Dnmt1-Related Disorder

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2021-01-18

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Summary

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.

Diagnosis

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

Sensory neuropathy that is predominantly loss of feeling to touch, pain, temperature, and proprioception of the feet and legs, with less severe loss in the hands. Pain tends to be minimal but can be lancinating or burning; some have described parathesias. Tendon reflexes tend to be depressed in the lower limbs. The face and trunk are characteristically spared. Age of onset ranges from early 20s to late 40s.
Autonomic neuropathy, manifest as loss of sweating (sudomotor abnormalities). Significant symptoms of autonomic neuropathy usually do not occur until the late 40s.
Laboratory-based tests such as tilt table testing for postural hypotension, quantitative sudomotor axon reflex testing, and thermoregulatory sweat testing can help to identify postganglionic sudomotor abnormalities that spare cardiovagal and adrenergic autonomic functions.
Special quantitative sensory testing and histopathologic preparations can assist in studying the sensory fibers implicated in autonomic involvement. The pan sensory neuropathy affects large proprioceptive and vibratory sensing fibers as well as small heat-, pain-, and temperature-sensing fibers.
Cerebellar ataxia manifest as impaired coordination, loss of balance, unsteady gait, difficulty performing fine motor tasks, and changes in speech. Age of onset ranges from the late 30s to late 40s.
Dementia that typically first manifests as progressive decline in cognition and behavior. Wechsler Adult Intelligence and Memory Scales as well as Boston naming test and the Mini Mental State Exam (MMSE) can be used to identify diffuse cortical dementia. Dementia usually starts in the mid-40s.
Moderate to severe progressive sensorineural hearing loss (i.e., 70- to 80-db loss at 4,000 Hz) beginning in the teens or early 20s
Early- or late-onset narcolepsy/cataplexy syndrome. Narcolepsy is a chronic sleep disorder characterized by overwhelming daytime drowsiness and sudden attacks of sleep. Cataplexy refers to a sudden loss of muscle tone. Age of onset ranges from early 20s to late 40s.

Electrophysiologic testing shows:

Length-dependent sensory axonal loss including both small fiber loss (drC and Aσ) and large fiber proprioceptive Aβ loss;
Absent or reduced sensory nerve action potentials with normal motor nerve conduction velocities.

Brain imaging can help to determine the existence of global atrophy without intraparenchymal signal change.

Family history is consistent with autosomal dominant inheritance, including simplex cases (i.e., a single occurrence in a family) caused by a de novo pathogenic variant.

Establishing the Diagnosis

The diagnosis of DNMT1 disorder is established in a proband with suggestive findings and a heterozygous pathogenic variant in DNMT1 identified by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of DNMT1-related disorder is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with progressive sensorineural hearing loss, pure sensory neuropathy, and/or cognitive decline are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of DNMT1-related disorder, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:

Single-gene testing. Sequence analysis of DNMT1 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, heterozygous exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If no pathogenic variant is identified, gene-targeted deletion/duplication analysis can be considered to detect intragenic deletions or duplications; however, to date such variants have not been identified as a cause of DNMT1-related disorder.
A multigene panel that includes DNMT1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Of note, given the rarity of DNMT1-related disorder, some panels for hearing loss and/or dementia may not include this gene. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the phenotype is indistinguishable from many other inherited disorders characterized by sensory neuropathy, and/or hearing loss, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.

If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance – exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis. Note: To date such variants have not been identified as a cause of DNMT1-related disorder.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in DNMT1-Related Disorder

Gene ¹	Method	Proportion of Probands with a Pathogenic Variant ² Detectable by Method
DNMT1	Sequence analysis ³	100% of variants reported to date ⁴
DNMT1	Gene-targeted deletion/duplication analysis ⁵	Unknown ⁶

1.: See Table A. Genes and Databases for chromosome locus and protein.
2.: See Molecular Genetics for information on allelic variants detected in this gene.
3.: Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
4.: Klein et al [2011], Winkelmann et al [2012], Baets et al [2015]
5.: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
6.: No data on detection rate of gene-targeted deletion/duplication analysis are available.

Clinical Characteristics

Clinical Description

DNMT1-related disorder is a degenerative disorder of the central and peripheral nervous systems characterized by sensory impairment, sudomotor dysfunction (loss of sweating), dementia, and sensorineural hearing loss. In some patients, late-onset narcolepsy/cataplexy syndrome presents as the prominent manifestation along with: ataxia that appears to be cerebellar in nature, deafness, sensory neuropathy, and memory loss [Klein et al 2011, Winkelmann et al 2012]. Affected persons are normal in their youth but begin to manifest progressive findings, such as sensorineural hearing loss, sensory neuropathy, and/or narcolepsy/cataplexy, by their late teens or early 20s.

In a cohort of 45 affected individuals, the average age of onset was estimated to be 37.7 years; the most common initial manifestation was hearing loss (36%), followed by sensory loss, ulcerations and/or arthropathy (33%), cognitive decline (7%), and gait imbalance (7%). It is likely that the range of phenotypes will expand as more affected individuals are identified [Baets et al 2015].

Sensory impairment, which can manifest as early as the second decade of life starting with loss of sensation leading to painless extremity injuries, is associated with hyporeflexia. Sensory impairment predominantly affects the distal lower extremities with minimal to no motor involvement. The sensory alterations are associated with gait unsteadiness and mutilating acropathy with ulcers and/or amputations of distal extremities in approximately 50% of affected persons.

Autonomic dysfunction is limited to loss of sweating (sudomotor) on the distal aspects of the upper and lower limbs.

Dementia manifests as progressive cognitive, executive function, and behavioral decline usually by the fourth decade. Behavior changes including anger and change in personality may precede decline in memory. Memory loss, apathy, indifference, inattention, and somnolence have all been described [Wright & Dyck 1995, Hojo et al 1999]. Irritability, delusions, and delirium are also reported.

Moderate-to-severe sensorineural hearing loss (i.e., 70- to 80-db loss at 4,000 Hz) typically begins in the teens or early 20s.

Gait ataxia is common and is usually the result of sensory loss in the feet, but rarely may be cerebellar ataxia.

Narcolepsy/cataplexy syndrome sometimes presents as the prominent manifestation.

Other clinical findings observed on occasion include visual hallucinations, myoclonic seizures, and renal failure.

Other findings

PET and SPECT imaging have been used to show medial frontal and thalamic hypometabolism.
Sural nerve biopsy shows marked loss of myelinated fibers without onion bulb change.
Brain neuropathology at autopsy has shown diffuse neuronal loss without distinctive histologic features and no amyloid, tau, or α-synuclein inclusions [Klein et al 2011].

Genotype-Phenotype Correlations

All pathogenic variants that cause DNMT1-related disorder are located in the targeting sequence (TS) domain of the DNMT1 protein (see Molecular Genetics, Normal gene product).

Variants resulting in the HSAN1E phenotype (a predominantly sensory neuropathy) are in the N-terminus or middle part of the TS domain [Baets et al 2015].
Variants that cause autosomal dominant cerebellar ataxia, deafness and narcolepsy are located in the C-terminus of the TS domain [Baets et al 2015].

Penetrance

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

Nomenclature

This GeneReview, formerly titled "DNMT1-related dementia, deafness, and sensory neuropathy," was renamed "DMNT1-related disorder" to reflect the broader phenotypic spectrum now known to be associated with pathogenic variants in DNMT1.

Hereditary sensory and autonomic neuropathy type IE (HSAN1E) is considered a sensory-predominant neuropathy.

Prevalence

To date, a total of 21 families with DNMT1 disorder have been reported.

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.

Management

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.

Because behavioral changes and the loss of insight and judgment in individuals often present a considerable burden for partners or other caregivers, information about the disease and psychological support for partners or other caregivers are essential.

Surveillance

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.

Agents/Circumstances to Avoid

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

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

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.