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 57 76 53 25 59 75 37 29 13 55 6 73
Fumaric Aciduria 57 76 53 25 59 75 73
Fumarate Hydratase Deficiency 53 25
Fmrd 57 75
Deficiency, Fumarase 40

Characteristics:

Orphanet epidemiological data:

59
fumaric aciduria
Inheritance: Autosomal recessive; Prevalence: <1/1000000 (Worldwide); Age of onset: Infancy,Neonatal; Age of death: early childhood;

OMIM:

57
Inheritance:
autosomal recessive

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


HPO:

32
fumarase deficiency:
Inheritance autosomal recessive inheritance


Classifications:



Summaries for Fumarase Deficiency

Genetics Home Reference : 25 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 seizures 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, and related phenotypes are hypertelorism and agenesis of corpus callosum

NIH Rare Diseases : 53 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.

OMIM : 57 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 : 75 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.

Wikipedia : 76 Fumarase deficiency (or fumaric aciduria) is an exceedingly rare autosomal recessive metabolic disorder... more...

Related Diseases for Fumarase Deficiency

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

# Related Disease Score Top Affiliating Genes
1 fumarate hydratase deficiency 11.6
2 encephalopathy 10.1
3 leiomyoma, uterine 9.9
4 leiomyoma 9.9
5 biliary atresia 9.9
6 cerebritis 9.9
7 polyhydramnios 9.9
8 mitochondrial encephalomyopathy 9.9
9 encephalomyopathy 9.9
10 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:

57
Head And Neck Eyes:
hypertelorism
visual impairment
optic atrophy
optic pallor

Neurologic Central Nervous System:
seizures
polymicrogyria
status epilepticus
cerebral atrophy
open operculum
more
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 Face:
frontal bossing

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:

32 (show all 31)
# Description HPO Frequency HPO Source Accession
1 hypertelorism 32 HP:0000316
2 agenesis of corpus callosum 32 HP:0001274
3 frontal bossing 32 HP:0002007
4 high palate 32 HP:0000218
5 muscular hypotonia 32 HP:0001252
6 failure to thrive 32 HP:0001508
7 neurological speech impairment 32 HP:0002167
8 global developmental delay 32 HP:0001263
9 depressed nasal bridge 32 HP:0005280
10 microcephaly 32 HP:0000252
11 anteverted nares 32 HP:0000463
12 visual impairment 32 HP:0000505
13 optic atrophy 32 HP:0000648
14 aminoaciduria 32 HP:0003355
15 pallor 32 HP:0000980
16 lactic acidosis 32 HP:0003128
17 cholestasis 32 HP:0001396
18 intellectual disability, profound 32 HP:0002187
19 hepatic failure 32 HP:0001399
20 metabolic acidosis 32 HP:0001942
21 polymicrogyria 32 HP:0002126
22 polycythemia 32 HP:0001901
23 status epilepticus 32 HP:0002133
24 cerebral atrophy 32 HP:0002059
25 relative macrocephaly 32 HP:0004482
26 generalized hypotonia 32 HP:0001290
27 reduced subcutaneous adipose tissue 32 HP:0003758
28 open operculum 32 HP:0100954
29 cutaneous leiomyoma 32 HP:0007620
30 hypoplasia of the brainstem 32 HP:0002365
31 choroid plexus cyst 32 HP:0002190

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 29 FH

Anatomical Context for Fumarase Deficiency

MalaCards organs/tissues related to Fumarase Deficiency:

41
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
Mild fumarase deficiency and a trial of low protein diet. ( 22595425 )
2012
9
Fumarase Deficiency Associated With Non-Inflammatory Biliary Atresia. ( 22922375 )
2012
10
Detection of a novel FH whole gene deletion in the propositus leading to subsequent prenatal diagnosis in a sibship with fumarase deficiency. ( 22069215 )
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:

75
# 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 top 50) (show all 452)
# 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.793G> A (p.Ala265Thr) single nucleotide variant Pathogenic rs387906545 GRCh38 Chromosome 1, 241506114: 241506114
3 FH NM_000143.3(FH): c.1084G> C (p.Glu362Gln) single nucleotide variant Pathogenic rs121913119 GRCh37 Chromosome 1, 241667366: 241667366
4 FH NM_000143.3(FH): c.1084G> C (p.Glu362Gln) single nucleotide variant Pathogenic rs121913119 GRCh38 Chromosome 1, 241504066: 241504066
5 FH NM_000143.3(FH): c.301C> T (p.Arg101Ter) single nucleotide variant Pathogenic rs121913120 GRCh37 Chromosome 1, 241676980: 241676980
6 FH NM_000143.3(FH): c.301C> T (p.Arg101Ter) single nucleotide variant Pathogenic rs121913120 GRCh38 Chromosome 1, 241513680: 241513680
7 FH NM_000143.3(FH): c.1027C> T (p.Arg343Ter) single nucleotide variant Pathogenic rs121913122 GRCh37 Chromosome 1, 241667423: 241667423
8 FH NM_000143.3(FH): c.1027C> T (p.Arg343Ter) single nucleotide variant Pathogenic rs121913122 GRCh38 Chromosome 1, 241504123: 241504123
9 FH NM_000143.3(FH): c.698G> A (p.Arg233His) single nucleotide variant Pathogenic rs121913123 GRCh37 Chromosome 1, 241671943: 241671943
10 FH NM_000143.3(FH): c.698G> A (p.Arg233His) single nucleotide variant Pathogenic rs121913123 GRCh38 Chromosome 1, 241508643: 241508643
11 FH FH, DEL deletion Pathogenic
12 FH NM_000143.3(FH): c.1255T> C (p.Ser419Pro) single nucleotide variant Pathogenic/Likely pathogenic rs200004220 GRCh37 Chromosome 1, 241663872: 241663872
13 FH NM_000143.3(FH): c.1255T> C (p.Ser419Pro) single nucleotide variant Pathogenic/Likely pathogenic rs200004220 GRCh38 Chromosome 1, 241500572: 241500572
14 FH NM_000143.3(FH): c.1293delA (p.Glu432Lysfs) deletion Pathogenic rs398123163 GRCh37 Chromosome 1, 241663834: 241663834
15 FH NM_000143.3(FH): c.1293delA (p.Glu432Lysfs) deletion Pathogenic rs398123163 GRCh38 Chromosome 1, 241500534: 241500534
16 FH NM_000143.3(FH): c.560C> G (p.Ser187Ter) single nucleotide variant Pathogenic rs398123166 GRCh37 Chromosome 1, 241672081: 241672081
17 FH NM_000143.3(FH): c.560C> G (p.Ser187Ter) single nucleotide variant Pathogenic rs398123166 GRCh38 Chromosome 1, 241508781: 241508781
18 FH NM_000143.3(FH): c.760C> T (p.Gln254Ter) single nucleotide variant Pathogenic rs398123167 GRCh37 Chromosome 1, 241669447: 241669447
19 FH NM_000143.3(FH): c.760C> T (p.Gln254Ter) single nucleotide variant Pathogenic rs398123167 GRCh38 Chromosome 1, 241506147: 241506147
20 FH NM_000143.3(FH): c.952C> T (p.His318Tyr) single nucleotide variant Pathogenic/Likely pathogenic rs398123168 GRCh37 Chromosome 1, 241667498: 241667498
21 FH NM_000143.3(FH): c.952C> T (p.His318Tyr) single nucleotide variant Pathogenic/Likely pathogenic rs398123168 GRCh38 Chromosome 1, 241504198: 241504198
22 FH NM_000143.3(FH): c.697C> T (p.Arg233Cys) single nucleotide variant Pathogenic rs587781682 GRCh37 Chromosome 1, 241671944: 241671944
23 FH NM_000143.3(FH): c.697C> T (p.Arg233Cys) single nucleotide variant Pathogenic rs587781682 GRCh38 Chromosome 1, 241508644: 241508644
24 FH NM_000143.3(FH): c.1434T> C (p.Asn478=) single nucleotide variant Likely benign rs786202199 GRCh37 Chromosome 1, 241661227: 241661227
25 FH NM_000143.3(FH): c.1434T> C (p.Asn478=) single nucleotide variant Likely benign rs786202199 GRCh38 Chromosome 1, 241497927: 241497927
26 FH NM_000143.3(FH): c.1428C> T (p.His476=) single nucleotide variant Likely benign rs199887605 GRCh37 Chromosome 1, 241661233: 241661233
27 FH NM_000143.3(FH): c.1428C> T (p.His476=) single nucleotide variant Likely benign rs199887605 GRCh38 Chromosome 1, 241497933: 241497933
28 FH NM_000143.3(FH): c.786_806del21 (p.Lys263_Ile269del) deletion Conflicting interpretations of pathogenicity rs786202220 GRCh37 Chromosome 1, 241669401: 241669421
29 FH NM_000143.3(FH): c.786_806del21 (p.Lys263_Ile269del) deletion Conflicting interpretations of pathogenicity rs786202220 GRCh38 Chromosome 1, 241506101: 241506121
30 FH NM_000143.3(FH): c.700A> G (p.Thr234Ala) single nucleotide variant Conflicting interpretations of pathogenicity rs372505976 GRCh37 Chromosome 1, 241671941: 241671941
31 FH NM_000143.3(FH): c.700A> G (p.Thr234Ala) single nucleotide variant Conflicting interpretations of pathogenicity rs372505976 GRCh38 Chromosome 1, 241508641: 241508641
32 FH NM_000143.3(FH): c.437G> A (p.Gly146Glu) single nucleotide variant Conflicting interpretations of pathogenicity rs11545654 GRCh37 Chromosome 1, 241675385: 241675385
33 FH NM_000143.3(FH): c.437G> A (p.Gly146Glu) single nucleotide variant Conflicting interpretations of pathogenicity rs11545654 GRCh38 Chromosome 1, 241512085: 241512085
34 FH NM_000143.3(FH): c.358A> G (p.Ile120Val) single nucleotide variant Uncertain significance rs199641124 GRCh37 Chromosome 1, 241676923: 241676923
35 FH NM_000143.3(FH): c.358A> G (p.Ile120Val) single nucleotide variant Uncertain significance rs199641124 GRCh38 Chromosome 1, 241513623: 241513623
36 FH NM_000143.3(FH): c.305C> T (p.Ala102Val) single nucleotide variant Uncertain significance rs61753295 GRCh37 Chromosome 1, 241676976: 241676976
37 FH NM_000143.3(FH): c.305C> T (p.Ala102Val) single nucleotide variant Uncertain significance rs61753295 GRCh38 Chromosome 1, 241513676: 241513676
38 FH NM_000143.3(FH): c.217G> A (p.Val73Met) single nucleotide variant Uncertain significance rs201878591 GRCh37 Chromosome 1, 241680532: 241680532
39 FH NM_000143.3(FH): c.217G> A (p.Val73Met) single nucleotide variant Uncertain significance rs201878591 GRCh38 Chromosome 1, 241517232: 241517232
40 FH NM_000143.3(FH): c.122C> T (p.Ala41Val) single nucleotide variant Likely benign rs201486221 GRCh37 Chromosome 1, 241682901: 241682901
41 FH NM_000143.3(FH): c.122C> T (p.Ala41Val) single nucleotide variant Likely benign rs201486221 GRCh38 Chromosome 1, 241519601: 241519601
42 FH NM_000143.3(FH): c.63C> T (p.Ala21=) single nucleotide variant Likely benign rs555404867 GRCh37 Chromosome 1, 241682960: 241682960
43 FH NM_000143.3(FH): c.63C> T (p.Ala21=) single nucleotide variant Likely benign rs555404867 GRCh38 Chromosome 1, 241519660: 241519660
44 FH NM_000143.3(FH): c.6C> T (p.Tyr2=) single nucleotide variant Benign/Likely benign rs199971078 GRCh37 Chromosome 1, 241683017: 241683017
45 FH NM_000143.3(FH): c.6C> T (p.Tyr2=) single nucleotide variant Benign/Likely benign rs199971078 GRCh38 Chromosome 1, 241519717: 241519717
46 FH NM_000143.3(FH): c.912_918delTTTTGTC (p.Phe305Leufs) deletion Pathogenic rs794727836 GRCh37 Chromosome 1, 241667532: 241667538
47 FH NM_000143.3(FH): c.912_918delTTTTGTC (p.Phe305Leufs) deletion Pathogenic rs794727836 GRCh38 Chromosome 1, 241504232: 241504238
48 FH NM_000143.3(FH): c.1430_1437dupAAAATGGA (p.Ser480Lysfs) duplication Pathogenic rs863223994 GRCh37 Chromosome 1, 241661224: 241661231
49 FH NM_000143.3(FH): c.1430_1437dupAAAATGGA (p.Ser480Lysfs) duplication Pathogenic rs863223994 GRCh38 Chromosome 1, 241497924: 241497931
50 FH NM_000143.3(FH): c.1370_1371insTCAC (p.Ala458Hisfs) insertion Pathogenic rs863223992 GRCh38 Chromosome 1, 241500456: 241500457

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:

37
# 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
17 ExPASy
19 FMA
28 GO
29 GTR
30 HGMD
31 HMDB
32 HPO
33 ICD10
34 ICD10 via Orphanet
35 ICD9CM
36 IUPHAR
37 KEGG
38 LifeMap
40 LOVD
42 MedGen
44 MeSH
45 MESH via Orphanet
46 MGI
49 NCI
50 NCIt
51 NDF-RT
54 NINDS
55 Novoseek
57 OMIM
58 OMIM via Orphanet
62 PubMed
64 QIAGEN
69 SNOMED-CT via HPO
70 SNOMED-CT via Orphanet
71 TGDB
72 Tocris
73 UMLS
74 UMLS via Orphanet
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