Hereditary sensory neuropathy type IE is an autosomal dominant neurodegenerative disorder characterized by adult onset of progressive peripheral sensory loss associated with progressive hearing impairment and early-onset dementia (summary by Klein et al., 2011).
For a ... Hereditary sensory neuropathy type IE is an autosomal dominant neurodegenerative disorder characterized by adult onset of progressive peripheral sensory loss associated with progressive hearing impairment and early-onset dementia (summary by Klein et al., 2011). For a discussion of genetic heterogeneity of HSN, see HSAN1A (162400).
Wright and Dyck (1995) reported a 7-generation kindred with autosomal dominant inheritance of sensory neuropathy with sensorineural hearing loss and early-onset dementia. The neurologic deficits began between the second and fourth decades and were progressive, with death occurring ... Wright and Dyck (1995) reported a 7-generation kindred with autosomal dominant inheritance of sensory neuropathy with sensorineural hearing loss and early-onset dementia. The neurologic deficits began between the second and fourth decades and were progressive, with death occurring in the fifth and sixth decades. The proband was a 42-year-old man with onset of distal sensory impairment primarily affecting the lower limbs in his early thirties followed by progressive memory and hearing impairment in his late thirties. There were no autonomic or motor symptoms. Physical studies showed severe peripheral sensorineural neuropathy with absent sensory nerve action potentials and moderate to severe hearing loss; brain imaging showed mild diffuse cerebral atrophy. Sural nerve biopsy showed almost complete absence of myelinated fibers of all sizes, without onion bulb formation or regenerating clusters. There were reduced numbers of unmyelinated fibers. Wright and Dyck (1995) classified the disorder as a subtype of HSAN type I. Hojo et al. (1999) reported 3 Japanese sibs with onset of peripheral sensory neuropathy affecting all modalities in young adulthood, followed by hearing loss and progressive frontal dementia in the later thirties and forties. The neuropathy resulted in ulceration of the feet necessitating amputation of the toes in all patients. Two patients reported lancinating pains. Sural nerve biopsy showed almost complete loss of myelinated fibers with moderate loss of unmyelinated fibers. The dementia was characterized by memory loss, irritability, apathy, impulsivity, delusions, somnolence, and decreased speech output. Functional imaging of 2 patients showed frontal and thalamic hypometabolism, and brain imaging of 1 showed frontal atrophy. Their affected mother had died in the fifth decade with painless foot ulcers and dementia. Cerebellar and autonomic dysfunction were not present. Klein et al. (2011) reported 2 additional families with HSN1E. Affected individuals were healthy in their youth, but developed worsening sensorineural deafness and sensory neuropathy by the age of 20 to 35 years. Progressive cognitive and behavioral declines developed by the fourth decade. Brain imaging of the affected persons showed global atrophy, and there was reduced weight of the autopsied brains. Quantitative sensory testing, nerve conductions, and nerve biopsy were indicative of length-dependent progressive sensory axonal loss. Neuropathologic examination of 1 patient who died at age 48 years showed ascending spinal sensory tract degeneration with myelin and axonal loss involving the gracile fasciculus in the posterior columns at all spinal levels. There was also generalized cerebral atrophy, chronic cerebellar Purkinje cell swelling and axonal loss, and severe neuronal loss and gliosis of the inferior olivary nucleus.
By linkage analysis followed by exome sequencing, Klein et al. (2011) identified 2 different heterozygous mutations in the DNMT1 gene (126375.0001 and 126375.0002) in 4 unrelated families with autosomal dominant inheritance of hereditary sensory neuropathy type IE. Two ... By linkage analysis followed by exome sequencing, Klein et al. (2011) identified 2 different heterozygous mutations in the DNMT1 gene (126375.0001 and 126375.0002) in 4 unrelated families with autosomal dominant inheritance of hereditary sensory neuropathy type IE. Two of the families had been reported by Wright and Dyck (1995) and Hojo et al. (1999). In vitro functional expression studies in E. coli and HeLa cells showed that the mutations affected proper folding of DNMT1 and resulted in premature degradation, reduced methyltransferase activity, and impaired heterochromatin binding during the G2 cell cycle phase, leading to global hypomethylation and site-specific hypermethylation. These changes indicated epigenetic dysregulation. The results provided a direct link between DNMT1 defects and a neurodegenerative disorder affecting both the central and peripheral nervous systems, and suggested that DNMT1 participates in a precise mechanism of dynamic regulation of neuronal survival.
The diagnosis of DNMT1-related dementia, deafness, and sensory neuropathy (HSAN IE) is established in individuals with the following: ...
DiagnosisClinical Diagnosis The diagnosis of DNMT1-related dementia, deafness, and sensory neuropathy (HSAN IE) is established in individuals with the following: Sensory impairment, which 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. The face and trunk are characteristically spared.Autonomic dysfunction, manifest as loss of sweating (sudomotor abnormalities). Laboratory-based tests such as tilt table testing for postural hypotension, quantitative sudomotor axon reflex testing (QSART), and thermoregulatory sweat testing (TST) 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 HSAN IE pan sensory neuropathy affects large proprioceptive and vibratory sensing fibers as well as small heat-, pain-, and temperature-sensing fibers.Dementia. Progressive decline in cognition and behavior is usually the first manifestations of dementia. 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. Brain imaging of affected persons can also help to determine the existence of global atrophy without intraparenchymal signal change.Moderate to severe sensorineural hearing loss (i.e., 70- to 80-db loss at 4000 Hz) beginning in the teens or early 20sMolecular Genetic Testing Gene. DNMT1 is the only gene in which mutations are known to cause DNMT1-related dementia, deafness, and sensory neuropathy.Table 1. Summary of Molecular Genetic Testing Used in DNMT1-Related Dementia, Deafness, and Sensory NeuropathyView in own windowGene SymbolTest MethodMutations Detected Mutation Detection Frequency by Test Method 1Test AvailabilityDNMT1Targeted mutation analysisc. 1484A>G c.1470_1472delTCCinsATA c.1483T>C100% for the targeted variant 2Research onlySequence analysisSequence variants including the 3 known pathologic variants above 3100%Clinical1. The ability of the test method used to detect a mutation that is present in the indicated gene2. In 6/6 families identified to date, all affected family members had a heterozygous mutation in the targeting sequence domain of DNMT1. See Molecular Genetics. 3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole gene deletions/duplications are not detected.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (Table A. Genes and Databases and/or Pathologic allelic variants).Testing Strategy To confirm/establish the diagnosis in a probandPerform targeted mutation analysis if clinical examination reveals: Young adult-onset hearing lossFoot ulcersLoss of sensation in the feetDepressed tendon reflexes in the lower limbsSigns of memory loss or abnormal behaviorIf no mutation is detected, sequence analysis of the coding region and related intron junctions of DNMT1 may be performed. Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) Disorders No other phenotypes are known to be associated with mutations in DNMT1.
DNMT1-related dementia, deafness, and sensory neuropathy (HSAN IE) 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 [Klein et al 2011]. Affected persons are normal in their youth but begin to manifest progressive sensorineural deafness and sensory neuropathy by age 20 to 35 years....
Natural HistoryDNMT1-related dementia, deafness, and sensory neuropathy (HSAN IE) 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 [Klein et al 2011]. Affected persons are normal in their youth but begin to manifest progressive sensorineural deafness and sensory neuropathy by age 20 to 35 years.Winkelmann et al [2012] have reported four families with mutations in DNMT1 associated with early onset (18-44 years) of a narcolepsy/cataplexy syndrome followed by ataxia, deafness, sensory neuropathy and memory loss. The ataxia appeared to be cerebellar in nature.Sensory impairment can manifest as early as the second decade of life, starting with loss of sensation leading to painless extremity injuries, and is associated with hyporeflexia. The disease predominantly affects the distal lower extremities with minimal to no motor involvement. The sensory alterations are associated with gait unsteadiness from sensory ataxia and mutilating acropathy with ulcers and/or amputations of distal extremities in approximately 50% of affected persons. Autonomic dysfunction that 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 4000 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. 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. 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].
Autosomal dominant hereditary sensory and autonomic neuropathies are genetically heterogeneous, but hereditary sensory and autonomic neuropathy type IE (HSAN IE) that includes dementia and hearing loss represents a unique phenotype. See Table 2. ...
Differential DiagnosisAutosomal dominant hereditary sensory and autonomic neuropathies are genetically heterogeneous, but hereditary sensory and autonomic neuropathy type IE (HSAN IE) that includes dementia and hearing loss represents a unique phenotype. See Table 2. Table 2. Hereditary Sensory and Autonomic Neuropathies (HSAN)View in own windowHSAN TypePhenotypePhenotype OMIM NumberGene SymbolGene OMIM NumberHSANIAHSAN IA162400SPTLC1605712HSNIBHSN IB608088NA608088HSANICHSAN IC613640SPTLC2605713HSNIDHSN ID613708ATL1606439HSNIEHSAN IE 614116DNMT1126375HSANIIAHSAN II201300WNK1605232HSANIIB613115FAM134B613114HSNIIC614213KIF1A601255HSANIIIFamilial dysautonomia223900IKBKAP603722HSANIVHSAN IV256800NTRK1191315HSANVHSAN V608654NGF162030HSAN = hereditary sensory and autonomic neuropathyNA= not applicableData from www.omim.org/phenotypicSeries/162400The combination of neuropathy with hearing loss can be confused with some forms of Charcot-Marie-Tooth (CMT) and the dementia is similar to that found in frontotemporal dementia (FTD) 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.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease and needs of an individual diagnosed with DNMT1-related dementia, deafness, and sensory neuropathy (HSAN IE), the following evaluations are recommended:...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with DNMT1-related dementia, deafness, and sensory neuropathy (HSAN IE), the following evaluations are recommended:Neurologic examination to determine the extent of sensory involvement, including sensory testing and observation for skin ulcerationPast medical history to determine extent of autonomic involvementEvaluation of central nervous system involvement, using tests of cognitive function and brain imagingAudiologic examination to determine if hearing loss is present and, if present, its type and severityMedical genetics consultationTreatment of ManifestationsCurrently no effective treatment exists for any type of HSAN. The emphasis of management is to help parents and affected individuals 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 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.Prevention of Secondary ComplicationsTo prevent injury to extremities with decreased sensation, protect the skin with appropriate socks and shoes and avoid exposure of feet to hot water. SurveillanceSensory impairment. Examine feet on a daily basis to screen for skin injury.Dementia. Perform annual routine clinical testing for dementia:Observation of behaviorUse of tools such as the Mini Mental State Exam (MMSE)Hearing loss. Perform annual audiogram.Agents/Circumstances to AvoidAvoid sharp objects and hot water, which may damage skin.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials,gov for access to information on clinical studies for a wide range of diseases and conditions.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. DNMT1-Related Dementia, Deafness, and Sensory Neuropathy: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDDNMT119p13.2DNA (cytosine-5)-methyltransferase 1DNMT1 @ LOVDDNMT1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for DNMT1-Related Dementia, Deafness, and Sensory Neuropathy (View All in OMIM) View in own window 126375DNA METHYLTRANSFERASE 1; DNMT1 614116NEUROPATHY, HEREDITARY SENSORY, TYPE IE; HSN1EMolecular Genetic Pathogenesis DNMT1 maintains patterns of methylated cytosine residues in the mammalian genome. Studies of individuals with DNMT1-related dementia, deafness, and sensory neuropathy (HSAN IE) have provided a direct link between DNMT1 defects and a neurodegenerative disorder affecting both the central and peripheral nervous systems, and suggest that DNMT1 participates in a precise mechanism of dynamic regulation of neuronal survival [Klein et al 2011].Normal allelic variants. Two transcript variants encoding different isoforms have been found for this gene [provided by RefSeq, Aug 2008]. The transcript variant NM_001379.2 (Table 3) comprises 40 coding exons, numbered 1-41 but without exon 5. Pathologic allelic variants. In 6/6 families identified to date, all affected family members had a heterozygous mutation in the targeting sequence domain of DNMT1. The mutations identified are listed in Table 3.Table 3. Selected DNMT1 Pathologic Allelic Variants View in own windowDNA Nucleotide Change (Alias 1) Protein Amino Acid Change (Alias 1)Reference Sequencesc.1484A>Gp.Tyr495CysNM_001379.2 NP_001370.1c.1470_1472delTCCinsATA (1470TCC-1472ATA)p.Asp490_Pro491delinsGluTyr (D490E-P491Y)c.1483T>Cp.Tyr495HisSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 1. Variant designation that does not conform to current naming conventionsNormal gene product. NP_001370.1 encodes a DNA (cytosine-5)-methyltransferase 1 with 1616 amino acids. This isoform has the same N- and C-termini but is shorter than the isoform NP_001124295.1, which has 1632 amino acids. The mutations occurred in the targeting-sequence domain of the protein, the N-terminal regulatory region shown to be an important factor for the structure, function, and localization of DNA (cytosine-5)-methyltransferase 1 required for enzymatic function; see Klein et al [2011] for domain structure.Abnormal gene product. Expression of either mutated DNMT1 expressing p.Tyr495Cys or p.Asp490_Pro491delinsGluTyr showed misfolded DNA (cytosine-5)-methyltransferase 1 and resulted in premature protein degradation, reduced methyltransferase activity, and impaired heterochromatin binding during the G2 cell cycle phase. The pathogenic mechanism of mutant DNMT1 is potentially complex and provides a new direction for the study of neurodegeneration. DNMT1 is highly expressed in postmitotic neurons and the adult central nervous system. It interacts with a series of important cell cycle-regulating proteins and is likely involved in neuronal differentiation and migration and neural connection [Spada et al 2006]. It remains to be determined how DNMT1 participates in a precise mechanism of dynamic regulation of the nervous system.