MTDPS4A
MCID: MTC056
MIFTS: 62

Mitochondrial Dna Depletion Syndrome 4a (MTDPS4A)

Categories: Bone diseases, Cardiovascular diseases, Eye diseases, Gastrointestinal diseases, Genetic diseases, Liver diseases, Metabolic diseases, Muscle diseases, Nephrological diseases, Neuronal diseases, Rare diseases, Respiratory diseases

Aliases & Classifications for Mitochondrial Dna Depletion Syndrome 4a

MalaCards integrated aliases for Mitochondrial Dna Depletion Syndrome 4a:

Name: Mitochondrial Dna Depletion Syndrome 4a 57 12 72 13
Alpers Syndrome 57 12 20 43 58 72 36 54 70
Alpers-Huttenlocher Syndrome 57 12 20 43 58 72 15
Alpers Progressive Infantile Poliodystrophy 57 12 20 43 72
Progressive Sclerosing Poliodystrophy 12 43 53 29 6
Alpers Diffuse Degeneration of Cerebral Gray Matter with Hepatic Cirrhosis 57 20 43 72
Alpers Disease 12 73 20 43
Diffuse Cerebral Sclerosis of Schilder 12 43 70
Pndc 57 20 72
Neuronal Degeneration of Childhood with Liver Disease, Progressive 57 20
Mtdps4a 57 72
Neuronal Degeneration of Childhood with Liver Disease, Progressive; Pndc 57
Progressive Neuronal Degeneration of Childhood with Liver Disease 58
Neuronal Degeneration of Childhood with Liver Disease Progressive 72
Mitochondrial Dna Depletion Syndrome 4a Alpers Type 72
Alpers Progressive Sclerosing Poliodystrophy 58
Alpers' Disease or Gray-Matter Degeneration 12
Diffuse Cerebral Degeneration in Infancy 20
Poliodystrophia Cerebri Progressiva 20
Progressive Cerebral Poliodystrophy 20
Infantile Poliodystrophy 20
Alper's Syndrome 12
Alpers' Disease 53
Ahs 72

Characteristics:

Orphanet epidemiological data:

58
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;

OMIM®:

57 (Updated 05-Apr-2021)
Miscellaneous:
rapidly progressive
onset in infancy after normal birth and neonatal period
death usually by age 3 years
later onset (late childhood to young adult) has been reported
increased sensitivity to valproic acid toxicity

Inheritance:
autosomal recessive


HPO:

31
mitochondrial dna depletion syndrome 4a:
Inheritance autosomal recessive inheritance
Onset and clinical course infantile onset rapidly progressive


Classifications:

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


Summaries for Mitochondrial Dna Depletion Syndrome 4a

NINDS : 53 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 mitochondrial dna depletion syndrome and polg-related disorders, and has symptoms including ataxia, vomiting 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 are Mitochondrial Gene Expression and tRNA Aminoacylation. The drugs Prednisolone acetate and Prednisolone phosphate have been mentioned in the context of this disorder. Affiliated tissues include liver, brain and cortex, and related phenotypes are ataxia and developmental regression

Disease Ontology : 12 A mitochondrial DNA depletion syndrome that is characterized by a clinical triad of psychomotor retardation, intractable epilepsy, and liver failure in infants and young children, and has material basis in autosomal recessive inheritance of homozygous or compound heterozygous mutation in the nuclear gene encoding mitochondrial DNA polymerase gamma on chromosome 15q26.

MedlinePlus Genetics : 43 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.People with Alpers-Huttenlocher syndrome usually have additional signs and symptoms. Most have problems with coordination and balance (ataxia) and disturbances in nerve function (neuropathy). Neuropathy can lead to abnormal or absent reflexes (areflexia). In addition, affected individuals may develop weak muscle tone (hypotonia) that worsens until they lose the ability to control their muscles and movement. Some people with Alpers-Huttenlocher syndrome lose the ability to walk, sit, or feed themselves. Other movement-related symptoms in affected individuals can include involuntary muscle twitches (myoclonus), uncontrollable movements of the limbs (choreoathetosis), or a pattern of movement abnormalities known as parkinsonism.Affected individuals may have other brain-related signs and symptoms. Migraine headaches, often with visual sensations or auras, are common. Additionally, people with this condition may have decreased brain function that is demonstrated as sleepiness, inability to concentrate, irritability, or loss of language skills or memory. Some people with the condition may lose their eyesight or hearing. People with Alpers-Huttenlocher syndrome can survive from a few months to more than 10 years after the condition first appears.

GARD : 20 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.

OMIM® : 57 Mitochondrial DNA depletion syndrome-4A, also known as Alpers syndrome, is an autosomal recessive disorder characterized by a clinical triad of psychomotor retardation, intractable epilepsy, and liver failure in infants and young children. Pathologic findings include neuronal loss in the cerebral gray matter with reactive astrocytosis and liver cirrhosis. The disorder is progressive and often leads to death from hepatic failure or status epilepticus before age 3 years (review by Milone and Massie, 2010). Some affected individuals may show mild intermittent 3-methylglutaconic aciduria and defects in mitochondrial oxidative phosphorylation (Wortmann et al., 2009). For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (603041). Neuropathologic changes characteristic of Alpers syndrome, namely laminar cortical necrosis, may also be seen in some patients with combined oxidative phosphorylation deficiency-14 (COXPD14; 614946), caused by mutation in the FARS2 gene (611592), and COXPD24 (616239), caused by mutation in the NARS2 gene (612803). (203700) (Updated 05-Apr-2021)

KEGG : 36 Alpers syndrome is a rare mitochondrial disease associated with mutations in the POLG1 gene encoding the mitochondrial DNA polymerase gamma. Alpers syndrome affects children and young adults and is characterized by the clinical triad of refractory seizures, psychomotor regression, and characteristic liver disease. The tempo of disease progression and onset varies among patients. The majority of patients are healthy before disease onset, and seizures herald the disorder in most patients.

UniProtKB/Swiss-Prot : 72 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.

Wikipedia : 73 Mitochondrial DNA depletion syndrome (MDS or MDDS), or Alper's disease, is any of a group of autosomal... more...

Related Diseases for Mitochondrial Dna Depletion Syndrome 4a

Diseases in the Mitochondrial Dna Depletion Syndrome family:

Mitochondrial Dna Depletion Syndrome 4a Mitochondrial Dna Depletion Syndrome 9
Mitochondrial Dna Depletion Syndrome 3 Mitochondrial Dna Depletion Syndrome 6
Mitochondrial Dna Depletion Syndrome 7 Mitochondrial Dna Depletion Syndrome 1
Mitochondrial Dna Depletion Syndrome 2 Mitochondrial Dna Depletion Syndrome 5
Mitochondrial Dna Depletion Syndrome 8a Mitochondrial Dna Depletion Syndrome 4b
Mitochondrial Dna Depletion Syndrome 11 Mitochondrial Dna Depletion Syndrome 12b , Autosomal Recessive
Mitochondrial Dna Depletion Syndrome 13 Mitochondrial Dna Depletion Syndrome 14
Mitochondrial Dna Depletion Syndrome 15 Mitochondrial Dna Depletion Syndrome 12a , Autosomal Dominant
Mitochondrial Dna Depletion Syndrome 16 Mitochondrial Dna Depletion Syndrome 17
Mitochondrial Dna Depletion Syndrome 18 Mitochondrial Dna Depletion Syndrome 19
Mitochondrial Dna Depletion Syndrome 12a Mitochondrial Dna Depletion Syndrome 12b
Mitochondrial Dna Deletion Syndromes Multiple Mitochondrial Dna Deletion Syndrome

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

(show top 50) (show all 125)
# Related Disease Score Top Affiliating Genes
1 mitochondrial dna depletion syndrome 31.5 TWNK SUCLG1 SUCLA2 RRM2B POLG2 POLG
2 polg-related disorders 31.2 TWNK POLG
3 progressive external ophthalmoplegia with mitochondrial dna deletions, autosomal recessive 1 31.0 POLG FANCI
4 ataxia neuropathy spectrum 31.0 TWNK POLG
5 mitochondrial neurogastrointestinal encephalomyopathy 30.7 RRM2B POLG EDAR
6 mitochondrial disorders 30.5 TWNK RRM2B POLG2 POLG DGUOK
7 lactic acidosis 30.5 SUCLG1 RRM2B POLG2 POLG FARS2
8 mitochondrial encephalomyopathy 30.4 TWNK SUCLG1 SUCLA2 POLG FARS2 DGUOK
9 mitochondrial metabolism disease 30.3 TWNK SUCLG1 SUCLA2 RRM2B POLG2 POLG
10 sensory ataxic neuropathy, dysarthria, and ophthalmoparesis 30.1 TWNK SUCLG1 SUCLA2 SSBP1 RRM2B POLG2
11 mitochondrial dna depletion syndrome 4b 30.1 TWNK SUCLG1 SSBP1 RRM2B POLG2 POLG
12 leigh syndrome 29.8 TWNK SUCLG1 SUCLA2 RRM2B POLG2 POLG
13 3-methylglutaconic aciduria, type iii 29.7 TWNK SUCLG1 SUCLA2 RARS2 POLG2 POLG
14 balo concentric sclerosis 11.7
15 myelinoclastic diffuse sclerosis 11.5
16 sudanophilic cerebral sclerosis 11.4
17 adrenoleukodystrophy 11.4
18 pelizaeus-merzbacher disease 11.4
19 combined oxidative phosphorylation deficiency 14 11.0
20 combined oxidative phosphorylation deficiency 24 11.0
21 atrial standstill 1 10.9
22 hemochromatosis, type 1 10.9
23 aplastic anemia 10.9
24 long qt syndrome 10.9
25 hemolytic anemia 10.9
26 alien hand syndrome 10.9
27 myotonic cataract 10.5 TWNK POLG
28 camptocormism 10.5 RRM2B POLG
29 mitochondrial complex iii deficiency, nuclear type 2 10.4 TWNK POLG
30 fanconi anemia, complementation group i 10.4 POLG FANCI ERCC6
31 deafness, autosomal recessive 94 10.4 NARS2 FARS2
32 mitochondrial dna depletion syndrome 11 10.4 MPV17 MGME1
33 liver disease 10.4
34 motor peripheral neuropathy 10.4 POLG MPV17 DGUOK
35 3-methylglutaconic aciduria with deafness, encephalopathy, and leigh-like syndrome 10.4 SUCLA2 POLG MPV17
36 cranial nerve disease 10.4 TWNK POLG ERCC6
37 dysphagia 10.4 TWNK POLG
38 visual cortex disease 10.4 POLG2 POLG
39 deafness, autosomal recessive 89 10.4 RARS2 NARS2
40 visual pathway disease 10.4 POLG2 POLG
41 mitochondrial dna depletion syndrome, encephalomyopathic form 10.4 SUCLG1 SUCLA2 RRM2B
42 axonal neuropathy 10.4 TWNK RRM2B POLG
43 mitochondrial dna depletion syndrome 8a 10.4 RRM2B MGME1
44 pontocerebellar hypoplasia, type 6 10.4 RARS2 DARS2
45 mitochondrial dna depletion syndrome 1 10.4 POLG MPV17 MGME1 FANCI
46 combined oxidative phosphorylation deficiency 12 10.4 RARS2 FARS2 DARS2
47 metabolic acidosis 10.4 RRM2B POLG2 MPV17
48 cerebellar disease 10.4 TWNK POLG ERCC6
49 fanconi anemia, complementation group r 10.3 FANCI ERCC6
50 headache 10.3

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

Human phenotypes related to Mitochondrial Dna Depletion Syndrome 4a:

58 31 (show all 48)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 ataxia 58 31 frequent (33%) Frequent (79-30%) HP:0001251
2 developmental regression 58 31 frequent (33%) Frequent (79-30%) HP:0002376
3 global developmental delay 58 31 frequent (33%) Frequent (79-30%) HP:0001263
4 microcephaly 58 31 frequent (33%) Frequent (79-30%) HP:0000252
5 myoclonus 58 31 frequent (33%) Frequent (79-30%) HP:0001336
6 areflexia 58 31 frequent (33%) Frequent (79-30%) HP:0001284
7 progressive spasticity 58 31 frequent (33%) Frequent (79-30%) HP:0002191
8 choreoathetosis 58 31 frequent (33%) Frequent (79-30%) HP:0001266
9 coma 58 31 frequent (33%) Frequent (79-30%) HP:0001259
10 spastic paraparesis 58 31 frequent (33%) Frequent (79-30%) HP:0002313
11 focal-onset seizure 58 31 frequent (33%) Frequent (79-30%) HP:0007359
12 hypotonia 31 frequent (33%) HP:0001252
13 bilateral tonic-clonic seizure 31 frequent (33%) HP:0002069
14 blindness 58 31 occasional (7.5%) Occasional (29-5%) HP:0000618
15 spasticity 58 Frequent (79-30%)
16 failure to thrive 31 HP:0001508
17 muscular hypotonia 58 Frequent (79-30%)
18 hepatomegaly 31 HP:0002240
19 abnormality of visual evoked potentials 31 HP:0000649
20 hypertonia 31 HP:0001276
21 vomiting 31 HP:0002013
22 abnormality of movement 58 Frequent (79-30%)
23 elevated hepatic transaminase 31 HP:0002910
24 abnormality of the eye 58 Frequent (79-30%)
25 abnormality of vision 58 Frequent (79-30%)
26 increased serum lactate 31 HP:0002151
27 hepatic failure 31 HP:0001399
28 generalized tonic-clonic seizures 58 Frequent (79-30%)
29 cerebellar atrophy 31 HP:0001272
30 status epilepticus 31 HP:0002133
31 dementia 31 HP:0000726
32 generalized hypotonia 31 HP:0001290
33 visual loss 31 HP:0000572
34 paraparesis 58 Frequent (79-30%)
35 cerebral visual impairment 31 HP:0100704
36 abnormality of mitochondrial metabolism 31 HP:0003287
37 3-methylglutaconic aciduria 31 HP:0003535
38 neuronal loss in central nervous system 31 HP:0002529
39 paralysis 31 HP:0003470
40 gliosis 31 HP:0002171
41 astrocytosis 31 HP:0002446
42 microvesicular hepatic steatosis 31 HP:0001414
43 increased csf protein 31 HP:0002922
44 micronodular cirrhosis 31 HP:0001413
45 ethylmalonic aciduria 31 HP:0003219
46 epilepsia partialis continua 31 HP:0012847
47 bile duct proliferation 31 HP:0001408
48 cerebral cortical neurodegeneration 31 HP:0006964

Symptoms via clinical synopsis from OMIM®:

57 (Updated 05-Apr-2021)
Growth Other:
failure to thrive

Abdomen Liver:
hepatomegaly
micronodular cirrhosis
bile duct proliferation
liver failure
biopsy shows microvesicular steatosis
more
Laboratory Abnormalities:
increased serum lactate
increased csf protein
elevated liver function tests
decreased dna polymerase-gamma (polg, ) activity
intermittent 3-methylglutaconic aciduria
more
Head And Neck Eyes:
loss of vision
visual disturbances
cortical blindness
abnormal visual evoked potential (vep)

Neurologic Central Nervous System:
ataxia
hypertonia
myoclonus
cerebellar atrophy
status epilepticus
more
Abdomen Gastrointestinal:
vomiting

Muscle Soft Tissue:
hypotonia
decreased mitochondrial respiratory chain complex activity
mitochondrial dna depletion

Clinical features from OMIM®:

203700 (Updated 05-Apr-2021)

UMLS symptoms related to Mitochondrial Dna Depletion Syndrome 4a:


ataxia; vomiting; myoclonus; visual disturbance; unspecified visual loss

MGI Mouse Phenotypes related to Mitochondrial Dna Depletion Syndrome 4a:

46
# Description MGI Source Accession Score Top Affiliating Genes
1 mortality/aging MP:0010768 10.06 DARS2 DGUOK EDAR ERCC6 FANCI FARS2
2 adipose tissue MP:0005375 9.8 DGUOK EDAR ERCC6 MGME1 MPV17 POLG
3 pigmentation MP:0001186 9.5 DGUOK EDAR MGME1 MPV17 NARS2 POLG
4 skeleton MP:0005390 9.28 EDAR ERCC6 FARS2 MGME1 MPV17 POLG

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 7)
# Name Status Phase Clinical Trials Cas Number PubChem Id
1
Prednisolone acetate Approved, Vet_approved Phase 3 52-21-1
2
Prednisolone phosphate Approved, Vet_approved Phase 3 302-25-0
3
Prednisolone Approved, Vet_approved Phase 3 50-24-8 5755
4
Methylprednisolone Approved, Vet_approved Phase 3 83-43-2 6741
5
Methylprednisolone hemisuccinate Approved Phase 3 2921-57-5
6
Prednisolone hemisuccinate Experimental Phase 3 2920-86-7
7 Methylprednisolone Acetate Phase 3

Interventional clinical trials:


# Name Status NCT ID Phase Drugs
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 Efficacy and Safety Study of Vatiquinone for the Treatment of Mitochondrial Disease Subjects With Refractory Epilepsy Recruiting NCT04378075 Phase 2, Phase 3 Vatiquinone
3 Natural History Study of Alpers Huttenlocher Syndrome Recruiting NCT03034512

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:

# Genetic test Affiliating Genes
1 Progressive Sclerosing Poliodystrophy 29 POLG

Anatomical Context for Mitochondrial Dna Depletion Syndrome 4a

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

40
Liver, Brain, Cortex, Eye, Skin

Publications for Mitochondrial Dna Depletion Syndrome 4a

Articles related to Mitochondrial Dna Depletion Syndrome 4a:

(show top 50) (show all 223)
# Title Authors PMID Year
1
A novel POLG gene mutation in 4 children with Alpers-like hepatocerebral syndromes. 54 61 57 6
20142534 2010
2
POLG mutations in Alpers syndrome. 57 6 61 54
16177225 2005
3
POLG mutations associated with Alpers syndrome and mitochondrial DNA depletion. 6 54 57 61
16130100 2005
4
POLG mutations and Alpers syndrome. 57 6 61 54
15929042 2005
5
POLG mutations associated with Alpers' syndrome and mitochondrial DNA depletion. 54 61 57 6
15122711 2004
6
POLG1 manifestations in childhood. 61 57 6
21357833 2011
7
Depletion of mitochondrial DNA in fibroblast cultures from patients with POLG1 mutations is a consequence of catalytic mutations. 61 6 57
18487244 2008
8
Juvenile Alpers disease. 54 6 57
18195149 2008
9
Multiple oxidative phosphorylation deficiencies in severe childhood multi-system disorders due to polymerase gamma (POLG1) mutations. 61 57 6
16957900 2007
10
Infantile hepatocerebral syndromes associated with mutations in the mitochondrial DNA polymerase-gammaA. 61 57 6
15689359 2005
11
Disease mutations in the human mitochondrial DNA polymerase thumb subdomain impart severe defects in mitochondrial DNA replication. 6 54 61
19478085 2009
12
Homozygous W748S mutation in the POLG1 gene in patients with juvenile-onset Alpers syndrome and status epilepticus. 54 61 6
18294203 2008
13
Molecular analysis of ANT1, TWINKLE and POLG in patients with multiple deletions or depletion of mitochondrial DNA by a dHPLC-based assay. 6 61 54
16639411 2006
14
Molecular diagnosis of Alpers syndrome. 61 54 6
16545482 2006
15
Functional defects due to spacer-region mutations of human mitochondrial DNA polymerase in a family with an ataxia-myopathy syndrome. 61 6 54
15917273 2005
16
Mitochondrial DNA polymerase gamma deficiency and mtDNA depletion in a child with Alpers' syndrome. 54 61 57
9894877 1999
17
Alpers disease mutations in human DNA polymerase gamma cause catalytic defects in mitochondrial DNA replication by distinct mechanisms. 6 61
25914719 2015
18
Quantitative multiplex PCR of short fluorescent fragments for the detection of large intragenic POLG rearrangements in a large French cohort. 61 6
23921535 2014
19
Variations of mitochondrial DNA polymerase γ in patients with Parkinson's disease. 61 6
24122062 2013
20
Mutations in human DNA polymerase γ confer unique mechanisms of catalytic deficiency that mirror the disease severity in mitochondrial disorder patients. 61 6
23208208 2013
21
Polymerase gamma deficiency (POLG): clinical course in a child with a two stage evolution from infantile myocerebrohepatopathy spectrum to an Alpers syndrome and neuropathological findings of Leigh's encephalopathy. 6 61
22342071 2012
22
A novel POLG gene mutation in a patient with SANDO. 61 6
24265579 2012
23
Alpers syndrome with mutations in POLG: clinical and investigative features. 61 6
22000311 2011
24
Gender variability in presentation with Alpers' syndrome: a report of eight patients from the UAE. 6 61
21305355 2011
25
Molecular and biochemical characterisation of a novel mutation in POLG associated with Alpers syndrome. 61 6
21235791 2011
26
POLG exon 22 skipping induced by different mechanisms in two unrelated cases of Alpers syndrome. 61 6
20691285 2011
27
Purification and functional characterization of human mitochondrial DNA polymerase gamma harboring disease mutations. 6 61
20176107 2010
28
POLG DNA testing as an emerging standard of care before instituting valproic acid therapy for pediatric seizure disorders. 6 54
20138553 2010
29
Polymerase gamma 1 mutations: clinical correlations. 57 61
20220442 2010
30
Novel POLG1 mutations associated with neuromuscular and liver phenotypes in adults and children. 54 6
19251978 2009
31
Molecular and clinical genetics of mitochondrial diseases due to POLG mutations. 61 6
18546365 2008
32
Abundance of the POLG disease mutations in Europe, Australia, New Zealand, and the United States explained by single ancient European founders. 6 61
17426723 2007
33
The spectrum of clinical disease caused by the A467T and W748S POLG mutations: a study of 26 cases. 61 6
16638794 2006
34
Mitochondrial and nuclear DNA defects in Saccharomyces cerevisiae with mutations in DNA polymerase gamma associated with progressive external ophthalmoplegia. 6 61
16368709 2006
35
The common A467T mutation in the human mitochondrial DNA polymerase (POLG) compromises catalytic efficiency and interaction with the accessory subunit. 6 61
16024923 2005
36
Respiratory chain deficiency in Alpers syndrome. 61 57
11521212 2001
37
Alpers progressive infantile neuronal poliodystrophy: an acute neonatal form with findings of the fetal akinesia syndrome. 61 57
8368248 1993
38
Targeted exome analysis identifies the genetic basis of disease in over 50% of patients with a wide range of ataxia-related phenotypes. 6
29915382 2019
39
Spectrum of movement disorders and neurotransmitter abnormalities in paediatric POLG disease. 6
30167885 2018
40
Alpers-Huttenlocher Syndrome First Presented with Hepatic Failure: Can Liver Transplantation Be Considered as Treatment Option? 6
29302508 2017
41
The clinical spectrum and natural history of early-onset diseases due to DNA polymerase gamma mutations. 6
28471437 2017
42
Enrichment of deleterious variants of mitochondrial DNA polymerase gene (POLG1) in bipolar disorder. 6
27987238 2017
43
Synergistic Effects of the in cis T251I and P587L Mitochondrial DNA Polymerase γ Disease Mutations. 6
28154168 2017
44
De novo mtDNA point mutations are common and have a low recurrence risk. 6
27450679 2017
45
The wide POLG-related spectrum: An integrated view. 6
27538604 2016
46
PRICKLE2 Mutations Might Not Be Involved in Epilepsy. 6
26942291 2016
47
Response to Sandford et al.: PRICKLE2 Variants in Epilepsy: A Call for Precision Medicine. 6
26942292 2016
48
A Clinical, Neuropathological and Genetic Study of Homozygous A467T POLG-Related Mitochondrial Disease. 6
26735972 2016
49
Yeast model analysis of novel polymerase gamma variants found in patients with autosomal recessive mitochondrial disease. 6
26077851 2015
50
Myocerebrohepatopathy spectrum disorder due to POLG mutations: A clinicopathological report. 6
25466440 2015

Variations for Mitochondrial Dna Depletion Syndrome 4a

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

6 (show top 50) (show all 853)
# Gene Name Type Significance ClinVarId dbSNP ID Position
1 POLG NM_002693.2(POLG):c.2617G>T (p.Glu873Ter) SNV Pathogenic 13504 rs121918047 GRCh37: 15:89864473-89864473
GRCh38: 15:89321242-89321242
2 POLG NM_002693.2(POLG):c.3057G>A (p.Trp1019Ter) SNV Pathogenic 13511 rs1567185775 GRCh37: 15:89862506-89862506
GRCh38: 15:89319275-89319275
3 POLG NM_001126131.2(POLG):c.3087_3088GA[2] (p.Glu1031fs) Microsatellite Pathogenic 458710 rs1555452607 GRCh37: 15:89862471-89862472
GRCh38: 15:89319240-89319241
4 POLG NM_002693.2(POLG):c.3155dup (p.Thr1053fs) Duplication Pathogenic 458711 rs1447799185 GRCh37: 15:89862279-89862280
GRCh38: 15:89319048-89319049
5 POLG NM_002693.2(POLG):c.3523C>T (p.Gln1175Ter) SNV Pathogenic 566733 rs1567184117 GRCh37: 15:89860727-89860727
GRCh38: 15:89317496-89317496
6 POLG NM_002693.2(POLG):c.646del (p.Ser216fs) Deletion Pathogenic 567927 rs1567193844 GRCh37: 15:89876340-89876340
GRCh38: 15:89333109-89333109
7 POLG NM_002693.2(POLG):c.1345C>T (p.Gln449Ter) SNV Pathogenic 619305 rs1567191417 GRCh37: 15:89870486-89870486
GRCh38: 15:89327255-89327255
8 POLG NM_001126131.2(POLG):c.2674dup (p.Asp892fs) Duplication Pathogenic 619306 rs1283198587 GRCh37: 15:89864415-89864416
GRCh38: 15:89321184-89321185
9 POLG NM_002693.2(POLG):c.3067C>T (p.Gln1023Ter) SNV Pathogenic 619307 rs1567185770 GRCh37: 15:89862496-89862496
GRCh38: 15:89319265-89319265
10 POLG NM_002693.2(POLG):c.3104+1G>A SNV Pathogenic 619308 rs138917386 GRCh37: 15:89862458-89862458
GRCh38: 15:89319227-89319227
11 POLG NM_002693.2(POLG):c.3149del (p.Lys1050fs) Deletion Pathogenic 619309 rs1567185603 GRCh37: 15:89862286-89862286
GRCh38: 15:89319055-89319055
12 POLG NM_002693.2(POLG):c.3241C>T (p.Arg1081Ter) SNV Pathogenic 619310 rs767708989 GRCh37: 15:89862194-89862194
GRCh38: 15:89318963-89318963
13 POLG NM_001126131.2(POLG):c.3430_3433dup (p.Asp1145fs) Duplication Pathogenic 619311 rs1567185048 GRCh37: 15:89861820-89861821
GRCh38: 15:89318589-89318590
14 POLG NM_002693.2(POLG):c.3447dup (p.Ala1150fs) Duplication Pathogenic 619312 rs1567185026 GRCh37: 15:89861806-89861807
GRCh38: 15:89318575-89318576
15 POLG NM_002693.2(POLG):c.2217_2230dup (p.Ile744fs) Duplication Pathogenic 577990 rs1282521429 GRCh37: 15:89866669-89866670
GRCh38: 15:89323438-89323439
16 POLG NM_002693.2(POLG):c.2827C>T (p.Arg943Cys) SNV Pathogenic 619301 rs1567186614 GRCh37: 15:89864151-89864151
GRCh38: 15:89320920-89320920
17 POLG NM_002693.2(POLG):c.2828G>A (p.Arg943His) SNV Pathogenic 619302 rs1567186613 GRCh37: 15:89864150-89864150
GRCh38: 15:89320919-89320919
18 POLG NM_002693.2(POLG):c.705G>A (p.Trp235Ter) SNV Pathogenic 619303 rs1567192879 GRCh37: 15:89873462-89873462
GRCh38: 15:89330231-89330231
19 POLG NM_002693.2(POLG):c.2662G>A (p.Gly888Ser) SNV Pathogenic 619332 rs1567186787 GRCh37: 15:89864428-89864428
GRCh38: 15:89321197-89321197
20 POLG NM_002693.2(POLG):c.3572A>G (p.Lys1191Arg) SNV Pathogenic 619340 rs1567183988 GRCh37: 15:89860678-89860678
GRCh38: 15:89317447-89317447
21 POLG NM_002693.2(POLG):c.1120C>T (p.Arg374Ter) SNV Pathogenic 619394 rs960142425 GRCh37: 15:89871966-89871966
GRCh38: 15:89328735-89328735
22 POLG NM_002693.2(POLG):c.2551A>G (p.Thr851Ala) SNV Pathogenic 619395 rs775445970 GRCh37: 15:89865014-89865014
GRCh38: 15:89321783-89321783
23 POLG NM_002693.2(POLG):c.3104+3A>T SNV Pathogenic 587863 rs778573169 GRCh37: 15:89862456-89862456
GRCh38: 15:89319225-89319225
24 POLG NM_002693.2(POLG):c.2038del (p.Leu680fs) Deletion Pathogenic 619396 rs1567188632 GRCh37: 15:89867370-89867370
GRCh38: 15:89324139-89324139
25 POLG NM_002693.2(POLG):c.2070+1G>A SNV Pathogenic 619397 rs1567188588 GRCh37: 15:89867337-89867337
GRCh38: 15:89324106-89324106
26 POLG NM_002693.2(POLG):c.2143C>T (p.Gln715Ter) SNV Pathogenic 619398 rs1254855971 GRCh37: 15:89867060-89867060
GRCh38: 15:89323829-89323829
27 POLG NM_002693.2(POLG):c.2426+1G>C SNV Pathogenic 619399 rs1567187745 GRCh37: 15:89865972-89865972
GRCh38: 15:89322741-89322741
28 POLG NM_002693.2(POLG):c.2480+1G>A SNV Pathogenic 619400 rs1567187326 GRCh37: 15:89865192-89865192
GRCh38: 15:89321961-89321961
29 POLG NM_002693.2(POLG):c.2543_2544dup (p.Thr849fs) Duplication Pathogenic 619401 rs1567187103 GRCh37: 15:89865020-89865021
GRCh38: 15:89321789-89321790
30 POLG NM_001126131.2(POLG):c.3490_3493dup (p.Ala1165fs) Duplication Pathogenic 619402 rs778115255 GRCh37: 15:89860756-89860757
GRCh38: 15:89317525-89317526
31 POLG NM_002693.2(POLG):c.698dup (p.Tyr233Ter) Duplication Pathogenic 619403 rs1567192884 GRCh37: 15:89873468-89873469
GRCh38: 15:89330237-89330238
32 POLG NM_002693.2(POLG):c.1289T>C (p.Met430Thr) SNV Pathogenic 619407 rs1567191474 GRCh37: 15:89870542-89870542
GRCh38: 15:89327311-89327311
33 POLG NM_002693.2(POLG):c.2564T>C (p.Val855Ala) SNV Pathogenic 619420 rs963553787 GRCh37: 15:89865001-89865001
GRCh38: 15:89321770-89321770
34 POLG NM_002693.2(POLG):c.2851T>A (p.Tyr951Asn) SNV Pathogenic 619425 rs1567186591 GRCh37: 15:89864127-89864127
GRCh38: 15:89320896-89320896
35 POLG NM_002693.2(POLG):c.1562del (p.Pro521fs) Deletion Pathogenic 619448 rs1567191094 GRCh37: 15:89870166-89870166
GRCh38: 15:89326935-89326935
36 POLG , FANCI NM_001113378.2(FANCI):c.*339dup Duplication Pathogenic 619449 rs1567183122 GRCh37: 15:89860028-89860029
GRCh38: 15:89316797-89316798
37 POLG NM_002693.2(POLG):c.660G>A (p.Trp220Ter) SNV Pathogenic 648373 rs1596360430 GRCh37: 15:89873507-89873507
GRCh38: 15:89330276-89330276
38 POLG NM_002693.2(POLG):c.951_961dup (p.Lys321fs) Duplication Pathogenic 694426 rs1596359629 GRCh37: 15:89872235-89872236
GRCh38: 15:89329004-89329005
39 POLG NM_002693.2(POLG):c.75G>A (p.Trp25Ter) SNV Pathogenic 694427 rs1021719232 GRCh37: 15:89876911-89876911
GRCh38: 15:89333680-89333680
40 POLG NM_002693.2(POLG):c.2157+5_2157+6delinsAG Indel Pathogenic 619500 rs1596354607 GRCh37: 15:89867040-89867041
GRCh38: 15:89323809-89323810
41 POLG , RLBP1 NM_000326.5(RLBP1):c.504_508del (p.Ser168fs) Deletion Pathogenic 595846 rs1379405913 GRCh37: 15:89758308-89758312
GRCh38: 15:89215077-89215081
42 POLG NM_002693.2(POLG):c.844T>G (p.Tyr282Asp) SNV Pathogenic 803122 rs1290567099 GRCh37: 15:89873323-89873323
GRCh38: 15:89330092-89330092
43 POLG NM_002693.3(POLG):c.2884dup (p.Ala962fs) Duplication Pathogenic 845148 GRCh37: 15:89864093-89864094
GRCh38: 15:89320862-89320863
44 POLG NM_002693.2(POLG):c.3643+2T>C SNV Pathogenic 597808 rs1335880349 GRCh37: 15:89860605-89860605
GRCh38: 15:89317374-89317374
45 POLG NM_002693.3(POLG):c.1251-2A>G SNV Pathogenic 933883 GRCh37: 15:89870582-89870582
GRCh38: 15:89327351-89327351
46 POLG NM_002693.3(POLG):c.1818del (p.Trp607fs) Deletion Pathogenic 936926 GRCh37: 15:89868812-89868812
GRCh38: 15:89325581-89325581
47 POLG NM_002693.3(POLG):c.1887del (p.Asp629fs) Deletion Pathogenic 942821 GRCh37: 15:89868743-89868743
GRCh38: 15:89325512-89325512
48 POLG NM_002693.3(POLG):c.172C>T (p.Gln58Ter) SNV Pathogenic 959671 GRCh37: 15:89876814-89876814
GRCh38: 15:89333583-89333583
49 POLG NM_002693.3(POLG):c.1947C>A (p.Tyr649Ter) SNV Pathogenic 969298 GRCh37: 15:89868683-89868683
GRCh38: 15:89325452-89325452
50 POLG NM_002693.2(POLG):c.2794C>T (p.His932Tyr) SNV Pathogenic 13500 rs121918048 GRCh37: 15:89864184-89864184
GRCh38: 15:89320953-89320953

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

72 (show all 17)
# 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.Gly848Ser VAR_023675 rs113994098
5 POLG p.Arg1096Cys VAR_023686 rs201732356
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 rs108530774
17 POLG p.Glu1136Lys VAR_065092 rs56047213

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

GO Terms for Mitochondrial Dna Depletion Syndrome 4a

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

# Name GO ID Score Top Affiliating Genes
1 mitochondrion GO:0005739 9.83 TWNK SUCLG1 SUCLA2 SSBP1 RRM2B RARS2
2 mitochondrial nucleoid GO:0042645 9.46 TWNK SSBP1 POLG2 POLG
3 mitochondrial matrix GO:0005759 9.36 TWNK SUCLG1 SUCLA2 SSBP1 RARS2 POLG2
4 gamma DNA polymerase complex GO:0005760 9.26 POLG2 POLG

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

(show all 12)
# Name GO ID Score Top Affiliating Genes
1 DNA repair GO:0006281 9.72 RRM2B POLG2 MGME1 FANCI ERCC6
2 translation GO:0006412 9.65 RARS2 PARS2 NARS2 FARS2 DARS2
3 mitochondrion organization GO:0007005 9.58 TWNK SSBP1 POLG2
4 DNA replication GO:0006260 9.55 TWNK SSBP1 RRM2B POLG2 POLG
5 response to gamma radiation GO:0010332 9.51 POLG ERCC6
6 DNA-dependent DNA replication GO:0006261 9.49 POLG2 POLG
7 mitochondrion morphogenesis GO:0070584 9.48 SSBP1 POLG2
8 DNA unwinding involved in DNA replication GO:0006268 9.46 TWNK SSBP1
9 tRNA aminoacylation GO:0043039 9.43 FARS2 DARS2
10 mitochondrial genome maintenance GO:0000002 9.37 MPV17 MGME1
11 tRNA aminoacylation for protein translation GO:0006418 9.35 RARS2 PARS2 NARS2 FARS2 DARS2
12 mitochondrial DNA replication GO:0006264 9.1 TWNK SSBP1 RRM2B POLG2 POLG MGME1

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

# Name GO ID Score Top Affiliating Genes
1 ATP binding GO:0005524 9.91 TWNK SUCLA2 RARS2 PARS2 NARS2 FARS2
2 nucleotide binding GO:0000166 9.85 TWNK SUCLG1 SUCLA2 RARS2 PARS2 NARS2
3 DNA-directed DNA polymerase activity GO:0003887 9.43 POLG2 POLG
4 DNA polymerase binding GO:0070182 9.4 POLG2 FANCI
5 succinate-CoA ligase (GDP-forming) activity GO:0004776 9.37 SUCLG1 SUCLA2
6 aminoacyl-tRNA ligase activity GO:0004812 9.35 RARS2 PARS2 NARS2 FARS2 DARS2
7 succinate-CoA ligase (ADP-forming) activity GO:0004775 9.32 SUCLG1 SUCLA2
8 ligase activity GO:0016874 9.17 SUCLG1 SUCLA2 RARS2 PARS2 NARS2 FARS2

Sources for Mitochondrial Dna Depletion Syndrome 4a

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