MMSDHD
MCID: MTH013
MIFTS: 31

Methylmalonate Semialdehyde Dehydrogenase Deficiency (MMSDHD)

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

Aliases & Classifications for Methylmalonate Semialdehyde Dehydrogenase Deficiency

MalaCards integrated aliases for Methylmalonate Semialdehyde Dehydrogenase Deficiency:

Name: Methylmalonate Semialdehyde Dehydrogenase Deficiency 57 72 36 29 13 6 39 70
Mmsdh Deficiency 57 72
Mmsdhd 57 72
Developmental Delay Due to Methylmalonate Semialdehyde Dehydrogenase Deficiency 58
Developmental Delay Due to Aldh6a1 Deficiency 58
Developmental Delay Due to Mmsdh Deficiency 58

Characteristics:

Orphanet epidemiological data:

58
developmental delay due to methylmalonate semialdehyde dehydrogenase deficiency
Inheritance: Autosomal recessive; Age of onset: Infancy,Neonatal;

OMIM®:

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

Miscellaneous:
highly variable phenotype
onset in infancy or early childhood
dysmorphic facial features are variable
four unrelated patients have been reported (last curated august 2015)
one patient was asymptomatic and detected by neonatal screening


HPO:

31
methylmalonate semialdehyde dehydrogenase deficiency:
Inheritance autosomal recessive inheritance


Classifications:

Orphanet: 58  
Inborn errors of metabolism


Summaries for Methylmalonate Semialdehyde Dehydrogenase Deficiency

KEGG : 36 Methylmalonate semialdehyde dehydrogenase (MMSDH) deficiency is a rare autosomal recessive disorder with varied metabolite abnormalities, including accumulation of 3-hydroxyisobutyric, 3-hydroxypropionic, and methylmalonic acids, as well as beta-alanine. Reported clinical presentations vary from a mild or uneventful clinical course. Severe developmental delay may be present. Dysmorphic facial features and congenital brain dysgenesis with intracerebral calcifications have also been described. Mutations in the ALDH6A1 gene coding for MMSDH are associated with this disease.

MalaCards based summary : Methylmalonate Semialdehyde Dehydrogenase Deficiency, also known as mmsdh deficiency, is related to gastroesophageal reflux and methylmalonic acidemia. An important gene associated with Methylmalonate Semialdehyde Dehydrogenase Deficiency is ALDH6A1 (Aldehyde Dehydrogenase 6 Family Member A1), and among its related pathways/superpathways are Valine, leucine and isoleucine degradation and beta-Alanine metabolism. Related phenotypes are abnormal facial shape and frontal bossing

OMIM® : 57 Methylmalonate semialdehyde dehydrogenase deficiency is a rare autosomal recessive inborn error of metabolism with a highly variable phenotype. Some patients may be asymptomatic, whereas others show global developmental delay, nonspecific dysmorphic features, and delayed myelination on brain imaging. Laboratory studies typically show increased urinary 3-hydroxyisobutyric acid, although additional metabolic abnormalities may also be observed (summary by Marcadier et al., 2013). (614105) (Updated 05-Apr-2021)

UniProtKB/Swiss-Prot : 72 Methylmalonate semialdehyde dehydrogenase deficiency: A metabolic disorder characterized by elevated beta-alanine, 3- hydroxypropionic acid, and both isomers of 3-amino and 3- hydroxyisobutyric acids in urine organic acids.

Related Diseases for Methylmalonate Semialdehyde Dehydrogenase Deficiency

Diseases related to Methylmalonate Semialdehyde Dehydrogenase Deficiency via text searches within MalaCards or GeneCards Suite gene sharing:

# Related Disease Score Top Affiliating Genes
1 gastroesophageal reflux 10.3
2 methylmalonic acidemia 10.3
3 isolated methylmalonic acidemia 10.3
4 hypotonia 10.3

Symptoms & Phenotypes for Methylmalonate Semialdehyde Dehydrogenase Deficiency

Human phenotypes related to Methylmalonate Semialdehyde Dehydrogenase Deficiency:

31 (show all 22)
# Description HPO Frequency HPO Source Accession
1 abnormal facial shape 31 frequent (33%) HP:0001999
2 frontal bossing 31 HP:0002007
3 high palate 31 HP:0000218
4 cataract 31 HP:0000518
5 global developmental delay 31 HP:0001263
6 depressed nasal bridge 31 HP:0005280
7 hypertelorism 31 HP:0000316
8 short nose 31 HP:0003196
9 microcephaly 31 HP:0000252
10 epicanthus 31 HP:0000286
11 downslanted palpebral fissures 31 HP:0000494
12 microphthalmia 31 HP:0000568
13 long philtrum 31 HP:0000343
14 bulbous nose 31 HP:0000414
15 high forehead 31 HP:0000348
16 dystonia 31 HP:0001332
17 tented upper lip vermilion 31 HP:0010804
18 hypoplasia of the corpus callosum 31 HP:0002079
19 feeding difficulties 31 HP:0011968
20 metabolic acidosis 31 HP:0001942
21 generalized hypotonia 31 HP:0001290
22 delayed myelination 31 HP:0012448

Symptoms via clinical synopsis from OMIM®:

57 (Updated 05-Apr-2021)
Metabolic Features:
metabolic acidosis
metabolic decompensation during febrile illness (patient b)

Head And Neck Face:
dysmorphic facial features, variable
long philtrum (patient b)
tall forehead (patient c)
frontal bossing (patient c)

Head And Neck Head:
microcephaly (patient a, b,)

Head And Neck Nose:
short nose (patients a and c)
depressed nasal bridge (patient a)
bulbous nose (patient b)
hypoplastic nasae alae (patient b)

Muscle Soft Tissue:
hypotonia (patients a and c)

Neurologic Central Nervous System:
delayed psychomotor development
dystonia (patient c)
delayed myelination (patients a and c)
thin corpus callosum (patients a and c)

Abdomen Gastrointestinal:
poor feeding (patient a)

Head And Neck Eyes:
cataracts (patient a)
microphthalmia (patient a)
downslanting palpebral fissures (patient a)
epicanthal folds (patient c)
hypertelorism (patient c)

Head And Neck Mouth:
high-arched palate (patient c)
tented mouth (patient c)

Laboratory Abnormalities:
increased urinary 3-hydroxyisobutyric acid
increased urinary 3-aminoisobutyric acid
increased urinary beta-alanine
increased urinary 3-hydroxypropionate (in some patients)
increased lactate (in some patients)
more

Clinical features from OMIM®:

614105 (Updated 05-Apr-2021)

Drugs & Therapeutics for Methylmalonate Semialdehyde Dehydrogenase Deficiency

Search Clinical Trials , NIH Clinical Center for Methylmalonate Semialdehyde Dehydrogenase Deficiency

Genetic Tests for Methylmalonate Semialdehyde Dehydrogenase Deficiency

Genetic tests related to Methylmalonate Semialdehyde Dehydrogenase Deficiency:

# Genetic test Affiliating Genes
1 Methylmalonate Semialdehyde Dehydrogenase Deficiency 29 ALDH6A1

Anatomical Context for Methylmalonate Semialdehyde Dehydrogenase Deficiency

Publications for Methylmalonate Semialdehyde Dehydrogenase Deficiency

Articles related to Methylmalonate Semialdehyde Dehydrogenase Deficiency:

# Title Authors PMID Year
1
Clinical, biochemical, mitochondrial, and metabolomic aspects of methylmalonate semialdehyde dehydrogenase deficiency: Report of a fifth case. 6 57 61
32151545 2020
2
3-Hydroxyisobutyrate aciduria and mutations in the ALDH6A1 gene coding for methylmalonate semialdehyde dehydrogenase. 57 6 61
21863277 2012
3
Molecular characterization of methylmalonate semialdehyde dehydrogenase deficiency. 6 61 57
10947204 2000
4
Mutations in ALDH6A1 encoding methylmalonate semialdehyde dehydrogenase are associated with dysmyelination and transient methylmalonic aciduria. 57 6
23835272 2013
5
3-Hydroxyisobutyric aciduria: phenotypic heterogeneity within a single family. 6 57
11446412 2001
6
Methylmalonic semialdehyde dehydrogenase deficiency: demonstration of defective valine and beta-alanine metabolism and reduced malonic semialdehyde dehydrogenase activity in cultured fibroblasts. 57 6
3117077 1987
7
Excessive excretion of beta-alanine and of 3-hydroxypropionic, R- and S-3-aminoisobutyric, R- and S-3-hydroxyisobutyric and S-2-(hydroxymethyl)butyric acids probably due to a defect in the metabolism of the corresponding malonic semialdehydes. 57 6
3939535 1985

Variations for Methylmalonate Semialdehyde Dehydrogenase Deficiency

ClinVar genetic disease variations for Methylmalonate Semialdehyde Dehydrogenase Deficiency:

6 (show top 50) (show all 104)
# Gene Name Type Significance ClinVarId dbSNP ID Position
1 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.1336G>A (p.Gly446Arg) SNV Pathogenic 6617 rs72552258 GRCh37: 14:74531952-74531952
GRCh38: 14:74065249-74065249
2 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.1156C>T (p.Arg386Ter) SNV Pathogenic 522934 rs781767219 GRCh37: 14:74533476-74533476
GRCh38: 14:74066773-74066773
3 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.514T>C (p.Tyr172His) SNV Pathogenic 208073 rs869320672 GRCh37: 14:74538114-74538114
GRCh38: 14:74071411-74071411
4 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.184C>T (p.Pro62Ser) SNV Pathogenic 208071 rs796065046 GRCh37: 14:74539242-74539242
GRCh38: 14:74072539-74072539
5 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.785C>A (p.Ser262Tyr) SNV Pathogenic 208070 rs879255579 GRCh37: 14:74535630-74535630
GRCh38: 14:74068927-74068927
6 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.1261C>T (p.Pro421Ser) SNV Pathogenic 915881 GRCh37: 14:74532027-74532027
GRCh38: 14:74065324-74065324
7 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.936del (p.Ala313fs) Deletion Pathogenic 1033012 GRCh37: 14:74534189-74534189
GRCh38: 14:74067486-74067486
8 ALDH6A1 NM_005589.4(ALDH6A1):c.-7G>A SNV Uncertain significance 888193 GRCh37: 14:74551104-74551104
GRCh38: 14:74084401-74084401
9 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.194A>G (p.Asn65Ser) SNV Uncertain significance 872052 GRCh37: 14:74539060-74539060
GRCh38: 14:74072357-74072357
10 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.1307A>G (p.Gln436Arg) SNV Uncertain significance 1033011 GRCh37: 14:74531981-74531981
GRCh38: 14:74065278-74065278
11 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.*991G>A SNV Uncertain significance 888081 GRCh37: 14:74526354-74526354
GRCh38: 14:74059651-74059651
12 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.921G>A (p.Gly307=) SNV Uncertain significance 888129 GRCh37: 14:74534204-74534204
GRCh38: 14:74067501-74067501
13 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.856G>T (p.Ala286Ser) SNV Uncertain significance 888130 GRCh37: 14:74534269-74534269
GRCh38: 14:74067566-74067566
14 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.112-15G>T SNV Uncertain significance 888192 GRCh37: 14:74539329-74539329
GRCh38: 14:74072626-74072626
15 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.*97T>C SNV Uncertain significance 886857 GRCh37: 14:74527248-74527248
GRCh38: 14:74060545-74060545
16 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.*2861C>T SNV Uncertain significance 887991 GRCh37: 14:74524484-74524484
GRCh38: 14:74057781-74057781
17 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.*2774G>C SNV Uncertain significance 887993 GRCh37: 14:74524571-74524571
GRCh38: 14:74057868-74057868
18 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.*1050C>G SNV Uncertain significance 888075 GRCh37: 14:74526295-74526295
GRCh38: 14:74059592-74059592
19 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.*2422C>A SNV Uncertain significance 887997 GRCh37: 14:74524923-74524923
GRCh38: 14:74058220-74058220
20 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.*1011C>A SNV Uncertain significance 888079 GRCh37: 14:74526334-74526334
GRCh38: 14:74059631-74059631
21 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.112-1G>A SNV Uncertain significance 631712 rs1566834093 GRCh37: 14:74539315-74539315
GRCh38: 14:74072612-74072612
22 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.80G>A (p.Trp27Ter) SNV Uncertain significance 631713 rs764104981 GRCh37: 14:74541689-74541689
GRCh38: 14:74074986-74074986
23 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.1603C>T (p.Arg535Cys) SNV Uncertain significance 208072 rs367863044 GRCh37: 14:74527350-74527350
GRCh38: 14:74060647-74060647
24 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.874_877dup (p.Met293fs) Duplication Uncertain significance 631711 rs751748364 GRCh37: 14:74534247-74534248
GRCh38: 14:74067544-74067545
25 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.112-31GTTT[7] Microsatellite Uncertain significance 314184 rs370924173 GRCh37: 14:74539321-74539322
GRCh38: 14:74072618-74072619
26 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.1479A>G (p.Gly493=) SNV Uncertain significance 314170 rs886050730 GRCh37: 14:74531549-74531549
GRCh38: 14:74064846-74064846
27 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.112-14T>G SNV Uncertain significance 314187 rs886050732 GRCh37: 14:74539328-74539328
GRCh38: 14:74072625-74072625
28 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.799G>A (p.Glu267Lys) SNV Uncertain significance 314176 rs763810979 GRCh37: 14:74535616-74535616
GRCh38: 14:74068913-74068913
29 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.1221C>G (p.Val407=) SNV Uncertain significance 314173 rs756896845 GRCh37: 14:74533411-74533411
GRCh38: 14:74066708-74066708
30 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.189C>T (p.Ala63=) SNV Uncertain significance 314182 rs886050731 GRCh37: 14:74539065-74539065
GRCh38: 14:74072362-74072362
31 ALDH6A1 NM_005589.4(ALDH6A1):c.-59A>C SNV Uncertain significance 314188 rs886050733 GRCh37: 14:74551156-74551156
GRCh38: 14:74084453-74084453
32 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.908A>G (p.Asn303Ser) SNV Uncertain significance 314174 rs376852895 GRCh37: 14:74534217-74534217
GRCh38: 14:74067514-74067514
33 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.1400G>A (p.Gly467Glu) SNV Uncertain significance 314171 rs747566637 GRCh37: 14:74531888-74531888
GRCh38: 14:74065185-74065185
34 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.*234C>T SNV Uncertain significance 314164 rs117311919 GRCh37: 14:74527111-74527111
GRCh38: 14:74060408-74060408
35 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.*43C>G SNV Uncertain significance 314167 rs545399557 GRCh37: 14:74527302-74527302
GRCh38: 14:74060599-74060599
36 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.186+6C>T SNV Uncertain significance 314183 rs188543079 GRCh37: 14:74539234-74539234
GRCh38: 14:74072531-74072531
37 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.1551_1553AGA[2] (p.Glu519del) Microsatellite Uncertain significance 314169 rs771596943 GRCh37: 14:74527394-74527396
GRCh38: 14:74060691-74060693
38 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.1397T>C (p.Val466Ala) SNV Uncertain significance 314172 rs764356053 GRCh37: 14:74531891-74531891
GRCh38: 14:74065188-74065188
39 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.*377C>A SNV Uncertain significance 314162 rs886050729 GRCh37: 14:74526968-74526968
GRCh38: 14:74060265-74060265
40 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.*2328C>T SNV Uncertain significance 884860 GRCh37: 14:74525017-74525017
GRCh38: 14:74058314-74058314
41 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.*2261T>C SNV Uncertain significance 884862 GRCh37: 14:74525084-74525084
GRCh38: 14:74058381-74058381
42 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.*1963C>T SNV Uncertain significance 884864 GRCh37: 14:74525382-74525382
GRCh38: 14:74058679-74058679
43 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.*1938A>G SNV Uncertain significance 884865 GRCh37: 14:74525407-74525407
GRCh38: 14:74058704-74058704
44 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.*839T>G SNV Uncertain significance 884940 GRCh37: 14:74526506-74526506
GRCh38: 14:74059803-74059803
45 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.*558A>G SNV Uncertain significance 884944 GRCh37: 14:74526787-74526787
GRCh38: 14:74060084-74060084
46 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.759C>T (p.Asp253=) SNV Uncertain significance 885007 GRCh37: 14:74535656-74535656
GRCh38: 14:74068953-74068953
47 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.748G>T (p.Asp250Tyr) SNV Uncertain significance 885008 GRCh37: 14:74535667-74535667
GRCh38: 14:74068964-74068964
48 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.*1887A>C SNV Uncertain significance 885788 GRCh37: 14:74525458-74525458
GRCh38: 14:74058755-74058755
49 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.*1759C>T SNV Uncertain significance 885790 GRCh37: 14:74525586-74525586
GRCh38: 14:74058883-74058883
50 ALDH6A1 , BBOF1 NM_005589.4(ALDH6A1):c.*1655C>T SNV Uncertain significance 885791 GRCh37: 14:74525690-74525690
GRCh38: 14:74058987-74058987

UniProtKB/Swiss-Prot genetic disease variations for Methylmalonate Semialdehyde Dehydrogenase Deficiency:

72
# Symbol AA change Variation ID SNP ID
1 ALDH6A1 p.Gly446Arg VAR_010244 rs72552258

Expression for Methylmalonate Semialdehyde Dehydrogenase Deficiency

Search GEO for disease gene expression data for Methylmalonate Semialdehyde Dehydrogenase Deficiency.

Pathways for Methylmalonate Semialdehyde Dehydrogenase Deficiency

Pathways related to Methylmalonate Semialdehyde Dehydrogenase Deficiency according to KEGG:

36
# Name Kegg Source Accession
1 Valine, leucine and isoleucine degradation hsa00280
2 beta-Alanine metabolism hsa00410
3 Propanoate metabolism hsa00640

GO Terms for Methylmalonate Semialdehyde Dehydrogenase Deficiency

Sources for Methylmalonate Semialdehyde Dehydrogenase Deficiency

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 ExPASy
19 FMA
20 GARD
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
44 MeSH
45 MESH via Orphanet
46 MGI
49 NCI
50 NCIt
51 NDF-RT
53 NINDS
54 Novoseek
56 OMIM via Orphanet
57 OMIM® (Updated 05-Apr-2021)
61 PubMed
63 QIAGEN
68 SNOMED-CT via HPO
69 Tocris
70 UMLS
71 UMLS via Orphanet
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