DNMT1-Related Disorder

Clinical characteristics: DNMT1-related disorder is a degenerative disorder of the central and peripheral nervous systems comprising a phenotypic spectrum that includes hereditary sensory and autonomic neuropathy type 1E (HSAN1E) and autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN). DNMT1 disorder is often characterized by moderate-to-severe sensorineural hearing loss beginning in the teens or early 20s, sensory impairment, sudomotor dysfunction (loss of sweating), and dementia usually beginning in the mid-40s. In some affected individuals, narcolepsy/cataplexy syndrome and ataxia are predominant findings.

Diagnosis/testing: The diagnosis of DNMT1 disorder is established by identification of a heterozygous pathogenic variant in DNMT1 by molecular genetic testing.

Management: Treatment of manifestations: No cure for DNMT1 disorder currently exists. The emphasis of management is to help affected individuals and their caregivers understand the sudomotor defect and injury prevention when sensory impairment is significant. Because hearing loss may be severe, initial use of hearing aids and/or assistive communication methods may be needed. Sedative or antipsychotic drugs help to reduce extreme restlessness, roaming behavior, delusions, and hallucinations associated with dementia. Because behavioral changes and the loss of insight and judgment often present a considerable burden for partners or other caregivers, information about the disorder and psychological support for partners or other caregivers are essential.

Surveillance: Examination of feet daily for evidence of skin injury; annual routine clinical testing for dementia and audiogram to monitor hearing loss.

Agents/circumstances to avoid: To prevent injury to extremities with decreased sensation, protect the skin with appropriate socks and shoes and avoid exposure of feet to hot water.

Genetic counseling: DNMT1 disorder is inherited in an autosomal dominant manner. Most affected individuals have an affected parent; the proportion of affected individuals with a de novo DNMT1 pathogenic variant is unknown.

Each child of an individual with DNMT1 disorder has a 50% chance of inheriting the pathogenic variant. Once the DNMT1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.