Infantile-Onset Spinocerebellar Ataxia

Synonym: IOSCA

Nikali K, Lönnqvist T.

Publication Details

Summary

Clinical 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 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.

Diagnosis/testing.

The diagnosis is based on clinical findings and can be confirmed by the presence of pathogenic variants in TWNK (previously C10orf2, 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 affected individuals.

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 pathogenic variants 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 molecular genetic testing (see Testing Strategy).

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

Table 1.

Table 1.

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

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 variant in TWNK (C10orf2)
  • Compound heterozygosity for the founder IOSCA-causing variant in TWNK and another pathogenic variant

An alternative genetic testing strategy is use of a multi-gene panel that includes TWNK and other genes of interest (see Differential Diagnosis). Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time.

For more information on multi-gene panels click here.

More comprehensive genomic testing (when available) including exome sequencing, mitochondrial sequencing, and genome sequencing may be considered if serial single-gene testing (and/or use of a multi-gene panel that includes TWNK) fails to confirm a diagnosis in an individual with features of IOSCA. For more information on comprehensive genomic testing click here.

Clinical Characteristics

Clinical Description

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 7 years). By adolescence sensory axonal neuropathy, optic atrophy, and hypergonadotropic 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 variant show similar early-onset symptoms and clinical course, except for the onset of epilepsy [Koskinen et al 1994b]. The c.[1523A>G]+[1287C>T] 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 TWNK (C10orf2) transcripts are thus not sufficient to rescue the IOSCA phenotype caused by the c.1523A>G pathogenic variant, 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].

Atypical IOSCA. The clinical course is more rapid and severe in c.[1523A>G]+[952G>A] 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 variant 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 pathogenic variants 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 TWNK (C10orf2) pathogenic variants 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 TWNK pathogenic variants and the disorders caused by POLG pathogenic variants. Of note, disorders caused by POLG pathogenic variants are more common than disorders caused by TWNK pathogenic variants.

The syndromes associated with autosomal recessive POLG pathogenic variants range from an infantile hepatoencephalopathy (Alpers-Huttenlocher syndrome) [Ferrari et al 2005, Nguyen 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 pathogenic variants in ATM. If the clinical diagnosis can be established with certainty and the specific pathogenic variants cannot be identified in an affected family member, linkage analysis may be used for genetic counseling of at-risk family members.

IOSCA is distinguished from A-T by: normal chromosome studies, normal immune function, loss of deep-tendon reflexes, early ophthalmoplegia, and deafness; and by absence of telangiectasias.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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
  • Other. Clinical genetics consultation

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. Computers may be a valuable aid in support of communication and learning.
  • 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 evaluation every six to 12 months
  • Neurophysiologic studies when clinically indicated
  • Brain MRI every three to five years

Adolescents and adults

  • Neurologic examination annually
  • 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 ClinicalTrials.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 individual are obligate heterozygotes (i.e., carriers of one TWNK [C10orf2] pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

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 of one TWNK pathogenic variant is 2/3.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

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 of a TWNK pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the TWNK pathogenic variants 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 and Preimplantation Genetic Diagnosis

Once the TWNK pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for IOSCA are possible.

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
    Suite 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
    Lincoln House, Kennington Park, 1-3 Brixton Road
    London SW9 6DE
    United Kingdom
    Phone: +44 (0) 207 582 1444
    Email: smillman@ataxia.org.uk
  • 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
  • National Ataxia Foundation
    2600 Fernbrook Lane
    Suite 119
    Minneapolis MN 55447
    Phone: 763-553-0020
    Email: naf@ataxia.org
  • CoRDS Registry
    Sanford Research
    2301 East 60th Street North
    Sioux Falls SD 57104
    Phone: 605-312-6423
    Email: sanfordresearch@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.

Table A.

Infantile-Onset Spinocerebellar Ataxia: Genes and Databases

Table B.

Table B.

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

Molecular Genetic Pathogenesis

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

Gene structure. The longest TWNK transcript comprises five exons, which encode the major splice variant Twinkle (NM_021830.4; 3640 bp). Transcript variant NM_001163812.1 is a minor splice variant that encodes the protein known as Twinky (AF292005; 3684 bp).

This 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]. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants (see Table 2)

  • Most individuals with IOSCA (88%; 21/24) are homozygous for the IOSCA founder variant c.1523A>G in exon 3 of TWNK, 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 the c.1523A>G pathogenic variant in his maternal TWNK allele and a synonymous c.1287C>T transition in exon 2 in his paternal TWNK allele. The silent c.1287C>T transition variant 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 variant and a novel c.952G>A variant [Hakonen et al 2007].
  • All pathogenic variants underlying IOSCA have been observed only in the genetically isolated Finnish population.
  • The c.1287C>T pathogenic variant was observed in an affected individual who was a compound heterozygote with the second allele having the c.1523A>G pathogenic variant. 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.

Table 2.

Selected TWNK (C10orf2) Pathogenic Variants

Normal gene product. TWNK (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 TWNK 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 c.1523A>G (p.Tyr508Cys) variant, even though the pathogenic variant is also present in the Twinky protein.

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

  • In general. The founder IOSCA variant (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 single-nucleotide variants (SNVs) observed in all tissues analyzed, including the brain [Nikali et al 2005, Hakonen et al 2008].
  • In vitro. The founder IOSCA variant (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 SNVs. 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 pathogenic variant in Twinkle causes mtDNA depletion remains to be investigated.

References

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Chapter Notes

Revision History

  • 15 January 2015 (me) Comprehensive update posted live
  • 22 July 2010 (me) Comprehensive update posted live
  • 27 January 2009 (me) Review posted live
  • 17 September 2008 (kn) Original submission