Ocular manifestations of microcephaly with or without chorioretinopathy, lymphedema or intellectual disability (MCLID) syndrome associated with mutations in KIF11

Abstract

ABSTRACT.Purpose: Microcephaly with or without chorioretinopathy, lymphedema or intellectual disability (MCLID) is an autosomal dominant condition. Mutations in KIF11 have been found to be causative in approximately 75% of cases. This study describes the ocular phenotype in patients with confirmed KIF11 mutations. Methods: Standard ophthalmic examination and investigation including visual acuity, refraction and fundus examination was carried out in all patients. Fundus autofluorescence imaging (FAF) was performed in three patients, and four patients underwent spectral domain optical coherence tomography (OCT). Flash electroretinography (ERG) was performed in seven patients, and five underwent additional pattern electroretinography (PERG). Results: The patients ranged in age from 2 to 10 years. Most presented with visual acuity loss. Fundus examination revealed lacunae of chorioretinal atrophy. Pigmentary macular changes and optic disc pallor were present in three of seven patients. Fundus autofluorescence demonstrated hypoautofluorescence at the macula in two of three patients. The lacunae of chorioretinal atrophy were hypoautofluorescent. The OCT showed atrophic maculae in three of four patients. Follow-up in one patient showed no deterioration of the vision over a 9-year period. The lesions appear not to be progressive on the follow-up imaging. Electrophysiology showed generalized rod and cone dysfunction and severe macular dysfunction. Inner retinal dysfunction was evident in three of seven patients. Conclusions: Patients with KIF11 mutations show a specific ocular phenotype with variable expressivity and intrafamilial variability. Macular atrophy and dysfunction have not been consistently documented before. The fundus lesions appear non-progressive. The findings assist in providing an accurate diagnosis and thus improving the management and follow-up of patients with this syndrome.

New insights into the genetic component of non-infectious uveitis through an Immunochip strategy

“…In this regard, the association observed in the HHEX/EXOC6 region seemed to be due to an eQTL influencing the expression of EXOC6 and KIF11. EXOC6 is one of three genes included in a chromosomal microdeletion leading to an autosomal dominant form of non-syndromic optic nerve aplasia,48 whereas mutations in KIF11 cause an autosomal dominant disorder characterised by chorioretinopathy 49. SNPs within the CASP10/TRAK2 locus were found to affect the expression of two genes located in the same haplotype block; CFLAR , a regulator of apoptosis, and PPIL3 , involved in protein folding.…”

Retinal and optic nerve changes in microcephaly

“… 13 The present findings are also in line with a recent OCT study reporting atrophic maculae and parafoveal discontinuation of the EZ and the outer retinal bands in patients with pathologic KIF11 mutations. 5 , 27 In this study, macular atrophy was reported for the first time in 3 out of 4 individuals with microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability and is most probably associated with the identification of KIF11 mutations in all affected patients. 5 It appears that the variety of ocular findings in this syndrome represent variable expression of a single genetic entity, attributed to the KIF11 mutations.…”

“… 8 In recent studies, the majority of patients with autosomal recessive microcephaly with chorioretinopathy had hypermetropic astigmatism. 5 , 21 , 22 Patients with nanophthalmos and posterior microphthalmos can show macular folds and foveal hypoplasia with absence of foveal depression due to continuation of all retinal layers throughout the macular area. 23 , 24 In our study, 2 siblings with MLCRD (patients 17 and 18) with high hypermetropia had foveal hypoplasia with mild macular elevation and low visual acuity, without macular folds.…”

“…Recently, optical coherence tomography (OCT) in 4 patients with KIF11 mutations and microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability revealed atrophic maculae and disruption of the photoreceptor inner segment ellipsoid and the outer retinal bands. 5 Foveal hypoplasia, retinal pigment epithelium (RPE) thinning, and a disruption of the ellipsoid zone (EZ) also have been found. 12 In addition, children with congenital Zika syndrome showed retinal and choroidal thinning.…”

A Novel Mutation of KIF11 in a Child with 22q11.2 Deletion Syndrome Associated with MCLMR

“…Lacunar chorioretinopathy was found in approximately 60% of the patients. Balikova et al [2016] showed generalized rod-cone and severe macular dysfunction in 7 and optic disc pallor in 3 patients with KIF11 mutations. The longterm observation of 3 of the KIF11 mutation-positive patients with chorioretinal atrophy over 2, 6, and 9 years revealed no progression of fundus examinations.…”