM_015702.3(MMADHC):c.22_23AG[1] (p.Arg8fs) Microsatellite Pathogenic 487521 rs1553454436 GRCh37: 2:150438770-150438771
GRCh38: 2:149582256-149582257
9 MMADHC NM_015702.3(MMADHC):c.295_296del (p.Leu99fs) Deletion Pathogenic 639047 rs1573878695 GRCh37: 2:150436021-150436022
GRCh38: 2:149579507-149579508
10 MMADHC NC_000002.12:g.(?_149569964)_(149587107_?)del Deletion Pathogenic 831549 GRCh37: 2:150426478-150443621
GRCh38:
11 MMADHC NC_000002.12:g.(?_149569954)_(149587117_?)del Deletion Pathogenic 832146 GRCh37: 2:150426468-150443631
GRCh38:
12 MMADHC NM_015702.3(MMADHC):c.544dup (p.Thr182fs) Duplication Pathogenic 837579 GRCh37: 2:150432289-150432290
GRCh38: 2:149575775-149575776
13 MMADHC NM_015702.3(MMADHC):c.554_555AT[1] (p.Met186fs) Microsatellite Pathogenic 848430 GRCh37: 2:150432277-150432278
GRCh38: 2:149575763-149575764
14 MMADHC NM_015702.3(MMADHC):c.646C>T (p.Arg216Ter) SNV Pathogenic 960731 GRCh37: 2:150427649-150427649
GRCh38: 2:149571135-149571135
15 MMADHC NM_015702.3(MMADHC):c.57_64del (p.Cys19_Ser20insTer) Deletion Pathogenic 764 rs397509361 GRCh37: 2:150438731-150438738
GRCh38: 2:149582217-149582224
16 MMADHC NM_015702.3(MMADHC):c.160C>T (p.Arg54Ter) SNV Pathogenic 765 rs118204047 GRCh37: 2:150436157-150436157
GRCh38: 2:149579643-149579643
17 MMADHC NM_015702.3(MMADHC):c.307_324dup (p.Leu103_Ser108dup) Duplication Pathogenic 766 rs397509362 GRCh37: 2:150435992-150435993
GRCh38: 2:149579478-149579479
18 MMADHC NM_015702.3(MMADHC):c.60_61insAT (p.Leu21fs) Insertion Pathogenic 219001 rs864309742 GRCh37: 2:150438734-150438735
GRCh38: 2:149582220-149582221
19 MMADHC NM_015702.3(MMADHC):c.160C>T (p.Arg54Ter) SNV Pathogenic 765 rs118204047 GRCh37: 2:150436157-150436157
GRCh38: 2:149579643-149579643
20 MMADHC NM_015702.3(MMADHC):c.307_324dup (p.Leu103_Ser108dup) Duplication Pathogenic 766 rs397509362 GRCh37: 2:150435992-150435993
GRCh38: 2:149579478-149579479
21 MMADHC NM_015702.3(MMADHC):c.455dup (p.Cys153fs) Duplication Pathogenic 219002 rs864309743 GRCh37: 2:150432973-150432974
GRCh38: 2:149576459-149576460
22 MMADHC NM_015702.3(MMADHC):c.57_64del (p.Cys19_Ser20insTer) Deletion Pathogenic 764 rs397509361 GRCh37: 2:150438731-150438738
GRCh38: 2:149582217-149582224
23 MMADHC NM_015702.3(MMADHC):c.133dup (p.Ala45fs) Duplication Pathogenic 218999 rs864309740 GRCh37: 2:150438661-150438662
GRCh38: 2:149582147-149582148
24 MMADHC NM_015702.3(MMADHC):c.702dup (p.Gly235fs) Duplication Likely pathogenic 982056 GRCh37: 2:150426676-150426677
GRCh38: 2:149570162-149570163
25 MMADHC NM_015702.3(MMADHC):c.10-1G>C SNV Likely pathogenic 856813 GRCh37: 2:150438786-150438786
GRCh38: 2:149582272-149582272
26 MMADHC NM_015702.3(MMADHC):c.154+1G>A SNV Likely pathogenic 648105 rs1385597423 GRCh37: 2:150438640-150438640
GRCh38: 2:149582126-149582126
27 MMADHC NM_015702.3(MMADHC):c.515A>C (p.Lys172Thr) SNV Conflicting interpretations of pathogenicity 331377 rs147318949 GRCh37: 2:150432319-150432319
GRCh38: 2:149575805-149575805
28 MMADHC NM_015702.3(MMADHC):c.735T>G (p.Thr245=) SNV Conflicting interpretations of pathogenicity 703884 rs530553915 GRCh37: 2:150426644-150426644
GRCh38: 2:149570130-149570130
29 MMADHC NM_015702.3(MMADHC):c.578T>C (p.Val193Ala) SNV Conflicting interpretations of pathogenicity 285847 rs147370143 GRCh37: 2:150432256-150432256
GRCh38: 2:149575742-149575742
30 MMADHC NM_015702.3(MMADHC):c.646C>G (p.Arg216Gly) SNV Conflicting interpretations of pathogenicity 203837 rs141093638 GRCh37: 2:150427649-150427649
GRCh38: 2:149571135-149571135
31 MMADHC NM_015702.3(MMADHC):c.737A>G (p.Asp246Gly) SNV Uncertain significance 839892 GRCh37: 2:150426642-150426642
GRCh38: 2:149570128-149570128
32 MMADHC NM_015702.3(MMADHC):c.406A>G (p.Ser136Gly) SNV Uncertain significance 1031933 GRCh37: 2:150433023-150433023
GRCh38: 2:149576509-149576509
33 MMADHC NM_015702.3(MMADHC):c.152T>C (p.Ile51Thr) SNV Uncertain significance 1038306 GRCh37: 2:150438643-150438643
GRCh38: 2:149582129-149582129
34 MMADHC NM_015702.3(MMADHC):c.743G>A (p.Arg248His) SNV Uncertain significance 808820 rs756858861 GRCh37: 2:150426636-150426636
GRCh38: 2:149570122-149570122
35 MMADHC NM_015702.3(MMADHC):c.609+6T>C SNV Uncertain significance 1008950 GRCh37: 2:150432219-150432219
GRCh38: 2:149575705-149575705
36 MMADHC NM_015702.3(MMADHC):c.414A>C (p.Glu138Asp) SNV Uncertain significance 1016695 GRCh37: 2:150433015-150433015
GRCh38: 2:149576501-149576501
37 MMADHC NM_015702.3(MMADHC):c.764C>G (p.Ser255Cys) SNV Uncertain significance 957054 GRCh37: 2:150426615-150426615
GRCh38: 2:149570101-149570101
38 MMADHC NM_015702.3(MMADHC):c.557T>C (p.Met186Thr) SNV Uncertain significance 965486 GRCh37: 2:150432277-150432277
GRCh38: 2:149575763-149575763
39 MMADHC NM_015702.3(MMADHC):c.699T>C (p.Phe233=) SNV Uncertain significance 892599 GRCh37: 2:150426680-150426680
GRCh38: 2:149570166-149570166
40 MMADHC NM_015702.3(MMADHC):c.697-3C>T SNV Uncertain significance 892600 GRCh37: 2:150426685-150426685
GRCh38: 2:149570171-149570171
41 MMADHC NM_015702.3(MMADHC):c.696+13C>A SNV Uncertain significance 892601 GRCh37: 2:150427586-150427586
GRCh38: 2:149571072-149571072
42 MMADHC NM_015702.3(MMADHC):c.166G>A (p.Val56Met) SNV Uncertain significance 892642 GRCh37: 2:150436151-150436151
GRCh38: 2:149579637-149579637
43 MMADHC-DT , MMADHC NM_015702.3(MMADHC):c.-136G>C SNV Uncertain significance 893755 GRCh37: 2:150444261-150444261
GRCh38: 2:149587747-149587747
44 MMADHC NM_015702.3(MMADHC):c.373G>C (p.Gly125Arg) SNV Uncertain significance 894648 GRCh37: 2:150433056-150433056
GRCh38: 2:149576542-149576542
45 MMADHC NM_015702.3(MMADHC):c.311C>T (p.Ala104Val) SNV Uncertain significance 856679 GRCh37: 2:150436006-150436006
GRCh38: 2:149579492-149579492
46 MMADHC NM_015702.3(MMADHC):c.73G>T (p.Val25Phe) SNV Uncertain significance 203838 GRCh37: 2:150438722-150438722
GRCh38: 2:149582208-149582208
47 MMADHC NM_015702.3(MMADHC):c.73G>T (p.Val25Phe) SNV Uncertain significance 203838 GRCh37: 2:150438722-150438722
GRCh38: 2:149582208-149582208
48 MMADHC NM_015702.3(MMADHC):c.735T>G (p.Thr245=) SNV Uncertain significance 703884 rs530553915 GRCh37: 2:150426644-150426644
GRCh38: 2:149570130-149570130
49 MMADHC NM_015702.3(MMADHC):c.578T>C (p.Val193Ala) SNV Uncertain significance 285847 rs147370143 GRCh37: 2:150432256-150432256
GRCh38: 2:149575742-149575742
50 MMADHC NM_015702.3(MMADHC):c.455C>G (p.Thr152Arg) SNV Uncertain significance 657556 rs146795035 GRCh37: 2:150432974-150432974
GRCh38: 2:149576460-149576460

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

72
# Symbol AA change Variation ID SNP ID
1 MMADHC p.Thr182Asn VAR_043844 rs118204045
2 MMADHC p.Tyr249Cys VAR_043846 rs118204046
3 MMADHC p.Leu259Pro VAR_043847 rs118204044

Expression for Methylmalonic Aciduria and Homocystinuria, Cbld Type

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

Pathways for Methylmalonic Aciduria and Homocystinuria, Cbld Type

GO Terms for Methylmalonic Aciduria and Homocystinuria, Cbld Type

Sources for Methylmalonic Aciduria and Homocystinuria, Cbld Type

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 ExPASy
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28 GO
29 GTR
30 HMDB
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32 ICD10
33 ICD10 via Orphanet
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44 MeSH
45 MESH via Orphanet
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56 OMIM via Orphanet
57 OMIM® (Updated 05-Apr-2021)
61 PubMed
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69 Tocris
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71 UMLS via Orphanet
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