Cognitive aspects of MELAS and CARASAL

Abstract

Monogenic diseases, although rare, should be always considered in the diagnostic work up of vascular dementia (VaD), particularly in patients with early onset and a familial history of dementia or cerebrovascular disease. They include, other than CADASIL, Fabry disease, Col4A1-A2 related disorders, which are well recognized causes of VaD, other heritable diseases such as mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and cathepsin-A related arteriopathy strokes and leukoencephalopathy (CARASAL). MELAS, caused by mtDNA (80% of adult cases m.3243A>G mutations) and more rarely POLG1 mutations, has minimum prevalence of 3.5/100,000. CARASAL, which is caused by mutations in the CTSA gene, has been described in about 19 patients so far. In both these two disorders cognitive features have not been fully explored and are described only in case series or families. This review paper is aimed at providing an update on the clinical manifestations, with particular focus on cognitive aspects, but also neuroradiological and genetic features of these less frequent monogenic diseases associated with VaD.

Keywords: CARASAL; CARASAL, cathepsin-A related arteriopathy strokes and leukoencephalopathy; COL4A1/A2, gene encoding type IV collagen alpha 1–2 chain; Cerebral small vessel disease; Cognitive impairment; EAN, European academy of neurology; Heritable; MELAS; MELAS, mitochondrial encephalopathy, lactic acidosis and stroke-like episodes; MRI, magnetic resonance imaging; Monogenic diseases; OXPHOS, oxidative phosphorylation system; SLEs, stroke-like episodes; TIA, transitory ischemic attack; VCI, vascular cognitive impairment; VaD, vascular dementia; Vascular dementia; WMHs, white matter hyperintensities; cSVD, cerebral small vessel disease.

Fig. 1

Pathogenic mechanism of MELAS.

Fig. 2

MELAS Neuroimaging Cerebral MRI of a 14-year-old male with MELAS carrying the variant m.3243A>G showing a stroke-like lesion in the frontal and occipito-temporal regions, bilaterally. DWI and FLAIR (A,B) sequences show an acute stroke-like lesion in the right frontal lobe (red arrow), with an older bigger stroke-like lesion in the right temporal lobe (red arrow) (C). The asterisk (D) shows lactate peak at the proton spectroscopy .

Fig. 3

Pathophysiological features of CARASAL.

Fig. 4

CARASAL neuroimaging Cerebral MRI T2 axial images show the lack of the anterior temporal lobe involvement (left image), an extensive involvement of internal and external capsules (red arrow), basal ganglia and thalami (middle image) and periventricular and deep white matter (red arrow) (right). Images have been provided with the courtesy of Professor J. Finsterer and reproduced with permission from Finsterer et al. .