Infantile onset spinocerebellar ataxia

Other Names: Ophthalmoplegia, hypotonia, ataxia, hypacusis, and athetosis; OHAHA syndrome; IOSCA; Spinocerebellar ataxia 8 (formerly); SCA8 (formerly); Spinocerebellar ataxia infantile with sensory neuropathy; Ophthalmoplegia - hypotonia - ataxia - hypoacusis - athetosis; Ophthalmoplegia-hypotonia-ataxia-hypoacusis-athetosis syndrome

Infantile-onset spinocerebellar ataxia (IOSCA) is a hereditary neurological disorder with early and severe involvement of both the peripheral and central nervous systems. It has only been described in Finnish families.

Epidemiology

So far, 24 cases have been reported. In Finland, IOSCA has a population carrier frequency of more than 1:230.

Cause

IOSCA is caused by mutations in the C10orf2 gene (10q24) encoding the mitochondrial helicase Twinkle. The c.1523A>G (p.Y508C) causative mutation has been postulated to be a founder mutation. Twenty-one of the reported patients were homozygous for this mutation, and three were compound heterozygotes: c.952G>A/c.1523A>G (two patients) and c.1523A>G/c.1287C>T (one patient). The mutations lead to mtDNA depletion in the brain and the liver, but not in the muscle.

Inheritance

Autosomal recessive inheritance, a 25% chance

IOSCA is inherited in an autosomal recessive manner. Genetic counseling is an important clinical tool for preventing new cases, especially for couples with an affected first child: the risk of having an affected child in further pregnancies is 25%.

Signs and symptoms

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. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed.

80%-99% of people have these symptoms

• Abnormality of the autonomic nervous system
• Ataxia
• Hearing impairment(Deafness)
• Ophthalmoplegia(Eye muscle paralysis)
• Optic atrophy
• Reduced tendon reflexes

5%-29% of people have these symptoms

• Elevated hepatic transaminase(High liver enzymes)

Diagnosis

The diagnosis is based on clinical and pathological findings. Studies of sural nerve biopsies reveal an early and rapidly progressive axonal neuropathy. Neuroimaging studies revealing cerebellar atrophy and genetic testing for the c.1523A>G mutation may also help to confirm the diagnosis.

Differential diagnosis Differential diagnoses include early-onset cerebellar ataxias with sensory axonal neuropathy and epileptic encephalopathy, mitochondrial disorders with axonal neuropathy (such as Friedreich ataxia), progressive external ophthalmoplegia (PEO), juvenile- or adult-onset mitochondrial recessive ataxia syndrome (MIRAS), and POLG-related disorders (see theseterms).

Antenatal diagnosis Prenatal testing may be available for families in which the disease-causing mutations have already been identified.

Treatment

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 (phenytoin and phenobarbital) are ineffective in most affected individuals .

Some affected individuals have benefited from lamotrigine, levetiracetam, topiramate, or lacosamide. 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.

Prognosis

Prognosis is unfavorable. Patients are wheelchair-bound by adolescence. Early death is common due to severe seizures. The clinical course seems to be more rapid and severe (with death during infancy) in c.952G>A/ c.1523A>G compound heterozygotes.

NIH genetic and rare disease info

• NIH info on Infantile onset spinocerebellar ataxia

Infantile onset spinocerebellar ataxia is a rare disease.

Infantile onset spinocerebellar ataxia Resources
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