Infantile onset spinocerebellar ataxia

General Information (adopted from Orphanet):

Synonyms, Signs: IOSCA
MTDPS7
SCA8, Formerly
Ophthalmoplegia - hypotonia - ataxia - hypoacusis - athetosis
Spinocerebellar Ataxia 8, formerly
Spinocerebellar Ataxia, infantile-onset
ohaha syndrome
Ophthalmoplegia, Hypotonia, Ataxia, Hypacusis, and Athetosis
Spinocerebellar Ataxia, infantile,with Sensory Neuropathy
Number of Symptoms 31
OrphanetNr: 1186
OMIM Id: 271245
ICD-10: G11.1
UMLs: C1849096
MeSH: C535523
MedDRA:
Snomed:

Prevalence, inheritance and age of onset:

Prevalence: < 0.1 of 100 000
Inheritance: Monogenic
Autosomal recessive
18775955 [IBIS]
Age of onset: Infancy
21888047 [IBIS]

Disease classification (adopted from Orphanet):

Parent Diseases: Autosomal recessive degenerative and progressive cerebellar ataxia
 -Rare eye disease
 -Rare genetic disease
 -Rare neurologic disease
Mitochondrial DNA depletion syndrome, hepatocerebral form
 -Rare developmental defect during embryogenesis
 -Rare eye disease
 -Rare gastroenterologic disease
 -Rare genetic disease
 -Rare neurologic disease

Comment:

Infantile-onset spinocerebellar ataxia (IOSCA) is a difficult, progressive degenerative disease causing damage to the peripheral and central nervous system. All known 24 patients are Finnish. The patients are progressively severely disabled from the age of approx. eighteen months. The pathogenesis is unknown and there is no curative treatment for the disease (PMID:21888047). IOSCA is caused by the recessive mutation in PEO1 (C10orf2, IOSCA, SCA8), leading to an Y508C change in the mitochondrial helicase Twinkle, in its helicase domain. IOSCA brains do not harbor mtDNA deletions or increased amount of mtDNA point mutations, but show mtDNA depletion in the brain and the liver. Large neurons show respiratory chain complex I (CI) deficiency, but also CIV is decreased (PMID:18775955). In a Korean family compound heterozygous mutations c.1460C>T and c.1485-1G>A in C10orf2 were identified as causative of IOSCA. Signs of motor neuropathy and myopathy were discovered for the first time in IOSCA patients with C10orf2 mutations. These results suggest that the clinical spectrum of IOSCA caused by C10orf2 mutations may be more variable than previously reported (PubMed:24816431). Involved gene: C10orf2 (PubMed:24816431);

Symptom Information: Sort by abundance 

1
(HPO:0000134) Female hypogonadism 18775955 IBIS 5 / 7739
2
(HPO:0000815) Hypergonadotropic hypogonadism 21888047 IBIS 48 / 7739
3
(HPO:0000648) Optic atrophy Very frequent [Orphanet] 21888047 IBIS 238 / 7739
4
(HPO:0000639) Nystagmus 22928142 IBIS 555 / 7739
5
(HPO:0000602) Ophthalmoplegia Very frequent [Orphanet] hallmark [HPO] 21888047 IBIS 56 / 7739
6
(HPO:0000496) Abnormality of eye movement 22928142 IBIS 79 / 7739
7
(HPO:0000365) Hearing impairment Very frequent [Orphanet] 21888047 IBIS 539 / 7739
8
(HPO:0002312) Clumsiness 8133312 IBIS 28 / 7739
9
(HPO:0002305) Athetosis 21888047 IBIS 31 / 7739
10
(HPO:0001249) Intellectual disability 24816431 IBIS 1089 / 7739
11
(HPO:0001328) Specific learning disability 8133312 IBIS 114 / 7739
12
(HPO:0001251) Ataxia Very frequent [Orphanet] hallmark [HPO] 21888047 IBIS 413 / 7739
13
(HPO:0003390) Sensory axonal neuropathy 21888047 IBIS 26 / 7739
14
(HPO:0001284) Areflexia Very frequent [Orphanet] hallmark [HPO] 21827899 IBIS 198 / 7739
15
(HPO:0001315) Reduced tendon reflexes Very frequent [Orphanet] 24816431 IBIS 160 / 7739
16
(HPO:0001271) Polyneuropathy 21402391 IBIS 56 / 7739
17
(HPO:0200134) Epileptic encephalopathy 18775955 IBIS 42 / 7739
18
(HPO:0006957) Loss of ability to walk 24816431 IBIS 7 / 7739
19
(HPO:0100022) Abnormality of movement Very frequent [Orphanet] 24816431 IBIS 129 / 7739
20
(HPO:0002133) Status epilepticus 8133312 IBIS 59 / 7739
21
(HPO:0001250) Seizures 21827899 IBIS 1245 / 7739
22
(HPO:0002910) Elevated hepatic transaminases 22928142 IBIS 158 / 7739
23
(HPO:0200125) Mitochondrial respiratory chain defects 18775955 IBIS 6 / 7739
24
(HPO:0001252) Muscular hypotonia 21888047 IBIS 990 / 7739
25
(HPO:0001324) Muscle weakness 24816431 IBIS 859 / 7739
26
(OMIM) Mitochondrial DNA depletion in brain tissue 18775955 IBIS 1 / 7739
27
(OMIM) Brainstem atrophy 18775955 IBIS 5 / 7739
28
(MedDRA:10059396) Mitochondrial DNA depletion 18775955 IBIS 5 / 7739
29
(HPO:0001272) Cerebellar atrophy 18775955 IBIS 197 / 7739
30
(HPO:0006827) Atrophy of the spinal cord 18775955 IBIS 5 / 7739
31
(OMIM) Decreased mitochondrial respiratory chain complex activity 18775955 IBIS 2 / 7739

Associated genes:

C10orf2;

ClinVar (via SNiPA)

Gene symbol Variation Clinical significance Reference

Additional Information:

Description: (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 ...
Clinical Description OMIM Santavuori and Vihavainen (1981) observed 8 patients in 5 families (3 pairs of sibs; brother and sister pairs) with sudden onset of deafness at an age after they had learned to speak, a peculiar ophthalmoplegia with only convergence ...
Molecular genetics OMIM In Finnish patients with infantile-onset spinocerebellar ataxia, Nikali et al. (2005) identified a founder mutation in the C10ORF2 gene: Y508C (606075.0012). One Finnish patient was compound heterozygous for the Y508C mutation inherited from his mother and a silent ...
Population genetics OMIM Nikali et al. (2005) stated that IOSCA is a typical representative of the Finnish disease heritage, having been described in 21 Finnish patients in 15 nuclear families and not found elsewhere in the world. IOSCA is the second ...
Diagnosis GeneReviews The diagnostic criteria for infantile-onset spinocerebellar ataxia (IOSCA) were detailed by Koskinen et al [1994a] and Koskinen et al [1994b]. After normal early development, children with IOSCA typically present in successive order from the second year of life onward with the following:...
Clinical Description GeneReviews Infantile-onset spinocerebellar ataxia (IOSCA) is a severe, progressive neurodegenerative disorder [Koskinen et al 1994b]. Affected children are born after an uneventful pregnancy and develop normally until age one year, when the first clinical symptoms of ataxia, muscle hypotonia, loss of deep-tendon reflexes, and athetosis appear. Ophthalmoplegia and sensorineural deafness develop by school age (age seven years). By adolescence sensory axonal neuropathy, optic atrophy, and hypergonadotrophic hypogonadism in females become evident. Migraine, psychiatric symptoms, and epilepsy are late manifestations....
Genotype-Phenotype Correlations GeneReviews Classic IOSCA. Within and between families, individuals with IOSCA who are homozygous for the c.1523A>G founder mutation show similar early-onset symptoms and clinical course, except for the onset of epilepsy [Koskinen et al 1994b]. The c.[1287C>T]+[1523A>G] compound heterozygote, whose paternal c.1287C>T disease allele is expressed in a greatly reduced level, shows a phenotype similar to c.1523A>G homozygotes. Small amounts of normal C10orf2 transcripts are thus not sufficient to rescue the IOSCA phenotype caused by the p.Tyr508Cys mutation, whereas a full amount of mRNAs expressed from at least one normal allele is required to preserve the development of a healthy individual [Nikali et al 2005]....
Differential Diagnosis GeneReviews Differential diagnosis for infantile-onset spinocerebellar ataxia (IOSCA) or at least for recessive C10orf2 mutations should be considered for all early-onset cerebellar ataxias with sensory axonal neuropathy and epileptic encephalopathy. ...
Management GeneReviews To establish the extent of disease in an individual diagnosed with infantile-onset spinocerebellar ataxia (IOSCA), the following are recommended:...
Molecular genetics GeneReviews Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....