Highlights
- •Homozygous mutations are extremely rare in CADASIL.
- •We report the largest series to date on NOTCH3 homozygous mutation and compare the phenotype to heterozygous patients.
- •Homozygous C3769T mutation was found in 7 family members, while heterozygous mutation was found in 6 members.
- •The phenotype of homozygous individuals is within the spectrum of CADASIL, although slightly at the severe end when compared to heterozygotes.
- •Genetic modifiers and environmental factors may play a role in the severity of the clinical phenotype and imaging features of CADASIL patients.
Abstract
Background
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy
(CADASIL) is a hereditary microangiopathy caused by mutations in NOTCH3, very rarely homoallelic.
Objective
To describe the clinical, radiological, and neuropsychological features in an extended
CADASIL family including members with either a homozygous or heterozygous NOTCH3 R1231C mutation.
Methods
The pedigree included 3 generations of a family with 13 affected individuals. The
patients were examined clinically and radiologically. Neuropsychological testing was
performed on the proband. Sequencing of the entire coding DNA sequence (CDS) and flanking
regions of NOTCH3 was undertaken using PCR amplification and direct Sanger sequencing.
Results
Homozygous C3769T mutation, predicting R1231C in exon 22 of NOTCH3 was found in 7 family members. Six other family members harbored the same in the
heterozygous state. Homozygous individuals showed a slightly more severe clinical
and radiological phenotype of earlier onset compared to their heterozygous counterparts.
Conclusion
This study reports the largest number of patients with homozygous NOTCH3 mutation. The phenotype and imaging features of homozygous individuals is within
the spectrum of CADASIL, although slightly at the severe end when compared to heterozygotes
carrying the same mutation. Both genetic modifiers and environmental factors may play
an essential role in modification and alteration of the clinical phenotype and white
matter changes among CADASIL patients.
Keywords
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Article info
Publication history
Published online: June 01, 2016
Accepted:
May 31,
2016
Received in revised form:
May 10,
2016
Received:
September 22,
2015
Identification
Copyright
© 2016 Elsevier B.V. All rights reserved.
