MMDS2
MCID: MLT150
MIFTS: 36

Multiple Mitochondrial Dysfunctions Syndrome 2 with Hyperglycinemia (MMDS2)

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

Aliases & Classifications for Multiple Mitochondrial Dysfunctions Syndrome 2 with...

MalaCards integrated aliases for Multiple Mitochondrial Dysfunctions Syndrome 2 with Hyperglycinemia:

Name: Multiple Mitochondrial Dysfunctions Syndrome 2 with Hyperglycinemia 57 12 72
Multiple Mitochondrial Dysfunctions Syndrome 2 12 29 13 6 15 70
Mmds2 57 58 72
Bola3 Deficiency 12 58
Mitochondrial Dysfunctions Syndrome, Multiple, Type 2 39
Multiple Mitochondrial Dysfunctions Syndrome Type 2 58

Characteristics:

Orphanet epidemiological data:

58
multiple mitochondrial dysfunctions syndrome type 2
Inheritance: Autosomal recessive; Prevalence: <1/1000000 (Worldwide); Age of onset: Neonatal;

OMIM®:

57 (Updated 20-May-2021)
Inheritance:
autosomal recessive

Miscellaneous:
onset in infancy
death in early childhood may occur


HPO:

31
multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemia:
Onset and clinical course death in infancy infantile onset
Inheritance autosomal recessive inheritance


Classifications:

Orphanet: 58  
Rare neurological diseases
Inborn errors of metabolism


Summaries for Multiple Mitochondrial Dysfunctions Syndrome 2 with...

OMIM® : 57 Multiple mitochondrial dysfunctions syndrome-2 (MMDS2) with hyperglycinemia is a severe autosomal recessive disorder characterized by developmental regression in infancy. Affected children have an encephalopathic disease course with seizures, spasticity, loss of head control, and abnormal movement. Additional more variable features include optic atrophy, cardiomyopathy, and leukodystrophy. Laboratory studies show increased serum glycine and lactate. Most patients die in childhood. The disorder represents a form of 'variant' nonketotic hyperglycinemia and is distinct from classic nonketotic hyperglycinemia (NKH, or GCE; 605899), which is characterized by significantly increased CSF glycine. Several forms of 'variant' NKH, including MMDS2, appear to result from defects of mitochondrial lipoate biosynthesis (summary by Baker et al., 2014). For a general description and a discussion of genetic heterogeneity of multiple mitochondrial dysfunctions syndrome, see MMDS1 (605711). (614299) (Updated 20-May-2021)

MalaCards based summary : Multiple Mitochondrial Dysfunctions Syndrome 2 with Hyperglycinemia, also known as multiple mitochondrial dysfunctions syndrome 2, is related to mitochondrial metabolism disease and lipoic acid biosynthesis defects, and has symptoms including vomiting, abnormality of extrapyramidal motor function and lethargy. An important gene associated with Multiple Mitochondrial Dysfunctions Syndrome 2 with Hyperglycinemia is BOLA3 (BolA Family Member 3). Affiliated tissues include spinal cord, and related phenotypes are ataxia and visual impairment

Disease Ontology : 12 A multiple mitochondrial dysfunctions syndrome that is characterized by increased serum glycine and lactate, developmental regression in infancy, an encephalopathic disease course with seizures, spasticity, loss of head control, and abnormal movement, and has material basis in autosomal recessive inheritance of homozygous mutation in the bolA family member 3 gene on chromosome 2p13.

UniProtKB/Swiss-Prot : 72 Multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemia: A severe disorder of systemic energy metabolism, resulting in weakness, respiratory failure, lack of neurologic development, lactic acidosis, hyperglycinemia and early death. Some patients show failure to thrive, pulmonary hypertension, hypotonia and irritability. Biochemical features include severe combined deficiency of the 2- oxoacid dehydrogenases, defective lipoic acid synthesis and reduction in activity of mitochondrial respiratory chain complexes.

Related Diseases for Multiple Mitochondrial Dysfunctions Syndrome 2 with...

Graphical network of the top 20 diseases related to Multiple Mitochondrial Dysfunctions Syndrome 2 with Hyperglycinemia:



Diseases related to Multiple Mitochondrial Dysfunctions Syndrome 2 with Hyperglycinemia

Symptoms & Phenotypes for Multiple Mitochondrial Dysfunctions Syndrome 2 with...

Human phenotypes related to Multiple Mitochondrial Dysfunctions Syndrome 2 with Hyperglycinemia:

31 (show all 21)
# Description HPO Frequency HPO Source Accession
1 ataxia 31 occasional (7.5%) HP:0001251
2 visual impairment 31 occasional (7.5%) HP:0000505
3 optic atrophy 31 occasional (7.5%) HP:0000648
4 myoclonus 31 occasional (7.5%) HP:0001336
5 spasticity 31 HP:0001257
6 developmental regression 31 HP:0002376
7 global developmental delay 31 HP:0001263
8 hepatomegaly 31 HP:0002240
9 vomiting 31 HP:0002013
10 hypertrophic cardiomyopathy 31 HP:0001639
11 dilated cardiomyopathy 31 HP:0001644
12 abnormality of extrapyramidal motor function 31 HP:0002071
13 lethargy 31 HP:0001254
14 respiratory failure 31 HP:0002878
15 leukodystrophy 31 HP:0002415
16 poor head control 31 HP:0002421
17 lactic acidosis 31 HP:0003128
18 generalized hypotonia 31 HP:0001290
19 epileptic encephalopathy 31 HP:0200134
20 decreased activity of mitochondrial respiratory chain 31 HP:0008972
21 seizure 31 HP:0001250

Symptoms via clinical synopsis from OMIM®:

57 (Updated 20-May-2021)
Neurologic Central Nervous System:
spasticity
lethargy
poor head control
epileptic encephalopathy
extrapyramidal signs
more
Abdomen Gastrointestinal:
vomiting

Respiratory:
respiratory failure

Muscle Soft Tissue:
hypotonia

Laboratory Abnormalities:
increased serum and urinary lactate
increased urinary 2-hydroxybutyrate
decreased activity of pyruvate dehydrogenase complex
decreased activity of 2-oxoacid dehydrogenases
increased serum glycine
more
Abdomen Liver:
hepatomegaly

Cardiovascular Heart:
hypertrophic cardiomyopathy
dilated cardiomyopathy

Metabolic Features:
lactic acidosis

Head And Neck Eyes:
optic atrophy (in some patients)
visual impairment (in some patients)

Clinical features from OMIM®:

614299 (Updated 20-May-2021)

UMLS symptoms related to Multiple Mitochondrial Dysfunctions Syndrome 2 with Hyperglycinemia:


vomiting; abnormality of extrapyramidal motor function; lethargy; muscle spasticity

Drugs & Therapeutics for Multiple Mitochondrial Dysfunctions Syndrome 2 with...

Search Clinical Trials , NIH Clinical Center for Multiple Mitochondrial Dysfunctions Syndrome 2 with Hyperglycinemia

Genetic Tests for Multiple Mitochondrial Dysfunctions Syndrome 2 with...

Genetic tests related to Multiple Mitochondrial Dysfunctions Syndrome 2 with Hyperglycinemia:

# Genetic test Affiliating Genes
1 Multiple Mitochondrial Dysfunctions Syndrome 2 29 BOLA3

Anatomical Context for Multiple Mitochondrial Dysfunctions Syndrome 2 with...

MalaCards organs/tissues related to Multiple Mitochondrial Dysfunctions Syndrome 2 with Hyperglycinemia:

40
Spinal Cord

Publications for Multiple Mitochondrial Dysfunctions Syndrome 2 with...

Articles related to Multiple Mitochondrial Dysfunctions Syndrome 2 with Hyperglycinemia:

# Title Authors PMID Year
1
Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5. 6 57
24334290 2014
2
Homozygous missense mutation in BOLA3 causes multiple mitochondrial dysfunctions syndrome in two siblings. 6 57
22562699 2013
3
Mutations in iron-sulfur cluster scaffold genes NFU1 and BOLA3 cause a fatal deficiency of multiple respiratory chain and 2-oxoacid dehydrogenase enzymes. 57 6
21944046 2011
4
A novel syndrome affecting multiple mitochondrial functions, located by microcell-mediated transfer to chromosome 2p14-2p13. 6 57
11156534 2001
5
Imaging phenotype of multiple mitochondrial dysfunction syndrome 2, a rare BOLA3-associated leukodystrophy. 57
30302924 2018
6
Ban proposed on cerebellar electrical stimulation. 6
302924 1977
7
Severe Leukoencephalopathy with Clinical Recovery Caused by Recessive BOLA3 Mutations. 61
29654549 2019

Variations for Multiple Mitochondrial Dysfunctions Syndrome 2 with...

ClinVar genetic disease variations for Multiple Mitochondrial Dysfunctions Syndrome 2 with Hyperglycinemia:

6 (show all 19)
# Gene Name Type Significance ClinVarId dbSNP ID Position
1 BOLA3 NM_212552.3(BOLA3):c.123dup (p.Glu42fs) Duplication Pathogenic 31020 rs869320737 GRCh37: 2:74372361-74372362
GRCh38: 2:74145234-74145235
2 BOLA3 NM_212552.3(BOLA3):c.200T>A (p.Ile67Asn) SNV Pathogenic 816698 rs550855238 GRCh37: 2:74369457-74369457
GRCh38: 2:74142330-74142330
3 BOLA3 NM_212552.3(BOLA3):c.220_222del (p.Glu74del) Deletion Pathogenic 816938 rs1209052568 GRCh37: 2:74369435-74369437
GRCh38: 2:74142308-74142310
4 BOLA3 NM_212552.3(BOLA3):c.136C>T (p.Arg46Ter) SNV Pathogenic 224514 rs143492730 GRCh37: 2:74372349-74372349
GRCh38: 2:74145222-74145222
5 BOLA3 NM_212552.3(BOLA3):c.258+9A>C SNV Conflicting interpretations of pathogenicity 390067 rs201380456 GRCh37: 2:74369390-74369390
GRCh38: 2:74142263-74142263
6 BOLA3 NM_212552.3(BOLA3):c.131T>G (p.Phe44Cys) SNV Uncertain significance 1029540 GRCh37: 2:74372354-74372354
GRCh38: 2:74145227-74145227
7 BOLA3 NM_212552.3(BOLA3):c.317A>G (p.Lys106Arg) SNV Uncertain significance 1029541 GRCh37: 2:74362727-74362727
GRCh38: 2:74135600-74135600
8 BOLA3 NM_212552.3(BOLA3):c.76T>C (p.Phe26Leu) SNV Uncertain significance 1029542 GRCh37: 2:74372409-74372409
GRCh38: 2:74145282-74145282
9 BOLA3 NM_212552.3(BOLA3):c.21C>T (p.Ala7=) SNV Uncertain significance 895391 GRCh37: 2:74374981-74374981
GRCh38: 2:74147854-74147854
10 BOLA3 NM_212552.3(BOLA3):c.19G>A (p.Ala7Thr) SNV Uncertain significance 895392 GRCh37: 2:74374983-74374983
GRCh38: 2:74147856-74147856
11 BOLA3 NM_212552.3(BOLA3):c.*134T>C SNV Uncertain significance 898379 GRCh37: 2:74362586-74362586
GRCh38: 2:74135459-74135459
12 BOLA3 NM_212552.3(BOLA3):c.-35C>T SNV Uncertain significance 337060 rs761339384 GRCh37: 2:74375036-74375036
GRCh38: 2:74147909-74147909
13 BOLA3 NM_212552.3(BOLA3):c.181G>A (p.Ala61Thr) SNV Uncertain significance 337057 rs747762311 GRCh37: 2:74369476-74369476
GRCh38: 2:74142349-74142349
14 BOLA3 NM_212552.3(BOLA3):c.*31T>C SNV Uncertain significance 337055 rs886056326 GRCh37: 2:74362689-74362689
GRCh38: 2:74135562-74135562
15 BOLA3 NM_212552.3(BOLA3):c.319C>T (p.Arg107Cys) SNV Uncertain significance 214170 rs150626228 GRCh37: 2:74362725-74362725
GRCh38: 2:74135598-74135598
16 BOLA3 NM_212552.3(BOLA3):c.137G>A (p.Arg46Gln) SNV Uncertain significance 337058 rs144366005 GRCh37: 2:74372348-74372348
GRCh38: 2:74145221-74145221
17 BOLA3 NM_212552.3(BOLA3):c.256C>G (p.Gln86Glu) SNV Uncertain significance 337056 rs149964046 GRCh37: 2:74369401-74369401
GRCh38: 2:74142274-74142274
18 BOLA3 NM_212552.3(BOLA3):c.*190G>A SNV Uncertain significance 337054 rs886056325 GRCh37: 2:74362530-74362530
GRCh38: 2:74135403-74135403
19 BOLA3 NM_212552.3(BOLA3):c.-8G>A SNV Uncertain significance 337059 rs886056327 GRCh37: 2:74375009-74375009
GRCh38: 2:74147882-74147882

UniProtKB/Swiss-Prot genetic disease variations for Multiple Mitochondrial Dysfunctions Syndrome 2 with Hyperglycinemia:

72
# Symbol AA change Variation ID SNP ID
1 BOLA3 p.His96Arg VAR_076180 rs148674363
2 BOLA3 p.Ile67Asn VAR_077911 rs550855238

Expression for Multiple Mitochondrial Dysfunctions Syndrome 2 with...

Search GEO for disease gene expression data for Multiple Mitochondrial Dysfunctions Syndrome 2 with Hyperglycinemia.

Pathways for Multiple Mitochondrial Dysfunctions Syndrome 2 with...

GO Terms for Multiple Mitochondrial Dysfunctions Syndrome 2 with...

Cellular components related to Multiple Mitochondrial Dysfunctions Syndrome 2 with Hyperglycinemia according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 mitochondrial matrix GO:0005759 9.35 NUBPL LIAS ISCA2 ISCA1 IBA57
2 mitochondrion GO:0005739 9.23 NUBPL NFU1 LIAS ISCA2 ISCA1 IBA57

Biological processes related to Multiple Mitochondrial Dysfunctions Syndrome 2 with Hyperglycinemia according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 cellular iron ion homeostasis GO:0006879 9.37 BOLA2B BOLA2
2 iron-sulfur cluster assembly GO:0016226 9.35 NUBPL NFU1 ISCA2 ISCA1 IBA57
3 interleukin-12-mediated signaling pathway GO:0035722 9.32 BOLA2B BOLA2
4 small molecule metabolic process GO:0044281 9.26 ISCA2 ISCA1
5 [2Fe-2S] cluster assembly GO:0044571 9.16 BOLA2B BOLA2
6 protein maturation by iron-sulfur cluster transfer GO:0097428 9.02 NFU1 ISCA2 ISCA1 BOLA2B BOLA2

Molecular functions related to Multiple Mitochondrial Dysfunctions Syndrome 2 with Hyperglycinemia according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 4 iron, 4 sulfur cluster binding GO:0051539 9.26 NUBPL NFU1 LIAS ISCA2
2 iron-sulfur cluster binding GO:0051536 9.17 NUBPL NFU1 LIAS ISCA2 ISCA1 BOLA2B
3 2 iron, 2 sulfur cluster binding GO:0051537 9.16 ISCA2 ISCA1

Sources for Multiple Mitochondrial Dysfunctions Syndrome 2 with...

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 20-May-2021)
61 PubMed
63 QIAGEN
68 SNOMED-CT via HPO
69 Tocris
70 UMLS
71 UMLS via Orphanet
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