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Neuronal intranuclear inclusion disease(NIID)

MedGen UID:
355075
Concept ID:
C1863843
Disease or Syndrome
Synonym: NIID
SNOMED CT: Neuronal intranuclear inclusion disease (715437003)
 
Gene (location): NOTCH2NLC (1q21.2)
 
Monarch Initiative: MONDO:0011327
OMIM®: 603472
Orphanet: ORPHA2289

Definition

Neuronal intranuclear inclusion disease (NIID) is an autosomal dominant, slowly progressive neurodegenerative disorder characterized by a wide range of clinical manifestations, including pyramidal and extrapyramidal symptoms, cerebellar ataxia, cognitive decline and dementia, peripheral neuropathy, and autonomic dysfunction. The age at onset varies, but most individuals present as adults between about 30 and 70 years of age. Pathologic investigation shows eosinophilic intranuclear inclusions in almost all cell types, including neurons, skin cells, fibroblasts, and skeletal muscle. Brain imaging shows a characteristic leukoencephalopathy with high intensity signals in the corticomedullary junction on diffusion-weighted imaging (DWI), as well as white matter abnormalities in subcortical and brainstem regions. Skin biopsy combined with brain imaging is useful for diagnosis (summary by Sone et al., 2016). The phenotype in some cases is suggestive of Parkinson disease (see 168600) and/or Alzheimer disease (see 104300), consistent with an evolving phenotypic spectrum of adult-onset NIID (summary by Tian et al., 2019). [from OMIM]

Clinical features

From HPO
Urinary incontinence
MedGen UID:
22579
Concept ID:
C0042024
Finding
Loss of the ability to control the urinary bladder leading to involuntary urination.
Syncope
MedGen UID:
21443
Concept ID:
C0039070
Sign or Symptom
Syncope is a syndrome in which loss of consciousness is of relatively sudden onset, temporary (usually less than 1 to 2 minutes), self-terminating, and of usually rapid recovery. Syncope leads to a generalized weakness of muscles with loss of postural tone, inability to stand upright, and loss of consciousness. Once the patient is in a horizontal position, blood flow to the brain is no longer hindered by gravitation and consciousness is regained. Unconsciousness usually lasts for seconds to minutes. Headache and drowsiness (which usually follow seizures) do not follow a syncopal attack. Syncope results from a sudden impairment of brain metabolism usually due to a reduction in cerebral blood flow.
Episodic vomiting
MedGen UID:
333228
Concept ID:
C1838993
Finding
Paroxysmal, recurrent episodes of vomiting.
Atypical behavior
MedGen UID:
14048
Concept ID:
C0004941
Sign or Symptom
Atypical behavior is an abnormality in a person's actions that can be controlled or modulated by the will of the individual. While abnormal behaviors can be difficult to control, they are distinct from other abnormal actions that cannot be affected by the individual's will.
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).
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Tremor
MedGen UID:
21635
Concept ID:
C0040822
Sign or Symptom
An unintentional, oscillating to-and-fro muscle movement about a joint axis.
Loss of consciousness
MedGen UID:
52915
Concept ID:
C0041657
Finding
Loss of alertness and orientation to place and time.
CSF pleocytosis
MedGen UID:
56247
Concept ID:
C0151857
Disease or Syndrome
An increased white blood cell count in the cerebrospinal fluid.
Leukoencephalopathy
MedGen UID:
78722
Concept ID:
C0270612
Disease or Syndrome
This term describes abnormality of the white matter of the cerebrum resulting from damage to the myelin sheaths of nerve cells.
Cognitive impairment
MedGen UID:
90932
Concept ID:
C0338656
Mental or Behavioral Dysfunction
Abnormal cognition is characterized by deficits in thinking, reasoning, or remembering.
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.
Gait disturbance
MedGen UID:
107895
Concept ID:
C0575081
Finding
The term gait disturbance can refer to any disruption of the ability to walk.
Hyporeflexia
MedGen UID:
195967
Concept ID:
C0700078
Finding
Reduction of neurologic reflexes such as the knee-jerk reaction.
Increased CSF protein concentration
MedGen UID:
329971
Concept ID:
C1806780
Finding
Increased concentration of protein in the cerebrospinal fluid.
Decreased sensory nerve conduction velocity
MedGen UID:
336512
Concept ID:
C1849148
Finding
Reduced speed of conduction of the action potential along a sensory nerve.
Decreased motor nerve conduction velocity
MedGen UID:
388130
Concept ID:
C1858729
Finding
A type of decreased nerve conduction velocity that affects the motor neuron.
Ventriculomegaly
MedGen UID:
480553
Concept ID:
C3278923
Finding
An increase in size of the ventricular system of the brain.
Somatic sensory dysfunction
MedGen UID:
1790456
Concept ID:
C5551413
Finding
An abnormality of the primary sensation that is mediated by peripheral nerves (pain, temperature, touch, vibration, joint position). The word hypoesthesia (or hypesthesia) refers to a reduction in cutaneous sensation to a specific type of testing.
Rigidity
MedGen UID:
7752
Concept ID:
C0026837
Sign or Symptom
Continuous involuntary sustained muscle contraction. When an affected muscle is passively stretched, the degree of resistance remains constant regardless of the rate at which the muscle is stretched. This feature helps to distinguish rigidity from muscle spasticity.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
Reduced strength of muscles.
EMG: decremental response of compound muscle action potential to repetitive nerve stimulation
MedGen UID:
892749
Concept ID:
C4021728
Finding
A compound muscle action potential (CMAP) is a type of electromyography (EMG). CMAP refers to a group of almost simultaneous action potentials from several muscle fibers in the same area evoked by stimulation of the supplying motor nerve and are recorded as one multipeaked summated action potential. This abnormality refers to a greater than normal decrease in the amplitude during the course of the investigation.
Miosis
MedGen UID:
6409
Concept ID:
C0026205
Disease or Syndrome
Abnormal (non-physiological) constriction of the pupil.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVNeuronal intranuclear inclusion disease
Follow this link to review classifications for Neuronal intranuclear inclusion disease in Orphanet.

Professional guidelines

PubMed

Fan Y, Xu Y, Shi C
J Med Genet 2022 Jan;59(1):1-9. Epub 2021 Oct 21 doi: 10.1136/jmedgenet-2021-107883. PMID: 34675123
Koh J, Ito H
Nihon Rinsho 2017 Jan;75(1):56-62. PMID: 30566295

Recent clinical studies

Etiology

Zhang Z, Xu Q, Li J, Zhang C, Bai Z, Chai X, Xu K, Xiao C, Chen F, Liu T, Gu H, Xing W, Lu G, Zhang Z
J Neuroradiol 2024 May;51(3):274-280. Epub 2023 Sep 25 doi: 10.1016/j.neurad.2023.09.004. PMID: 37758172
Yan Y, Cao L, Gu L, Xu C, Fang W, Tian J, Yin X, Zhang B, Zhao G
Neurol Sci 2023 Sep;44(9):3189-3197. Epub 2023 Apr 26 doi: 10.1007/s10072-023-06822-9. PMID: 37099235
Tian Y, Zhou L, Gao J, Jiao B, Zhang S, Xiao Q, Xue J, Wang Y, Liang H, Liu Y, Ji G, Mao C, Liu C, Dong L, Zhang L, Zhang S, Yi J, Zhao G, Luo Y, Sun Q, Zhou Y, Yi F, Chen X, Zhou C, Xie N, Luo M, Yao L, Hu Y, Zhang M, Zeng Q, Fang L, Long HY, Xie Y, Weng L, Chen S, Du J, Xu Q, Feng L, Huang Q, Hou X, Wang J, Xie B, Zhou L, Long L, Guo JF, Wang J, Yan X, Jiang H, Xu H, Duan R, Tang B, Shen L
J Neurol Neurosurg Psychiatry 2022 Dec;93(12):1289-1298. Epub 2022 Sep 23 doi: 10.1136/jnnp-2022-329772. PMID: 36150844Free PMC Article
Zhou ZD, Jankovic J, Ashizawa T, Tan EK
Nat Rev Neurol 2022 Mar;18(3):145-157. Epub 2022 Jan 12 doi: 10.1038/s41582-021-00612-7. PMID: 35022573
Sone J, Mori K, Inagaki T, Katsumata R, Takagi S, Yokoi S, Araki K, Kato T, Nakamura T, Koike H, Takashima H, Hashiguchi A, Kohno Y, Kurashige T, Kuriyama M, Takiyama Y, Tsuchiya M, Kitagawa N, Kawamoto M, Yoshimura H, Suto Y, Nakayasu H, Uehara N, Sugiyama H, Takahashi M, Kokubun N, Konno T, Katsuno M, Tanaka F, Iwasaki Y, Yoshida M, Sobue G
Brain 2016 Dec;139(Pt 12):3170-3186. Epub 2016 Oct 25 doi: 10.1093/brain/aww249. PMID: 27797808Free PMC Article

Diagnosis

Ren X, Tan D, Deng J, Wang Z, Hong D
J Dermatol 2023 Nov;50(11):1367-1372. Epub 2023 Sep 18 doi: 10.1111/1346-8138.16966. PMID: 37718652
Kwan JR, Moy WL, Narasimhalu K, Yong KP
Pract Neurol 2023 Jun;23(3):246-248. Epub 2023 Feb 20 doi: 10.1136/pn-2022-003582. PMID: 36808080
Chintalaphani SR, Pineda SS, Deveson IW, Kumar KR
Acta Neuropathol Commun 2021 May 25;9(1):98. doi: 10.1186/s40478-021-01201-x. PMID: 34034831Free PMC Article
Lu X, Hong D
J Neural Transm (Vienna) 2021 Mar;128(3):295-303. Epub 2021 Feb 18 doi: 10.1007/s00702-021-02313-3. PMID: 33599827
Sone J, Mori K, Inagaki T, Katsumata R, Takagi S, Yokoi S, Araki K, Kato T, Nakamura T, Koike H, Takashima H, Hashiguchi A, Kohno Y, Kurashige T, Kuriyama M, Takiyama Y, Tsuchiya M, Kitagawa N, Kawamoto M, Yoshimura H, Suto Y, Nakayasu H, Uehara N, Sugiyama H, Takahashi M, Kokubun N, Konno T, Katsuno M, Tanaka F, Iwasaki Y, Yoshida M, Sobue G
Brain 2016 Dec;139(Pt 12):3170-3186. Epub 2016 Oct 25 doi: 10.1093/brain/aww249. PMID: 27797808Free PMC Article

Therapy

Yu D, Li J, Tai H, Ma J, Zhang Z, Tang W
J Int Med Res 2024 Mar;52(3):3000605241233159. doi: 10.1177/03000605241233159. PMID: 38436278Free PMC Article
Yadav N, Raja P, Shetty SS, Jitender S, Prasad C, Kamble NL, Mahadevan A, M N
Alzheimer Dis Assoc Disord 2019 Oct-Dec;33(4):359-361. doi: 10.1097/WAD.0000000000000312. PMID: 31094708
Anderson DB, Zanella CA, Henley JM, Cimarosti H
Adv Exp Med Biol 2017;963:261-281. doi: 10.1007/978-3-319-50044-7_16. PMID: 28197918
Lai SC, Jung SM, Grattan-Smith P, Sugo E, Lin YW, Chen RS, Chen CC, Wu-Chou YH, Lang AE, Lu CS
Mov Disord 2010 Jul 15;25(9):1274-9. doi: 10.1002/mds.22876. PMID: 20629123
Palo J, Haltia M, Carpenter S, Karpati G, Mushynski W
Ann Neurol 1984 Apr;15(4):322-8. doi: 10.1002/ana.410150404. PMID: 6331276

Prognosis

Shen Y, Jiang K, Liang H, Xiong Y, Song Z, Wang B, Zhu M, Qiu Y, Tan D, Wu C, Deng J, Wang Z, Hong D
Neurol Sci 2024 Sep;45(9):4501-4511. Epub 2024 Mar 26 doi: 10.1007/s10072-024-07492-x. PMID: 38532189
Wang F, Ma X, Shi Y, Jia L, Zuo X, Yu Y, Jin H, Tang Y, Guo D, Jia J
Neurol Sci 2021 Jun;42(6):2487-2495. Epub 2020 Nov 2 doi: 10.1007/s10072-020-04864-x. PMID: 33140307
Ataka T, Kimura N, Matsubara E
Intern Med 2021 Mar 15;60(6):941-944. Epub 2020 Oct 21 doi: 10.2169/internalmedicine.5743-20. PMID: 33087670Free PMC Article
Vermilion J, Johnson M, Srinivasan J, Mink JW
J Child Neurol 2019 Nov;34(13):801-805. Epub 2019 Jul 15 doi: 10.1177/0883073819860566. PMID: 31304825Free PMC Article
Takahashi-Fujigasaki J, Nakano Y, Uchino A, Murayama S
Geriatr Gerontol Int 2016 Mar;16 Suppl 1:51-6. doi: 10.1111/ggi.12725. PMID: 27018283

Clinical prediction guides

Ren X, Tan D, Deng J, Wang Z, Hong D
J Dermatol 2023 Nov;50(11):1367-1372. Epub 2023 Sep 18 doi: 10.1111/1346-8138.16966. PMID: 37718652
Bao L, Zuo D, Li Q, Chen H, Cui G
Neurol Sci 2023 Jun;44(6):1881-1889. Epub 2023 Feb 16 doi: 10.1007/s10072-023-06677-0. PMID: 36795299
Tian Y, Zhou L, Gao J, Jiao B, Zhang S, Xiao Q, Xue J, Wang Y, Liang H, Liu Y, Ji G, Mao C, Liu C, Dong L, Zhang L, Zhang S, Yi J, Zhao G, Luo Y, Sun Q, Zhou Y, Yi F, Chen X, Zhou C, Xie N, Luo M, Yao L, Hu Y, Zhang M, Zeng Q, Fang L, Long HY, Xie Y, Weng L, Chen S, Du J, Xu Q, Feng L, Huang Q, Hou X, Wang J, Xie B, Zhou L, Long L, Guo JF, Wang J, Yan X, Jiang H, Xu H, Duan R, Tang B, Shen L
J Neurol Neurosurg Psychiatry 2022 Dec;93(12):1289-1298. Epub 2022 Sep 23 doi: 10.1136/jnnp-2022-329772. PMID: 36150844Free PMC Article
Sone J, Mori K, Inagaki T, Katsumata R, Takagi S, Yokoi S, Araki K, Kato T, Nakamura T, Koike H, Takashima H, Hashiguchi A, Kohno Y, Kurashige T, Kuriyama M, Takiyama Y, Tsuchiya M, Kitagawa N, Kawamoto M, Yoshimura H, Suto Y, Nakayasu H, Uehara N, Sugiyama H, Takahashi M, Kokubun N, Konno T, Katsuno M, Tanaka F, Iwasaki Y, Yoshida M, Sobue G
Brain 2016 Dec;139(Pt 12):3170-3186. Epub 2016 Oct 25 doi: 10.1093/brain/aww249. PMID: 27797808Free PMC Article
Takahashi-Fujigasaki J, Nakano Y, Uchino A, Murayama S
Geriatr Gerontol Int 2016 Mar;16 Suppl 1:51-6. doi: 10.1111/ggi.12725. PMID: 27018283

Recent systematic reviews

Wang R, Nie X, Xu S, Zhang M, Dong Z, Yu S
Headache 2020 Feb;60(2):382-395. Epub 2019 Nov 8 doi: 10.1111/head.13687. PMID: 31701545

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