CADASIL

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Classification according to ICD-10
I67.8 Other specified cerebrovascular diseases
ICD-10 online (WHO version 2019)
The autosomal dominant inheritance

CADASIL ( C erebral A utosomal D ominant A rteriopathy with S ubcortical I nfarcts and L eukoencephalopathy ; German cerebral autosomal dominant arteriopathy with subcortical infarcts-and leukoencephalopathy ) is can cause a genetic disease characterized by heaping family stroke in middle age. In contrast to the classic cerebral infarction , which is often caused by arteriosclerosis or other stenosing processes, there is a mutation in the NOTCH3 gene on the short arm of chromosome 19 , which leads to a microangiopathy of the blood vessels supplying the brain. An important early symptom of CADASIL are migraine-like headaches that are triggered by the characteristic vascular changes. In the radiological imaging one observes a detectable subcortical involvement with frontal emphasis. CADASIL is a rare disease , but with around five diseases per 100,000 people, it is the most common monogenic stroke disease.

Diagnosis

Axial FLAIR (A, B, C) and T2-weighted magnetic resonance imaging of CADASIL patients. A and B are asymptomatic patients with depression . In B, lesions of the temporal lobe are detectable. In A and D there are diffuse ischemic changes in the white matter around the cerebral ventricles (periventricular) and multiple small infarcts (status lacunaris) in the thalamus , pons and basal ganglia .

Despite the headache (often with neurological symptoms in the sense of an aura ), the diagnosis is usually first made as a result of a stroke . This is also because up to 20% of the population have migraine-like headaches, while CADASIL is a very rare disease. Because of the autosomal dominant inheritance, the children could then be examined earlier. If there is a corresponding suspicion, the genetic defect can be detected using molecular genetic methods. Finally, an electron microscopic examination of a skin biopsy reveals groundbreaking findings on the muscle cells of the vessel walls.

Imaging procedures

In magnetic resonance imaging of the brain , T2-weighted recordings show signal enhancements in the white matter , typically in particular temporally .

pathology

A tissue examination reveals an accumulation of transparent substances ( hyalinosis ) in the walls of small and medium-sized arteries , arterioles and capillaries . It comes to the fragmentation (dismemberment) and degeneration of the smooth vascular muscle cells . When examining with an electron microscope, granular deposits are found in the vicinity of the affected vascular muscle cells , which can be stained with osmium tetroxide ( osmiophilic material). Components of the NOTCH3 protein can be detected in the osmiophilic deposits by immunohistochemical examination .

Genetic examination

The disease is caused by a missense mutation of NOTCH3 - gene caused. The NOTCH3 protein is a membrane receptor consisting of two different subunits (= heterodimeric ) , which is expressed exclusively by vascular smooth muscle cells . NOTCH3 belongs to the NOTCH gene family. The NOTCH genes code for highly conserved membrane receptors that are involved in the control of cell fate, particularly in the development of the blood vessel system . NOTCH3 is involved in cell-cell interaction, control of cell growth and differentiation as well as programmed cell death (apoptosis) . In patients with CADASIL, there is an addition or a loss of cysteine in the area of ​​the extracellular domain of the NOTCH3 protein.

course

Over the years there are repeated small strokes that affect the white matter ( marrow beds ) of the cerebrum. This ultimately leads to dementia , i.e. a decline in intellectual performance. The clinical picture is reminiscent of subcortical arteriosclerotic encephalopathy (Binswanger's disease), but CADASIL lacks high blood pressure. Otherwise, all symptoms of minor strokes (so-called lacunar syndromes) can be encountered. The course is very variable and there are very different courses within a family. With regard to life expectancy, at least for women, there is no significant restriction compared to healthy people. Some carriers of the mutation are even symptom-free into old age.

The following, published by Verin et al. The postulated division into stages (which is not used in clinical practice) is therefore only to be understood as a possible course of the disease:

I. stage (20–40 years of age)
* frequent migraine-like episodes
* Anomalies in the MRI
II stage (40-60 years of age)
* recurring stroke-like episodes
* psychiatric abnormalities
* increasing damage to the medullary bed and basal ganglia
III. Stage (60th - 80th year of life)
* Dementia
* Spasticity movement disorder ,
* Pseudo bulbar paralysis
IV. Final stage:
* Persistent vegetative state requiring artificial nutrition (PEG)

Further organ manifestations

Since arterioles can be affected in all organs, there are other organ manifestations:

  • Asymptomatic changes in the retina are often found in the eye area: narrowing of arteries and veins, increased vascular reflexes, elongated course of the arterioles.
  • In the area of ​​the skin vessels there are also changes that allow a diagnosis by means of a skin biopsy.
  • Renal involvement with chronic renal impairment , mild proteinuria and microhematuria is rare . The tissue examination reveals the typical vascular changes with granular osmiophilic deposits in the kidneys.

Differential diagnosis

Other diseases of the white matter of the brain ( leukoencephalopathies ) are important differential diagnoses to CADASIL. These include, for example, inflammatory (e.g. multiple sclerosis , CNS vasculitis ) and metabolic (e.g. Fabry disease) diseases in adulthood. The common leukodystrophies (e.g. metachromatic leukodystrophy ) tend to occur in childhood and therefore usually do not represent a relevant differential diagnosis. CARASIL differs mainly in its more severe course and recessive inheritance.

therapy

There is no known effective treatment. To prevent strokes, in addition to ASA , it is advisable to minimize the other risk profile (such as blood pressure, blood sugar, blood lipids). Ultimately, however, this cannot stop the disease. This also puts the need for early diagnosis into perspective. An early living will is recommended in the case of stage IV.

Notoriety

In the film " The Sea in Me " the lawyer Julia suffers from the disease. In the series “In all friendship”, episode 627 from December 10, 2013, “The bells never ring sweeter”, the patient Petra Klett, played by Marion Kracht, suffers from this rare disease. The famous composer Felix Mendelssohn Bartholdy and his sister were most likely sick with CADASIL and both died of a stroke in the same year.

Christoff Kessler, a recognized specialist in brain diseases, published the book "Wahn" in 2013, a fictional but fact-based short story called "Cadasil" about a young man and how he dealt with this diagnosis.

swell

  • A. Joutel et al .: Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. In: Nature . Volume 383, 1996, pp. 707-710. PMID 8878478
  • H. Chabriat et al .: Autosomal dominant migraine with MRI white-matter abnormalities mapping to the CADASIL locus. In: Neurology . Volume 45, 1995, pp. 1086-1091. PMID 7783868
  • M. Verin et al .: New phenotype of the cerebral autosomal dominant arteriopathy mapped to chromosome 19: migraine as the prominent clinical feature. In: Journal of Neurology, Neurosurgery, and Psychiatry . Volume 59, 1995, pp. 579-585. PMID 7500094
  • C. Opherk et al .: Long-term prognosis and causes of death in CADASIL: a retrospective study in 411 patients. In: Brain . Volume 127, 2004, pp. 2533-2539. PMID 15364702
  • M. Dichgans et al .: The phenotypic spectrum of CADASIL: clinical findings in 102 cases. In: Annals of Neurology . Volume 44, 1998, pp. 731-739. PMID 9818928
  • D. Guerrot et al .: Nephroangiosclerosis in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: is NOTCH3 mutation the common culprit? In: Am J Kidney Dis . Volume 52, 2008, pp. 340-345. PMID 18572291
  • Hara et al .: Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease. In: N Engl J Med . 2009; 360: pp. 1729-1739. PMID 19387015

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