MMDS4
MCID: MLT139
MIFTS: 35

Multiple Mitochondrial Dysfunctions Syndrome 4 (MMDS4)

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

Aliases & Classifications for Multiple Mitochondrial Dysfunctions Syndrome 4

MalaCards integrated aliases for Multiple Mitochondrial Dysfunctions Syndrome 4:

Name: Multiple Mitochondrial Dysfunctions Syndrome 4 56 12 73 29 6 15
Mmds4 56 58 73
Mitochondrial Dysfunctions, Multiple, Syndrome, Type 4 39
Multiple Mitochondrial Dysfunctions Syndrome Type 4 58

Characteristics:

Orphanet epidemiological data:

58
multiple mitochondrial dysfunctions syndrome type 4
Inheritance: Autosomal recessive; Prevalence: <1/1000000 (Worldwide); Age of onset: Infancy; Age of death: early childhood,infantile;

OMIM:

56
Inheritance:
autosomal recessive

Miscellaneous:
progressive disorder
onset in the first year of life
death in early childhood may occur


HPO:

31
multiple mitochondrial dysfunctions syndrome 4:
Inheritance autosomal recessive inheritance
Onset and clinical course progressive


Classifications:

Orphanet: 58  
Rare neurological diseases
Rare eye diseases
Inborn errors of metabolism


External Ids:

Disease Ontology 12 DOID:0080136
OMIM 56 616370
OMIM Phenotypic Series 56 PS605711
MeSH 43 D028361
ICD10 via Orphanet 33 E88.8
Orphanet 58 ORPHA457406

Summaries for Multiple Mitochondrial Dysfunctions Syndrome 4

OMIM : 56 MMDS4 is an autosomal recessive neurodegenerative disorder that usually results in death in early childhood. Affected individuals have normal development for the first months of life, but thereafter show progressive loss of motor and social skills with hypotonia, spasticity, and nystagmus. Patients regress to a vegetative state with lack of eye contact and speech, and poor feeding. Most patients have optic atrophy, and some may develop seizures. Brain imaging shows diffuse leukodystrophy in the subcortical region, brainstem, cerebellum, and spinal cord. Laboratory studies tend to show increased CSF glycine and decreased activity of mitochondrial complex II; there may be additional biochemical evidence of mitochondrial dysfunction (summary by Alaimo et al., 2018). For a general description and a discussion of genetic heterogeneity of multiple mitochondrial dysfunctions syndrome, see MMDS1 (605711). (616370)

MalaCards based summary : Multiple Mitochondrial Dysfunctions Syndrome 4, also known as mmds4, is related to multiple mitochondrial dysfunctions syndrome and isca2-related mitochondrial disorder. An important gene associated with Multiple Mitochondrial Dysfunctions Syndrome 4 is ISCA2 (Iron-Sulfur Cluster Assembly 2). Affiliated tissues include eye, cerebellum and spinal cord, and related phenotypes are visual impairment and optic atrophy

Disease Ontology : 12 A multiple mitochondrial dysfunctions syndrome that is characterized by normal development for the first months of life, followed by progressive loss of motor and social skills with hypotonia, spasticity, and nystagmus, resulting in death in early childhood, and has material basis in autosomal recessive inheritance of homozygous or compound heterozygous mutation in the iron-sulfur cluster assembly 2 gene on chromosome 14q24.

UniProtKB/Swiss-Prot : 73 Multiple mitochondrial dysfunctions syndrome 4: A severe disorder of systemic energy metabolism, resulting in weakness, respiratory failure, lack of neurologic development, lactic acidosis, hyperglycinemia and early death.

Related Diseases for Multiple Mitochondrial Dysfunctions Syndrome 4

Diseases in the Multiple Mitochondrial Dysfunctions Syndrome family:

Multiple Mitochondrial Dysfunctions Syndrome 1 Multiple Mitochondrial Dysfunctions Syndrome 3
Multiple Mitochondrial Dysfunctions Syndrome 4 Multiple Mitochondrial Dysfunctions Syndrome 5
Multiple Mitochondrial Dysfunctions Syndrome 6 Isca1-Related Multiple Mitochondrial Dysfunctions Syndrome

Diseases related to Multiple Mitochondrial Dysfunctions Syndrome 4 via text searches within MalaCards or GeneCards Suite gene sharing:

(show all 16)
# Related Disease Score Top Affiliating Genes
1 multiple mitochondrial dysfunctions syndrome 27.3 NFU1 LIAS ISCA2 ISCA1 IBA57 BOLA3
2 isca2-related mitochondrial disorder 11.5
3 3-methylglutaconic aciduria, type iii 9.9
4 pathologic nystagmus 9.9
5 combined oxidative phosphorylation deficiency 19 9.8 ISCA2 BOLA3
6 anemia, sideroblastic, 1 9.5 ISCA2 IBA57
7 pyruvate dehydrogenase e1-alpha deficiency 9.3 NFU1 IBA57 BOLA3
8 respiratory failure 9.1 NFU1 IBA57 BOLA3
9 multiple mitochondrial dysfunctions syndrome 1 9.0 NFU1 LIAS IBA57 BOLA3
10 anemia, sideroblastic, and spinocerebellar ataxia 8.8 NFU1 ISCA2 ISCA1 IBA57
11 leukodystrophy 8.7 NFU1 ISCA2 ISCA1 IBA57
12 lactic acidosis 8.7 NFU1 LIAS ISCA2 IBA57 BOLA3
13 multiple mitochondrial dysfunctions syndrome 3 8.2 NFU1 LIAS ISCA2 ISCA1 IBA57 BOLA3
14 multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemia 8.1 NFU1 LIAS ISCA2 ISCA1 IBA57 BOLA3
15 glycine encephalopathy 8.1 NFU1 LIAS ISCA2 ISCA1 IBA57 BOLA3
16 mitochondrial metabolism disease 8.1 NFU1 LIAS ISCA2 ISCA1 IBA57 BOLA3

Graphical network of the top 20 diseases related to Multiple Mitochondrial Dysfunctions Syndrome 4:



Diseases related to Multiple Mitochondrial Dysfunctions Syndrome 4

Symptoms & Phenotypes for Multiple Mitochondrial Dysfunctions Syndrome 4

Human phenotypes related to Multiple Mitochondrial Dysfunctions Syndrome 4:

31 (show all 10)
# Description HPO Frequency HPO Source Accession
1 visual impairment 31 HP:0000505
2 optic atrophy 31 HP:0000648
3 spasticity 31 HP:0001257
4 nystagmus 31 HP:0000639
5 absent speech 31 HP:0001344
6 hyperreflexia 31 HP:0001347
7 leukodystrophy 31 HP:0002415
8 generalized hypotonia 31 HP:0001290
9 abnormality of the periventricular white matter 31 HP:0002518
10 vegetative state 31 HP:0031358

Symptoms via clinical synopsis from OMIM:

56
Head And Neck Eyes:
visual impairment
optic atrophy
nystagmus
loss of eye contact

Muscle Soft Tissue:
hypotonia
atrophic fibers seen on biopsy
some abnormal aggregation of mitochondria

Neurologic Central Nervous System:
spasticity
absent speech
hyperreflexia
periventricular white matter abnormalities
neurodevelopmental regression to a vegetative state
more
Laboratory Abnormalities:
increased csf glycine, glutamate, and lactate
fibroblasts show decreased mitochondrial complex ii activity
mildly decreased complex iv activity
decreased mtdna levels
decreased mitochondrial membrane potential
more

Clinical features from OMIM:

616370

Drugs & Therapeutics for Multiple Mitochondrial Dysfunctions Syndrome 4

Search Clinical Trials , NIH Clinical Center for Multiple Mitochondrial Dysfunctions Syndrome 4

Genetic Tests for Multiple Mitochondrial Dysfunctions Syndrome 4

Genetic tests related to Multiple Mitochondrial Dysfunctions Syndrome 4:

# Genetic test Affiliating Genes
1 Multiple Mitochondrial Dysfunctions Syndrome 4 29 ISCA2

Anatomical Context for Multiple Mitochondrial Dysfunctions Syndrome 4

MalaCards organs/tissues related to Multiple Mitochondrial Dysfunctions Syndrome 4:

40
Eye, Cerebellum, Spinal Cord, Brain

Publications for Multiple Mitochondrial Dysfunctions Syndrome 4

Articles related to Multiple Mitochondrial Dysfunctions Syndrome 4:

# Title Authors PMID Year
1
Neonatal mitochondrial leukoencephalopathy with brain and spinal involvement and high lactate: expanding the phenotype of ISCA2 gene mutations. 56 6
29359243 2018
2
Loss-of-function mutations in ISCA2 disrupt 4Fe-4S cluster machinery and cause a fatal leukodystrophy with hyperglycinemia and mtDNA depletion. 6 56
29297947 2018
3
Further delineation of the phenotypic spectrum of ISCA2 defect: A report of ten new cases. 6 56
29122497 2018
4
ISCA2 mutation causes infantile neurodegenerative mitochondrial disorder. 6 56
25539947 2015
5
ISCA2-Related Mitochondrial Disorder 6
29470032 2018
6
Expanding the genotype-phenotype spectrum of ISCA2-related multiple mitochondrial dysfunction syndrome-cavitating leukoencephalopathy and prolonged survival. 61
32424628 2020
7
A novel ISCA2 variant responsible for an early-onset neurodegenerative mitochondrial disorder: a case report of multiple mitochondrial dysfunctions syndrome 4. 61
31279336 2019
8
Multiple Mitochondrial Dysfunctions Syndrome 4 Due to ISCA2 Gene Defects: A Review. 61
31106229 2019
9
ISCA1 mutation in a patient with infantile-onset leukodystrophy causes defects in mitochondrial [4Fe-4S] proteins. 61
29767723 2018

Variations for Multiple Mitochondrial Dysfunctions Syndrome 4

ClinVar genetic disease variations for Multiple Mitochondrial Dysfunctions Syndrome 4:

6 ‎‎ ‎‎ ‎‎ ‎‎
# Gene Name Type Significance ClinVarId dbSNP ID GRCh37 Pos GRCh38 Pos
1 ISCA2 NM_194279.4(ISCA2):c.334A>G (p.Ser112Gly)SNV Pathogenic 523611 rs767352340 14:74961572-74961572 14:74494869-74494869
2 ISCA2 NM_194279.4(ISCA2):c.229G>A (p.Gly77Ser)SNV Pathogenic/Likely pathogenic 183353 rs730882246 14:74961032-74961032 14:74494329-74494329
3 ISCA2 NM_194279.4(ISCA2):c.297del (p.Phe99fs)deletion Likely pathogenic 545531 rs778755775 14:74961533-74961533 14:74494830-74494830
4 ISCA2 NM_194279.4(ISCA2):c.355G>A (p.Ala119Thr)SNV Uncertain significance 638308 14:74961593-74961593 14:74494890-74494890

UniProtKB/Swiss-Prot genetic disease variations for Multiple Mitochondrial Dysfunctions Syndrome 4:

73
# Symbol AA change Variation ID SNP ID
1 ISCA2 p.Gly77Ser VAR_073794 rs730882246

Expression for Multiple Mitochondrial Dysfunctions Syndrome 4

Search GEO for disease gene expression data for Multiple Mitochondrial Dysfunctions Syndrome 4.

Pathways for Multiple Mitochondrial Dysfunctions Syndrome 4

GO Terms for Multiple Mitochondrial Dysfunctions Syndrome 4

Cellular components related to Multiple Mitochondrial Dysfunctions Syndrome 4 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 mitochondrial matrix GO:0005759 9.26 LIAS ISCA2 ISCA1 IBA57
2 mitochondrion GO:0005739 9.1 NFU1 LIAS ISCA2 ISCA1 IBA57 BOLA3

Biological processes related to Multiple Mitochondrial Dysfunctions Syndrome 4 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 small molecule metabolic process GO:0044281 9.16 ISCA2 ISCA1
2 protein maturation by iron-sulfur cluster transfer GO:0097428 9.13 NFU1 ISCA2 ISCA1
3 iron-sulfur cluster assembly GO:0016226 8.92 NFU1 ISCA2 ISCA1 IBA57

Molecular functions related to Multiple Mitochondrial Dysfunctions Syndrome 4 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 structural molecule activity GO:0005198 9.32 ISCA2 ISCA1
2 iron ion binding GO:0005506 9.26 NFU1 ISCA2
3 2 iron, 2 sulfur cluster binding GO:0051537 9.16 ISCA2 ISCA1
4 4 iron, 4 sulfur cluster binding GO:0051539 9.13 NFU1 LIAS ISCA2
5 iron-sulfur cluster binding GO:0051536 8.92 NFU1 LIAS ISCA2 ISCA1

Sources for Multiple Mitochondrial Dysfunctions Syndrome 4

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 ExPASy
19 FMA
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
43 MeSH
44 MESH via Orphanet
45 MGI
48 NCI
49 NCIt
50 NDF-RT
53 NINDS
54 Novoseek
56 OMIM
57 OMIM via Orphanet
61 PubMed
63 QIAGEN
68 SNOMED-CT via HPO
69 TGDB
70 Tocris
71 UMLS
72 UMLS via Orphanet
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