MTDPS4A
MCID: MTC056
MIFTS: 48

Mitochondrial Dna Depletion Syndrome 4a (MTDPS4A) malady

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

Aliases & Classifications for Mitochondrial Dna Depletion Syndrome 4a

Aliases & Descriptions for Mitochondrial Dna Depletion Syndrome 4a:

Name: Mitochondrial Dna Depletion Syndrome 4a 54 12 12 66 13
Alpers Syndrome 12 50 24 25 56 66 52 14 69
Alpers-Huttenlocher Syndrome 12 50 24 25 56 66
Alpers Progressive Infantile Poliodystrophy 12 50 24 25 66
Progressive Sclerosing Poliodystrophy 12 25 51 29
Alpers Diffuse Degeneration of Cerebral Gray Matter with Hepatic Cirrhosis 50 25 66
Progressive Neuronal Degeneration of Childhood with Liver Disease 24 56
Diffuse Cerebral Sclerosis of Schilder 25 69
Alpers Disease 50 25
Pndc 50 66
Neuronal Degeneration of Childhood with Liver Disease, Progressive 50
Neuronal Degeneration of Childhood with Liver Disease Progressive 66
Mitochondrial Dna Depletion Syndrome 4a Alpers Type 66
Alpers Progressive Sclerosing Poliodystrophy 56
Alpers' Disease or Gray-Matter Degeneration 12
Diffuse Cerebral Degeneration in Infancy 50
Poliodystrophia Cerebri Progressiva 50
Progressive Cerebral Poliodystrophy 50
Infantile Poliodystrophy 50
Alper's Syndrome 12
Alpers' Disease 51
Mtdps4a 66
Ahs 66

Characteristics:

Orphanet epidemiological data:

56
alpers-huttenlocher syndrome
Inheritance: Autosomal recessive; Prevalence: 1-9/1000000 (Europe); Age of onset: Adolescent,Adult,Childhood,Infancy; Age of death: adolescent,adult,late childhood,young Adult;

HPO:

32
mitochondrial dna depletion syndrome 4a:
Inheritance autosomal recessive inheritance
Onset and clinical course infantile onset rapidly progressive


Classifications:



External Ids:

OMIM 54 203700
Disease Ontology 12 DOID:0080122 DOID:1442
ICD10 33 G31.81
MeSH 42 D002549
NCIt 47 C35257
SNOMED-CT 64 20415001
Orphanet 56 ORPHA726
ICD10 via Orphanet 34 G31.8
MESH via Orphanet 43 D002549
UMLS via Orphanet 70 C0205710
MedGen 40 C0205710
UMLS 69 C0205710

Summaries for Mitochondrial Dna Depletion Syndrome 4a

NINDS : 51 Alpers' disease is a progressive, neurodevelopmental, mitochondrial DNA depletion syndrome characterized by three co-occurring clinical symptoms: psychomotor regression (dementia); seizures; and liver disease.  It is an autosomal recessive disease caused by mutation in the gene for the mitochondrial DNA polymerase POLG.  The disease occurs in about one in 100,000 persons.  Most individuals with Alpers' disease do not show symptoms at birth and develop normally for weeks to years before the onset of symptoms.  Diagnosis is established by testing for the POLG gene.  Symptoms typically occur months before tissue samples show the mitochondrial DNA depletion, so that these depletion studies cannot be used for early diagnosis.  About 80 percent of individuals with Alpers' disease develop symptoms in the first two years of life, and 20 percent develop symptoms between ages 2 and 25.  The first symptoms of the disorder are usually nonspecific and may include hypoglycemia secondary to underlying liver disease, failure to thrive, infection-associated encephalopathy, spasticity, myoclonus (involuntary jerking of a muscle or group of muscles), seizures, or liver failure.  An increased protein level is seen in cerebrospinal fluid analysis.  Cortical blindness (loss of vision due to damage to the area of the cortex that controls vision) develops in about 25 percent of cases. Gastrointestinal dysfunction and cardiomyopathy may occur.  Dementia is typically episodic and often associated with an infection that occurs while another disease is in process.  Seizures may be difficult to control and unrelenting seizures can cause developmental regression as well.  "Alpers-like" disorders  without liver disease are genetically different and have a different clinical course.  Fewer than one-third of individuals with the "Alpers-like" phenotype without liver disease have POLG mutations.

MalaCards based summary : Mitochondrial Dna Depletion Syndrome 4a, also known as alpers syndrome, is related to ah amyloidosis and tumefactive multiple sclerosis, and has symptoms including convulsions, ataxia and myoclonus. An important gene associated with Mitochondrial Dna Depletion Syndrome 4a is POLG (DNA Polymerase Gamma, Catalytic Subunit), and among its related pathways/superpathways is tRNA Aminoacylation. The drugs Prednisolone and Methylprednisolone have been mentioned in the context of this disorder. Affiliated tissues include liver, cortex and testes.

Disease Ontology : 12 A cerebral degeneration that results in progressive degeneration of grey matter in the cerebrum and has symptom convulsions.

Genetics Home Reference : 25 Alpers-Huttenlocher syndrome is one of the most severe of a group of conditions called the POLG-related disorders. The conditions in this group feature a range of similar signs and symptoms involving muscle-, nerve-, and brain-related functions. Alpers-Huttenlocher syndrome typically becomes apparent in children between ages 2 and 4. People with this condition usually have three characteristic features: recurrent seizures that do not improve with treatment (intractable epilepsy), loss of mental and movement abilities (psychomotor regression), and liver disease.

NIH Rare Diseases : 50 alpers syndrome is a progressive neurologic disorder that begins during childhood and is complicated in many instances by serious liver disease. symptoms include increased muscle tone with exaggerated reflexes (spasticity), seizures, and loss of cognitive ability (dementia).   most often alpers syndrome is caused by mutations in the polg gene. last updated: 1/24/2011

OMIM : 54 Mitochondrial DNA depletion syndrome-4A, also known as Alpers syndrome, is an autosomal recessive disorder... (203700) more...

UniProtKB/Swiss-Prot : 66 Mitochondrial DNA depletion syndrome 4A: An autosomal recessive hepatocerebral syndrome due to mitochondrial dysfunction. The typical course of the disease includes severe developmental delay, intractable seizures, liver failure, and death in childhood. Refractory seizures, cortical blindness, progressive liver dysfunction, and acute liver failure after exposure to valproic acid are considered diagnostic features. The neuropathological hallmarks are neuronal loss, spongiform degeneration, and astrocytosis of the visual cortex. Liver biopsy results show steatosis, often progressing to cirrhosis.

Related Diseases for Mitochondrial Dna Depletion Syndrome 4a

Diseases related to Mitochondrial Dna Depletion Syndrome 4a via text searches within MalaCards or GeneCards Suite gene sharing:

(show all 41)
id Related Disease Score Top Affiliating Genes
1 ah amyloidosis 11.9
2 tumefactive multiple sclerosis 11.3
3 adrenoleukodystrophy 11.3
4 pelizaeus-merzbacher disease 11.2
5 myelinoclastic diffuse sclerosis 11.2
6 sudanophilic cerebral sclerosis 11.2
7 balo concentric sclerosis 11.2
8 combined oxidative phosphorylation deficiency 24 11.0
9 hypotrichosis 7 11.0
10 mitochondrial dna depletion syndrome 1 10.9
11 combined oxidative phosphorylation deficiency 14 10.8
12 adrenal hyperplasia, congenital, due to 21-hydroxylase deficiency 10.7
13 adrenal hyperplasia, congenital, due to 11-beta-hydroxylase deficiency 10.7
14 17-alpha-hydroxylase/17,20-lyase deficiency 10.7
15 3-beta-hydroxysteroid dehydrogenase, type ii, deficiency 10.7
16 breast cancer 10.1
17 mitochondrial encephalomyopathy 10.1
18 encephalomyopathy 10.1
19 hypotonia 10.1
20 bbs2-related bardet-biedl syndrome 10.0 POLG POLG2
21 nonsyndromic 46,xx testicular disorders of sex development 10.0 POLG TYMP
22 megalencephalic leukoencephalopathy with subcortical cysts 10.0 POLG TYMP
23 idiopathic dropped head syndrome 10.0 POLG TYMP
24 mental retardation with spastic paraplegia 10.0 POLG TYMP
25 chronic lacrimal gland enlargement 9.9 POLG TYMP
26 dyscalculia 9.8 POLG POLG2 TYMP
27 pontocerebellar hypoplasia 9.8 POLG TYMP
28 growth hormone deficiency, isolated partial 9.8 DARS2 POLG TYMP
29 neuronitis 9.8
30 hepatitis 9.8
31 cerebral degeneration 9.8
32 cerebritis 9.8
33 hypoglycemia 9.7
34 creutzfeldt-jakob disease 9.7
35 encephalopathy 9.7
36 autoimmune hepatitis 9.7
37 liver disease 9.7
38 status epilepticus 9.7
39 nkx2-1-related disorders 9.7 DGUOK POLG POLG2 TYMP
40 myoclonic epilepsy associated with ragged-red fibers 9.5 DARS2 FARS2 POLG TYMP
41 deafness, autosomal dominant 30 9.2 DARS2 DGUOK FARS2 POLG POLG2 TYMP

Graphical network of the top 20 diseases related to Mitochondrial Dna Depletion Syndrome 4a:



Diseases related to Mitochondrial Dna Depletion Syndrome 4a

Symptoms & Phenotypes for Mitochondrial Dna Depletion Syndrome 4a

Symptoms by clinical synopsis from OMIM:

203700

Clinical features from OMIM:

203700

Symptoms:

12
  • convulsions

Human phenotypes related to Mitochondrial Dna Depletion Syndrome 4a:

56 32 (show all 43)
id Description HPO Frequency Orphanet Frequency HPO Source Accession
1 ataxia 56 32 Frequent (79-30%) HP:0001251
2 myoclonus 56 32 Frequent (79-30%) HP:0001336
3 muscular hypotonia 56 32 Frequent (79-30%) HP:0001252
4 developmental regression 56 32 Frequent (79-30%) HP:0002376
5 global developmental delay 56 32 Frequent (79-30%) HP:0001263
6 microcephaly 56 32 Frequent (79-30%) HP:0000252
7 blindness 56 32 Occasional (29-5%) HP:0000618
8 generalized tonic-clonic seizures 56 32 Frequent (79-30%) HP:0002069
9 coma 56 32 Frequent (79-30%) HP:0001259
10 areflexia 56 32 Frequent (79-30%) HP:0001284
11 focal seizures 56 32 Frequent (79-30%) HP:0007359
12 progressive spasticity 56 32 Frequent (79-30%) HP:0002191
13 choreoathetosis 56 32 Frequent (79-30%) HP:0001266
14 spastic paraparesis 56 32 Frequent (79-30%) HP:0002313
15 vomiting 32 HP:0002013
16 paraparesis 56 Frequent (79-30%)
17 spasticity 56 Frequent (79-30%)
18 failure to thrive 32 HP:0001508
19 hepatomegaly 32 HP:0002240
20 abnormality of visual evoked potentials 32 HP:0000649
21 hypertonia 32 HP:0001276
22 abnormality of the eye 56 Frequent (79-30%)
23 abnormality of vision 56 Frequent (79-30%)
24 abnormality of movement 56 Frequent (79-30%)
25 elevated hepatic transaminases 32 HP:0002910
26 increased serum lactate 32 HP:0002151
27 visual loss 32 HP:0000572
28 paralysis 32 HP:0003470
29 dementia 32 HP:0000726
30 hepatic failure 32 HP:0001399
31 cerebellar atrophy 32 HP:0001272
32 astrocytosis 32 HP:0002446
33 increased csf protein 32 HP:0002922
34 neuronal loss in central nervous system 32 HP:0002529
35 gliosis 32 HP:0002171
36 cortical visual impairment 32 HP:0100704
37 microvesicular hepatic steatosis 32 HP:0001414
38 3-methylglutaconic aciduria 32 HP:0003535
39 micronodular cirrhosis 32 HP:0001413
40 ethylmalonic aciduria 32 HP:0003219
41 bile duct proliferation 32 HP:0001408
42 cerebral cortical neurodegeneration 32 HP:0006964
43 epilepsia partialis continua 32 HP:0012847

UMLS symptoms related to Mitochondrial Dna Depletion Syndrome 4a:


ataxia, myoclonus, vomiting, visual disturbance, unspecified visual loss

Drugs & Therapeutics for Mitochondrial Dna Depletion Syndrome 4a

Drugs for Mitochondrial Dna Depletion Syndrome 4a (from DrugBank, HMDB, Dgidb, PharmGKB, IUPHAR, NovoSeek, BitterDB):

(show all 18)
id Name Status Phase Clinical Trials Cas Number PubChem Id
1
Prednisolone Approved, Vet_approved Phase 3 50-24-8 5755
2
Methylprednisolone Approved, Vet_approved Phase 3 83-43-2 6741
3 Prednisolone acetate Phase 3
4 glucocorticoids Phase 3
5 Gastrointestinal Agents Phase 3
6 Neuroprotective Agents Phase 3
7 Hormone Antagonists Phase 3
8 Hormones Phase 3
9 Peripheral Nervous System Agents Phase 3
10 Hormones, Hormone Substitutes, and Hormone Antagonists Phase 3
11 Prednisolone hemisuccinate Phase 3
12 Prednisolone phosphate Phase 3
13 Protective Agents Phase 3
14 Antiemetics Phase 3
15 Anti-Inflammatory Agents Phase 3
16 Methylprednisolone acetate Phase 3
17 Methylprednisolone Hemisuccinate Phase 3
18 Autonomic Agents Phase 3

Interventional clinical trials:


id Name Status NCT ID Phase
1 Phase III Randomized, Double-Blind, Sham-Controlled Study of Plasma Exchange for Acute Severe Attacks of Inflammatory Demyelinating Disease Refractory to Intravenous Methylprednisolone Unknown status NCT00004645 Phase 3
2 Alpers Huttenlocher Natural History Study Recruiting NCT03034512
3 Combination of Multiparametric MRI and Electrophysiology for the Development of New Biomarkers in Spinal Cord Diseases Recruiting NCT02885870
4 North American Mitochondrial Disease Consortium Patient Registry and Biorepository (NAMDC) Recruiting NCT01694940
5 Prehospital Resuscitation Intranasal Cooling Effects Seen in MRI of the Brain After Cardiac Arrest Active, not recruiting NCT02179060

Search NIH Clinical Center for Mitochondrial Dna Depletion Syndrome 4a

Genetic Tests for Mitochondrial Dna Depletion Syndrome 4a

Genetic tests related to Mitochondrial Dna Depletion Syndrome 4a:

id Genetic test Affiliating Genes
1 Progressive Sclerosing Poliodystrophy 29
2 Alpers-Huttenlocher Syndrome 24 POLG

Anatomical Context for Mitochondrial Dna Depletion Syndrome 4a

MalaCards organs/tissues related to Mitochondrial Dna Depletion Syndrome 4a:

39
Liver, Cortex, Testes, Brain, Eye

Publications for Mitochondrial Dna Depletion Syndrome 4a

Variations for Mitochondrial Dna Depletion Syndrome 4a

UniProtKB/Swiss-Prot genetic disease variations for Mitochondrial Dna Depletion Syndrome 4a:

66 (show all 17)
id Symbol AA change Variation ID SNP ID
1 POLG p.Ala467Thr VAR_012155 rs113994095
2 POLG p.Thr251Ile VAR_023664 rs113994094
3 POLG p.Pro587Leu VAR_023671 rs113994096
4 POLG p.Trp748Ser VAR_023673 rs113994097
5 POLG p.Gly848Ser VAR_023675 rs113994098
6 POLG p.Arg232Gly VAR_058870
7 POLG p.Leu244Pro VAR_058872
8 POLG p.Ala767Asp VAR_058886
9 POLG p.Gln879His VAR_058890
10 POLG p.Thr885Ser VAR_058891
11 POLG p.Thr914Pro VAR_058892 rs139590686
12 POLG p.Ala957Pro VAR_058893
13 POLG p.Arg1096His VAR_058894 rs368435864
14 POLG p.His1110Tyr VAR_058895
15 POLG p.His1134Arg VAR_058896
16 POLG p.Lys1191Asn VAR_058898
17 POLG p.Glu1136Lys VAR_065092 rs56047213

ClinVar genetic disease variations for Mitochondrial Dna Depletion Syndrome 4a:

6
id Gene Variation Type Significance SNP ID Assembly Location
1 POLG NM_002693.2(POLG): c.1399G> A (p.Ala467Thr) single nucleotide variant Pathogenic/Likely pathogenic rs113994095 GRCh37 Chromosome 15, 89870432: 89870432
2 POLG NM_002693.2(POLG): c.2542G> A (p.Gly848Ser) single nucleotide variant Pathogenic rs113994098 GRCh37 Chromosome 15, 89865023: 89865023
3 POLG NM_002693.2(POLG): c.2617G> T (p.Glu873Ter) single nucleotide variant Pathogenic rs121918047 GRCh37 Chromosome 15, 89864473: 89864473
4 POLG NM_002693.2(POLG): c.2243G> C (p.Trp748Ser) single nucleotide variant Pathogenic rs113994097 GRCh37 Chromosome 15, 89866657: 89866657
5 POLG POLG, TRP1020TER undetermined variant Pathogenic
6 POLG NM_002693.2(POLG): c.3218C> T (p.Pro1073Leu) single nucleotide variant Pathogenic rs267606959 GRCh37 Chromosome 15, 89862217: 89862217
7 POLG NM_002693.2(POLG): c.2870C> T (p.Ala957Val) single nucleotide variant Pathogenic/Likely pathogenic rs753160398 GRCh37 Chromosome 15, 89864108: 89864108
8 POLG NM_002693.2(POLG): c.3612_3613insAACT (p.Gly1205Asnfs) insertion Pathogenic rs886043241 GRCh37 Chromosome 15, 89860637: 89860638

Expression for Mitochondrial Dna Depletion Syndrome 4a

Search GEO for disease gene expression data for Mitochondrial Dna Depletion Syndrome 4a.

Pathways for Mitochondrial Dna Depletion Syndrome 4a

Pathways related to Mitochondrial Dna Depletion Syndrome 4a according to GeneCards Suite gene sharing:

id Super pathways Score Top Affiliating Genes
1
Show member pathways
10.87 DARS2 FARS2

GO Terms for Mitochondrial Dna Depletion Syndrome 4a

Cellular components related to Mitochondrial Dna Depletion Syndrome 4a according to GeneCards Suite gene sharing:

id Name GO ID Score Top Affiliating Genes
1 mitochondrion GO:0005739 9.35 DARS2 DGUOK FARS2 POLG POLG2
2 mitochondrial nucleoid GO:0042645 9.16 POLG POLG2
3 mitochondrial matrix GO:0005759 8.92 DARS2 DGUOK FARS2 POLG2

Biological processes related to Mitochondrial Dna Depletion Syndrome 4a according to GeneCards Suite gene sharing:

id Name GO ID Score Top Affiliating Genes
1 DNA replication GO:0006260 9.32 POLG POLG2
2 tRNA aminoacylation for protein translation GO:0006418 9.26 DARS2 FARS2
3 DNA biosynthetic process GO:0071897 9.16 POLG POLG2
4 DNA-dependent DNA replication GO:0006261 8.96 POLG POLG2
5 tRNA aminoacylation GO:0043039 8.62 DARS2 FARS2

Molecular functions related to Mitochondrial Dna Depletion Syndrome 4a according to GeneCards Suite gene sharing:

id Name GO ID Score Top Affiliating Genes
1 transferase activity GO:0016740 9.62 DGUOK POLG POLG2 TYMP
2 ligase activity GO:0016874 9.37 DARS2 FARS2
3 nucleotidyltransferase activity GO:0016779 9.26 POLG POLG2
4 tRNA binding GO:0000049 9.16 DARS2 FARS2
5 aminoacyl-tRNA ligase activity GO:0004812 8.96 DARS2 FARS2
6 DNA-directed DNA polymerase activity GO:0003887 8.62 POLG POLG2

Sources for Mitochondrial Dna Depletion Syndrome 4a

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
16 ExPASy
18 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 MedGen
42 MeSH
43 MESH via Orphanet
44 MGI
46 NCI
47 NCIt
48 NDF-RT
51 NINDS
52 Novoseek
54 OMIM
55 OMIM via Orphanet
59 PubMed
60 QIAGEN
65 SNOMED-CT via Orphanet
67 TGDB
68 Tocris
69 UMLS
70 UMLS via Orphanet
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