Subcortical angiopathic encephalopathy in a German kindred suggests an autosomal dominant disorder distinct from CADASIL

Abstract

A cerebral arteriopathy with subcortical infarcts and leukoencephalopathy is described with a pedigree suggestive for an autosomal dominant condition. In contrast to the vasculopathy designated with the acronym CADASIL, no deposits of granular osmiophilic material were detected in the vasculature and no point mutations in the NOTCH 3 gene were found. The disease occurred in a family living near Hamburg, Germany, and affected 11 women and 11 men over the last six generations. Onset of the disease was between the age of 12 and 50. Clinical symptoms included gait disturbances, dysarthria, sensomotoric deficits and a progressive dementia. Migraine-like complaints and epileptic seizures were observed in one case each. Cranial computer tomography and magnetic resonance imaging scans showed large confluent areas with decreased density in the white matter and small necroses in the brain stem, the basal ganglia and the white matter. A correlation with factors predisposing for vascular diseases could not be demonstrated. In five cases an autopsy was performed which disclosed an angiopathy affecting predominantly the penetrating arteries with consecutive lacunar infarcts, diffuse demyelination and rarefication of the subcortical white matter and degeneration of the pyramidal tracts. Histologically, the vessels showed concentric and excentric intimal proliferation, an elastosis and hyalinosis, splitting of the lamina elastica interna and a degeneration of the tunica muscularis. Electron microscopy revealed fragmentation and thickening of the basal lamina but electron-dense granules characteristic for CADASIL were not detected.

MRI Features of Pontine Autosomal Dominant Microangiopathy and Leukoencephalopathy (PADMAL)

“…Eighteen offspring aged 35 to 77 years from different generations of a large German family studied by Hagel et al 13 were investigated. The pedigree of the family had been followed back to the 16th century over 15 generations.…”

“…Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a monogenic nosological entity of SVD caused by mutations in the NOTCH3 gene, 6–12 is the most common form of familial SVD and has raised considerable attention to search for further genetic factors promoting SVDs. Different from what had been found in CADASIL, Hagel et al described in 2004 a new cerebral arteriopathy with autosomal dominant inheritance in a German kindred 13 . In the investigation by Hagel et al direct polymerase chain reaction (PCR)‐sequencing of Notch 3 exons 3 and 4 was performed on samples from 12 subjects from both the 3′‐end and 5′‐end using primers hybridizing to the adjacent intron sites.…”

“…No NOTCH3 mutations were found in affected subjects by sequencing of genomic DNA, and no granular osmiophilic material was demonstrated upon electron microscopic studies of both skin biopsies and autoptic brain tissue. Further, diabetic and hypertensive microangiopathy, as well as homocyteinuria, were excluded clinically, as was cerebral amyloid angiopathy by immunohistochemistry of post mortem brains 13 . Although the genetic background of this disease is not yet known, a distinct MRI characteristic would support the argument for a new nosological entity.…”

Review: Molecular genetics and pathology of hereditary small vessel diseases of the brain

“…[19] had described ‘chronic familial vascular encephalopathy’ in an English family with a comparable phenotype. Several other individual cases with vascular dementia from European and American families characterized as Binswanger's syndrome, subcortical arteriosclerotic encephalopathy or familiäre zerebrale Gefässerkrankung [20] have been described in the intervening years [21–25]. With the advent of better neuroimaging techniques and refined morphological and genetic methods, several of these disorders have now been identified to be cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), an acronym coined in 1993 by Bousser and Tournier‐Lasserve [15].…”

“…Upon rigorous scrutiny of the clinical, genetic and morphological features it is identified to be a novel SVD whose genetic identity still remains unknown [28]. In the case of the encephalopathy described in the large German family [25] it is now appreciated that these individuals also exhibit lacunar infarcts in the pons strikingly different from CADASIL so that SAE has been aptly described as pontine autosomal dominant microangiopathy and leukoencephalopathy or PADMAL [29].…”