MCID: MTC054
MIFTS: 41

Mitochondrial Dna Depletion Syndrome 7

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

Aliases & Classifications for Mitochondrial Dna Depletion Syndrome 7

MalaCards integrated aliases for Mitochondrial Dna Depletion Syndrome 7:

Name: Mitochondrial Dna Depletion Syndrome 7 57 12 24 75 29 13 6 15
Ohaha Syndrome 57 12 53 25 59 75
Iosca 57 24 53 25 59 75
Infantile Onset Spinocerebellar Ataxia 12 53 59 15 73
Infantile-Onset Spinocerebellar Ataxia 24 25 29
Ophthalmoplegia-Hypotonia-Ataxia-Hypoacusis-Athetosis Syndrome 53 59
Ophthalmoplegia, Hypotonia, Ataxia, Hypacusis, and Athetosis 53 25
Spinocerebellar Ataxia Infantile with Sensory Neuropathy 53 75
Spinocerebellar Ataxia 8 75 73
Mtdps7 57 75
Ophthalmoplegia, Hypotonia, Ataxia, Hypoacusis, and Athetosis 57
Ophthalmoplegia - Hypotonia - Ataxia - Hypoacusis - Athetosis 53
Spinocerebellar Ataxia, Infantile, with Sensory Neuropathy 57
Mitochondrial Dna Depletion Syndrome 7 Hepatocerebral Type 75
Ophthalmoplegia Hypotonia Ataxia Hypoacusis and Athetosis 75
Spinocerebellar Ataxia 8, Formerly; Sca8, Formerly 57
Spinocerebellar Ataxia, Infantile-Onset; Iosca 57
Mitochondrial Dna Depletion Syndrome , Type 7 40
Pure Spinocerebellar Ataxia Japanese Type 75
Spinocerebellar Ataxia, Infantile-Onset 57
Spinocerebellar Ataxia Infantile-Onset 75
Spinocerebellar Ataxia 8, Formerly 57
Sca4 Pure Japanese Type 75
Sca8, Formerly 57
Sca8 75

Characteristics:

Orphanet epidemiological data:

59
infantile onset spinocerebellar ataxia
Inheritance: Autosomal recessive; Prevalence: <1/1000000 (Worldwide); Age of onset: Infancy; Age of death: adolescent,early childhood,infantile,late childhood,young Adult;

OMIM:

57
Inheritance:
autosomal recessive

Miscellaneous:
progressive disorder
onset 6 to 18 months
some features occur in adolescence, including migraine, seizures, and psychiatric disorders
severe epilepsy may lead to early death
carrier frequency in finland is 1 in 230


HPO:

32
mitochondrial dna depletion syndrome 7:
Onset and clinical course progressive
Inheritance autosomal recessive inheritance


Classifications:



Summaries for Mitochondrial Dna Depletion Syndrome 7

NIH Rare Diseases : 53 The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.Orpha Number: 1186Disease definitionInfantile-onset spinocerebellar ataxia (IOSCA) is a hereditary neurological disorder with early and severe involvement of both the peripheral and central nervous systems. It has only been described in Finnish families.EpidemiologySo far, 24 cases have been reported. In Finland, IOSCA has a population carrier frequency of more than 1:230.Clinical descriptionIOSCA is characterized by very early ataxia, athetosis and reduced tendon reflexes (between 9 and 18 months of age). Ophthalmoplegia and sensorineural hearing loss are diagnosed in childhood. Other features, such as optic atrophy and sensory neuropathy with progressive loss of myelinated fibers in the sural nerve, appear later in the disease course. Hypogonadism may occur in females. Some patients show intellectual deficit. Epilepsy is a late manifestation and seizures may be life-threatening.EtiologyIOSCA is caused by mutations in the C10orf2 gene (10q24) encoding the mitochondrial helicase Twinkle. The c.1523A>G (p.Y508C) causative mutation has been postulated to be a founder mutation. Twenty-one of the reported patients were homozygous for this mutation, and three were compound heterozygotes: c.952G>A/c.1523A>G (two patients) and c.1523A>G/c.1287C>T (one patient). The mutations lead to mtDNA depletion in the brain and the liver, but not in the muscle.Diagnostic methodsThe diagnosis is based on clinical and pathological findings. Studies of sural nerve biopsies reveal an early and rapidly progressive axonal neuropathy. Neuroimaging studies revealing cerebellar atrophy and genetic testing for the c.1523A>G mutation may also help to confirm the diagnosis.Differential diagnosisDifferential diagnoses include early-onset cerebellar ataxias with sensory axonal neuropathy and epileptic encephalopathy, mitochondrial disorders with axonal neuropathy (such as Friedreich ataxia), progressive external ophthalmoplegia (PEO), juvenile- or adult-onset mitochondrial recessive ataxia syndrome (MIRAS), and POLG-related disorders (see theseterms).Antenatal diagnosisPrenatal testing may be available for families in which the disease-causing mutations have already been identified.Genetic counselingIOSCA is inherited in an autosomal recessive manner. Genetic counseling is an important clinical tool for preventing new cases, especially for couples with an affected first child: the risk of having an affected child in further pregnancies is 25%.Management and treatmentIOSCA patients are often managed by a multidisciplinary team, involving a pediatrician, neurologist, psychiatrist, orthopedic surgeon, physical and occupational therapists, genetic counselor, and social worker. Treatment is symptomatic and may include: (1) hearing aids, speech therapy and sign language for deafness; (2) physical therapy, orthotic devices and orthopedic surgery for sensory axonal neuropathy; (3) walking aids, a wheelchair, physiotherapy and occupational therapy for ataxia; (4) antiepileptic drugs for seizures and (5) antipsychotics and antidepressants for psychiatric symptoms.PrognosisPrognosis is unfavorable. Patients are wheelchair-bound by adolescence. Early death is common due to severe seizures. The clinical course seems to be more rapid and severe (with death during infancy) in c.952G>A/ c.1523A>G compound heterozygotes.Visit the Orphanet disease page for more resources.

MalaCards based summary : Mitochondrial Dna Depletion Syndrome 7, also known as ohaha syndrome, is related to spinocerebellar ataxia 8 and spinocerebellar ataxia 31, and has symptoms including muscle spasticity, tremor and abnormal pyramidal signs. An important gene associated with Mitochondrial Dna Depletion Syndrome 7 is TWNK (Twinkle MtDNA Helicase). Affiliated tissues include brain, liver and testes, and related phenotypes are ataxia and hearing impairment

OMIM : 57 Mitochondrial DNA depletion syndrome-7 is an autosomal recessive severe neurodegenerative disorder characterized primarily by hypotonia, ataxia, ophthalmoplegia, hearing loss, seizures, and sensory axonal neuropathy. Although originally classified as a form of spinocerebellar ataxia (see, e.g., SCA1, 164400) (Koskinen et al., 1994), it has been reclassified as a mitochondrial DNA depletion syndrome (Hakonen et al., 2008) based on the finding of mtDNA depletion in the brain and liver of affected individuals. For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (603041). (271245)

UniProtKB/Swiss-Prot : 75 Mitochondrial DNA depletion syndrome 7: A severe disease associated with mitochondrial dysfunction. Some patients are affected by progressive atrophy of the cerebellum, brain stem, the spinal cord, and sensory axonal neuropathy. Clinical features include hypotonia, athetosis, ataxia, ophthalmoplegia, sensorineural hearing deficit, sensory axonal neuropathy, epileptic encephalopathy and female hypogonadism. In some individuals liver dysfunction and multi-organ failure is present.

Genetics Home Reference : 25 Infantile-onset spinocerebellar ataxia (IOSCA) is a progressive disorder that affects the nervous system. Babies with IOSCA develop normally during the first year of life. During early childhood, however, they begin experiencing difficulty coordinating movements (ataxia); very weak muscle tone (hypotonia); involuntary writhing movements of the limbs (athetosis); and decreased reflexes. By their teenage years affected individuals require wheelchair assistance.

GeneReviews: NBK3795

Related Diseases for Mitochondrial Dna Depletion Syndrome 7

Graphical network of the top 20 diseases related to Mitochondrial Dna Depletion Syndrome 7:



Diseases related to Mitochondrial Dna Depletion Syndrome 7

Symptoms & Phenotypes for Mitochondrial Dna Depletion Syndrome 7

Symptoms via clinical synopsis from OMIM:

57
Head And Neck Eyes:
nystagmus
optic atrophy
ophthalmoplegia
poor eye contact
abnormal eye movements

Muscle Soft Tissue:
muscle weakness
hypotonia
decreased complex i activity (rare)

Neurologic Behavioral Psychiatric Manifestations:
psychosis
mood disorders
somnolence
uncontrolled rage

Abdomen Liver:
mitochondrial dna depletion

Endocrine Features:
hypergonadotrophic hypogonadism (in females in adolescence)

Neurologic Central Nervous System:
ataxia
clumsiness
cerebellar atrophy
status epilepticus
athetosis
more
Neurologic Peripheral Nervous System:
sensory axonal neuropathy
loss of deep tendon reflexes

Head And Neck Ears:
deafness
loss of vestibular caloric response

Genitourinary Internal Genitalia Female:
hypergonadotrophic hypogonadism (in females in adolescence)

Laboratory Abnormalities:
abnormal liver enzymes (rare)


Clinical features from OMIM:

271245

Human phenotypes related to Mitochondrial Dna Depletion Syndrome 7:

59 32 (show all 31)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 ataxia 59 32 hallmark (90%) Very frequent (99-80%) HP:0001251
2 hearing impairment 59 32 hallmark (90%) Very frequent (99-80%) HP:0000365
3 optic atrophy 59 32 hallmark (90%) Very frequent (99-80%) HP:0000648
4 reduced tendon reflexes 59 32 hallmark (90%) Very frequent (99-80%) HP:0001315
5 ophthalmoplegia 59 32 hallmark (90%) Very frequent (99-80%) HP:0000602
6 abnormality of the autonomic nervous system 59 32 hallmark (90%) Very frequent (99-80%) HP:0002270
7 nystagmus 32 HP:0000639
8 intellectual disability 32 HP:0001249
9 muscular hypotonia 32 HP:0001252
10 muscle weakness 32 HP:0001324
11 abnormality of movement 59 Very frequent (99-80%)
12 specific learning disability 32 HP:0001328
13 elevated hepatic transaminases 32 occasional (7.5%) HP:0002910
14 sensory axonal neuropathy 32 HP:0003390
15 migraine 32 HP:0002076
16 cerebral cortical atrophy 32 HP:0002120
17 psychosis 32 HP:0000709
18 hypergonadotropic hypogonadism 32 HP:0000815
19 areflexia 32 HP:0001284
20 clumsiness 32 HP:0002312
21 cerebellar atrophy 32 HP:0001272
22 encephalopathy 32 HP:0001298
23 atrophy/degeneration affecting the brainstem 32 HP:0007366
24 status epilepticus 32 HP:0002133
25 athetosis 32 HP:0002305
26 excessive daytime somnolence 32 HP:0001262
27 generalized hypotonia 32 HP:0001290
28 epileptic encephalopathy 32 HP:0200134
29 poor eye contact 32 HP:0000817
30 loss of ability to walk 32 HP:0006957
31 epilepsia partialis continua 32 HP:0012847

UMLS symptoms related to Mitochondrial Dna Depletion Syndrome 7:


muscle spasticity, tremor, abnormal pyramidal signs, ataxia, athetosis, ophthalmoplegia, muscle weakness, clumsiness

Drugs & Therapeutics for Mitochondrial Dna Depletion Syndrome 7

Search Clinical Trials , NIH Clinical Center for Mitochondrial Dna Depletion Syndrome 7

Genetic Tests for Mitochondrial Dna Depletion Syndrome 7

Genetic tests related to Mitochondrial Dna Depletion Syndrome 7:

# Genetic test Affiliating Genes
1 Mitochondrial Dna Depletion Syndrome 7 (hepatocerebral Type) 29 TWNK
2 Infantile-Onset Spinocerebellar Ataxia 29

Anatomical Context for Mitochondrial Dna Depletion Syndrome 7

MalaCards organs/tissues related to Mitochondrial Dna Depletion Syndrome 7:

41
Brain, Liver, Testes, Spinal Cord, Cerebellum, Eye

Publications for Mitochondrial Dna Depletion Syndrome 7

Articles related to Mitochondrial Dna Depletion Syndrome 7:

(show all 18)
# Title Authors Year
1
Sporadic infantile-onset spinocerebellar ataxia caused by missense mutations of the inositol 1,4,5-triphosphate receptor type 1 gene. ( 25794864 )
2015
2
Recessive C10orf2 mutations in a family with infantile-onset spinocerebellar ataxia, sensorimotor polyneuropathy, and myopathy. ( 24816431 )
2014
3
Infantile Onset Spinocerebellar Ataxia 2 (SCA2): A Clinical Report With Review of Previous Cases. ( 24300164 )
2014
4
Germ-line CAG repeat instability causes extreme CAG repeat expansion with infantile-onset spinocerebellar ataxia type 2. ( 23047744 )
2013
5
Case of infantile onset spinocerebellar ataxia type 5. ( 22914369 )
2013
6
Novel Autosomal Recessive c10orf2 Mutations Causing Infantile-Onset Spinocerebellar Ataxia. ( 22928142 )
2012
7
Identification of a novel Twinkle mutation in a family with infantile onset spinocerebellar ataxia by whole exome sequencing. ( 22353293 )
2012
8
Infantile-onset spinocerebellar ataxia and mitochondrial recessive ataxia syndrome are associated with neuronal complex I defect and mtDNA depletion. ( 18775955 )
2008
9
Infantile onset spinocerebellar ataxia is caused by recessive mutations in mitochondrial proteins Twinkle and Twinky. ( 16135556 )
2005
10
cDNA cloning, expression profile and genomic structure of a novel human transcript on chromosome 10q24, and its analyses as a candidate gene for infantile onset spinocerebellar ataxia. ( 12459258 )
2002
11
Infantile onset spinocerebellar ataxia with sensory neuropathy (IOSCA): neuropathological features. ( 9879682 )
1998
12
Tracing an ancestral mutation: genealogical and haplotype analysis of the infantile onset spinocerebellar ataxia locus. ( 8889554 )
1996
13
Primary hypogonadism in females with infantile onset spinocerebellar ataxia. ( 8552218 )
1995
14
Infantile-onset spinocerebellar ataxia: MR and CT findings. ( 7484627 )
1995
15
Infantile onset spinocerebellar ataxia represents an allelic disease distinct from other hereditary ataxias. ( 7877879 )
1994
16
Infantile onset spinocerebellar ataxia with sensory neuropathy: a new inherited disease. ( 8133312 )
1994
17
Sensory neuropathy in infantile onset spinocerebellar ataxia (IOSCA). ( 8159181 )
1994
18
Infantile-Onset Spinocerebellar Ataxia ( 20301746 )
1993

Variations for Mitochondrial Dna Depletion Syndrome 7

UniProtKB/Swiss-Prot genetic disease variations for Mitochondrial Dna Depletion Syndrome 7:

75
# Symbol AA change Variation ID SNP ID
1 TWNK p.Thr457Ile VAR_039045 rs80356544
2 TWNK p.Tyr508Cys VAR_043797 rs80356540
3 TWNK p.Ala318Thr VAR_065104 rs80356542
4 TWNK p.Leu360Gly VAR_065107
5 TWNK p.Leu456Val VAR_067722 rs386834145

ClinVar genetic disease variations for Mitochondrial Dna Depletion Syndrome 7:

6
(show all 16)
# Gene Variation Type Significance SNP ID Assembly Location
1 TWNK NM_021830.4(TWNK): c.1370C> T (p.Thr457Ile) single nucleotide variant Pathogenic rs80356544 GRCh37 Chromosome 10, 102749527: 102749527
2 TWNK NM_021830.4(TWNK): c.1370C> T (p.Thr457Ile) single nucleotide variant Pathogenic rs80356544 GRCh38 Chromosome 10, 100989770: 100989770
3 TWNK NM_021830.4(TWNK): c.1523A> G (p.Tyr508Cys) single nucleotide variant Pathogenic rs80356540 GRCh37 Chromosome 10, 102750231: 102750231
4 TWNK NM_021830.4(TWNK): c.1523A> G (p.Tyr508Cys) single nucleotide variant Pathogenic rs80356540 GRCh38 Chromosome 10, 100990474: 100990474
5 TWNK NM_021830.4(TWNK): c.952G> A (p.Ala318Thr) single nucleotide variant Pathogenic rs80356542 GRCh37 Chromosome 10, 102748919: 102748919
6 TWNK NM_021830.4(TWNK): c.952G> A (p.Ala318Thr) single nucleotide variant Pathogenic rs80356542 GRCh38 Chromosome 10, 100989162: 100989162
7 TWNK NM_021830.4(TWNK): c.1287C> T (p.Ala429=) single nucleotide variant Pathogenic rs80356541 GRCh37 Chromosome 10, 102749444: 102749444
8 TWNK NM_021830.4(TWNK): c.1287C> T (p.Ala429=) single nucleotide variant Pathogenic rs80356541 GRCh38 Chromosome 10, 100989687: 100989687
9 TWNK NM_021830.4(TWNK): c.1387C> T (p.Arg463Trp) single nucleotide variant Likely pathogenic rs386834146 GRCh37 Chromosome 10, 102749544: 102749544
10 TWNK NM_021830.4(TWNK): c.1387C> T (p.Arg463Trp) single nucleotide variant Likely pathogenic rs386834146 GRCh38 Chromosome 10, 100989787: 100989787
11 TWNK NM_021830.4(TWNK): c.1196A> G (p.Asn399Ser) single nucleotide variant Conflicting interpretations of pathogenicity rs863223921 GRCh37 Chromosome 10, 102749163: 102749163
12 TWNK NM_021830.4(TWNK): c.1196A> G (p.Asn399Ser) single nucleotide variant Conflicting interpretations of pathogenicity rs863223921 GRCh38 Chromosome 10, 100989406: 100989406
13 TWNK NM_021830.4(TWNK): c.333delT (p.Leu112Serfs) deletion Pathogenic rs886037832 GRCh37 Chromosome 10, 102748300: 102748300
14 TWNK NM_021830.4(TWNK): c.333delT (p.Leu112Serfs) deletion Pathogenic rs886037832 GRCh38 Chromosome 10, 100988543: 100988543
15 TWNK NM_021830.4(TWNK): c.904C> T (p.Arg302Trp) single nucleotide variant Likely pathogenic rs374997012 GRCh37 Chromosome 10, 102748871: 102748871
16 TWNK NM_021830.4(TWNK): c.904C> T (p.Arg302Trp) single nucleotide variant Likely pathogenic rs374997012 GRCh38 Chromosome 10, 100989114: 100989114

Expression for Mitochondrial Dna Depletion Syndrome 7

Search GEO for disease gene expression data for Mitochondrial Dna Depletion Syndrome 7.

Pathways for Mitochondrial Dna Depletion Syndrome 7

GO Terms for Mitochondrial Dna Depletion Syndrome 7

Cellular components related to Mitochondrial Dna Depletion Syndrome 7 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 mitochondrion GO:0005739 9.02 ATCAY MRPL43 SACS SLC25A4 TWNK

Sources for Mitochondrial Dna Depletion Syndrome 7

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69 SNOMED-CT via HPO
70 SNOMED-CT via Orphanet
71 TGDB
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74 UMLS via Orphanet
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