MCID: 3MT015
MIFTS: 44

3-Methylglutaconic Aciduria, Type I

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

Aliases & Classifications for 3-Methylglutaconic Aciduria, Type I

MalaCards integrated aliases for 3-Methylglutaconic Aciduria, Type I:

Name: 3-Methylglutaconic Aciduria, Type I 57 25 13 40
3-Methylglutaconyl-Coa Hydratase Deficiency 57 12 53 25 59 75
Mga1 57 12 25 59 75
3-Methylglutaconic Aciduria Type 1 12 59 15 73
3mg-Coa Hydratase Deficiency 12 59 75
Mga Type I 12 53 75
Mgca1 57 25 75
3 Methylglutaconyl Coa Hydratase Deficiency 76 53
3-Mg-Coa-Hydratase Deficiency 57 25
Mga, Type I 57 25
Megaloblastic Anemia Due to Inborn Errors of Metabolism 73
3-Alpha-Methylglutaconyl-Coa Hydratase Deficiency 75
3 Alpha Methylglutaconic Aciduria Type I 53
3-Alpha-Methylglutaconic Aciduria Type 1 75
3-@methylglutaconic Aciduria, Type I 73
Primary 3-Methylglutaconic Aciduria 25
3-Methylglutaconic Aciduria Type I 12
3 Methylglutaconic Aciduria Type 1 53
3-Methylglutaconic Aciduria 1 75
3mg Coa Hydratase Deficiency 53
Mga, Type I; Mga1 57
3-Mgca Type I 53
Auh Defect 25

Characteristics:

Orphanet epidemiological data:

59
3-methylglutaconic aciduria type 1
Inheritance: Autosomal recessive; Prevalence: <1/1000000 (Worldwide); Age of onset: Infancy,Neonatal;

OMIM:

57
Inheritance:
autosomal recessive

Miscellaneous:
onset in infancy
highly variable phenotype
adult onset of symptoms has been reported
some patients have no clinical symptoms and are detected by routine newborn screening


HPO:

32
3-methylglutaconic aciduria, type i:
Onset and clinical course phenotypic variability infantile onset
Inheritance autosomal recessive inheritance


Classifications:

Orphanet: 59  
Inborn errors of metabolism


Summaries for 3-Methylglutaconic Aciduria, Type I

NIH Rare Diseases : 53 The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.Orpha Number: 67046Disease definition3-methylglutaconic aciduria (3-MGA) type I is an inborn error of leucine metabolism with a variable clinical phenotype ranging from mildly delayed speech to psychomotor retardation, coma, failure to thrive, metabolic acidosis and dystonia.EpidemiologyThe disorder is very rare with less than 20 cases reported in the literature.Clinical descriptionClinical manifestations usually become apparent in the neonatal period or during infancy but the diagnosis may not be made until childhood. Some of the reported patients also displayed hypoglycaemia, spastic quadriparesis, microcephaly, progressive neurological deficit, seizures, vomiting, atrophy of the basal ganglia, severe hypotonia and hepatomegly.EtiologyThe syndrome is caused by mutations in the AUH gene (chromosome 9) encoding 3-methylglutaconyl-CoA hydratase, an enzyme involved in leucine degradation.Diagnostic methodsAs the clinical picture is variable and nonspecific, diagnosis can be made by assay of 3-methylglutaconyl-CoA hydratase activity in fibroblasts or leukocytes, quantitative analysis of urinary organic acid excretion or, more recently, analysis of bodily fluids by NMR spectroscopy.Differential diagnosisPatients with 3-MGA type I can be distinguished from those with other forms of 3-MGA (types II, III and IV; see these terms) by the distinctive pattern of metabolite excretion: 3-methylglutaconic acid levels are highly elevated (higher than those detected in other forms of 3-MGA) whereas methylglutaric acid levels are usually only slightly elevated, and there is a high level of 3-hydroxyisovaleric acid excretion (not present in other forms of 3-MGA).Antenatal diagnosisPrenatal diagnosis should be possible through detection of high levels of 3-hydroxyisovaleric acid in the amniotic fluid or through enzyme analysis of cultured amniocytes.Genetic counselingThe syndrome is inherited as an autosomal recessivetrait.Management and treatmentTreatment is largely symptomatic but dietary management with a modest leucine restriction and supplementation with L-carnitine may be beneficial in some cases.Visit the Orphanet disease page for more resources.

MalaCards based summary : 3-Methylglutaconic Aciduria, Type I, also known as 3-methylglutaconyl-coa hydratase deficiency, is related to megaloblastic anemia 1 and megaloblastic anemia, and has symptoms including athetosis and cerebellar ataxia. An important gene associated with 3-Methylglutaconic Aciduria, Type I is AUH (AU RNA Binding Methylglutaconyl-CoA Hydratase), and among its related pathways/superpathways are Valine, leucine and isoleucine degradation and Diseases of metabolism. Affiliated tissues include brain, eye and skin, and related phenotypes are seizures and failure to thrive

OMIM : 57 Type I MGCA is a rare autosomal recessive disorder of leucine catabolism. The metabolic landmark is urinary excretion of 3-methylglutaconic acid (3-MGA) and its derivatives 3-methylglutaric acid (3-MG) and 3-hydroxyisovaleric acid (3-HIVA). Two main presentations have been described: 1 with onset in childhood associated with the nonspecific finding of psychomotor retardation, and the other with onset in adulthood of a progressive neurodegenerative disorder characterized by ataxia, spasticity, and sometimes dementia; these patients develop white matter lesions in the brain. However, some asymptomatic pediatric patients have been identified by newborn screening and show no developmental abnormalities when reexamined later in childhood (summary by Wortmann et al., 2010). (250950)

UniProtKB/Swiss-Prot : 75 3-methylglutaconic aciduria 1: An inborn error of leucine metabolism. It leads to an autosomal recessive syndrome with variable clinical phenotype, ranging from delayed speech development to severe psychomotor retardation, coma, failure to thrive, metabolic acidosis and dystonia. MGA1 can be distinguished from other forms of MGA by the pattern of metabolite excretion: 3-methylglutaconic acid levels are higher than those detected in other forms, whereas methylglutaric acid levels are usually only slightly elevated and there is a high level of 3- hydroxyisovaleric acid excretion (not present in other MGA forms).

Genetics Home Reference : 25 3-methylglutaconyl-CoA hydratase deficiency is an inherited condition that causes neurological problems. Beginning in infancy to early childhood, children with this condition often have delayed development of mental and motor skills (psychomotor delay), speech delay, involuntary muscle cramping (dystonia), and spasms and weakness of the arms and legs (spastic quadriparesis). Affected individuals can also have optic atrophy, which is the degeneration (atrophy) of nerve cells that carry visual information from the eyes to the brain.

Disease Ontology : 12 A 3-methylglutaconic aciduria that has material basis in homozygous or compound heterozygous mutation in the AUH gene on chromosome 9q22.

Wikipedia : 76 3-Methylglutaconic aciduria (MGA) is any of at least five metabolic disorders that impair the body\'s... more...

Related Diseases for 3-Methylglutaconic Aciduria, Type I

Graphical network of the top 20 diseases related to 3-Methylglutaconic Aciduria, Type I:



Diseases related to 3-Methylglutaconic Aciduria, Type I

Symptoms & Phenotypes for 3-Methylglutaconic Aciduria, Type I

Symptoms via clinical synopsis from OMIM:

57
Neurologic Central Nervous System:
dysarthria
hyperreflexia
cognitive impairment
dystonia
athetosis
more
Head And Neck Eyes:
optic atrophy

Genitourinary Bladder:
urinary incontinence (adult)

Growth Other:
failure to thrive

Metabolic Features:
metabolic acidosis

Laboratory Abnormalities:
increased urinary 3-methylglutaconic acid
increased urinary hydroxyisovaleric acid
decreased activity of 3-methylglutaconyl-coa hydratase


Clinical features from OMIM:

250950

Human phenotypes related to 3-Methylglutaconic Aciduria, Type I:

59 32 (show all 27)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 seizures 59 32 occasional (7.5%) Occasional (29-5%) HP:0001250
2 failure to thrive 59 32 hallmark (90%) Very frequent (99-80%) HP:0001508
3 global developmental delay 59 32 occasional (7.5%) Frequent (79-30%) HP:0001263
4 hepatomegaly 59 32 occasional (7.5%) Occasional (29-5%) HP:0002240
5 delayed speech and language development 59 32 frequent (33%) Frequent (79-30%) HP:0000750
6 microcephaly 59 32 occasional (7.5%) Occasional (29-5%) HP:0000252
7 hypoglycemia 59 32 occasional (7.5%) Occasional (29-5%) HP:0001943
8 dystonia 59 32 occasional (7.5%) Occasional (29-5%) HP:0001332
9 coma 59 32 occasional (7.5%) Occasional (29-5%) HP:0001259
10 progressive cerebellar ataxia 59 32 occasional (7.5%) Occasional (29-5%) HP:0002073
11 spastic tetraparesis 59 32 occasional (7.5%) Occasional (29-5%) HP:0001285
12 abnormality of the basal ganglia 59 32 occasional (7.5%) Occasional (29-5%) HP:0002134
13 3-methylglutaconic aciduria 59 32 hallmark (90%) Very frequent (99-80%) HP:0003535
14 ataxia 32 HP:0001251
15 dysarthria 32 HP:0001260
16 hyperreflexia 32 HP:0001347
17 optic atrophy 32 HP:0000648
18 cognitive impairment 32 HP:0100543
19 spastic tetraplegia 32 HP:0002510
20 febrile seizures 32 HP:0002373
21 metabolic acidosis 32 HP:0001942
22 motor delay 32 HP:0001270
23 urinary incontinence 32 HP:0000020
24 cerebral atrophy 32 HP:0002059
25 athetosis 32 HP:0002305
26 short attention span 32 HP:0000736
27 leukoencephalopathy 32 HP:0002352

UMLS symptoms related to 3-Methylglutaconic Aciduria, Type I:


athetosis, cerebellar ataxia

Drugs & Therapeutics for 3-Methylglutaconic Aciduria, Type I

Search Clinical Trials , NIH Clinical Center for 3-Methylglutaconic Aciduria, Type I

Genetic Tests for 3-Methylglutaconic Aciduria, Type I

Anatomical Context for 3-Methylglutaconic Aciduria, Type I

MalaCards organs/tissues related to 3-Methylglutaconic Aciduria, Type I:

41
Brain, Eye, Skin

Publications for 3-Methylglutaconic Aciduria, Type I

Articles related to 3-Methylglutaconic Aciduria, Type I:

(show all 12)
# Title Authors Year
1
Phenotypic heterogeneity in two siblings with 3-methylglutaconic aciduria type I caused by a novel intragenic deletion. ( 21840233 )
2011
2
3-Methylglutaconic aciduria type I redefined: a syndrome with late-onset leukoencephalopathy. ( 20855850 )
2010
3
NMR spectroscopic studies on the late onset form of 3-methylglutaconic aciduria type I and other defects in leucine metabolism. ( 16541463 )
2006
4
3-Methylglutaconic aciduria type I causes leukoencephalopathy of adult onset. ( 17130438 )
2006
5
A molecular lesion in a Japanese patient with severe phenotype of 3-methylglutaconic aciduria type I. ( 16354225 )
2005
6
Direct nonisotopic assay of 3-methylglutaconyl-CoA hydratase in cultured human skin fibroblasts to specifically identify patients with 3-methylglutaconic aciduria type I. ( 15192029 )
2004
7
3-methylglutaconic aciduria type I in a boy with fever-associated seizures. ( 15033206 )
2004
8
Mutations in the AUH gene cause 3-methylglutaconic aciduria type I. ( 12655555 )
2003
9
3-methylglutaconic aciduria type I is caused by mutations in AUH. ( 12434311 )
2002
10
3-Methylglutaconyl-CoA hydratase deficiency: a new patient with speech retardation as the leading sign. ( 10896289 )
2000
11
3-Methylglutaconic aciduria type I: clinical heterogeneity as a neurometabolic disease. ( 10070612 )
1999
12
[3-Methylglutaconyl-CoA hydratase deficiency]. ( 9590049 )
1998

Variations for 3-Methylglutaconic Aciduria, Type I

UniProtKB/Swiss-Prot genetic disease variations for 3-Methylglutaconic Aciduria, Type I:

75
# Symbol AA change Variation ID SNP ID
1 AUH p.Ala240Val VAR_016911 rs769894315

ClinVar genetic disease variations for 3-Methylglutaconic Aciduria, Type I:

6
(show top 50) (show all 52)
# Gene Variation Type Significance SNP ID Assembly Location
1 AUH NM_001698.2(AUH): c.589C> T (p.Arg197Ter) single nucleotide variant Pathogenic rs121434636 GRCh37 Chromosome 9, 94060275: 94060275
2 AUH NM_001698.2(AUH): c.589C> T (p.Arg197Ter) single nucleotide variant Pathogenic rs121434636 GRCh38 Chromosome 9, 91297993: 91297993
3 AUH NM_001698.2(AUH): c.895-1G> A single nucleotide variant Pathogenic rs730880309 GRCh37 Chromosome 9, 93978389: 93978389
4 AUH NM_001698.2(AUH): c.895-1G> A single nucleotide variant Pathogenic rs730880309 GRCh38 Chromosome 9, 91216107: 91216107
5 AUH NM_001698.2(AUH): c.80delG (p.Ser27Metfs) deletion Pathogenic rs730880310 GRCh37 Chromosome 9, 94124092: 94124092
6 AUH NM_001698.2(AUH): c.80delG (p.Ser27Metfs) deletion Pathogenic rs730880310 GRCh38 Chromosome 9, 91361810: 91361810
7 AUH NM_001698.2(AUH): c.263-2A> G single nucleotide variant Pathogenic rs730880311 GRCh37 Chromosome 9, 94118439: 94118439
8 AUH NM_001698.2(AUH): c.263-2A> G single nucleotide variant Pathogenic rs730880311 GRCh38 Chromosome 9, 91356157: 91356157
9 AUH NM_001698.2(AUH): c.943-2A> G single nucleotide variant Pathogenic rs730880312 GRCh38 Chromosome 9, 91214427: 91214427
10 AUH NM_001698.2(AUH): c.943-2A> G single nucleotide variant Pathogenic rs730880312 GRCh37 Chromosome 9, 93976709: 93976709
11 MT-TL1 m.3243A> G single nucleotide variant Pathogenic rs199474657 GRCh37 Chromosome MT, 3243: 3243
12 MT-TL1 m.3243A> G single nucleotide variant Pathogenic rs199474657 GRCh38 Chromosome MT, 3243: 3243
13 AUH NM_001698.2(AUH): c.559G> A (p.Gly187Ser) single nucleotide variant Pathogenic rs387906755 GRCh37 Chromosome 9, 94060305: 94060305
14 AUH NM_001698.2(AUH): c.559G> A (p.Gly187Ser) single nucleotide variant Pathogenic rs387906755 GRCh38 Chromosome 9, 91298023: 91298023
15 AUH NM_001698.2(AUH): c.650G> A (p.Gly217Asp) single nucleotide variant Pathogenic rs387906756 GRCh37 Chromosome 9, 94058308: 94058308
16 AUH NM_001698.2(AUH): c.650G> A (p.Gly217Asp) single nucleotide variant Pathogenic rs387906756 GRCh38 Chromosome 9, 91296026: 91296026
17 AUH NM_001698.2(AUH): c.373C> T (p.Arg125Trp) single nucleotide variant Likely pathogenic rs200030276 GRCh37 Chromosome 9, 94118210: 94118210
18 AUH NM_001698.2(AUH): c.373C> T (p.Arg125Trp) single nucleotide variant Likely pathogenic rs200030276 GRCh38 Chromosome 9, 91355928: 91355928
19 AUH NM_001698.2(AUH): c.598+10A> C single nucleotide variant Conflicting interpretations of pathogenicity rs186203318 GRCh38 Chromosome 9, 91297974: 91297974
20 AUH NM_001698.2(AUH): c.598+10A> C single nucleotide variant Conflicting interpretations of pathogenicity rs186203318 GRCh37 Chromosome 9, 94060256: 94060256
21 AUH NM_001698.2(AUH): c.381A> G (p.Ile127Met) single nucleotide variant Uncertain significance rs146227896 GRCh38 Chromosome 9, 91355920: 91355920
22 AUH NM_001698.2(AUH): c.381A> G (p.Ile127Met) single nucleotide variant Uncertain significance rs146227896 GRCh37 Chromosome 9, 94118202: 94118202
23 AUH NM_001698.2(AUH): c.182C> A (p.Pro61His) single nucleotide variant Conflicting interpretations of pathogenicity rs181327211 GRCh37 Chromosome 9, 94123990: 94123990
24 AUH NM_001698.2(AUH): c.182C> A (p.Pro61His) single nucleotide variant Conflicting interpretations of pathogenicity rs181327211 GRCh38 Chromosome 9, 91361708: 91361708
25 AUH NM_001698.2(AUH): c.331-6G> A single nucleotide variant Likely benign rs10991898 GRCh37 Chromosome 9, 94118258: 94118258
26 AUH NM_001698.2(AUH): c.331-6G> A single nucleotide variant Likely benign rs10991898 GRCh38 Chromosome 9, 91355976: 91355976
27 AUH NM_001698.2(AUH): c.84G> T (p.Ala28=) single nucleotide variant Uncertain significance rs1057515676 GRCh37 Chromosome 9, 94124088: 94124088
28 AUH NM_001698.2(AUH): c.84G> T (p.Ala28=) single nucleotide variant Uncertain significance rs1057515676 GRCh38 Chromosome 9, 91361806: 91361806
29 AUH NM_001698.2(AUH): c.*107A> G single nucleotide variant Likely benign rs75505223 GRCh37 Chromosome 9, 93976523: 93976523
30 AUH NM_001698.2(AUH): c.*107A> G single nucleotide variant Likely benign rs75505223 GRCh38 Chromosome 9, 91214241: 91214241
31 AUH NM_001698.2(AUH): c.*29G> A single nucleotide variant Uncertain significance rs200499826 GRCh37 Chromosome 9, 93976601: 93976601
32 AUH NM_001698.2(AUH): c.*29G> A single nucleotide variant Uncertain significance rs200499826 GRCh38 Chromosome 9, 91214319: 91214319
33 AUH NM_001698.2(AUH): c.*432C> T single nucleotide variant Uncertain significance rs746233646 GRCh38 Chromosome 9, 91213916: 91213916
34 AUH NM_001698.2(AUH): c.*432C> T single nucleotide variant Uncertain significance rs746233646 GRCh37 Chromosome 9, 93976198: 93976198
35 AUH NM_001698.2(AUH): c.*218_*219delAG deletion Uncertain significance rs1057515675 GRCh37 Chromosome 9, 93976411: 93976412
36 AUH NM_001698.2(AUH): c.*218_*219delAG deletion Uncertain significance rs1057515675 GRCh38 Chromosome 9, 91214129: 91214130
37 AUH NM_001698.2(AUH): c.951A> T (p.Pro317=) single nucleotide variant Conflicting interpretations of pathogenicity rs530710210 GRCh37 Chromosome 9, 93976699: 93976699
38 AUH NM_001698.2(AUH): c.951A> T (p.Pro317=) single nucleotide variant Conflicting interpretations of pathogenicity rs530710210 GRCh38 Chromosome 9, 91214417: 91214417
39 AUH NM_001698.2(AUH): c.-30C> G single nucleotide variant Uncertain significance rs1057515677 GRCh37 Chromosome 9, 94124201: 94124201
40 AUH NM_001698.2(AUH): c.-30C> G single nucleotide variant Uncertain significance rs1057515677 GRCh38 Chromosome 9, 91361919: 91361919
41 AUH NM_001698.2(AUH): c.*259_*262delTTTA deletion Uncertain significance rs377176126 GRCh38 Chromosome 9, 91214086: 91214089
42 AUH NM_001698.2(AUH): c.*259_*262delTTTA deletion Uncertain significance rs377176126 GRCh37 Chromosome 9, 93976368: 93976371
43 AUH NM_001698.2(AUH): c.807G> A (p.Arg269=) single nucleotide variant Likely benign rs145208407 GRCh37 Chromosome 9, 93983123: 93983123
44 AUH NM_001698.2(AUH): c.807G> A (p.Arg269=) single nucleotide variant Likely benign rs145208407 GRCh38 Chromosome 9, 91220841: 91220841
45 AUH NM_001698.2(AUH): c.719C> T (p.Ala240Val) single nucleotide variant Uncertain significance rs769894315 GRCh37 Chromosome 9, 93983211: 93983211
46 AUH NM_001698.2(AUH): c.719C> T (p.Ala240Val) single nucleotide variant Uncertain significance rs769894315 GRCh38 Chromosome 9, 91220929: 91220929
47 AUH NM_001698.2(AUH): c.304T> A (p.Ser102Thr) single nucleotide variant Uncertain significance GRCh37 Chromosome 9, 94118396: 94118396
48 AUH NM_001698.2(AUH): c.304T> A (p.Ser102Thr) single nucleotide variant Uncertain significance GRCh38 Chromosome 9, 91356114: 91356114
49 AUH NM_001698.2(AUH): c.942+4dup duplication Uncertain significance GRCh38 Chromosome 9, 91216055: 91216055
50 AUH NM_001698.2(AUH): c.942+4dup duplication Uncertain significance GRCh37 Chromosome 9, 93978337: 93978337

Expression for 3-Methylglutaconic Aciduria, Type I

Search GEO for disease gene expression data for 3-Methylglutaconic Aciduria, Type I.

Pathways for 3-Methylglutaconic Aciduria, Type I

GO Terms for 3-Methylglutaconic Aciduria, Type I

Cellular components related to 3-Methylglutaconic Aciduria, Type I according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 apical part of cell GO:0045177 9.32 AMN CUBN
2 clathrin-coated pit GO:0005905 9.26 AMN CUBN
3 endocytic vesicle GO:0030139 9.16 AMN CUBN
4 mitochondrion GO:0005739 9.02 AUH DNAJC19 EHHADH OPA3 TMEM70
5 brush border membrane GO:0031526 8.96 AMN CUBN

Biological processes related to 3-Methylglutaconic Aciduria, Type I according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 fatty acid beta-oxidation GO:0006635 9.26 AUH EHHADH
2 cobalamin metabolic process GO:0009235 9.16 AMN CUBN
3 high-density lipoprotein particle clearance GO:0034384 8.96 AMN CUBN
4 cobalamin transport GO:0015889 8.62 AMN CUBN

Molecular functions related to 3-Methylglutaconic Aciduria, Type I according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 enoyl-CoA hydratase activity GO:0004300 8.62 AUH EHHADH

Sources for 3-Methylglutaconic Aciduria, Type I

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9 Cosmic
10 dbSNP
11 DGIdb
17 ExPASy
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45 MESH via Orphanet
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58 OMIM via Orphanet
62 PubMed
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69 SNOMED-CT via HPO
70 SNOMED-CT via Orphanet
71 TGDB
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74 UMLS via Orphanet
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