MCID: FMR004
MIFTS: 34

Fumarase Deficiency

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

Aliases & Classifications for Fumarase Deficiency

MalaCards integrated aliases for Fumarase Deficiency:

Name: Fumarase Deficiency 53 72 49 24 55 71 36 28 13 51 69
Fumaric Aciduria 53 72 49 24 55 71 69
Fumarate Hydratase Deficiency 49 24
Fmrd 53 71

Characteristics:

Orphanet epidemiological data:

55
fumaric aciduria
Inheritance: Autosomal recessive; Prevalence: <1/1000000 (Worldwide); Age of onset: Infancy,Neonatal; Age of death: early childhood;

OMIM:

53
Inheritance:
autosomal recessive

Miscellaneous:
allelic to hereditary multiple leiomyoma of skin (see ) and hereditary leiomyomatosis and renal cell cancer


HPO:

31
fumarase deficiency:
Inheritance autosomal recessive inheritance


Classifications:



Summaries for Fumarase Deficiency

Genetics Home Reference : 24 Fumarase deficiency is a condition that primarily affects the nervous system, especially the brain. Affected infants may have an abnormally small head size (microcephaly), abnormal brain structure, severe developmental delay, weak muscle tone (hypotonia), and failure to gain weight and grow at the expected rate (failure to thrive). They may also experience seizures. Some people with this disorder have unusual facial features, including a prominent forehead (frontal bossing), low-set ears, a small jaw (micrognathia), widely spaced eyes (ocular hypertelorism), and a depressed nasal bridge. An enlarged liver and spleen (hepatosplenomegaly) may also be associated with this disorder, as well as an excess of red blood cells (polycythemia) or deficiency of white blood cells (leukopenia) in infancy. Affected individuals usually survive only a few months, but a few have lived into early adulthood.

MalaCards based summary : Fumarase Deficiency, also known as fumaric aciduria, is related to fumarate hydratase deficiency and encephalopathy, and has symptoms including hypertelorism, agenesis of corpus callosum and frontal bossing. An important gene associated with Fumarase Deficiency is FH (Fumarate Hydratase), and among its related pathways/superpathways is Citrate cycle (TCA cycle). Affiliated tissues include brain, liver and eye.

OMIM : 53 Fumarase deficiency is a severe autosomal recessive metabolic disorder characterized by early-onset hypotonia, profound psychomotor retardation, and brain abnormalities, such as agenesis of the corpus callosum, gyral defects, and ventriculomegaly. Many patients show neonatal distress, metabolic acidosis, and/or encephalopathy (summary by Kerrigan et al., 2000 and Mroch et al., 2012). (606812)

UniProtKB/Swiss-Prot : 71 Fumarase deficiency: A severe autosomal recessive metabolic disorder characterized by early-onset hypotonia, profound psychomotor retardation, and brain abnormalities, such as agenesis of the corpus callosum, gyral defects, and ventriculomegaly. Many patients show neonatal distress, metabolic acidosis, and/or encephalopathy.

NIH Rare Diseases : 49 Fumarase deficiency is an inherited condition that affects the brain and other parts of the nervous system. Signs and symptoms may include a small head (microcephaly), severe developmental delay, poor feeding, weak muscle tone (hypotonia), failure to thrive, seizures, and distinctive facial features. Most people with this deficiency are not able to speak or walk. A variety of brain abnormalities may be detected on MRI. Fumarase deficiency is caused by mutations in the FH gene and inheritance isĀ autosomal recessive. Unfortunately, there is no effective treatment at this time. Management aims to improve symptoms and increase quality of life. Many children with fumarase deficiency do not survive past early childhood, but some are less severely affected, have mild cognitive impairment, and survive beyond this time. Last updated: 2/15/2018

Wikipedia : 72 Fumarase deficiency (or fumaric aciduria), also known as \"Polygamist Down\'s\", is an autosomal... more...

Related Diseases for Fumarase Deficiency

Diseases related to Fumarase Deficiency via text searches within MalaCards or GeneCards Suite gene sharing:

(show all 11)
# Related Disease Score Top Affiliating Genes
1 fumarate hydratase deficiency 11.2
2 encephalopathy 10.1
3 leiomyoma, uterine 9.9
4 mycobacterium tuberculosis 1 9.9
5 leiomyoma 9.9
6 biliary atresia 9.9
7 cerebritis 9.9
8 polyhydramnios 9.9
9 mitochondrial encephalomyopathy 9.9
10 encephalomyopathy 9.9
11 hypotonia 9.9

Graphical network of the top 20 diseases related to Fumarase Deficiency:



Diseases related to Fumarase Deficiency

Symptoms & Phenotypes for Fumarase Deficiency

Symptoms via clinical synopsis from OMIM:

53
Neurologic Central Nervous System:
seizures
polymicrogyria
status epilepticus
cerebral atrophy
developmental delay
more
Head And Neck Face:
frontal bossing

Head And Neck Nose:
depressed nasal bridge
anteverted nares

Metabolic Features:
metabolic acidosis

Head And Neck Mouth:
high-arched palate

Laboratory Abnormalities:
lactic acidemia
pyruvic acidemia
fumaric aciduria
fumarase activity (mitochondrial and cytosolic) is decreased
increased urinary citric acid cycle intermediates
more
Hematology:
polycythemia, neonatal
coagulopathy in those with liver failure

Head And Neck Eyes:
hypertelorism
visual impairment
optic atrophy
optic pallor

Growth Other:
failure to thrive

Abdomen Liver:
cholestasis
liver failure
iron deposition
fibrosis
abnormal swollen mitochondria with flat, haphazardly arranged cristae

Muscle Soft Tissue:
decreased subcutaneous fat
hypotonia
decreased muscle bulk

Head And Neck Head:
macrocephaly, relative

Skin Nails Hair Skin:
cutaneous leiomyomata (heterozygote carriers)


Clinical features from OMIM:

606812

Human phenotypes related to Fumarase Deficiency:

31 (show all 30)
# Description HPO Frequency HPO Source Accession
1 hypertelorism 31 HP:0000316
2 agenesis of corpus callosum 31 HP:0001274
3 frontal bossing 31 HP:0002007
4 high palate 31 HP:0000218
5 failure to thrive 31 HP:0001508
6 neurological speech impairment 31 HP:0002167
7 global developmental delay 31 HP:0001263
8 depressed nasal bridge 31 HP:0005280
9 microcephaly 31 HP:0000252
10 anteverted nares 31 HP:0000463
11 visual impairment 31 HP:0000505
12 optic atrophy 31 HP:0000648
13 aminoaciduria 31 HP:0003355
14 pallor 31 HP:0000980
15 lactic acidosis 31 HP:0003128
16 cholestasis 31 HP:0001396
17 intellectual disability, profound 31 HP:0002187
18 hepatic failure 31 HP:0001399
19 metabolic acidosis 31 HP:0001942
20 polymicrogyria 31 HP:0002126
21 polycythemia 31 HP:0001901
22 status epilepticus 31 HP:0002133
23 cerebral atrophy 31 HP:0002059
24 relative macrocephaly 31 HP:0004482
25 generalized hypotonia 31 HP:0001290
26 reduced subcutaneous adipose tissue 31 HP:0003758
27 cutaneous leiomyoma 31 HP:0007620
28 hypoplasia of the brainstem 31 HP:0002365
29 choroid plexus cyst 31 HP:0002190
30 open operculum 31 HP:0100954

UMLS symptoms related to Fumarase Deficiency:


seizures

Drugs & Therapeutics for Fumarase Deficiency

Search Clinical Trials , NIH Clinical Center for Fumarase Deficiency

Genetic Tests for Fumarase Deficiency

Genetic tests related to Fumarase Deficiency:

# Genetic test Affiliating Genes
1 Fumarase Deficiency 28 FH

Anatomical Context for Fumarase Deficiency

MalaCards organs/tissues related to Fumarase Deficiency:

38
Brain, Liver, Eye, Spleen, Skin

Publications for Fumarase Deficiency

Articles related to Fumarase Deficiency:

(show all 28)
# Title Authors Year
1
Fumarase Deficiency: A Safe and Potentially Disease Modifying Effect of High Fat/Low Carbohydrate Diet. ( 29052812 )
2017
2
Fumarase Deficiency Causes Protein and Metabolite Succination and Intoxicates Mycobacterium tuberculosis. ( 28219662 )
2017
3
Fumarase-deficient Uterine Leiomyomas: An Immunohistochemical, Molecular Genetic, and Clinicopathologic Study of 86 Cases. ( 27454940 )
2016
4
Fumarase deficiency: a rare disorder on the crossroads of clinical and metabolic genetics, neurology and cancer. ( 27541980 )
2016
5
Infantile metabolic encephalopathy due to fumarase deficiency. ( 22772160 )
2013
6
Mild clinical presentation and prolonged survival of a patient with fumarase deficiency due to the combination of a known and a novel mutation in FH gene. ( 23612258 )
2013
7
Fumarase deficiency in dichorionic diamniotic twins. ( 24182348 )
2013
8
Detection of a novel FH whole gene deletion in the propositus leading to subsequent prenatal diagnosis in a sibship with fumarase deficiency. ( 22069215 )
2012
9
Mild fumarase deficiency and a trial of low protein diet. ( 22595425 )
2012
10
Fumarase Deficiency Associated With Non-Inflammatory Biliary Atresia. ( 22922375 )
2012
11
Clinical and biochemical heterogeneity associated with fumarase deficiency. ( 21560188 )
2011
12
The FH mutation database: an online database of fumarate hydratase mutations involved in the MCUL (HLRCC) tumor syndrome and congenital fumarase deficiency. ( 18366737 )
2008
13
Fumarase deficiency caused by homozygous P131R mutation and paternal partial isodisomy of chromosome 1. ( 16575891 )
2006
14
Molecular and biochemical investigations in fumarase deficiency. ( 16510303 )
2006
15
Fumarase deficiency presenting with periventricular cysts. ( 16151915 )
2005
16
A novel mutation of the fumarase gene in a family with autosomal recessive fumarase deficiency. ( 15221078 )
2004
17
[Fumarase deficiency]. ( 12013993 )
2002
18
[Fumarase deficiency]. ( 11596337 )
2001
19
Abnormalities in succinylpurines in fumarase deficiency: possible role in pathogenesis of CNS impairment. ( 10896297 )
2000
20
Molecular analysis and prenatal diagnosis of human fumarase deficiency. ( 9635293 )
1998
21
[Fumarase deficiency]. ( 9590067 )
1998
22
Congenital fumarase deficiency presenting with hypotonia and areflexia. ( 8734035 )
1996
23
Mutation of the fumarase gene in two siblings with progressive encephalopathy and fumarase deficiency. ( 8200987 )
1994
24
Fumarase deficiency: two siblings with enlarged cerebral ventricles and polyhydramnios in utero. ( 1557269 )
1992
25
Fumarase deficiency is an autosomal recessive encephalopathy affecting both the mitochondrial and the cytosolic enzymes. ( 2314594 )
1990
26
A fourth case of fumarase deficiency. ( 2515378 )
1989
27
Fumarase deficiency. ( 3807970 )
1987
28
Fumarase deficiency: a new cause of mitochondrial encephalomyopathy. ( 3736629 )
1986

Variations for Fumarase Deficiency

UniProtKB/Swiss-Prot genetic disease variations for Fumarase Deficiency:

71
# Symbol AA change Variation ID SNP ID
1 FH p.Lys230Arg VAR_002445 rs752232718
2 FH p.Ala308Thr VAR_002446 rs121913118
3 FH p.Phe312Cys VAR_002447
4 FH p.Asp425Val VAR_002448

ClinVar genetic disease variations for Fumarase Deficiency:

6 (show all 43)
# Gene Variation Type Significance SNP ID Assembly Location
1 FH NM_000143.3(FH): c.793G> A (p.Ala265Thr) single nucleotide variant Pathogenic rs387906545 GRCh37 Chromosome 1, 241669414: 241669414
2 FH NM_000143.3(FH): c.1084G> C (p.Glu362Gln) single nucleotide variant Pathogenic rs121913119 GRCh37 Chromosome 1, 241667366: 241667366
3 FH NM_000143.3(FH): c.301C> T (p.Arg101Ter) single nucleotide variant Pathogenic rs121913120 GRCh37 Chromosome 1, 241676980: 241676980
4 FH NM_000143.3(FH): c.698G> A (p.Arg233His) single nucleotide variant Pathogenic rs121913123 GRCh37 Chromosome 1, 241671943: 241671943
5 FH FH, DEL deletion Pathogenic
6 FH NM_000143.3(FH): c.1255T> C (p.Ser419Pro) single nucleotide variant Pathogenic/Likely pathogenic rs200004220 GRCh37 Chromosome 1, 241663872: 241663872
7 FH NM_000143.3(FH): c.1293delA (p.Glu432Lysfs) deletion Pathogenic rs398123163 GRCh37 Chromosome 1, 241663834: 241663834
8 FH NM_000143.3(FH): c.560C> G (p.Ser187Ter) single nucleotide variant Pathogenic rs398123166 GRCh37 Chromosome 1, 241672081: 241672081
9 FH NM_000143.3(FH): c.760C> T (p.Gln254Ter) single nucleotide variant Pathogenic rs398123167 GRCh37 Chromosome 1, 241669447: 241669447
10 FH NM_000143.3(FH): c.697C> T (p.Arg233Cys) single nucleotide variant Pathogenic rs587781682 GRCh37 Chromosome 1, 241671944: 241671944
11 FH NM_000143.3(FH): c.912_918delTTTTGTC (p.Phe305Leufs) deletion Pathogenic rs794727836 GRCh37 Chromosome 1, 241667532: 241667538
12 FH NM_000143.3(FH): c.1430_1437dupAAAATGGA (p.Ser480Lysfs) duplication Pathogenic rs863223994 GRCh37 Chromosome 1, 241661224: 241661231
13 FH NM_000143.3(FH): c.1370_1371insTCAC (p.Ala458Hisfs) insertion Pathogenic rs863223992 GRCh38 Chromosome 1, 241500456: 241500457
14 FH NM_000143.3(FH): c.1189G> A (p.Gly397Arg) single nucleotide variant Pathogenic rs863224007 GRCh38 Chromosome 1, 241502490: 241502490
15 FH NM_000143.3(FH): c.1097G> A (p.Ser366Asn) single nucleotide variant Pathogenic/Likely pathogenic rs863224004 GRCh37 Chromosome 1, 241667353: 241667353
16 FH NM_000143.3(FH): c.1083_1086delTGAA (p.Glu362Glnfs) deletion Pathogenic rs756469140 GRCh37 Chromosome 1, 241667364: 241667367
17 FH NM_000143.3(FH): c.934T> C (p.Phe312Leu) single nucleotide variant Likely pathogenic rs863224000 GRCh37 Chromosome 1, 241667516: 241667516
18 FH NM_000143.3(FH): c.554A> G (p.Gln185Arg) single nucleotide variant Likely pathogenic rs779707997 GRCh37 Chromosome 1, 241675268: 241675268
19 FH NM_000143.3(FH): c.267+1G> C single nucleotide variant Pathogenic rs878853691 GRCh37 Chromosome 1, 241680481: 241680481
20 FH NM_000143.3(FH): c.1108+1G> T single nucleotide variant Likely pathogenic rs1057517734 GRCh37 Chromosome 1, 241667341: 241667341
21 FH NM_000143.3(FH): c.923C> G (p.Ala308Gly) single nucleotide variant Likely pathogenic rs1057524385 GRCh37 Chromosome 1, 241667527: 241667527
22 FH NC_000001.11: g.(?_241497557)_(241504245_?)del deletion Pathogenic GRCh37 Chromosome 1, 241660857: 241667545
23 FH NC_000001.11: g.(?_241497557)_(241519785_?)del deletion Pathogenic GRCh38 Chromosome 1, 241497557: 241519785
24 FH NM_000143.3(FH): c.738+2T> C single nucleotide variant Likely pathogenic rs1060500901 GRCh37 Chromosome 1, 241671901: 241671901
25 FH NM_000143.3(FH): c.1391-1G> A single nucleotide variant Likely pathogenic rs863223978 GRCh38 Chromosome 1, 241497971: 241497971
26 FH NM_000143.3(FH): c.1112delA (p.Lys371Argfs) deletion Pathogenic rs1060500904 GRCh38 Chromosome 1, 241502567: 241502567
27 FH NM_000143.3(FH): c.1052C> A (p.Ser351Ter) single nucleotide variant Pathogenic rs1060500896 GRCh38 Chromosome 1, 241504098: 241504098
28 FH NM_000143.3(FH): c.1021G> A (p.Asp341Asn) single nucleotide variant Likely pathogenic rs11545655 GRCh38 Chromosome 1, 241504129: 241504129
29 FH NM_000143.3(FH): c.267+1G> A single nucleotide variant Pathogenic rs878853691 GRCh38 Chromosome 1, 241517181: 241517181
30 FH NM_000143.3(FH): c.1157A> G (p.Gln386Arg) single nucleotide variant Likely pathogenic rs750447792 GRCh38 Chromosome 1, 241502522: 241502522
31 FH NM_000143.3(FH): c.679C> T (p.Gln227Ter) single nucleotide variant Pathogenic rs11545658 GRCh38 Chromosome 1, 241508662: 241508662
32 FH NM_000143.3(FH): c.204T> A (p.Tyr68Ter) single nucleotide variant Pathogenic rs1060500883 GRCh38 Chromosome 1, 241517245: 241517245
33 FH NM_000143.3(FH): c.1484_1488delAGCAG (p.Glu495Valfs) deletion Likely pathogenic rs1060500907 GRCh38 Chromosome 1, 241497873: 241497877
34 FH NM_000143.3(FH): c.1347delG (p.Met449Ilefs) deletion Pathogenic rs1060500903 GRCh38 Chromosome 1, 241500480: 241500480
35 FH NM_000143.3(FH): c.560C> A (p.Ser187Ter) single nucleotide variant Pathogenic rs398123166 GRCh38 Chromosome 1, 241508781: 241508781
36 FH NM_000143.3(FH): c.1445T> G (p.Leu482Ter) single nucleotide variant Pathogenic/Likely pathogenic rs1064796708 GRCh37 Chromosome 1, 241661216: 241661216
37 FH NM_000143.3(FH): c.689A> G (p.Lys230Arg) single nucleotide variant Pathogenic/Likely pathogenic rs752232718 GRCh37 Chromosome 1, 241671952: 241671952
38 FH NC_000001.11: g.(?_241505997)_(241506174_?)del deletion Pathogenic GRCh38 Chromosome 1, 241505997: 241506174
39 FH NM_000143.3(FH): c.634C> T (p.Gln212Ter) single nucleotide variant Pathogenic GRCh37 Chromosome 1, 241672007: 241672007
40 FH NM_000143.3(FH): c.1251dup (p.His418Thrfs) duplication Pathogenic GRCh37 Chromosome 1, 241663876: 241663876
41 FH NM_000143.3(FH): c.739-2A> C single nucleotide variant Likely pathogenic GRCh37 Chromosome 1, 241669470: 241669470
42 FH NM_000143.3(FH): c.379-1G> A single nucleotide variant Likely pathogenic GRCh37 Chromosome 1, 241675444: 241675444
43 FH NM_000143.3(FH): c.6C> G (p.Tyr2Ter) single nucleotide variant Pathogenic rs199971078 GRCh38 Chromosome 1, 241519717: 241519717

Copy number variations for Fumarase Deficiency from CNVD:

7
# CNVD ID Chromosom Start End Type Gene Symbol CNVD Disease
1 28402 1 222100000 228800000 Copy number FH Fumarase deficiency

Expression for Fumarase Deficiency

Search GEO for disease gene expression data for Fumarase Deficiency.

Pathways for Fumarase Deficiency

Pathways related to Fumarase Deficiency according to KEGG:

36
# Name Kegg Source Accession
1 Citrate cycle (TCA cycle) hsa00020

GO Terms for Fumarase Deficiency

Sources for Fumarase Deficiency

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
46 NCIt
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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