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Hereditary sensory neuropathy-deafness-dementia syndrome(HSN1E)

MedGen UID:
481515
Concept ID:
C3279885
Disease or Syndrome
Synonyms: DNMT1-Related Dementia, Deafness, and Sensory Neuropathy; Hereditary sensory neuropathy type IE; HSN IE; NEUROPATHY, HEREDITARY SENSORY, WITH HEARING LOSS AND DEMENTIA
SNOMED CT: Hereditary sensory autonomic neuropathy type IE (860812002)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): DNMT1 (19p13.2)
 
Monarch Initiative: MONDO:0013584
OMIM®: 614116
Orphanet: ORPHA456318

Definition

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. [from GeneReviews]

Additional descriptions

From OMIM
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).  http://www.omim.org/entry/614116
From MedlinePlus Genetics
Hereditary sensory and autonomic neuropathy type IE (HSAN IE) is a disorder that affects the nervous system. It is characterized by three main features: hearing loss, a decline of intellectual function (dementia), and a worsening loss of sensation in the feet and legs (peripheral neuropathy).

People with HSAN IE develop hearing loss that is caused by abnormalities in the inner ear (sensorineural hearing loss). The hearing loss, which affects both ears, gets worse over time and usually progresses to moderate or severe deafness between the ages of 20 and 35.

Affected individuals experience dementia typically beginning in their thirties. In some people with HSAN IE, changes in personality, such as irritability, apathy, or lack of impulse control, become apparent before problems with thinking skills.

Peripheral neuropathy is caused by impaired function of nerve cells called sensory neurons, which transmit information about sensations such as pain, temperature, and touch. Loss of sensation in the feet and legs, which usually begins in adolescence or early adulthood in people with HSAN IE and worsens over time, can cause difficulty walking. Affected individuals may not be aware of injuries to their feet, which can lead to complications such as open sores and infections. If these complications are severe, amputation of the affected areas may be required.

Some people with HSAN IE also experience recurrent seizures (epilepsy) and sleep problems. The severity of the signs and symptoms of HSAN IE and their age of onset are variable, even among affected members of the same family.  https://medlineplus.gov/genetics/condition/hereditary-sensory-and-autonomic-neuropathy-type-ie

Clinical features

From HPO
Sensorineural hearing loss disorder
MedGen UID:
9164
Concept ID:
C0018784
Disease or Syndrome
A type of hearing impairment in one or both ears related to an abnormal functionality of the cochlear nerve.
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Delirium
MedGen UID:
41445
Concept ID:
C0011206
Mental or Behavioral Dysfunction
A state of sudden and severe confusion.
Impulsivity
MedGen UID:
43850
Concept ID:
C0021125
Mental or Behavioral Dysfunction
Acting on the spur of the moment or on a momentary basis without consideration of outcomes; having difficulty establishing or following plans; experiencing a sense of urgency and engaging in behavior that is uninhibited, cannot be inhibited, and is uncontrolled. The possibility of repression is inconceivable.
Apathy
MedGen UID:
39083
Concept ID:
C0085632
Mental or Behavioral Dysfunction
Apathy is a quantitative reduction of interest, motivation and the initiation and persistence of goal-directed behavior, where often the accompanying emotions, thoughts, and social interactions are also diminished. The individual is typically non-reactive to provocations, positive or negative, and appears to not care. Distinguished from lethargy which involves lack of physical or mental energy.
Sensory neuropathy
MedGen UID:
101791
Concept ID:
C0151313
Disease or Syndrome
Peripheral neuropathy affecting the sensory nerves.
Memory impairment
MedGen UID:
68579
Concept ID:
C0233794
Mental or Behavioral Dysfunction
An impairment of memory as manifested by a reduced ability to remember things such as dates and names, and increased forgetfulness.
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Dementia
MedGen UID:
99229
Concept ID:
C0497327
Mental or Behavioral Dysfunction
A loss of global cognitive ability of sufficient amount to interfere with normal social or occupational function. Dementia represents a loss of previously present cognitive abilities, generally in adults, and can affect memory, thinking, language, judgment, and behavior.
Hyporeflexia
MedGen UID:
195967
Concept ID:
C0700078
Finding
Reduction of neurologic reflexes such as the knee-jerk reaction.
Decreased number of peripheral myelinated nerve fibers
MedGen UID:
346872
Concept ID:
C1858285
Finding
A loss of myelinated nerve fibers in the peripheral nervous system (in general, this finding can be observed on nerve biopsy).
Irritability
MedGen UID:
397841
Concept ID:
C2700617
Mental Process
A proneness to anger, i.e., a tendency to become easily bothered or annoyed.
Excessive daytime somnolence
MedGen UID:
1635612
Concept ID:
C4551761
Sign or Symptom
A state of abnormally strong desire for sleep during the daytime.
Distal muscle weakness
MedGen UID:
140883
Concept ID:
C0427065
Finding
Reduced strength of the musculature of the distal extremities.
Osteomyelitis
MedGen UID:
10497
Concept ID:
C0029443
Disease or Syndrome
Osteomyelitis is an inflammatory process accompanied by bone destruction and caused by an infecting microorganism.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVHereditary sensory neuropathy-deafness-dementia syndrome

Professional guidelines

PubMed

Adams D, Ando Y, Beirão JM, Coelho T, Gertz MA, Gillmore JD, Hawkins PN, Lousada I, Suhr OB, Merlini G
J Neurol 2021 Jun;268(6):2109-2122. Epub 2020 Jan 6 doi: 10.1007/s00415-019-09688-0. PMID: 31907599Free PMC Article
Kazachkov M, Palma JA, Norcliffe-Kaufmann L, Bar-Aluma BE, Spalink CL, Barnes EP, Amoroso NE, Balou SM, Bess S, Chopra A, Condos R, Efrati O, Fitzgerald K, Fridman D, Goldenberg RM, Goldhaber A, Kaufman DA, Kothare SV, Levine J, Levy J, Lubinsky AS, Maayan C, Moy LC, Rivera PJ, Rodriguez AJ, Sokol G, Sloane MF, Tan T, Kaufmann H
Respir Med 2018 Aug;141:37-46. Epub 2018 Jun 21 doi: 10.1016/j.rmed.2018.06.017. PMID: 30053970Free PMC Article
Lee AS, Gibbon FE
Cochrane Database Syst Rev 2015 Mar 25;2015(3):CD009383. doi: 10.1002/14651858.CD009383.pub2. PMID: 25805060Free PMC Article

Recent clinical studies

Etiology

McConnachie DJ, Stow JL, Mallett AJ
Am J Kidney Dis 2021 Mar;77(3):410-419. Epub 2020 Oct 9 doi: 10.1053/j.ajkd.2020.08.012. PMID: 33039432
Lee AS, Gibbon FE
Cochrane Database Syst Rev 2015 Mar 25;2015(3):CD009383. doi: 10.1002/14651858.CD009383.pub2. PMID: 25805060Free PMC Article
Fink JK
Acta Neuropathol 2013 Sep;126(3):307-28. Epub 2013 Jul 30 doi: 10.1007/s00401-013-1115-8. PMID: 23897027Free PMC Article
Axelrod FB, Hilz MJ
Semin Neurol 2003 Dec;23(4):381-90. doi: 10.1055/s-2004-817722. PMID: 15088259
Chance PF, Reilly M
Curr Opin Neurol 1994 Oct;7(5):372-80. doi: 10.1097/00019052-199410000-00002. PMID: 7804455

Diagnosis

Hayes LH, Sadjadi R
Continuum (Minneap Minn) 2023 Oct 1;29(5):1514-1537. doi: 10.1212/CON.0000000000001339. PMID: 37851041
Fink JK
Continuum (Minneap Minn) 2021 Feb 1;27(1):185-204. doi: 10.1212/CON.0000000000000934. PMID: 33522742
Finsterer J, Löscher WN, Wanschitz J, Iglseder S
J Neuromuscul Dis 2021;8(1):1-23. doi: 10.3233/JND-200518. PMID: 32986679Free PMC Article
Adams D, Ando Y, Beirão JM, Coelho T, Gertz MA, Gillmore JD, Hawkins PN, Lousada I, Suhr OB, Merlini G
J Neurol 2021 Jun;268(6):2109-2122. Epub 2020 Jan 6 doi: 10.1007/s00415-019-09688-0. PMID: 31907599Free PMC Article
Gwathmey KG
Muscle Nerve 2016 Jan;53(1):8-19. Epub 2015 Nov 23 doi: 10.1002/mus.24943. PMID: 26467754

Therapy

Smith AG, Singleton JR, Aperghis A, Coffey CS, Creigh P, Cudkowicz M, Conwit R, Ecklund D, Fedler JK, Gudjonsdottir A, Hauer P, Herrmann DN, Kearney M, Kissel J, Klingner E, Quick A, Revere C, Stino A; NeuroNEXT NN108 TopCSPN Study Team
JAMA Neurol 2023 Dec 1;80(12):1334-1343. doi: 10.1001/jamaneurol.2023.3711. PMID: 37870862Free PMC Article
Yang H, Brown RH Jr, Wang D, Strauss KA, Gao G
Trends Mol Med 2021 Jun;27(6):520-523. Epub 2021 Mar 10 doi: 10.1016/j.molmed.2021.02.004. PMID: 33714697Free PMC Article
Gess B, Baets J, De Jonghe P, Reilly MM, Pareyson D, Young P
Cochrane Database Syst Rev 2015 Dec 11;2015(12):CD011952. doi: 10.1002/14651858.CD011952. PMID: 26662471Free PMC Article
Lee AS, Gibbon FE
Cochrane Database Syst Rev 2015 Mar 25;2015(3):CD009383. doi: 10.1002/14651858.CD009383.pub2. PMID: 25805060Free PMC Article
Møller LB
J Trace Elem Med Biol 2015;31:173-7. Epub 2014 Aug 8 doi: 10.1016/j.jtemb.2014.07.022. PMID: 25172213

Prognosis

Hayes LH, Sadjadi R
Continuum (Minneap Minn) 2023 Oct 1;29(5):1514-1537. doi: 10.1212/CON.0000000000001339. PMID: 37851041
Poggio E, Barazzuol L, Salmaso A, Milani C, Deligiannopoulou A, Cazorla ÁG, Jang SS, Juliá-Palacios N, Keren B, Kopajtich R, Lynch SA, Mignot C, Moorwood C, Neuhofer C, Nigro V, Oostra A, Prokisch H, Saillour V, Schuermans N, Torella A, Verloo P, Yazbeck E, Zollino M, Jech R, Winkelmann J, Necpal J, Calì T, Brini M, Zech M
Genet Med 2023 Dec;25(12):100971. Epub 2023 Sep 4 doi: 10.1016/j.gim.2023.100971. PMID: 37675773
Hentati F, Hentati E, Amouri R
Handb Clin Neurol 2013;115:933-8. doi: 10.1016/B978-0-444-52902-2.00052-7. PMID: 23931822
Auer-Grumbach M
Orphanet J Rare Dis 2008 Mar 18;3:7. doi: 10.1186/1750-1172-3-7. PMID: 18348718Free PMC Article
Chance PF, Reilly M
Curr Opin Neurol 1994 Oct;7(5):372-80. doi: 10.1097/00019052-199410000-00002. PMID: 7804455

Clinical prediction guides

Fukami Y, Iijima M, Koike HH, Yagi S, Furukawa S, Mouri N, Ouchida J, Murakami A, Iida M, Yokoi S, Hashizume A, Iguchi Y, Imagama S, Katsuno M
Neurol Neuroimmunol Neuroinflamm 2024 Mar;11(2):e200199. Epub 2024 Jan 5 doi: 10.1212/NXI.0000000000200199. PMID: 38181320Free PMC Article
Smith AG, Singleton JR, Aperghis A, Coffey CS, Creigh P, Cudkowicz M, Conwit R, Ecklund D, Fedler JK, Gudjonsdottir A, Hauer P, Herrmann DN, Kearney M, Kissel J, Klingner E, Quick A, Revere C, Stino A; NeuroNEXT NN108 TopCSPN Study Team
JAMA Neurol 2023 Dec 1;80(12):1334-1343. doi: 10.1001/jamaneurol.2023.3711. PMID: 37870862Free PMC Article
Poggio E, Barazzuol L, Salmaso A, Milani C, Deligiannopoulou A, Cazorla ÁG, Jang SS, Juliá-Palacios N, Keren B, Kopajtich R, Lynch SA, Mignot C, Moorwood C, Neuhofer C, Nigro V, Oostra A, Prokisch H, Saillour V, Schuermans N, Torella A, Verloo P, Yazbeck E, Zollino M, Jech R, Winkelmann J, Necpal J, Calì T, Brini M, Zech M
Genet Med 2023 Dec;25(12):100971. Epub 2023 Sep 4 doi: 10.1016/j.gim.2023.100971. PMID: 37675773
Cavaletti G, Forsey K, Alberti P
J Peripher Nerv Syst 2023 Sep;28(3):295-307. Epub 2023 Jun 5 doi: 10.1111/jns.12566. PMID: 37249082
Auer-Grumbach M
Orphanet J Rare Dis 2008 Mar 18;3:7. doi: 10.1186/1750-1172-3-7. PMID: 18348718Free PMC Article

Recent systematic reviews

Cavaletti G, Forsey K, Alberti P
J Peripher Nerv Syst 2023 Sep;28(3):295-307. Epub 2023 Jun 5 doi: 10.1111/jns.12566. PMID: 37249082
Jennings MJ, Lochmüller A, Atalaia A, Horvath R
J Neuromuscul Dis 2021;8(3):383-400. doi: 10.3233/JND-200546. PMID: 32773395Free PMC Article
Finsterer J, Iglseder S, Wanschitz J, Topakian R, Löscher WN, Grisold W
Acta Neurol Scand 2019 Feb;139(2):92-105. Epub 2018 Oct 23 doi: 10.1111/ane.13035. PMID: 30295933
Kazachkov M, Palma JA, Norcliffe-Kaufmann L, Bar-Aluma BE, Spalink CL, Barnes EP, Amoroso NE, Balou SM, Bess S, Chopra A, Condos R, Efrati O, Fitzgerald K, Fridman D, Goldenberg RM, Goldhaber A, Kaufman DA, Kothare SV, Levine J, Levy J, Lubinsky AS, Maayan C, Moy LC, Rivera PJ, Rodriguez AJ, Sokol G, Sloane MF, Tan T, Kaufmann H
Respir Med 2018 Aug;141:37-46. Epub 2018 Jun 21 doi: 10.1016/j.rmed.2018.06.017. PMID: 30053970Free PMC Article
Lee AS, Gibbon FE
Cochrane Database Syst Rev 2015 Mar 25;2015(3):CD009383. doi: 10.1002/14651858.CD009383.pub2. PMID: 25805060Free PMC Article

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