The phenotypic spectrum of CADASIL: Clinical findings in 102 cases

Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an increasingly recognized autosomal dominant disorder that leads to cerebrovascular manifestations in early adulthood. This study delineates the phenotypic spectrum and the natural history of the disease in 102 affected individuals from 29 families with biopsy-proven CADASIL. Recurrent ischemic episodes (transient ischemic attack [TIA] or stroke) were the most frequent presentation found in 71% of the cases (mean age at onset, 46.1 years; range, 30-66 years; SD, 9.0 years). Forty-eight percent of the cases had developed cognitive deficits. Dementia (28%) was frequently accompanied by gait disturbance (90%), urinary incontinence (86%), and pseudobulbar palsy (52%). Thirty-nine patients (38%) had a history of migraine (mean age at onset, 26.0 years; SD, 8.2 years), which was classified as migraine with aura in 87% of the cases. Psychiatric disturbances were present in 30% of the cases, with adjustment disorder (24%) being the most frequent diagnosis. Ten patients (10%) had a history of epileptic seizures. To delineate the functional consequences of ischemic deficits, we studied the extent of disability in different age groups. The full spectrum of disability was seen in all groups older than age 45. Fifty-five percent of the patients older than age 60 were unable to walk without assistance. However, 14% in this age group exhibited no disability at all. Kaplan-Meier analysis disclosed median survival times of 64 years (males) and 69 years (females). An investigation of the 18 multiplex families revealed marked intrafamilial variations.

Two Japanese CADASIL Families with a R141C Mutation in the Notch3 Gene.

“…The disease is characterized by recurrent TIAs and strokes with progressive vascular dementia, migraine with aura, psychiatric disturbances, and pseudobulbar palsy (2)(3)(4). In 1996, Joutel et al reported Notch3 as the causative gene for CADASIL, and detected several point mutations (5,6).…”

Small in-frame deletions and missense mutations in CADASIL: 3D models predict misfolding of Notch3v EGF-like repeat domains

“…This adds to previous clinical and neuroimaging evidence indicating, that the Notch3 genotype has no major influence on the phenotype. 3,22 In conclusion we have found a number of new mutations including two small in-frame deletions. These deletions are relevant in that they substantiate the pivotal role of an odd number of cysteine residues within EGF-like repeat domains in the pathogenesis of CADASIL.…”

“…1 Affected individuals experience recurrent ischemic episodes with accumulating motor, sensory and cognitive deficits. 2,3 The majority of patients eventually become demented and additional manifestations have been reported including migraine (30-40%), psychiatric disturbance (30%) and epileptic seizures (10%). 2,3 Brain magnetic resonance imaging (MRI) displays diffuse white matter abnormalities and small cystic lesions suggestive of small infarcts.…”

“…2,3 The majority of patients eventually become demented and additional manifestations have been reported including migraine (30-40%), psychiatric disturbance (30%) and epileptic seizures (10%). 2,3 Brain magnetic resonance imaging (MRI) displays diffuse white matter abnormalities and small cystic lesions suggestive of small infarcts. 4 The penetrance of MRI abnormalities in CADASIL is complete by age 35.…”

“…2 However, symptom onset varies considerably (age 14-66 years). 3 The underlying pathology is mediated by a unique non-amyloid angiopathy involving small arteries (100-400 µm) and capillaries, particularly in the brain but also in other organs. 5 Recently, the Notch3 gene on chromosome 19p13 was identified as the CADASIL disease gene.…”