Hereditary causes of stroke single gene disorders and their clinical presentation

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CADASIL (cerebral autosomal dominant arteriopa-thy with subcortical infarcts and leukoencephalo-pathy), Fabry disease and MELAS (mitochondrial encephalopathy lactic acidosis and stroke) are genetic disorders associated with their own clinical and radiological presentation.

CADASIL

Genetic and pathological research suggests that the accumulation of the ectodomain of the NOTCH 3 protein is associated with severe ultrastructural alterations of the arteriolar wall [30]. The earliest clinical manifestation of CADASIL is migraine with aura at a mean age of 28 years. The aura may be visual or sensory but the frequency of attacks with basilar, hemiplegic and prolonged aura is high. At a mean age of 41 years, stroke becomes manifest in the course of disease. Two-thirds of patients present with lacunar syndromes such as pure motor, ataxic hemi-paresis, pure sensory or sensory motor stroke. With increasing load of subcortical white matter lesion, vascular dementia with deficits of executive functions, and attentional and memory deficits develops (mean age of 50 years). Twenty percent of patients have severe mood disorders, and focal or generalized seizures have been observed in about 8% of patients.

Microangiopathy or small-vessel disease (SVD) is the morphological presentation of the disease with multiple lacunar lesions and extensive white matter hyperintensities (WMHs), which may be accompanied by evidence of microbleeds (MBs). A first hint for CADASIL is the presence of extensive morphological abnormalities with SVD in the absence of vascular risk factors, especially in younger patients. Not infrequently, such a constellation may lead to a false suspicion of multiple sclerosis. Further evidence comes from the distribution of WMHs. In CADASIL, WMHs are characteristically located in the white matter of the anterior temporal lobe and the external capsule as early as in the third decade [31]. Location of WMHs and age of onset are unusual for other SVDs (Figure 9.8).

CADASIL is a rare genetic disorder causing small-vessel disease and multiple white matter lesions in young adults.

Fabry disease

Fabry's disease, also Anderson-Fabry's disease or angiokeratomy corporis diffusum, is an X-linked lysosomal storage disorder. Alpha-galactosidase deficiency leads to accumulation of glycolipids, mainly in endothelial and smooth muscle cells. A more recent study of 721 sufferers from acute cryptogenic stroke aged 18 to 55 years showed a rare but not negligible frequency of Fabry disease, which was 4.9% in male and 2.4% in female stroke patients [32]. The patients are mainly young and present with a variety of symptoms and signs which are caused by deposition

Narp Syndrome

Figure 9.9. MELAS. MELAS-related brain lesions appear bright on diffusion-weighted imaging (right-hand picture). A hint towards the correct diagnosis is that MELAS lesions usually tend to cross the known borders of the vascular territories of the brain. In this patient, the two vascular territories, posterior cerebralartery and middle cerebralartery, of the left hemisphere are involved. (Courtesy of Professor Franz Fazekas, University of Graz.)

Figure 9.9. MELAS. MELAS-related brain lesions appear bright on diffusion-weighted imaging (right-hand picture). A hint towards the correct diagnosis is that MELAS lesions usually tend to cross the known borders of the vascular territories of the brain. In this patient, the two vascular territories, posterior cerebralartery and middle cerebralartery, of the left hemisphere are involved. (Courtesy of Professor Franz Fazekas, University of Graz.)

of glycolipids in the tissue: skin manifestation with angiokeratomas (mainly in the bathing-trunk area) and hypohydrosis, small fiber neuropathy with burning pain and paresthesias in hands and feet, renal dysfunction or failure, vessel ectasia (particular basilar artery), corneal dystrophy, cardiomyopathy and stroke.

The early presence of incidental WMHs has been observed and there appears to be a predisposition for infarction to occur in the vertebrobasilar system. Vascular ectasia up to the megadolichobasilar artery has also been reported. The most specific abnormality, however, appears to be a hyperintense signal of the pulvinar thalami on Tl-weighted images [33]. Up to one-quarter of patients with Fabry disease may show this abnormality, which could be a consequence of microvascular calcification. Clinically silent or manifest strokes, both cortical and subcortical, are caused by occlusion of small vessels or by extasia of larger vessels, embolism from the heart, and rarely by intracranial hemorrhage.

Fabry disease presents with a variety of symptoms, including stroke.

MELAS (mitochondrial encephalopathy lactic acidosis and stroke)

MELAS is a mitochondrial disorder that causes stroke-like syndromes in young patients, occurring as early as the teenage years, with transient or permanent hemianopia, aphasia or hemiparesis. Sudden episodes of headache and seizure or vomiting occur.

Blood lactate levels are elevated, indicating dysfunction of the respiratory chain. Most commonly, MELAS is associated with a mitochondrial DNA point mutation at position 3243 within the tRNA encoding gene. Many different phenotypes, alone or in combinations, have been reported with this mutation (hearing impairment, cognitive decline, progressive external ophthalmoplegia, or epilepsy).

MELAS-related brain lesions appear bright on diffusion-weighted imaging with reduced diffusity on corresponding ADC maps and are thus frequently mistaken for acute infarction [34]. A hint towards the correct diagnosis comes from the fact that MELAS lesions usually tend to cross the known borders of the vascular territories of the brain and have a variable ADC. Posterior parietal and occipital locations appear to be most frequent (Figure 9.9). The lesions may also subside without remaining signal changes, which would be quite unusual for infarction, and have a tendency to slowly progress or to reoccur at other sites, sometimes within relatively short intervals of days to weeks [35]. Besides increased levels of lactate in the CSF during the attack, MR spectroscopy may also serve to demonstrate increased lactate in the brain parenchyma and cerebral lesions as well as in the CSF [36]. The most likely origin of strokelike episodes is a sudden metabolic failure with loss of function and transient or persistent cellular damage.

MELAS is a mitochondrial disorder causing strokelike syndromes, red-ragged fibers, myopathy and lactacidosis.

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