A Canadian CADASIL Kindred: How sensitive is a skin biopsy?
Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited arterial disease of mid-adulthood resulting from mutations of the Notch3 gene on chromosome 19. The presence of granular and osmiophilic material surrounding smooth muscle cells visualized under electron microscopy in a skin biopsy allows confirmation of the intra vitam diagnosis. The literature suggests that skin biopsy can establish the diagnosis with high certainty and that it be considered the diagnostic method of first choice. Until the sensitivity and specificity have rigorously been assessed, results from such tests should be interpreted with caution. Objective: To raise some concerns about the possible lack of sensitivity of skin biopsy in the early diagnosis of CADASIL by describing the second large Canadian kindred with this condition. Methods: All siblings of this family in which there was a clinical suspicion of CADASIL underwent neurological evaluation, magnetic resonance imaging (MRI), skin biopsy, and genetic testing. Findings: Nine siblings ranged in age from 40 to 63 years. Two (aged 60 and 62) presented with dementia, strokes, and depression, two (aged 58 and 63) presented with stroke and migraine with aura, three (aged 40, 48, and 51) presented with only migraine with aura, and two (aged 53 and 57) were asymptomatic. Eight consented to diagnostic evaluation. All eight siblings’ DNA-sequence analysis of the Notch3 gene revealed an Arg207Cys mutation in exon 4. All have MRI scans consistent with a diagnosis of CADASIL. Full thickness skin biopsies from all eight were submitted for histopathological and ultrastructural examination. Granular electron dense osmiophilic material was not found in any of the material submitted. Conclusions: In addition to providing an illustrative clinical example of the broad phenotypic variation of CADASIL in a Canadian kindred, this family demonstrates how insensitive the skin biopsy might be. The sensitivity and specificity of various non-genetic diagnostic tests such as skin and muscle biopsy must be rigorously assessed before claiming them as standards for screening or diagnosing CADASIL.