Autosomal Dominant Cerebellar Ataxia-Deafness-Narcolepsy Syndrome

A rare polymorphic disorder, subtype of autosomal dominant cerebellar ataxia type 1 (ADCA type 1), characterized by ataxia, sensorineural deafness and narcolepsy with cataplexy and dementia.

Epidemiology

Autosomal dominant cerebellar ataxia-deafness-narcolepsy syndrome (ADCA-DN) has been reported in more than 80 patients to date from Sweden, the United States, Italy, Brazil, Belgium, China, New Zealand, UK, Taiwan, Germany, and Canada.

Clinical description

Disease onset usually occurs in adulthood (from the ages of 30-40). Cases have been reported in adolescents. The clinical features include cerebellar ataxia, narcolepsy with cataplexy, sensorineural deafness and dementia including executive dysfunction and global cognitive impairement. Optic atrophy, cataracts, psychosis, depression, sensory neuropathy, pseudobulbar signs, incontinence and limb lymphedema have also been reported but present later in the disease course. Mild brain atrophy with cerebellum involvement is visible with magnetic resonance imaging (MRI).

Etiology

ADCA-DN is caused by a mutation in the DNA methyltransferase (DNMT1) gene located on chromosome 19p13.2. It encodes an enzyme essential for the repression of transcriptional activity in numerous postmitotic cells.

Diagnostic methods

Diagnosis is based on the characteristic clinical findings and molecular genetic testing, the finding of a mutation in the DNMT1 gene.

Differential diagnosis

Differential diagnosis includes other types of autosomal dominant cerebellar ataxia (ADCA), and hereditary.

Antenatal diagnosis

Antenatal diagnosis is possible in families with a known mutation.

Genetic counseling

ADCA-DN is inherited autosomal dominantly and genetic counseling is possible. Sporadic cases have also been reported. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.

Management and treatment

There is no cure for ADCA-DN and treatment is supportive. Physical therapy, as well as the use of canes and walkers, should be offered in order to maximize strength and maintain activity as well as to avoid falls. Wheelchairs are eventually necessary. Speech therapy and communication devices may be useful to those with dysarthria. Annual neurological examinations are recommended to monitor disease progression.

Prognosis

Disease duration from disease onset to death is estimated to be between 10 to 30 years. Almost all affected individuals survive at least until late 40's.