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Retinal vasculopathy with cerebral leukoencephalopathy and systemic
manifestations
#MMPMID27604306
Stam AH
; Kothari PH
; Shaikh A
; Gschwendter A
; Jen JC
; Hodgkinson S
; Hardy TA
; Hayes M
; Kempster PA
; Kotschet KE
; Bajema IM
; van Duinen SG
; Maat-Schieman MLC
; de Jong PTVM
; de Smet MD
; de Wolff-Rouendaal D
; Dijkman G
; Pelzer N
; Kolar GR
; Schmidt RE
; Lacey J
; Joseph D
; Fintak DR
; Grand MG
; Brunt EM
; Liapis H
; Hajj-Ali RA
; Kruit MC
; van Buchem MA
; Dichgans M
; Frants RR
; van den Maagdenberg AMJM
; Haan J
; Baloh RW
; Atkinson JP
; Terwindt GM
; Ferrari MD
Brain
2016[Nov]; 139
(11
): 2909-2922
PMID27604306
show ga
See Charidimou (doi:10.1093/aww253) for a scientific commentary on this article.
Cerebroretinal vasculopathy, hereditary vascular retinopathy, and hereditary
endotheliopathy, retinopathy, nephropathy and stroke are neurovascular syndromes
initially described as distinct entities. Recently they were shown to be one
disease caused by C-terminal frame-shift mutations in TREX1, which was termed
?retinal vasculopathy with cerebral leukodystrophy?. Here we defined the genetic
and clinicopathologic spectrum of this clinically and pathophysiologically poorly
characterized and frequently misdiagnosed fatal neurovascular disorder. We
identified five different TREX1 mutations in 78 members from 11 unrelated
families and by using a standardized study protocol we retrospectively reviewed
and aggregated the associated clinical, neuroimaging, and pathology data.
Findings were similar across mutations and families. Sixty-four mutation carriers
had vascular retinopathy. Neuroimaging revealed (i) punctate, hyperintense, white
matter lesions with or without nodular enhancement in 97% of them; (ii)
rim-enhancing mass lesions in 84%; and (iii) calcifications in the white matter
in 52%. Ninety per cent had clinical manifestations of brain disease, including
focal neurological deficits (68%), migraine (59%), cognitive impairment (56%),
psychiatric disturbances (42%), and seizures (17%). One mutation carrier had
enhancing brain lesions and neurological features but unknown retinopathy status.
Additional systemic features included liver disease (78%), anaemia (74%),
nephropathy (61%), hypertension (60%), mild Raynaud?s phenomenon (40%), and
gastro-intestinal bleeding (27%). Mean (± standard deviation) age at diagnosis
was 42.9 ± 8.3 years and at death 53.1 ± 9.6 years. Pathological examination
revealed systemic vasculopathy with luminal narrowing and multi-laminated
basement membranes. The 13 mutation carriers without retinopathy or brain lesions
were on average 8 years younger (mean age: 35.1 ± 10.6 years). Of them, 54% had
mild Raynaud?s phenomenon, 42% had migraine, and 23% had psychiatric
disturbances. Retinal vasculopathy with cerebral leukodystrophy is an autosomal
dominant systemic small-vessel disease due to specific TREX1 mutations and
clinically primarily characterized by (i) visual impairment from vascular
retinopathy; and (ii) neurological decline and premature death due to progressive
enhancing cerebral white matter lesions. Impaired liver and kidney function,
anaemia sometimes associated with gastrointestinal bleeding, hypertension,
migraine, and Raynaud?s phenomenon appear to be part of the clinical spectrum as
well. Penetrance seems high. Because of the pathogenetic basis and the emerging
clinical picture with systemic manifestations and conspicuous absence of
leukodystrophy, we renamed the disease ?retinal vasculopathy with cerebral
leukoencephalopathy and systemic manifestations?. We propose diagnostic criteria
to facilitate clinical recognition and future studies.
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