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.

Mutations in the TWNK gene cause IOSCA. The TWNK gene provides instructions for making two very similar proteins called Twinkle and Twinky. These proteins are found in the 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 or mtDNA, which is essential for the normal function of these structures. The Twinkle protein is involved in the production and maintenance of mtDNA. The function of the Twinky protein is unknown.

The TWNK gene mutations that cause IOSCA interfere with the function of the Twinkle protein and result in reduced quantities of mtDNA (mtDNA depletion). Impaired mitochondrial function in the nervous system, muscles, and other tissues that require a large amount of energy leads to neurological dysfunction and the other problems associated with IOSCA.

Normal Function

The TWNK gene provides instructions for making two very similar proteins called Twinkle and Twinky. These proteins are found in the mitochondria, which are structures in which a process called oxidative phosphorylation occurs to 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 is involved in the production and maintenance of mtDNA. It functions as a mitochondrial DNA helicase, which means it binds to DNA and temporarily unwinds the two spiral strands (double helix) of the DNA molecule. This unwinding is necessary for copying (replicating) mtDNA. The function of the Twinky protein is unknown.

Health Conditions Related to Genetic Changes

Ataxia neuropathy spectrum

Mutations in the TWNK gene have been found in a small number of people with ataxia neuropathy spectrum. This condition is characterized by problems with coordination and balance (ataxia) and disturbances in nerve function (neuropathy). The conditions previously named mitochondrial recessive ataxia syndrome (MIRAS) and sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO) are now included in ataxia neuropathy spectrum.

Mutations in the TWNK gene disrupt the function of Twinkle and lead to large deletions of mtDNA in the muscle tissue of affected individuals. However, it is unclear how mutations in the TWNK gene cause the signs and symptoms of ataxia neuropathy spectrum.

Infantile-onset spinocerebellar ataxia

At least six mutations in the TWNK gene have been found to cause infantile-onset spinocerebellar ataxia (IOSCA). The most common mutation replaces the protein building block (amino acid) tyrosine with the amino acid cysteine at position 508 in the Twinkle protein, written as Tyr508Cys or Y508C. Most affected individuals have two copies of this gene mutation in each cell. At least two additional mutations have been reported that are unique to particular families. In these cases, affected individuals have one copy of the family-specific mutation and one copy of the Tyr508Cys mutation in each cell.

The TWNK gene mutations that cause IOSCA interfere with the function of the Twinkle protein and result in reduced quantities of mtDNA (mtDNA depletion). Impaired mitochondrial function, especially in the nervous system (which requires a large amount of energy), leads to neurological dysfunction and other problems associated with IOSCA.

Perrault syndrome

At least four TWNK gene mutations have been identified in families with Perrault syndrome, a condition characterized by hearing loss in affected males and females and abnormalities of the ovaries in affected females. The mutations involved in this condition change single amino acids in the Twinkle protein. Researchers predict that these mutations impair the helicase activity of the protein. However, it is unclear exactly how TWNK gene mutations lead to hearing problems and ovarian abnormalities in affected individuals.

Progressive external ophthalmoplegia

At least 40 TWNK gene mutations have been identified in people with an eye condition called progressive external ophthalmoplegia. This disorder weakens the muscles that control eye movement and causes the eyelids to droop (ptosis). Researchers speculate that the mutated Twinkle protein has impaired helicase activity, which stalls the DNA replication process. Although the mechanism is unclear, replication stalling seems to result in large deletions of genetic material from mtDNA in muscle tissue. Researchers have not determined how deletions of mtDNA lead to the specific signs and symptoms of progressive external ophthalmoplegia, although the features of the condition may be related to impaired oxidative phosphorylation. It has been suggested that eye muscles are commonly affected by mitochondrial defects because they are especially dependent on oxidative phosphorylation for energy.

Other disorders

In a few families, TWNK gene mutations lead to mtDNA depletion syndrome, hepatocerebral form. People with this condition experience weak muscle tone (hypotonia), a decrease in liver function, developmental delay, seizures, and loss of sensation and weakness in the limbs (peripheral neuropathy).

Other Names for This Gene

• C10orf2
• chromosome 10 open reading frame 2
• PEO1
• PEO1_HUMAN
• progressive external ophthalmoplegia 1 protein
• T7 gp4-like protein with intramitochondrial nucleoid localization
• T7-like mitochondrial DNA helicase
• twinkle

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

More than 20 individuals with IOSCA have been identified in Finland. A few individuals with similar symptoms have been reported elsewhere in Europe.