Autosomal Dominant Cerebellar Ataxia with Deafness and Narcolepsy (ADCA-DN): An Emerging Syndrome Caused by DNMT1 Mutations (S43.003)

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.