Long-term prognosis and causes of death in CADASIL: a retrospective study in 411 patients

Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary angiopathy caused by mutations in the NOTCH3 gene. The clinical course is highly variable. Little is known about the long-term prognosis and the causes of death in CADASIL patients. Likewise, the impact of gender and NOTCH3 genotype on disease progression remains largely unexplored. We identified 411 subjects (196 men, 215 women) with a definite diagnosis of CADASIL. Age at onset for stroke, immobilization and death as well as the causes of death and clinical status at onset of the cause of death were determined systematically. Weibull regression models were used to calculate times to event, with gender and NOTCH3 genotype as covariates. At the time of the study, 73 patients had died. The median age at onset for stroke was 50.7 years [95% confidence interval (CI) = 48.2-53.1 years] in men and 52.5 years (95% CI = 50.0-54.9 years) in women (P = n.s.). The median ages at onset for inability to walk without assistance [men 58.9 years (95% CI = 56.6-61.3 years); women 62.1 years (59.7-64.4 years)], bedriddenness [men 62.1 years (59.6-64.7 years), women 66.5 years (63.9-69.1 years); and death [men 64.6 years (61.7-67.6 years); women 70.7 years (67.6-73.9 years)] were significantly lower in men than in women (all P < or = 0.01). The median survival time of men was significantly shorter than expected from German life tables (64.6 versus 69.3 years, P = 0.01). In contrast, the median survival time of women was not significantly reduced (70.7 versus 72.2 years). The C117F mutation was associated with a lower age at death and the C174Y mutation with a lower age at onset for stroke, immobilization and death (adjusted P values <0.05). At onset of the cause of death, 78% of the subjects were completely dependent. Sixty-three per cent were confined to bed. Pneumonia was the most frequent cause of death (38%), followed by sudden unexpected death (26%) and asphyxia (12%). We conclude that male sex is a risk factor for early immobilization and death in CADASIL. Our findings suggest possible genotype-phenotype correlations with regard to disease progression. The data presented may serve as source material for counselling CADASIL patients and for designing future interventional trials.

CADASIL: pathogenesis, clinical and radiological findings and treatment

“…Time to death is also highly variable -10 to 30 years. Death occurs around 65 (men) 70 years (women) on average, from accumulation of morbidities and clinical complications related to infection and immobility 40 .…”

“…In advanced stages, patients are unable to walk 40 and frequently apathetic/abulic, but rarely exhibit typical 'cortical' changes such as aphasia, apraxia and agnosia 86 . The dissociated pattern of memory loss (with relative preservation of recognition and some improvement with clues and hints) often remains.…”

CADASIL: A Case Report with an Atypical Presentation and Novel Mutation

“…The index patient's initial presentation was atypical, the imaging findings were not initially recognized, and the patient was found to have a previously unreported mutation in the NOTCH3 gene [5][6][7]. This patient's first presenting symptom of CADASIL occurred at the age of 58 and consisted of an episode of dysarthria and minor right-sided weakness.…”

Diagnosing Vascular Dementia by Skin Biopsy - Uniqueness of CADASIL

“…Comprehensive analysis of all these exons is time consuming and costly. Thus, most diagnostic laboratories screen only the exons that according to the previous reports harbour majority of the mutations (Dotti et al, 2005, Escary et al, 2000, Joutel et al, 1997, Kalimo et al, 2002, Opherk et al, 2004. Of the all reported pathogenic NOTCH3 mutations 62% locate in exons 3, 4, 5 and 8.…”