Autosomal dominant cerebellar ataxia, deafness, and narcolepsy
Autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCADN) is a rare neurological disorder that typically begins in mid‑adulthood, causing progressive ataxia, sensorineural hearing loss, and excessive daytime sleepiness with cataplexy.
Overview
ADCADN is a nervous system disorder with signs and symptoms that usually begin in mid‑adulthood and gradually worsen. People with ADCADN have difficulty coordinating movements (ataxia) and mild to moderate hearing loss caused by abnormalities of the auditory system (sensorineural deafness). Most have excessive daytime sleepiness (narcolepsy), often accompanied by cataplexy—a sudden brief loss of muscle tone in response to strong emotion. These characteristic signs and symptoms typically begin in a person's thirties. Eventually, people with ADCADN also experience a decline of intellectual function (dementia), beginning with impairment of executive function. Other features that can occur as the condition worsens include optic atrophy, sensory neuropathy, limb swelling, incontinence, depression, pseudobulbar signs, and psychosis. Affected individuals usually survive into their forties or fifties.
Symptoms
- Ataxia (difficulty coordinating movements)
- Mild to moderate sensorineural deafness
- Excessive daytime sleepiness (narcolepsy)
- Cataplexy (sudden brief loss of muscle tone)
- Progressive dementia with executive dysfunction
- Optic atrophy
- Sensory neuropathy (numbness, tingling, pain in arms and legs)
- Limb swelling (puffiness or edema)
- Incontinence (bowel or urinary)
- Depression
- Pseudobulbar signs (uncontrollable crying or laughing)
- Psychosis (distorted view of reality)
Causes & Risk Factors
ADCADN is caused by mutations in the DNMT1 gene, which encodes the enzyme DNA methyltransferase 1. This enzyme is involved in DNA methylation, adding methyl groups to cytosine nucleotides. Mutations affect a region that targets methylation to the correct DNA segments, leading to abnormal methylation and disrupted expression of multiple genes. Maintenance of neurons is disrupted, producing the signs and symptoms of ADCADN.
The condition is inherited in an autosomal dominant pattern, meaning one altered copy of the gene is sufficient to cause the disorder. In most cases, the mutation is inherited from a parent; other cases arise de novo in individuals with no family history. The prevalence of ADCADN is unknown, with at least 24 affected individuals described in the medical literature.
Diagnosis
Diagnosis is confirmed by genetic testing that identifies pathogenic variants in the DNMT1 gene.
Management
Specific treatment options are not detailed in the source material. Management typically focuses on symptomatic relief of ataxia, hearing loss, and narcolepsy, and monitoring for cognitive decline and other complications.
Other Names for This Condition
- ADCA-DN syndrome
- ADCADN
- Autosomal dominant cerebellar ataxia‑deafness‑narcolepsy syndrome
- Cerebellar ataxia, deafness, and narcolepsy, autosomal dominant
Additional Information & Resources
- Genetic Testing Registry: Autosomal dominant cerebellar ataxia, deafness and narcolepsy
- Genetic and Rare Diseases Information Center: Autosomal dominant cerebellar ataxia‑deafness‑narcolepsy syndrome
- National Organization for Rare Disorders (NORD)
- ClinicalTrials.gov
- Catalog of Genes and Diseases from OMIM: CEREBELLAR ATAXIA, DEAFNESS, AND NARCOLEPSY, AUTOSOMAL DOMINANT; ADCADN
- Scientific Articles on PubMed