Autosomal Dominant Cerebellar Ataxia with Deafness and Narcolepsy (ADCA-DN): An Emerging Syndrome Caused by DNMT1 Mutations (S43.003)
Citation Manager Formats
Make Comment
See Comments

Abstract
OBJECTIVE: To further characterize Autosomal Dominant Cerebellar Ataxia with sensorineural deafness and narcolepsy (ADCA-DN) phenotype.
BACKGROUND: ADCA-DN is a recently reported, rare, adult-onset, neurodegenerative disorder causing ataxia, tremor, sensorineural deafness, and narcolepsy and eventually variable sensory neuropathy, optic atrophy, dementia and seizures. ADCA-DN is caused by mutations in exon 21 of the DNMT1 gene.
DESIGN/METHODS: We investigated the clinical, neuroimaging, electrodiagnostic and genetic features of a large family with ADCA-DN with 6 affected individuals (4 living and 2 deceased) including a neuropathological evaluation of brain autopsy and histologic evaluation of a muscle biopsy specimen from 1 patient with ADCA-DN.
RESULTS: Deafness, tremor and ataxia were the first symptoms to appear in the fourth to fifth decade, followed by narcolepsy and cognitive decline. Later, patients variably develop psychosis, distal sensory loss, optic atrophy and visual decline, seizures, lymphedema and diabetes. Two patients had sensorineural hearing loss identified on routine occupational health testing approximately seven years prior to clinical deficits. The clinically affected patients had a heterozygous DNMT1 mutation, NM_001130823.1:c.1709C>T (exon21); NP_001124295.1:p.Ala570Val. The DNMT1 mutation was not present in seven unaffected family members. CT scan or MRI brain imaging revealed cerebral and cerebellar atrophy, and sinus mucosal thickening in 4 subjects. Electrodiagnostic studies demonstrated a severe sensory peripheral neuropathy. Neuropathological results revealed loss of purkinje cells in the cerebellum and a relative decrease in orexin immunostaining in the hypothalamus, with reactive astrocytes staining for GFAP, consistent with a clinical diagnosis of narcolepsy. Histological evaluation of a left quadriceps muscle biopsy revealed type 2 atrophy.
CONCLUSIONS: This report expands the phenotypical variability of the emerging syndrome adult-onset ADCA-DN caused by DNMT1 mutations. We describe earlier onset of deafness than was previously described, and this may be the initial presenting symptom to be identified on auditory testing.
Disclosure: Dr. Warman has nothing to disclose. Dr. Huang has nothing to disclose. Dr. Woulfe has nothing to disclose. Dr. Bourque has nothing to disclose. Dr. Smith has nothing to disclose. Dr. Dyment has nothing to disclose. Dr. Bulman has nothing to disclose. Dr. Boycott has nothing to disclose.
Thursday, March 21 2013, 12:00 pm-2:00 pm
- Copyright © 2013 by AAN Enterprises, Inc.
Disputes & Debates: Rapid online correspondence
NOTE: All authors' disclosures must be entered and current in our database before comments can be posted. Enter and update disclosures at http://submit.neurology.org. Exception: replies to comments concerning an article you originally authored do not require updated disclosures.
- Stay timely. Submit only on articles published within the last 8 weeks.
- Do not be redundant. Read any comments already posted on the article prior to submission.
- 200 words maximum.
- 5 references maximum. Reference 1 must be the article on which you are commenting.
- 5 authors maximum. Exception: replies can include all original authors of the article.
- Submitted comments are subject to editing and editor review prior to posting.
You May Also be Interested in
Related Articles
- No related articles found.