Eye and Brain Abnormalities in Congenital Muscular Dystrophies Caused by Fukutin-Related Protein Gene (FKRP) Mutations

Abstract

Background

Mutations in the fukutin-related protein gene account for a broad spectrum of phenotypes ranging from severe congenital muscular dystrophies to a much milder limb-girdle muscular dystrophy 2I. The involvement of the eyes is variable, with most patients having normal eye examination.

Objectives

We describe eye and brain abnormalities in a 16 month-old-boy with Walker-Warburg syndrome phenotype resulting from a novel fukutin-related protein gene mutation in exon 4 and compare these with other reported patients with fukutin-related protein gene mutation.

Methodology

All patients with reported fukutin-related protein gene mutations who had eye involvement were included. Their clinical features, brain magnetic resonance imaging, and eye findings were compared with our patient.

Conclusions

Patients with fukutin-related protein gene mutation tend to have no or mild eye involvement (generally strabismus), with very few cases reported of moderate to severe eye involvement. Our patient with a novel mutation c.558dupC(p.Ala187fs) represents one of the most severe phenotypes described in regard to eye involvement.

Introduction

The congenital muscular dystrophies (CMDs) are a heterogenous group of muscle diseases with variable genotype and phenotype. Clinical features include congenital or early-onset hypotonia, delayed motor development, and muscle weakness with the muscle biopsy showing generally a dystrophic/myopathic pattern.¹ Mutations in known or putative glycosyltransferase genes (i.e., POMGnT1, POMT1, POMT2, Fukutin, FKRP, LARGE, and ISPD) are associated with CMDs with alpha-dystroglycan deficiency.2, 3, 4

More severe alpha-dystroglycanopathy CMDs have cerebral and ocular abnormalities of varying degrees.⁵ Eye abnormalities described are extremely varied with involvement of both the anterior and posterior segments and include cataracts, microphthalmos, buphthalmos, Peters' anomaly, retinal detachment, retinal dysplasia, and optic nerve hypoplasia.6, 7, 8

Mutations in the FKRP gene result in a broad spectrum of phenotypes, ranging from severe CMD with Walker-Warburg syndrome (WWS) to a mild limb-girdle muscular dystrophy (LGMD) 2I.⁴ Ocular involvement can be variable, with most patients having a normal eye examination. We report a patient with a novel fukutin-related protein gene (FKRP) mutation and associated with complex congenital eye and brain abnormality. Only a few other CMD patients with severe eye involvement resulting from FKRP mutations have been reported and are reviewed here.