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Infantile-Onset Spinocerebellar Ataxia

IOSCA

, MD, PhD and , MD, PhD.

Author Information
, MD, PhD
Research Associate, Institute of Child Health
University College London
UK
, MD, PhD
Assistant Professor, Department of Child Neurology
Hospital for Children and Adolescents
Helsinki University Central Hospital
Finland

Initial Posting: ; Last Update: July 22, 2010.

Summary

Disease characteristics. 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 hypergonadotrophic 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.

Diagnosis/testing. The diagnosis is based on clinical findings and can be confirmed by the presence of disease-causing mutations in C10orf2 (previously PEO1), the only gene known to be associated with IOSCA.

Management. Treatment of manifestations: Hearing loss, sensory axonal neuropathy, ataxia, psychotic behavior, and severe depression are treated in the usual manner. Conventional antiepileptic drugs (AEDs) (phenytoin and phenobarbital) are ineffective in most patients.

Surveillance: Small children: neurologic, audiologic, and ophthalmologic evaluations every six to 12 months; neurophysiologic studies when indicated; brain MRI every three to five years. Adolescents and adults: neurologic examination yearly; audiologic and ophthalmologic examinations every one to two years; EEG and brain MRI at least during status epilepticus.

Agents/circumstances to avoid: Valproate, which can cause significant elevation of serum concentration of bilirubin and liver enzymes.

Genetic counseling. IOSCA is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if the disease-causing mutations in the family are known.

Diagnosis

Clinical Diagnosis

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:

  • Spinocerebellar ataxia
  • Muscle hypotonia
  • Athetoid movements
  • Loss of deep-tendon reflexes
  • Hearing deficit
  • Ophthalmoplegia
  • Optic atrophy
  • Epileptic encephalopathy
  • Female primary hypergonadotropic hypogonadism

The diagnosis is based on typical clinical findings and can be confirmed by the identification of one of the following:

  • Homozygosity of the founder IOSCA-causing mutation in C10orf2
  • Compound heterozygosity for the founder IOSCA-causing mutation in C10orf2 and another mutation.

Testing

All routine laboratory and metabolic screening tests are normal.

Muscle morphology and respiratory chain enzyme analyses are normal.

Mitochondrial DNA (mtDNA) deletion and/or depletion are not identified in muscle of individuals with IOSCA; however:

  • Mitochondrial DNA depletion has been shown in the liver of a few compound heterozygotes [Hakonen et al 2007];
  • Post-mortem material has revealed complex I (CI) deficiency and mtDNA depletion in the brain [Hakonen et al 2008].

Molecular Genetic Testing

Gene. C10orf2 (previously PEO1) is the only gene implicated in the pathogenesis of IOSCA [Nikali et al 1995, Nikali et al 2005].

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Infantile-Onset Spinocerebellar Ataxia

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
C10orf2 (PEO1)Targeted mutation analysisc.1523A>G100% 4
Sequence analysis 5Sequence variants100% 6

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. IOSCA, a representative of Finnish disease heritage, is typically not found elsewhere in the world.

5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; ; typically, partial-, whole-, or multigene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

6. In the exonic/flanking intronic regions sequenced; mutations in non-sequenced intronic and regulatory regions are not detected.

Testing Strategy

Confirming the diagnosis in a proband. The diagnosis is based on typical clinical findings and can be confirmed by the identification of one of the following:

  • Homozygosity of the founder IOSCA-causing mutation in C10orf2
  • Compound heterozygosity for the founder IOSCA-causing mutation in C10orf2 and another mutation.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

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.

By adolescence affected individuals are no longer ambulatory, being dependent on either a walker or wheelchair. The hearing deficit is severe (>100 dB) and communication relies on sign language. Progressive pes cavus foot deformity and neurogenic scoliosis are common, as well as autonomic nervous system dysfunction, which manifests as increased perspiration, difficulty with urination and/or urinary incontinence, and obstipation.

The supratentorial brain (i.e., cerebral cortex, cerebral white matter, basal ganglia, and other deep brain nuclei) is well preserved until the onset of epilepsy. In 15 children, epilepsy developed into a serious encephalopathy, beginning at ages two and four years in compound heterozygotes and between ages 15 and 34 years (mean age 24 years) in homozygotes. The seizures were myoclonic jerks or focal clonic seizures that progressed to epilepsia partialis continua and further to status epilepticus with loss of consciousness and tonic clonic seizures. Death of nine of these 15 individuals was directly or indirectly related to epilepsy.

The supratentorial findings of cortical edema and later cortical and central atrophy appear at the time of and after the onset of epilepsy.

The cortical edema is of a non-vascular distribution. The area of swollen cortex varied from multiple small lesions to the involvement of the whole hemisphere, thalamus, and caudate nucleus. In diffusion-weighted imaging (DWI), the lesions showed restricted diffusion, thus behaving like early ischemic changes. Some of these lesions were reversible, but a T1-weighted hyperintense cortical signal compatible with cortical laminar necrosis developed in individuals with recurrent status epilepticus. Supratentorial cortical and central atrophy was seen in all individuals with intractable status epilepticus, but not in children or adults without refractory epilepsy. Epileptic encephalopathy in IOSCA is similar to that seen in other mitochondrial disorders, including MELAS.

Neuroimaging. Spinocerebellar degeneration progresses gradually with increasing age. Serial MRI reveal cerebellar, cortical, and brain stem atrophy with increased signal intensity in the cerebellar white matter on T2-weighted images [Koskinen et al 1995b].

Neuropathology. Post-mortem studies show moderate brain stem and cerebellar atrophy, and severe atrophic changes in the dorsal roots, posterior columns, and posterior spinocerebellar tracts of the spinal cord [Koskinen et al 1994a, Lönnqvist et al 1998].

Genotype-Phenotype Correlations

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 benign allele is required to preserve the development of a healthy individual [Nikali et al 2005].

Atypical IOSCA. The clinical course is more rapid and severe in c.[952G>A]+[1523A>G] compound heterozygotes and is characterized by severe early-onset encephalopathy and signs of liver involvement. The clinical manifestations include hypotonia, athetosis, sensory neuropathy, ataxia, hearing deficit, ophthalmoplegia, intractable epilepsy, and elevation of serum transaminases. The liver shows mtDNA depletion, whereas the muscle mtDNA is only slightly affected. These compound heterozygous individuals died at age 4.5 years, whereas the oldest homozygous individual (without epilepsy) is alive at age 50 years.

Penetrance

Penetrance is complete in both homozygotes and compound heterozygotes.

Nomenclature

IOSCA was originally known as OHAHA (ophthalmoplegia, hypoacusis, ataxia, hypotonia, athetosis) syndrome [Kallio & Jauhiainen 1985].

Prevalence

To date, 24 individuals with IOSCA have been identified:

  • 21 homozygotes: c.[1523A>G]+[1523A>G]
  • Two compound heterozygotes: c.[1523A>G]+[952G>A]
  • One compound heterozygote: c.[1523A>G]+[1287C>T]

All individuals with IOSCA have been identified in the genetically isolated population of Finland, where IOSCA is the second-most-common inherited ataxia. No individuals with IOSCA have been reported outside Finland [Nikali et al 2005].

The carrier frequency of the c.1523A>G founder mutation varies between 0.44% (1:230) in all of Finland and 2.0%-2.4% (1:50-1:40) in selected subisolates in Ostrobothnia and Savo. The other two mutations observed in the compound heterozygous individuals have been identified only in the families reported.

Differential Diagnosis

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.

The spinocerebellar degeneration in IOSCA is similar to that in Friedreich ataxia (FA) and other mitochondrial disorders with axonal neuropathy.

POLG-related disorders. POLG (previously POLG1), a nuclear gene that encodes mitochondrial DNA polymerase gamma is a functional partner of Twinkle in the mtDNA replication fork [Hakonen et al 2007]. This close biologic relationship explains the phenotypic overlap of the disorders caused by C10orf2 mutations and the disorders caused by POLG mutations. Of note, disorders caused by POLG mutations are more common than disorders caused by C10orf2 mutations.

The syndromes associated with autosomal recessive POLG mutations range from an infantile hepatoencephalopathy (Alpers-Huttenlocher syndrome) [Nguyen et al 2005, Ferrari et al 2005] to a mitochondrial spinocerebellar ataxia-epilepsy syndrome (MSCAE; also called MIRAS [mitochondrial recessive ataxia syndrome]) [Hakonen et al 2005, Tzoulis et al 2006, Engelsen et al 2008].

Ataxia-telangiectasia (A-T) is characterized by progressive cerebellar ataxia beginning between age one and four years, oculomotor apraxia, frequent infections, choreoathetosis, telangiectasias of the conjunctivae, immunodeficiency, and an increased risk for malignancy, particularly leukemia and lymphoma. Individuals with A-T are unusually sensitive to ionizing radiation.

Diagnosis of A-T relies on clinical findings, including slurred speech, truncal ataxia, oculomotor apraxia, family history, and neuroimaging. Testing that supports the diagnosis includes serum alphafetoprotein concentration (elevated in >95% of individuals with A-T), identification of a 7;14 chromosome translocation on routine karyotype of peripheral blood, the presence of immunodeficiency, and in vitro radiosensitivity assay. A-T is caused by mutations in ATM. If the clinical diagnosis can be established with certainty and the specific disease-causing mutations cannot be identified in an affected family member, linkage analysis may be used for genetic counseling of at-risk family members.

As to IOSCA, normal chromosome studies and normal immune function, as well as the lack of telangiectasias, the loss of deep-tendon reflexes, the early ophthalmoplegia, and the deafness distinguish the disease from A-T.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with infantile-onset spinocerebellar ataxia (IOSCA), the following are recommended:

  • Neurologic examination to evaluate the grade of ataxia and neuropathy
  • Audiologic examination to evaluate the grade of hearing deficit and need for hearing aids
  • Ophthalmologic examination to evaluate the grade of ophthalmoparesis and optic atrophy
  • Neurophysiologic examinations
    • ENMG (electroneuromyography)
    • SEP (somatosensory evoked potentials). Note: Changes in SEP occur early in the disease course and correlate with sensory system involvement.
    • VEP (visual evoked potentials)
  • Neuroimaging. Brain MRI

Treatment of Manifestations

Treatment is symptomatic:

  • Deafness. Hearing aids, speech therapy, and sign language to support social adaptation and prevent educational problems in children with IOSCA
  • Sensory axonal neuropathy. Physiotherapy and orthoses to prevent foot and spine deformity; supportive shoes, splints, and braces; orthopedic surgery for foot deformities (pes cavus) and spine deformities (scoliosis); foot care to treat calluses and ulcerations
  • Ataxia. A walker, wheelchair, physiotherapy, occupational therapy
  • Epilepsy. Conventional antiepileptic drugs (AEDs) (phenytoin and phenobarbital) are ineffective in most patients [Lönnqvist et al 2009].
    • Some patients have benefited from lamotrigine or levetiracetam.
    • Benzodiazepines, especially midazolam-infusion, when started early in status epilepticus, were occasionally effective.
    • Oxcarbazepine has some effect, but hyponatremia is a troublesome side effect.
  • Psychiatric symptoms. Antipsychotics (neurolepts, risperidone, olanzpine) to prevent psychotic behavior and antidepressants (SSRIs) for severe depression

Surveillance

Small children

  • Neurologic, audiologic, and ophthalmologic evaluations every six to 12 months
  • Neurophysiologic studies when clinically indicated
  • Brain MRI every three to five years

Adolescents and adults

  • Neurologic examination yearly
  • Audiologic and ophthalmologic examinations every one to two years
  • EEG and brain MRI at least during status epilepticus

Agents/Circumstances to Avoid

Valproate is contraindicated in patients with IOSCA, as it is in other disorders that potentially affect mitochondrial function in liver. Valproate caused significant elevation of liver enzymes (alanine aminotransferase [ALAT] 232 units/L [normal: 10-35 U/L] and gamma-GT [GGT] 160 U/L [normal: 5-50 U/L]) and icterus with elevated bilirubin levels (total: 224 µmol/L [normal: 5-25 µmol/L]; conjugated: 160 µmol/L [normal:1-8 µmol/L]) in one patient, and similar elevation of liver transaminases in another. When valproate was discontinued, icterus disappeared and the liver enzymes normalized.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search Clinical Trials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Infantile-onset spinocerebellar ataxia (IOSCA) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutant allele).
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. Individuals with IOSCA do not reproduce. Females with IOSCA have hypergonadotropic hypogonadism, indicative of ovarian failure. Males with IOSCA are too severely disabled to reproduce [Koskinen et al 1995a].

Other family members of a proband. Each sib of the proband’s parents is at 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible once the disease-causing mutations have been identified in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for families in whom the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Alexander Graham Bell Association for the Deaf and Hard of Hearing
    3417 Volta Place Northwest
    Washington DC 20007
    Phone: 866-337-5220 (toll-free); 202-337-5220; 202-337-5221 (TTY)
    Fax: 202-337-8314
    Email: info@agbell.org
  • American Society for Deaf Children (ASDC)
    800 Florida Avenue Northeast
    #2047
    Washington DC 20002-3695
    Phone: 800-942-2732 (Toll-free Parent Hotline); 866-895-4206 (toll free voice/TTY)
    Fax: 410-795-0965
    Email: info@deafchildren.org; asdc@deafchildren.org
  • euro-ATAXIA (European Federation of Hereditary Ataxias)
    Ataxia UK
    9 Winchester House
    Kennington Park
    London SW9 6EJ
    United Kingdom
    Phone: +44 (0) 207 582 1444
    Email: marco.meinders@euro-ataxia.eu
  • Finnish Federation of the Hard of Hearing (FFHOH)
    Ilkantie 4
    PL 51
    Helsinki 00400
    Finland
    Phone: +358 (0)9 5803 830
    Fax: +358 (0)9 5803 331
    Email: etunimi.sukunimi@kuuloliitto.fi
  • International Network of Ataxia Friends (INTERNAF)
    Email: internaf-owner@yahoogroups.com
  • National Ataxia Foundation
    2600 Fernbrook Lane
    Suite 119
    Minneapolis MN 55447
    Phone: 763-553-0020
    Email: naf@ataxia.org
  • CoRDS Registry for the National Ataxia Foundation
    Sanford Research
    2301 East 60th Street North
    Sioux Falls SD 57104
    Phone: 605-312-6423
    Email: Cords@sanfordhealth.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Infantile-Onset Spinocerebellar Ataxia: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Infantile-Onset Spinocerebellar Ataxia (View All in OMIM)

271245MITOCHONDRIAL DNA DEPLETION SYNDROME 7 (HEPATOCEREBRAL TYPE); MTDPS7
606075CHROMOSOME 10 OPEN READING FRAME 2; C10ORF2

Molecular Genetic Pathogenesis

Infantile-onset spinocerebellar ataxia (IOSCA) is caused by mutations in C10orf2, a ubiquitously expressed nuclear gene encoding mitochondrial proteins Twinkle and Twinky [Nikali et al 2005].

Gene structure. C10orf2 comprises five exons, which encode the major splice variant Twinkle (AF292004; 2240 bp) and a minor splice variant Twinky (AF292005; 2284 bp). Twinky-cDNA results from the use of a downstream exon 4 splice-donor site and leads to a 43-base-pair (bp) insertion between the regular exon 4-exon 5 sequence, which causes a premature stop codon [Spelbrink et al 2001]. The whole linear mRNA consists of 3630 bp (NM_021830.3). For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants (see Table 2)

  • Most individuals with IOSCA (88%; 21/24) are homozygous for the IOSCA-founder c.1523A>G mutation in exon 3 of C10orf2, which changes tyrosine to cysteine (p.Tyr508Cys) in the corresponding proteins Twinkle and Twinky [Nikali et al 2005].
  • One individual affected with IOSCA is a compound heterozygote with c.1523A>G mutation in his maternal C10orf2 allele and a synonymous c.1287C>T transition in exon 2 in his paternal C10orf2 allele. The silent c.1287C>T transition mutation reduces the allelic expression level to 2.6 times lower than normal [Nikali et al 2005].
  • Two individuals with IOSCA with a slightly different phenotype are compound heterozygotes for the founder c.1523A>G mutation and a novel c.952G>A mutation [Hakonen et al 2007].
  • All mutations underlying IOSCA have been observed only in the genetically isolated Finnish population.
  • The c.1287C>T mutation was observed in an affected individual who was a compound heterozygote with the second allele having the c.1523A>G mutation. The c.1287C>T allele was expressed at a reduced level as a result of an unknown mechanism [Nikali et al 2005]. Reduced expression could be caused by the c.1287C>T variant or the variant could be in tight linkage disequilibrium with another unidentified pathogenic variant. The phenotype of this compound heterozygous individual was classic IOSCA.

Table 2. Selected C10orf2 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid Change
(Alias 1)
Reference Sequences
c.1523A>Gp.Tyr508CysNM_021830​.4
NP_068602​.2
c.1287C>Tp.= 2
(Ala429Ala)
c.952G>Ap.Ala318Thr
c.955A>G 3p.Lys319Glu
c.1370C>T 4p.Thr457Ile

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. p.(=) designates that the protein has not been analyzed, but no change is expected.

3. SANDO; see Genetically Related Disorders.

4. Hepatocerebral form of mtDNA depletion syndrome; see Genetically Related Disorders.

Normal gene product. C10orf2 was originally cloned and the proteins resulting from the variant splicing of the gene, Twinkle and Twinky, were characterized by Spelbrink et al [2001]. Twinkle and Twinky are nuclear-encoded evolutionarily conserved mitochondrial proteins, Twinkle being essentially involved in the maintenance of mtDNA.

Twinkle. The major splice variant Twinkle consists of 684 amino acids with a molecular mass of 77 kd. Twinkle forms stable hexamers that localize to mitochondrial nucleoids, mtDNA-protein complexes within which the coupled replication and transcription of mtDNA takes place. Twinkle contains a 42-bp N-terminal mitochondrial localization signal, followed by a primase-related domain, primase-helicase linker region, and a C-terminal helicase domain. Twinkle is structurally related to the bacteriophage T7 gene 4 protein (primase/helicase) and is known to perform as an essential mtDNA-specific replicative helicase. Twinkle homologs have been observed at least in Plasmodium chabaudi chabaudi, Caenorhabditis elegans, and Drosophila melanogaster, but not in Saccharomyces cerevisiae [Spelbrink et al 2001].

As a mtDNA-specific helicase, Twinkle catalyzes ATP-dependent unwinding of duplex DNA with 5’→3’ polarity [Korhonen et al 2003]. Its functional partner is mtDNA-polymerase gamma (POLG), with which it creates a processive replication machinery to use double-stranded DNA (dsDNA) as a template for single-stranded DNA (ssDNA) synthesis [Korhonen et al 2004]. In the carboxyl terminus, critical residues between amino acids 572 and 596 of the 613-amino acid polypeptide are essential for mtDNA helicase function in vivo, as shown in Drosophila cell cultures [Matsushima et al 2008]. The N-terminal part of Twinkle is needed for efficient binding to ssDNA. Truncations in this region reduce both helicase activity and functional efficacy of the mtDNA replisome [Farge et al 2008].

In addition to being essential for mtDNA integrity, Twinkle regulates mtDNA copy number, as shown by analyzing overexpression of wild-type Twinkle in mice and human osteosarcoma cell lines [Tyynismaa et al 2004]. In the mice, increased expression of Twinkle in muscle and heart resulted in a threefold increase in mtDNA copy number. In cultured human cells, reducing Twinkle expression by RNA interference mediated a rapid drop in mtDNA copy number.

Phylogenetic analyses showed that Twinkle is widespread in the eukaryotic radiation and suggested that it may also function as a primase [Shutt & Gray 2006]. Indeed, the minimal mtDNA replisome consisting of Twinkle, POLG, and mitochondrial single-strand binding protein (mtSSB) can support leading-strand mtDNA synthesis on a dsDNA template in vitro [Korhonen et al 2004], but human mitochondrial RNA polymerase primes lagging-strand synthesis in vitro [Wanrooij et al 2008].

The primase/helicase linker region of Twinkle is essential for hexamer formation, which is required for the ATP-hydrolyzing activity and DNA unwinding. Supposedly, the linker region interacts with amino acids in the helicase domain of the adjacent monomer to form functional multimers [Korhonen et al 2008].

Twinky. Approximately 20% of the C10orf2 transcripts in human lymphoblasts code for the minor splice variant Twinky [Nikali et al 2005; Nikali, unpublished data]. Twinky presents as a 66-kd product of 582 amino acids, lacking residues 579-684, as compared to Twinkle, and terminating with four unique amino acids. Twinky presents as a monomer, is located diffusely within mitochondria, and shows no helicase activity [Spelbrink et al 2001]. The function of Twinky remains unknown.

Abnormal gene product. The cellular pathogenesis of IOSCA originally remained largely unresolved, and current research has focused mainly on the major splice variant Twinkle and the founder p.Tyr508Cys mutation, even though the mutation is present also in the Twinky protein.

The behavior and function of the Twinkle protein isoform with the p.Tyr508Cys mutation are described:

  • In general. The founder IOSCA mutation (p.Tyr508Cys) is located in the helicase domain of Twinkle, just upstream of a conserved Walker B motif involved in dNTP binding [Nikali et al 2005]. It creates a conserved CXXCH-heme binding motif, observed in b-type cytochromes, but Twinkle-p.Tyr508Cys does not bind heme covalently [Hakonen et al 2008].
  • Integrity of mtDNA. In IOSCA, mtDNA stays intact, with no deletions or increased number of point mutations observed in all tissues analyzed, including the brain [Nikali et al 2005, Hakonen et al 2008].
  • In vitro. The founder IOSCA mutation (p.Tyr508Cys) does not alter the subcellular localization or half-life of either Twinkle or Twinky [Nikali et al 2005]. Also helicase activity, hexamerization, and nucleoid structure remain normal [Hakonen et al 2008].
  • In the brain of an individual affected with IOSCA. In post-mortem examination of an individual with IOSCA, the cerebellum and cerebrum showed mtDNA depletion (residual amounts 5%-20%), but did not harbor mtDNA deletions or a greater number of mtDNA point mutations. The cerebellar Purkinje and pyramidal cells showed reduced levels of respiratory chain complex I, and the large neurons of frontal cortex showed reduced levels of both complexes I and IV. IOSCA is associated with brain-specific depletion of mtDNA and reduced respiratory chain enzyme activities and can be concluded as a novel mtDNA depletion syndrome [Hakonen et al 2008]. However, the mechanism by which the p.Tyr508Cys mutation in Twinkle causes mtDNA depletion remains to be investigated.

References

Literature Cited

  1. Baloh RH, Salavaggione E, Milbrandt J, Pestronk A. Familial parkinsonism and ophthalmoplegia from a mutation in the mitochondrial DNA helicase twinkle. Arch Neurol. 2007;64:998–1000. [PubMed: 17620490]
  2. Bohlega S, Van Goethem G, Al Semari A, Löfgren A, Al Hamed M, Van Broeckhoven C, Kambouris M. Novel Twinkle gene mutation in autosomal dominant progressive external ophthalmoplegia and multisystem failure. Neuromuscul Disord. 2009;19:845–8. [PubMed: 19853444]
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Chapter Notes

Revision History

  • 22 July 2010 (me) Comprehensive update posted live
  • 27 January 2009 (me) Review posted live
  • 17 September 2008 (kn) Original submission
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