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Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1(CADASIL1)

MedGen UID:
1634330
Concept ID:
C4551768
Disease or Syndrome
Synonyms: Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1; Dementia, hereditary multi-infarct type
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): NOTCH3 (19p13.12)
 
Monarch Initiative: MONDO:0000914
OMIM®: 125310
Orphanet: ORPHA136

Disease characteristics

Excerpted from the GeneReview: CADASIL
CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is characterized by mid-adult onset of recurrent ischemic stroke, cognitive decline progressing to dementia, a history of migraine with aura, mood disturbance, apathy, and diffuse white matter lesions and subcortical infarcts on neuroimaging. [from GeneReviews]
Authors:
Remco J Hack  |  Julie Rutten  |  Saskia AJ Lesnik Oberstein   view full author information

Additional description

From MedlinePlus Genetics
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, usually called CADASIL, is an inherited condition that causes stroke and other impairments. This condition affects blood flow in small blood vessels, particularly cerebral vessels within the brain. The muscle cells surrounding these blood vessels (vascular smooth muscle cells) are abnormal and gradually die. In the brain, the resulting blood vessel damage (arteriopathy) can cause migraines, often with visual sensations or auras, or recurrent seizures (epilepsy).

Damaged blood vessels reduce blood flow and can cause areas of tissue death (infarcts) throughout the body. An infarct in the brain can lead to a stroke. In individuals with CADASIL, a stroke can occur at any time from childhood to late adulthood, but typically happens during mid-adulthood. People with CADASIL often have more than one stroke in their lifetime. Recurrent strokes can damage the brain over time. Strokes that occur in the subcortical region of the brain, which is involved in reasoning and memory, can cause progressive loss of intellectual function (dementia) and changes in mood and personality.

Many people with CADASIL also develop leukoencephalopathy, which is a change in a type of brain tissue called white matter that can be seen with magnetic resonance imaging (MRI).

The age at which the signs and symptoms of CADASIL first begin varies greatly among affected individuals, as does the severity of these features.

CADASIL is not associated with the common risk factors for stroke and heart attack, such as high blood pressure and high cholesterol, although some affected individuals might also have these health problems.  https://medlineplus.gov/genetics/condition/cerebral-autosomal-dominant-arteriopathy-with-subcortical-infarcts-and-leukoencephalopathy

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.
Stroke disorder
MedGen UID:
52522
Concept ID:
C0038454
Disease or Syndrome
Sudden impairment of blood flow to a part of the brain due to occlusion or rupture of an artery to the brain.
Varicose disease
MedGen UID:
21827
Concept ID:
C0042345
Disease or Syndrome
Enlarged and tortuous veins.
Vascular granular osmiophilic material deposition
MedGen UID:
348472
Concept ID:
C1859833
Finding
Accumulation of granular osmiophilic material in blood vessel walls. Osmiophilic material becomes black upon staining with osmium tetroxide. Deposition of granular osmiophilic material (GOM) is the vascular pathological hallmark of CADASIL, which is the most prevalent hereditary small vessel disease and is caused by missense mutations in the NOTCH3 gene. GOM have been shown to contain NOTCH3 ectodomain (NOTCH3ECD) and extracellular matrix proteins, and can be visualized ultrastructurally in the tunica media of small arteries and capillaries. These electron dense GOM deposits are located in the basement membrane of mural cells, i.e. vascular smooth muscle cells and pericytes. In both manifest and pre-manifest CADASIL patients, GOM deposits are present not only in brain vessels, but also in vessels of other organs, such as the skin.
Hemiparesis
MedGen UID:
6783
Concept ID:
C0018989
Finding
Loss of strength in the arm, leg, and sometimes face on one side of the body. Hemiplegia refers to a complete loss of strength, whereas hemiparesis refers to an incomplete loss of strength.
Peripheral neuropathy
MedGen UID:
18386
Concept ID:
C0031117
Disease or Syndrome
Peripheral neuropathy is a general term for any disorder of the peripheral nervous system. The main clinical features used to classify peripheral neuropathy are distribution, type (mainly demyelinating versus mainly axonal), duration, and course.
Pseudobulbar paralysis
MedGen UID:
10989
Concept ID:
C0033790
Disease or Syndrome
Bilateral impairment of the function of the cranial nerves 9-12, which control musculature involved in eating, swallowing, and speech. Pseudobulbar paralysis is characterized clinically by dysarthria, dysphonia, and dysphagia with bifacial paralysis, and may be accompanied by Pseudobulbar behavioral symptoms such as enforced crying and laughing.
Psychotic disorder
MedGen UID:
19568
Concept ID:
C0033975
Mental or Behavioral Dysfunction
A condition characterized by changes in personality and thought patterns, often accompanied by hallucinations and delusional beliefs, is known as psychosis.
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.
Migraine
MedGen UID:
57451
Concept ID:
C0149931
Disease or Syndrome
Migraine is a chronic neurological disorder characterized by episodic attacks of headache and associated symptoms.
Atypical behavior
MedGen UID:
535345
Concept ID:
C0233514
Mental or Behavioral Dysfunction
Atypical behavior is an abnormality in a person's actions, which 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.
Perseverative thought
MedGen UID:
66686
Concept ID:
C0233651
Mental or Behavioral Dysfunction
Manifestations of perseverative thoughts are behaviors that do not meet the demands of the situation, are not the product of deliberation, and may unfold despite counter intention.
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.
Personality changes
MedGen UID:
66817
Concept ID:
C0240735
Mental or Behavioral Dysfunction
An abnormal shift in patterns of thinking, acting, or feeling.
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.
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.
Abnormality of visual evoked potentials
MedGen UID:
105509
Concept ID:
C0522214
Finding
An anomaly of visually evoked potentials (VEP), which are electrical potentials, initiated by brief visual stimuli, which are recorded from the scalp overlying the visual cortex.
Gait disturbance
MedGen UID:
107895
Concept ID:
C0575081
Finding
The term gait disturbance can refer to any disruption of the ability to walk. In general, this can refer to neurological diseases but also fractures or other sources of pain that is triggered upon walking. However, in the current context gait disturbance refers to difficulty walking on the basis of a neurological or muscular disease.
Abulia
MedGen UID:
776735
Concept ID:
C0919974
Mental or Behavioral Dysfunction
Abulia is a severe form of apathy, characterized by difficulty in initiating and sustaining spontaneous movements, as well as reductions in emotional responsiveness, spontaneous speech, and social interaction.
Lacunar stroke
MedGen UID:
465269
Concept ID:
C3178801
Disease or Syndrome
A stroke related to a small infarct (2-20 mm in diameter) in the deep cerebral white matter, basal ganglia, or pons, that is presumed to result from the occlusion of a single small perforating artery supplying the subcortical areas of the brain.
Recurrent subcortical infarcts
MedGen UID:
870472
Concept ID:
C4024918
Disease or Syndrome
Subcortical dementia
MedGen UID:
870488
Concept ID:
C4024935
Disease or Syndrome
A particular type of dementia characterized by a pattern of mental defects consisting prominently of forgetfulness, slowness of thought processes, and personality or mood change.
Abnormal electroretinogram
MedGen UID:
96908
Concept ID:
C0476397
Finding
Any abnormality of the electrical responses of various cell types in the retina as measured by electroretinography.
Nonarteritic anterior ischemic optic neuropathy
MedGen UID:
338887
Concept ID:
C1852242
Disease or Syndrome
An acute condition characterized by sudden visual loss (usually discovered in the morning), optic disc edema at onset, optic disc-related visual field defects. Nonarteritic anterior ischemic optic neuropathy can be associated with flame hemorrhages on the swollen disk or nearby neuroretinal layer, and sometimes with nearby cotton-wool exudates.
Visual loss
MedGen UID:
784038
Concept ID:
C3665386
Finding
Loss of visual acuity (implying that vision was better at a certain time point in life). Otherwise the term reduced visual acuity should be used (or a subclass of that).

Professional guidelines

PubMed

Mancuso M, Arnold M, Bersano A, Burlina A, Chabriat H, Debette S, Enzinger C, Federico A, Filla A, Finsterer J, Hunt D, Lesnik Oberstein S, Tournier-Lasserve E, Markus HS
Eur J Neurol 2020 Jun;27(6):909-927. Epub 2020 Mar 20 doi: 10.1111/ene.14183. PMID: 32196841
Sacco S, Degan D, Carolei A
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Recent clinical studies

Etiology

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Diagnosis

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Chin Med J (Engl) 2020 Oct 26;134(2):178-184. doi: 10.1097/CM9.0000000000001176. PMID: 33109952Free PMC Article
Mancuso M, Arnold M, Bersano A, Burlina A, Chabriat H, Debette S, Enzinger C, Federico A, Filla A, Finsterer J, Hunt D, Lesnik Oberstein S, Tournier-Lasserve E, Markus HS
Eur J Neurol 2020 Jun;27(6):909-927. Epub 2020 Mar 20 doi: 10.1111/ene.14183. PMID: 32196841
de Vries B, Frants RR, Ferrari MD, van den Maagdenberg AM
Hum Genet 2009 Jul;126(1):115-32. Epub 2009 May 20 doi: 10.1007/s00439-009-0684-z. PMID: 19455354
Lastilla M
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Lancet Neurol 2002 Nov;1(7):426-36. doi: 10.1016/s1474-4422(02)00190-4. PMID: 12849365

Therapy

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Prognosis

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Brain Res Bull 2019 Feb;145:97-108. Epub 2018 May 25 doi: 10.1016/j.brainresbull.2018.05.018. PMID: 29807146Free PMC Article
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Clin Exp Pharmacol Physiol 2017 Jan;44(1):13-20. doi: 10.1111/1440-1681.12679. PMID: 27704594
Lastilla M
Clin Exp Hypertens 2006 Apr-May;28(3-4):205-15. doi: 10.1080/10641960600549082. PMID: 16833026

Clinical prediction guides

Liu JY, Zhu YC, Zhou LX, Wei YP, Mao CH, Cui LY, Peng B, Yao M
Chin Med J (Engl) 2020 Oct 26;134(2):178-184. doi: 10.1097/CM9.0000000000001176. PMID: 33109952Free PMC Article
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Recent systematic reviews

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