Infantile-onset spinocerebellar ataxia

Infantile-onset spinocerebellar ataxia (IOSCA) is a disorder that affects the nervous system and worsens over time. Babies with IOSCA develop normally during the first few months of life. Later, during infancy or childhood, signs and symptoms develop. Affected children often do not grow and gain weight as expected (faltering weight), and they may experience a gradual loss of existing skills (developmental regression). Individuals with IOSCA often develop movement problems, abnornal nerve function (neuropathy), vision problems, and additional signs and symptoms.

The movement problems in people with IOSCA consist of:

• Loss of coordination (ataxia)
• Involuntary muscle contractions that can lead to abnormal movements or postures (dystonia)
• Decreased muscle tone (hypotonia)
• Involuntary writhing movements of the limbs (athetosis)
• Abnormal or absent reflexes

By their teenage years, individuals with IOSCA often require wheelchair assistance.

People with IOSCA have nervous system problems that affect both the autonomic nervous system, which controls involuntary body functions, and the peripheral nervous system, which connects the brain and spinal cord to muscles and to cells that detect sensations.

Autonomic nervous system problems include:

• Excessive sweating
• Difficulty controlling urination (incontinence)
• Severe constipation

Peripheral nervous system problems include:

• Problems with peripheral nerve function (sensory axonal neuropathy)
• The loss of the protective covering that surrounds nerves and ensures the rapid transmission of nerve impulses (demyelination)
• Unusually large fluid-filled spaces near the center of the brain (ventriculomegaly)

People with IOSCA can have these vision problems:

• Weakness in the muscles that control eye movement (ophthalmoplegia)
• Involuntary, rapid, and rhythmic eye movements (nystagmus)
• Vision loss caused by the deterioration of the nerves that carry information from the eyes to the brain (optic atrophy)

Other signs and symptoms of IOSCA include:

• Hearing loss caused by nerve damage (sensorineural hearing loss)
• Recurrent seizures (epilepsy) that can lead to severe brain dysfunction (encephalopathy)
• Kidney or liver problems

People with IOSCA can survive into adulthood. However, individuals with IOSCA who have severe signs and symptoms generally do not live past age 5.

IOSCA was first described in Finland, but it has since been found in individuals worldwide. IOSCA is a very rare condition, although its exact prevalence is unknown.

Genetic changes that cause disease are called pathogenic variants. Pathogenic variants in the TWNK gene cause IOSCA. The TWNK gene provides instructions for making a protein called Twinkle. This protein is found in mitochondria, which are structures within cells that convert the energy from food into a form that cells can use.

Mitochondria each contain a small amount of DNA, known as mitochondrial DNA (mtDNA), which is essential for the normal function of these structures. The Twinkle protein acts as a helicase, which is an enzyme that binds to particular regions of DNA and temporarily unwinds the two spiral strands (double helix) of the DNA molecule. The Twinkle protein unwinds mtDNA so that it can be copied (replicated) when new mitochondria are made.

Pathogenic variants in the TWNK gene result in the production of Twinkle proteins with reduced or impaired function. As a result, mtDNA cannot be replicated efficiently, which reduces the amount of mtDNA (mtDNA depletion). Because of this, IOSCA is sometimes referred to as mitochondrial DNA depletion syndrome 7. Without mtDNA, mitochondria cannot produce as much energy. This affects tissues that require large amounts of energy to function, such as the nervous system and muscles, and leads to the neurological dysfunction and the other problems associated with IOSCA.

Genetic Testing Information

• Genetic Testing Registry: Infantile onset spinocerebellar ataxia

Genetic and Rare Diseases Information Center

• Infantile-onset spinocerebellar ataxia
• Mitochondrial DNA depletion syndrome

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Catalog of Genes and Diseases from OMIM

• MITOCHONDRIAL DNA DEPLETION SYNDROME 7 (HEPATOCEREBRAL TYPE); MTDPS7

Scientific Articles on PubMed

• PubMed

• El-Hattab AW, Craigen WJ, Wong LJC, Scaglia F. Mitochondrial DNA Maintenance Defects Overview. 2018 Mar 8. In: Adam MP, Bick S, Mirzaa GM, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from http://www.ncbi.nlm.nih.gov/books/NBK487393/ Citation on PubMed
• Hakonen AH, Goffart S, Marjavaara S, Paetau A, Cooper H, Mattila K, Lampinen M, Sajantila A, Lonnqvist T, Spelbrink JN, Suomalainen A. Infantile-onset spinocerebellar ataxia and mitochondrial recessive ataxia syndrome are associated with neuronal complex I defect and mtDNA depletion. Hum Mol Genet. 2008 Dec 1;17(23):3822-35. doi: 10.1093/hmg/ddn280. Epub 2008 Sep 5. Citation on PubMed
• Lonnqvist T, Paetau A, Valanne L, Pihko H. Recessive twinkle mutations cause severe epileptic encephalopathy. Brain. 2009 Jun;132(Pt 6):1553-62. doi: 10.1093/brain/awp045. Epub 2009 Mar 20. Citation on PubMed
• Lopriore P, Unluturk Z, Klopstock T, Karaa A, Rouzier C, Dominguez-Gonzalez C, Lamperti C, Mancuso M; Twinkle-Related Disorders International Consortium for Trial Readiness (TReDIC); Cecchi G, Montano V, Siciliano G, Nicoletta V, Maioli M, Primiano G, Servidei S, La Morgia C, Carelli V, Valentino ML, Caporali L, Arena IG, Musumeci O, Lopergolo D, Malandrini A, Gallus GN, Filosto M, Bello L, Pegoraro E, Comi GP, Magri F, Ronchi D, Di Fonzo A, Percetti M, Azzimonti M, Buchner B, Prokisch H, Bermejo-Guerrero L, Procaccio V, Gaignard P, Echaniz-Laguna A, Schiff M, Rotig A, Toutain A, Paquis-Flucklinger V, Morel G, Robin S, Nadaj-Pakleza A, Chanson JB, Chaussenot A, Ait-El-Mkadem Saadi S, Trimouille A, Tranchant C, Salort-Campana E, Bieth E, Sacconi S, Duval F, Restrepo Vera JL, Molnar MJ, Vissing J, Haas R, Larson A, Enns GM, Parikh S, Goldstein A, Hirano M. Clinical and Genotypic Spectrum of Twinkle-Related Disorders: Insights From a Multinational Cohort Study. Neurology. 2026 Feb 10;106(3):e214401. doi: 10.1212/WNL.0000000000214401. Epub 2026 Jan 15. Citation on PubMed
• Nikali K, Suomalainen A, Saharinen J, Kuokkanen M, Spelbrink JN, Lonnqvist T, Peltonen L. Infantile onset spinocerebellar ataxia is caused by recessive mutations in mitochondrial proteins Twinkle and Twinky. Hum Mol Genet. 2005 Oct 15;14(20):2981-90. doi: 10.1093/hmg/ddi328. Epub 2005 Aug 31. Citation on PubMed
• Pierce SB, Gulsuner S, Stapleton GA, Walsh T, Lee MK, Mandell JB, Morales A, Klevit RE, King MC, Rogers RC. Infantile onset spinocerebellar ataxia caused by compound heterozygosity for Twinkle mutations and modeling of Twinkle mutations causing recessive disease. Cold Spring Harb Mol Case Stud. 2016 Jul;2(4):a001107. doi: 10.1101/mcs.a001107. Citation on PubMed
• Remtulla S, Emilie Nguyen CT, Prasad C, Campbell C. Twinkle-Associated Mitochondrial DNA Depletion. Pediatr Neurol. 2019 Jan;90:61-65. doi: 10.1016/j.pediatrneurol.2018.08.007. Epub 2018 Aug 9. Citation on PubMed
• Sukhudyan B, Gevorgyan A, Sarkissian A, Boltshauser E. Expanding phenotype of mitochondrial depletion syndrome in association with TWNK mutations. Eur J Paediatr Neurol. 2019 May;23(3):537-540. doi: 10.1016/j.ejpn.2019.02.002. Epub 2019 Feb 14. Citation on PubMed