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Infantile onset spinocerebellar ataxia(MTDPS7)

MedGen UID:
338613
Concept ID:
C1849096
Disease or Syndrome
Synonyms: C10orf2-Related Mitochondrial DNA Depletion Syndrome, Hepatocerebral Form; Mitochondrial DNA depletion syndrome 7 (hepatocerebral type); MTDPS7; Ophthalmoplegia, hypotonia, ataxia, hypacusis, and athetosis; OPHTHALMOPLEGIA, HYPOTONIA, ATAXIA, HYPOACUSIS, AND ATHETOSIS; SCA8 (formerly); Spinocerebellar ataxia 8 (formerly); Spinocerebellar ataxia infantile with sensory neuropathy
SNOMED CT: Infantile onset spinocerebellar ataxia (724227000); Ohaha syndrome (724227000); Ophthalmoplegia, hypotonia, ataxia, hypoacusis, athetosis syndrome (724227000)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
 
Gene (location): TWNK (10q24.31)
 
OMIM®: 271245
Orphanet: ORPHA1186

Definition

Infantile-onset spinocerebellar ataxia (IOSCA) is a severe, progressive neurodegenerative disorder characterized by normal development until age one year, followed by onset of ataxia, muscle hypotonia, loss of deep-tendon reflexes, and athetosis. Ophthalmoplegia and sensorineural deafness develop by age seven years. By adolescence, affected individuals are profoundly deaf and no longer ambulatory; sensory axonal neuropathy, optic atrophy, autonomic nervous system dysfunction, and hypergonadotropic hypogonadism in females become evident. Epilepsy can develop into a serious and often fatal encephalopathy: myoclonic jerks or focal clonic seizures that progress to epilepsia partialis continua followed by status epilepticus with loss of consciousness. [from GeneReviews]

Additional descriptions

From OMIM
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).  http://www.omim.org/entry/271245
From GHR
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.People with IOSCA often develop problems with the autonomic nervous system, which controls involuntary body functions. As a result, they may experience excessive sweating, difficulty controlling urination, and severe constipation.IOSCA also leads to vision and hearing problems that begin by about age 7. Children with this disorder develop weakness in the muscles that control eye movement (ophthalmoplegia). In their teenage years they experience degeneration of the nerves that carry information from the eyes to the brain (optic atrophy), which can result in vision loss. Hearing loss caused by nerve damage (sensorineural hearing loss) typically occurs during childhood and progresses to profound deafness.Individuals with IOSCA may have recurrent seizures (epilepsy). These seizures can lead to severe brain dysfunction (encephalopathy).Most people with IOSCA survive into adulthood. However, a few individuals with IOSCA have an especially severe form of the disorder involving liver damage and encephalopathy that develops during early childhood. These children do not generally live past age 5.  https://ghr.nlm.nih.gov/condition/infantile-onset-spinocerebellar-ataxia

Clinical features

From HPO
Athetosis
MedGen UID:
2115
Concept ID:
C0004158
Disease or Syndrome
A dyskinesia characterized by an inability to maintain the fingers, toes, tongue, or other body parts in a stable position, resulting in continuous slow, sinusoidal, and flowing involuntary movements. This condition is frequently accompanied by CHOREA, where it is referred to as choreoathetosis. Athetosis may occur as a manifestation of BASAL GANGLIA DISEASES or DRUG TOXICITY. (From Adams et al., Principles of Neurology, 6th ed, p76)
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Muscular hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
A condition of decreased tone of the skeletal muscles and diminished resistance to passive stretching.
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Involuntary movements of the eye that are divided into two types, jerk and pendular. Jerk nystagmus has a slow phase in one direction followed by a corrective fast phase in the opposite direction, and is usually caused by central or peripheral vestibular dysfunction. Pendular nystagmus features oscillations that are of equal velocity in both directions and this condition is often associated with visual loss early in life. (Adams et al., Principles of Neurology, 6th ed, p272)
Ophthalmoplegia
MedGen UID:
45205
Concept ID:
C0029089
Sign or Symptom
Paralysis of one or more extraocular muscles that are responsible for eye movements.
Optic atrophy
MedGen UID:
18180
Concept ID:
C0029124
Disease or Syndrome
A disorder characterized by loss of optic nerve fibers. It may be inherited or acquired. Acquired causes include ischemia, optic nerve neuropathy, glaucoma, trauma, radiation, brain tumors, and multiple sclerosis. It leads to vision disturbances.
Psychosis
MedGen UID:
19568
Concept ID:
C0033975
Mental or Behavioral Dysfunction
A mental disorder characterized by personality change, impaired functioning, and loss of touch with reality.
Status epilepticus
MedGen UID:
11586
Concept ID:
C0038220
Disease or Syndrome
A life-threatening situation in which the brain is in a continuous state of seizure.
Epilepsia partialis continua
MedGen UID:
39303
Concept ID:
C0085543
Disease or Syndrome
A variant of EPILEPSY characterized by continuous focal jerking of a body part over a period of hours, days, or even years without spreading to other body regions. Contractions may be aggravated by movement and are reduced, but not abolished during sleep. ELECTROENCEPHALOGRAPHY demonstrates epileptiform (spike and wave) discharges over the hemisphere opposite to the affected limb in most instances. The repetitive movements may originate from the CEREBRAL CORTEX or from subcortical structures (e.g., BRAIN STEM; BASAL GANGLIA). This condition is associated with Russian Spring and Summer encephalitis (see ENCEPHALITIS, TICK BORNE); Rasmussen syndrome (see ENCEPHALITIS); MULTIPLE SCLEROSIS; DIABETES MELLITUS; BRAIN NEOPLASMS; and CEREBROVASCULAR DISORDERS. (From Brain, 1996 April;119(pt2):393-407; Epilepsia 1993;34;Suppl 1:S29-S36; and Adams et al., Principles of Neurology, 6th ed, p319)
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
A reduction in the strength of one or more muscles.
Clumsiness
MedGen UID:
66690
Concept ID:
C0233844
Sign or Symptom
Lack of physical coordination resulting in an abnormal tendency to drop items or bump into objects.
Areflexia
MedGen UID:
115943
Concept ID:
C0234146
Finding
A finding indicating the complete absence of neurological reflexes.
Epileptic encephalopathy
MedGen UID:
452596
Concept ID:
C0543888
Disease or Syndrome
A condition in which epileptiform abnormalities are believed to contribute to the progressive disturbance in cerebral function. Epileptic encephalaopathy is characterized by (1) electrographic EEG paroxysmal activity that is often aggressive, (2) seizures that are usually multiform and intractable, (3) cognitive, behavioral and neurological deficits that may be relentless, and (4) sometimes early death.
Excessive daytime somnolence
MedGen UID:
151959
Concept ID:
C0694563
Disease or Syndrome
A state of abnormally strong desire for sleep during the daytime.
Cerebellar atrophy
MedGen UID:
196624
Concept ID:
C0740279
Disease or Syndrome
Atrophy (wasting) of the cerebellum.
Hypergonadotropic hypogonadism
MedGen UID:
184926
Concept ID:
C0948896
Disease or Syndrome
Ovarian or testicular dysfunction associated with high levels of gonadotropins.
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A general term for the complete or partial loss of the ability to hear from one or both ears.
Poor eye contact
MedGen UID:
303190
Concept ID:
C1445953
Finding
Difficulty in looking at another person in the eye.
Sensory axonal neuropathy
MedGen UID:
334116
Concept ID:
C1842587
Finding
An axonal neuropathy of peripheral sensory nerves.
Intellectual disability
MedGen UID:
334384
Concept ID:
C1843367
Finding
Subnormal intellectual functioning which originates during the developmental period. Intellectual disability, previously referred to as mental retardation, has been defined as an IQ score below 70.
Elevated hepatic transaminases
MedGen UID:
338525
Concept ID:
C1848701
Finding
Elevations of the levels of SGOT and SGPT in the serum. SGOT (serum glutamic oxaloacetic transaminase) and SGPT (serum glutamic pyruvic transaminase) are transaminases primarily found in the liver and heart and are released into the bloodstream as the result of liver or heart damage. SGOT and SGPT are used clinically mainly as markers of liver damage.
Loss of ability to walk
MedGen UID:
338614
Concept ID:
C1849097
Finding
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Encephalopathy
MedGen UID:
368408
Concept ID:
C1963101
Finding
Migraine
MedGen UID:
854348
Concept ID:
C3887485
Finding
Migraine is the most common type of chronic, episodic headache, as summarized by Featherstone (1985). One locus for migraine with or without aura (MGR1) has been identified on chromosome 4q24. Other loci for migraine have been identified on 6p21.1-p12.2 (MGR3; 607498), 14q21.2-q22.3 (MGR4; 607501), 19p13 (MGR5; 607508), 1q31 (MGR6; 607516), 15q11-q13 (MGR7; 609179), 5q21 (with or without aura, MGR8, 609570; with aura, MGR9, 609670), 17p13 (MGR10; 610208), 18q12 (MGR11; 610209), 10q22-q23 (MGR12; 611706), and the X chromosome (MGR2; 300125). Mutation in the KCNK18 gene (613655) on chromosome 10q25 causes migraine with aura (MGR13; 613656). A subtype of autosomal dominant migraine with aura (MA), familial hemiplegic migraine (FHM; see 141500), is caused by mutation in the CACNA1A gene (601011) on chromosome 19p13 (FHM1; 141500), by mutation in the ATP1A2 gene (182340) on chromosome 1q21 (FHM2; 602481), or by mutation in the SCN1A gene (182389) on chromosome 2q24 (FHM3; 609634). Another locus for FHM has been mapped to chromosome 1q31 (FHM4; see 607516). There is evidence that a polymorphism in the estrogen receptor gene (ESR1; 133430.0005) and a polymorphism in the TNF gene (191160.0004) may confer susceptibility to migraine. A polymorphism in the endothelin receptor type A gene (EDNRA; 131243.0001) may confer resistance to migraine.
Atrophy/Degeneration affecting the brainstem
MedGen UID:
870454
Concept ID:
C4024900
Disease or Syndrome
Specific learning disability
MedGen UID:
871302
Concept ID:
C4025790
Mental or Behavioral Dysfunction
Impairment of certain skills such as reading or writing, coordination, self-control, or attention that interfere with the ability to learn. The impairment is not related to a global deficiency of intelligence.
Cerebral cortical atrophy
MedGen UID:
1646740
Concept ID:
C4551583
Disease or Syndrome
Atrophy of the cortex of the cerebrum.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Infantile onset spinocerebellar ataxia in Orphanet.

Recent clinical studies

Etiology

Singh A, Faruq M, Mukerji M, Dwivedi MK, Pruthi S, Kapoor S
J Child Neurol 2014 Jan;29(1):139-44. Epub 2013 Dec 2 doi: 10.1177/0883073813509015. PMID: 24300164
Vinther-Jensen T, Ek J, Duno M, Skovby F, Hjermind LE, Nielsen JE, Nielsen TT
Eur J Hum Genet 2013 Jun;21(6):626-9. Epub 2012 Oct 10 doi: 10.1038/ejhg.2012.231. PMID: 23047744Free PMC Article
Jacob FD, Ho ES, Martinez-Ojeda M, Darras BT, Khwaja OS
J Child Neurol 2013 Oct;28(10):1292-5. Epub 2012 Aug 21 doi: 10.1177/0883073812454331. PMID: 22914369
Koskinen T, Valanne L, Ketonen LM, Pihko H
AJNR Am J Neuroradiol 1995 Aug;16(7):1427-33. PMID: 7484627
Nikali K, Koskinen T, Suomalainen A, Pihko H, Peltonen L
Pediatr Res 1994 Nov;36(5):607-12. doi: 10.1203/00006450-199411000-00012. PMID: 7877879

Diagnosis

Domínguez-Ruiz M, García-Martínez A, Corral-Juan M, Pérez-Álvarez ÁI, Plasencia AM, Villamar M, Moreno-Pelayo MA, Matilla-Dueñas A, Menéndez-González M, Del Castillo I
J Transl Med 2019 Aug 28;17(1):290. doi: 10.1186/s12967-019-2041-x. PMID: 31455392Free PMC Article
Jacob FD, Ho ES, Martinez-Ojeda M, Darras BT, Khwaja OS
J Child Neurol 2013 Oct;28(10):1292-5. Epub 2012 Aug 21 doi: 10.1177/0883073812454331. PMID: 22914369
Dündar H, Ozgül RK, Yalnızoğlu D, Erdem S, Oğuz KK, Tuncel D, Temuçin CM, Dursun A
Pediatr Neurol 2012 Mar;46(3):172-7. doi: 10.1016/j.pediatrneurol.2011.12.006. PMID: 22353293
Koskinen T, Pihko H, Voutilainen R
Neuropediatrics 1995 Oct;26(5):263-6. doi: 10.1055/s-2007-979769. PMID: 8552218
Koskinen T, Valanne L, Ketonen LM, Pihko H
AJNR Am J Neuroradiol 1995 Aug;16(7):1427-33. PMID: 7484627

Therapy

Lönnqvist T, Paetau A, Valanne L, Pihko H
Brain 2009 Jun;132(Pt 6):1553-62. Epub 2009 Mar 20 doi: 10.1093/brain/awp045. PMID: 19304794
Nikali K, Suomalainen A, Terwilliger J, Koskinen T, Weissenbach J, Peltonen L
Am J Hum Genet 1995 May;56(5):1088-95. PMID: 7726163Free PMC Article

Prognosis

Nikkanen J, Forsström S, Euro L, Paetau I, Kohnz RA, Wang L, Chilov D, Viinamäki J, Roivainen A, Marjamäki P, Liljenbäck H, Ahola S, Buzkova J, Terzioglu M, Khan NA, Pirnes-Karhu S, Paetau A, Lönnqvist T, Sajantila A, Isohanni P, Tyynismaa H, Nomura DK, Battersby BJ, Velagapudi V, Carroll CJ, Suomalainen A
Cell Metab 2016 Apr 12;23(4):635-48. Epub 2016 Feb 25 doi: 10.1016/j.cmet.2016.01.019. PMID: 26924217
Lönnqvist T, Paetau A, Valanne L, Pihko H
Brain 2009 Jun;132(Pt 6):1553-62. Epub 2009 Mar 20 doi: 10.1093/brain/awp045. PMID: 19304794
Hakonen AH, Isohanni P, Paetau A, Herva R, Suomalainen A, Lönnqvist T
Brain 2007 Nov;130(Pt 11):3032-40. Epub 2007 Oct 5 doi: 10.1093/brain/awm242. PMID: 17921179
Koskinen T, Pihko H, Voutilainen R
Neuropediatrics 1995 Oct;26(5):263-6. doi: 10.1055/s-2007-979769. PMID: 8552218
Koskinen T, Valanne L, Ketonen LM, Pihko H
AJNR Am J Neuroradiol 1995 Aug;16(7):1427-33. PMID: 7484627

Clinical prediction guides

Nikkanen J, Forsström S, Euro L, Paetau I, Kohnz RA, Wang L, Chilov D, Viinamäki J, Roivainen A, Marjamäki P, Liljenbäck H, Ahola S, Buzkova J, Terzioglu M, Khan NA, Pirnes-Karhu S, Paetau A, Lönnqvist T, Sajantila A, Isohanni P, Tyynismaa H, Nomura DK, Battersby BJ, Velagapudi V, Carroll CJ, Suomalainen A
Cell Metab 2016 Apr 12;23(4):635-48. Epub 2016 Feb 25 doi: 10.1016/j.cmet.2016.01.019. PMID: 26924217
Park MH, Woo HM, Hong YB, Park JH, Yoon BR, Park JM, Yoo JH, Koo H, Chae JH, Chung KW, Choi BO, Koo SK
Neurogenetics 2014 Aug;15(3):171-82. Epub 2014 May 10 doi: 10.1007/s10048-014-0405-1. PMID: 24816431Free PMC Article
Bouhlal Y, El-Euch-Fayeche G, Amouri R, Hentati F
Acta Myol 2005 Oct;24(2):155-61. PMID: 16550933
Nikali K, Suomalainen A, Saharinen J, Kuokkanen M, Spelbrink JN, Lönnqvist T, Peltonen L
Hum Mol Genet 2005 Oct 15;14(20):2981-90. Epub 2005 Aug 31 doi: 10.1093/hmg/ddi328. PMID: 16135556
Nikali K, Suomalainen A, Terwilliger J, Koskinen T, Weissenbach J, Peltonen L
Am J Hum Genet 1995 May;56(5):1088-95. PMID: 7726163Free PMC Article

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