Homozygosity and severity of phenotypic presentation in a CADASIL family

Vinciguerra, Claudia; Rufa, Alessandra; Bianchi, Silvia; Sperduto, Antonio; Santis, M De; Malandrini, Alessandro; Dotti, Maria Teresa; Federico, Antonio

doi:10.1007/s10072-013-1580-9

Cited by 21 publications

(11 citation statements)

References 7 publications

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“…16 Although neither in-depth genealogical reconstruction nor haplotype analysis were performed in the APP mutation carriers belonging to this pedigree, we hypothesize that they are related to families previously described and probably originated from the same common ancestor before the 19th century. 16 In this study, AD behaves as a real dominant disease, similar to that reported for the rare homozygous CADASIL patients 39,40 and differently from that reported in the AD family with the recessive APP A673V mutation, 7 which causes disease only in the homozygous state, whereas heterozygous carriers were unaffected, consistent with a recessive trait of inheritance. All these data confirm that genetic AD may be considered a disease with dominant and recessive traits of inheritance, thus demonstrating the importance to search for recessive AD loci, for instance by analyzing homozygosity in consanguineous families and inbred populations.…”

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confidence: 73%

Homozygous carriers of APP A713T mutation in an autosomal dominant Alzheimer disease family

et al. 2015

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Objective: To report, for the first time, a large autosomal dominant Alzheimer disease (AD) family in which the APP A713T mutation is present in the homozygous and heterozygous state. To date, the mutation has been reported as dominant, and in the heterozygous state associated with familial AD and cerebrovascular lesions. Methods:The family described here has been genealogically reconstructed over 6 generations dating back to the 19th century. Plasma b-amyloid peptide was measured. Sequencing of causative AD genes was performed.Results: Twenty-one individuals, all but 1 born from 2 consanguineous unions, were studied: 8 were described as affected through history, 5 were studied clinically and genetically, and 8 were asymptomatic at-risk subjects. The A713T mutation was detected in the homozygous state in 3 patients and in the heterozygous state in 8 subjects (6 asymptomatic and 2 affected).Conclusions: Our findings, also supported by the b-amyloid plasma assay, confirm (1) the pathogenic role of the APP A713T mutation, (2) the specific phenotype (AD with cerebrovascular lesions) associated with this mutation, and (3) the large span of age at onset, not influenced by APOE, TOMM40, and TREM2 genes. No substantial differences concerning clinical phenotype were evidenced between heterozygous and homozygous patients, in line with the classic definition of dominance. Therefore, in this study, AD followed the classic definition of a dominant disease, contrary to that reported in a previously described AD family with recessive APP mutation. This confirms that genetic AD may be considered a disease with dominant and recessive traits of inheritance. Neurology ® 2015;84:2266-2273 GLOSSARY Ab 5 b-amyloid; AD 5 Alzheimer disease; ADL 5 activities of daily living; AMC 5 affected mutation carrier; APP 5 amyloid precursor protein; ASMC 5 asymptomatic mutation carrier; CVL 5 cerebrovascular lesion; FDG 5 fluorodeoxyglucose; HIS 5 Hachinski Ischemic Score; IADL 5 instrumental activities of daily living; MMSE 5 Mini-Mental State Examination; NMC 5 non-mutation carrier; PolyPhen-2 5 Polymorphism Phenotyping 2; PSEN1 5 presenilin 1; PSEN2 5 presenilin 2; SIFT 5 sorting intolerant from tolerant.

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confidence: 73%

Homozygous carriers of APP A713T mutation in an autosomal dominant Alzheimer disease family

et al. 2015

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“…This mode of pathogenesis suggests that CADASIL-causing NOTCH3 mutations are not loss of function; rather they are likely neomorphic or toxic. This is further supported by the observation that patients harboring homozygous CADASIL mutations experience similar or only slightly more severe symptoms (Abou Al-Shaar et al, 2016;Liem et al, 2008;Pippucci et al, 2015;Ragno et al, 2013;Soong et al, 2013;Tuominen et al, 2001;Vinciguerra et al, 2014); if the mutations were loss of function, homozygous patients would be expected to suffer more severe consequences. Interestingly, previous reports have described a clustering of CADASIL-related NOTCH3 mutations in exon 4 ( Fig.…”

Section: Notch3 In Development: a Cornucopia Of Congenital Disordersmentioning

confidence: 81%

The developmental biology of genetic Notch disorders

2017

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Notch signaling regulates a vast array of crucial developmental processes. It is therefore not surprising that mutations in genes encoding Notch receptors or ligands lead to a variety of congenital disorders in humans. For example, loss of function of Notch results in Adams-Oliver syndrome, Alagille syndrome, spondylocostal dysostosis and congenital heart disorders, while Notch gain of function results in Hajdu-Cheney syndrome, serpentine fibula polycystic kidney syndrome, infantile myofibromatosis and lateral meningocele syndrome. Furthermore, structure-abrogating mutations in NOTCH3 result in CADASIL. Here, we discuss these human congenital disorders in the context of known roles for Notch signaling during development. Drawing on recent analyses by the exome aggregation consortium (EXAC) and on recent studies of Notch signaling in model organisms, we further highlight additional Notch receptors or ligands that are likely to be involved in human genetic diseases.

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“…At present, five patients with homozygous cysteine mutations in NOTCH3 [Tuominen et al : p.Arg133Cys , Liem et al : p.Arg578Cys , Ragno et al : p.Gly528Cys , Soong et al : p.Arg544Cys and Vinciguerra et al : p.Cys183Ser ] have been reported.…”

Section: Genetics and Biochemistrymentioning

confidence: 99%

CADASIL and CARASIL

et al. 2014

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CADASIL and CARASIL are hereditary small vessel diseases leading to vascular dementia. CADASIL commonly begins with migraine followed by minor strokes in mid-adulthood. Dominantly inherited CADASIL is caused by mutations (n > 230) in NOTCH3 gene, which encodes Notch3 receptor expressed in vascular smooth muscle cells (VSMC). Notch3 extracellular domain (N3ECD) accumulates in arterial walls followed by VSMC degeneration and subsequent fibrosis and stenosis of arterioles, predominantly in cerebral white matter, where characteristic ischemic MRI changes and lacunar infarcts emerge. The likely pathogenesis of CADASIL is toxic gain of function related to mutation-induced unpaired cysteine in N3ECD. Definite diagnosis is made by molecular genetics but is also possible by electron microscopic demonstration of pathognomonic granular osmiophilic material at VSMCs or by positive immunohistochemistry for N3ECD in dermal arteries.In rare, recessively inherited CARASIL the clinical picture and white matter changes are similar as in CADASIL, but cognitive decline begins earlier. In addition, gait disturbance, low back pain and alopecia are characteristic features. CARASIL is caused by mutations (presently n = 10) in high-temperature requirement. A serine peptidase 1 (HTRA1) gene, which result in reduced function of HTRA1 as repressor of transforming growth factor-β (TGF β) -signaling. Cerebral arteries show loss of VSMCs and marked hyalinosis, but not stenosis.

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Homozygosity and severity of phenotypic presentation in a CADASIL family

Cited by 21 publications

References 7 publications

Homozygous carriers of APP A713T mutation in an autosomal dominant Alzheimer disease family

Homozygous carriers of APP A713T mutation in an autosomal dominant Alzheimer disease family

The developmental biology of genetic Notch disorders

CADASIL and CARASIL

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