Penetrance

The penetrance of DNMT1 disorder is 100% in both males and females. However, age of onset and rate of progression vary between individuals.

Source: GeneReviews — "DNMT1-Related Disorder"

Diagnostic Criteria

The phenotype of DNMT1-related disorder is a continuum ranging from hereditary sensory and autonomic neuropathy type 1E (HSAN1E) to autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN).

Suggestive Findings

DNMT1 disorder should be suspected in individuals with the following clinical, electrophysiologic, and neuroimaging findings and family history.

Clinical findings

Source: GeneReviews — "DNMT1-Related Disorder"

Differential Diagnosis

Autosomal dominant hereditary sensory and autonomic neuropathies are genetically heterogeneous, but hereditary sensory and autonomic neuropathy type IE (HSAN1E) that includes dementia and hearing loss represents a unique phenotype. The combination of neuropathy with hearing loss can be confused with some forms of Charcot-Marie-Tooth, and the dementia is similar to that found in frontotemporal dementia or, more commonly, global cognitive disorder. However, if it is recognized that the neuropathy, hearing loss, and dementia represent a single syndrome, the diagnosis should be clear when it occurs in persons younger than age 50 years. See Hereditary Sensory and Autonomic Neuropathy: OMIM Phenotypic Series to view genes associated with HSAN in OMIM.

Source: GeneReviews — "DNMT1-Related Disorder"

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with DNMT1-related disorder, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Neurologic examination to determine the extent of sensory involvement, including sensory testing and observation for skin ulceration

• Past medical history to determine extent of autonomic involvement

• Evaluation of central nervous system involvement, using tests of cognitive function and brain imaging

• Audiologic examination to determine if hearing loss is present and, if present, its type and severity

• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

No cure for DNMT1 disorder currently exists. The emphasis of management is to help parents and affected individuals understand the sudomotor defect and injury prevention when sensory impairment is significant. To prevent injury to extremities with decreased sensation, protect the skin with appropriate socks and shoes and avoid exposure of feet to hot water. Because hearing loss may be severe, initial use of hearing aids and/or assistive communication methods may be needed. See also Hereditary Hearing Loss and Deafness Overview. Sedative or antipsychotic drugs help to reduce extreme restlessness, roaming behavior, delusions, and hallucinations associated with dementia.

Source: GeneReviews — "DNMT1-Related Disorder"

Clinical Guidance

Avoid sharp objects and hot water, which may damage skin.

Source: GeneReviews — "DNMT1-Related Disorder"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "DNMT1-Related Disorder"

Surveillance Guidelines

Sensory impairment. Examine feet on a daily basis to screen for skin injury. Dementia. Perform annual routine clinical testing for dementia:

• Observation of behavior

• Use of tools such as the Mini Mental State Exam (MMSE)

Hearing loss. Perform annual audiogram.

Source: GeneReviews — "DNMT1-Related Disorder"