Clinical and genetic analysis of a large Dutch family with autosomal dominant vascular retinopathy, migraine and Raynaud's phenomenon

Abstract

We describe an extended Dutch family with a new hereditary disorder: autosomal dominant vascular retinopathy, migraine and Raynaud's phenomenon. Information was obtained on 289 family members (151 males, 138 females), of whom 198 were personally interviewed. Retinopathy was found in 20 (6.9%) of the family members, migraine in 65 (22.5%) and Raynaud's phenomenon in 50 (17.3%). A combination of all three symptoms was found in 11 subjects. In a genetic linkage analysis we firstly excluded several candidate loci. Subsequently, 75% of the autosomal genome was excluded in a genome-wide search. The following conclusions were drawn. First, genetic factors are involved in Raynaud's phenomenon. Secondly, the genetic linkage of migraine with vascular retinopathy and Raynaud's phenomenon supports a vascular aetiology of this disorder. Finding the gene for this family may help to elucidate the genetic background of migraine and of vascular disorders in general.

Hereditary Systemic Angiopathy (HSA) with cerebral calcifications, retinopathy, progressive nephropathy, and hepatopathy

“…These findings are reminiscent of the retinal pathology reported in subjects suffering from HRV [25]. Interestingly, in contrast to HSA, disease penetrance seems to be very low in HRV since only 6,9 % of all HRV family members present retinopathy, while retinopathy is present in all our affected HSA patients.…”

“…CADASIL is the prototypical example of a hereditary systemic small vessel disease and remains the only one which has been genetically characterized [9]. Other conditions with small vessel pathology include CARASIL [29], HERNS [7], CRV [5,28], HVR [17,23,25], HIHRTL [27] and a recently described syndrome with leukoencephalopathy, cerebral calcifications, and cysts [10,14]. HERNS, CRV and HRV have been linked to chromosome 3p21.1-3p21.3 [17] and may therefore have a common genetic origin.…”

Renal histopathological findings of retinal vasculopathy with cerebral leukodystrophy

“…One was detected as nephropathy prior to retinopathy. It differs by individual in terms of how the manifestations present [2,[4][5][6]8] and nephropathy can be the first manifestation found, as in this case. Therefore, clarifying the histopathology of the kidney assists in providing early RVCL diagnosis.…”

“…TREX1 is a 3′-5′ DNA exonuclease ubiquitously expressed in human organs, including kidney [1,3]. Genetic analysis in three diseases: cerebroretinal vasculopathy [4], hereditary vascular retinopathy [5] and hereditary endotheliopathy, retinopathy, nephropathy and stroke (HERNS) [6], revealed these diseases are associated with C-terminal frame-shift mutations in TREX1, thus they were consolidated to a single entity named RVCL in 2007 [1]. RVCL patients typically exhibit visual disturbance and neurological disorders in middle age, often accompanied by renal and liver dysfunction.…”

Genetic factors in cerebral small vessel disease and their impact on stroke and dementia

“…42 Retinal vasculopathy with cerebral leukodystrophy (RVCL) (OMIM: 192315) refers to a group of cerebroretinal syndromes originally described as separate disorders: cerebroretinal vasculopathy (CRV); 43 hereditary endotheliopathy with retinopathy, nephropathy and stroke (HERNS); 44 and hereditary vascular retinopathy (HVR). 45,46 They had initially been described as dominantly inherited vasculopathies with similar, but distinct phenotypes including ophthalmologic and neurologic symptoms. Most patients present with retinopathy (mean age of onset $45 years), but subsequently develop severe neurologic symptoms including focal neurologic deficits, cognitive impairment, and psychiatric disturbances.…”