Reduced bone mineral density and hyaloid vasculature remnants in a consanguineous recessive FEVR family with a mutation in LRP5

Abstract

Background/aims: Familial exudative vitreoretinopathy (FEVR) is an inherited blinding condition characterised by abnormal development of the retinal vasculature. FEVR has multiple modes of inheritance, and homozygous mutations in LRP5 have recently been reported as underlying the recessive form of this disease. The aim of this study was to examine LRP5 in a consanguineous recessive FEVR family and to clarify the eye and bone phenotype associated with recessive FEVR. Methods: All family members were examined by slit lamp biomicroscopy and indirect ophthalmoscopy. Linkage to LRP5 was determined by genotyping microsatellite markers, constructing haplotypes and calculating lod scores. Mutation screening of LRP5 was performed by polymerase chain reaction amplification of genomic DNA followed by direct sequencing. Bone mineral density (BMD) was evaluated in all family members using dual energy x ray absorptiometry (DEXA). Results:The clinical features observed in this family were consistent with a diagnosis of recessive FEVR. A homozygous LRP5 missense mutation, G550R, was identified in all affected individuals and all unaffected family members screened were heterozygous carriers of this mutation. Reduced BMD, hyaloid vasculature remnants, and nystagmus were features of the phenotype. Conclusion: Recessive mutations in LRP5 can cause FEVR with reduced BMD and hyaloid vasculature remnants. Assessment of a patient with a provisional diagnosis of FEVR should therefore include investigation of BMD, with reduced levels suggestive of an underlying LRP5 mutation.

Phenotypic Overlap of Familial Exudative Vitreoretinopathy (FEVR) with Persistent Fetal Vasculature (PFV) Caused byFZD4Mutations in two Distinct Pedigrees

“…2,3,6,7 Our cases provide further evidence that such features can be part of the FEVR spectrum, and that this diagnosis must be considered for the opposite eye in unilateral cases and for all relatives at risk. In support of this hypothesis is the finding of persistent hyaloid vasculature in 2 of 3 affected children with the autosomal recessive form of FEVR caused by a homozygous LRP5 missense mutation, 28 as well as in one member of another family with FEVR. 29 One explanation for the degree of severity of the disease is that another mutation(s) or polymorphism(s) in more than one FEVR gene is present in our cases.…”

Recessive Mutations inTSPAN12Cause Retinal Dysplasia and Severe Familial Exudative Vitreoretinopathy (FEVR)

“…5,6 Carrier parents of recessive FEVR patients with LRP5 mutations show no signs of eye disease, although reduced bone mass density has been reported. 6,17,41 However, as only a handful of recessive LRP5-FEVR families have been reported, and given the difficulty in detecting the mild phenotype, it is possible that this and other genetic forms of FEVR also are sensitive to dosage effects. Interestingly, a case report provides evidence for this possibility.…”

Pharmacologic Activation of Wnt Signaling by Lithium Normalizes Retinal Vasculature in a Murine Model of Familial Exudative Vitreoretinopathy

“…37 Hyaloidal vasculature is critical during embryonic ocular development and normally regresses as retinal vascular development proceeds. 38 At P8, Lrp5 À/À mice had approximately double the number of hyaloid vessels branching from the hyaloid artery as those from the age-matched WT controls ( Figure 2).…”