A novel de novo exon 21 DNMT1 mutation causes cerebellar ataxia, deafness, and narcolepsy in a Brazilian patient.

STUDY OBJECTIVES

Autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN) is caused by DNMT1 mutations. Diagnosing the syndrome can be difficult, as all clinical features may not be present at onset, HLA-DQB1*06:02 is often negative, and sporadic cases occur. We report on clinical and genetic findings in a 31-year-old woman with cerebellar ataxia, deafness, and narcolepsy, and discuss diagnostic challenges.

DESIGN

Clinical and genetic investigation in a patient and family members.

SETTING

Ataxia clinic, São Paulo, Brazil.

PATIENTS OR PARTICIPANTS

One patient and her family members.

INTERVENTIONS

N/A.

MEASUREMENTS AND RESULTS

Narcolepsy was supported by polysomnographic and multiple sleep latency testing. HLA-DQB1*06:02 was positive. CSF hypocretin-1 was 191 pg/mL (normal values > 200 pg/mL). Mild brain atrophy was observed on MRI, with cerebellar involvement. The patient, her asymptomatic mother, and 3 siblings gave blood samples for genetic analysis. DNMT1 exons 20 and 21 were sequenced. Haplotyping of polymorphic markers surrounding the mutation was performed. The proband had a novel DNMT1 mutation in exon 21, p.Cys596Arg, c.1786T > C. All 4 parental haplotypes could be characterized in asymptomatic siblings without the mutation, indicating that the mutation is de novo in the patient.

CONCLUSIONS

The Brazilian patient reported here further adds to the worldwide distribution of ADCA-DN. The mutation is novel, and illustrates a sporadic case with de novo mutation. We believe that many more cases with this syndrome are likely to be diagnosed in the near future, mandating knowledge of this condition and consideration of the diagnosis.