FKRP gene

Overview
Microphthalmia, anophthalmia, coloboma (MAC)
Anterior segment dysgenesis
Congenital cataract
Congenital glaucoma
References

Overview

Gene (OMIM No.)	FKRP (#606596)
Function of gene/protein	Protein: fukutin related protein (FKRP) FKRP is important for the glycosylation (converting carbohydrates to glycoproteins) of alpha-dystroglycan (DAG1), a crucial protein involved in the maintenance of tissue structure High level of expression in the brain, skeletal muscles and heart muscle
Clinical phenotype (OMIM phenotype no.)	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 5 (#613153) Also known as Walker-Warburg syndrome (WWS)/Muscle Eye Brain Disease (MEB) Muscular dystrophy-dystroglycanopathy (congenital with or without mental retardation), type B, 5 (#606612) Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 5 (#607155) Defects in the glycosylation of alpha-dystroglycans cause 3 overlapping syndromes/dystroglycanopathies: WWS, MEB and Fukuyama type Congenital Muscular Dystrophy (FCMD; #253800) WWS—most severe phenotype; MEB—intermediate phenotype; FCMD—mildest phenotype Phenotype severity is determined by the extent which the mutation affects DAG1 glycosylation
Inheritance	Autosomal recessive
Ocular features	Microphthalmia, anophthalmia, coloboma (MAC) spectrum Congenital cataract Anterior segment dysgenesis (ASD) Congenital glaucoma Persistent foetal vasculature Retinal dysplasia Retinal detachment Optic atrophy High myopia
Systemic features	Congenital muscular dystrophy Brain anomalies (cobblestone lissencephaly, hydrocephalus, hypoplastic cerebellar vermis, macrocephaly, microcephaly or anencephaly) Severe hypotonia Occasional seizures Intellectual disability Developmental delays Patients with WWS have a severely limited lifespan with significant CNS and ocular anomalies
Key investigations	B-scan USS to measure axial length to document microphthalmia Electrophysiology to determine visual potential Measurement of intraocular pressure Gonioscopy (if tolerated/EUA) or anterior segment OCT to identify angle abnormalities and any associated anterior segment dysgenesis MRI brain and orbit Systemic assessment with a paediatrician and other relevant specialists Bloods (elevated creatinine kinase) Skeletal muscle biopsy
Molecular diagnosis	Next generation sequencing Targeted gene panels Whole genome sequencing
Management	Ocular Management of MAC Management of congenital cataract Management of anterior segment dysgenesis Management of congenital glaucoma Surgery for dysplastic retina does not confer any visual benefit Rhegmatogenous retinal detachment associated with MEB may be amenable to scleral buckling or vitrectomies Systemic Multidisciplinary approach
Therapies under research	None at present
Further information	Medline Plus

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References

Esapa CT, Benson MA, Schröder JE, et al. Functional requirements for fukutin-related protein in the Golgi apparatus. Hum Mol Genet 2002; 11: 3319–3331
Willer T, Inamori KI, Venzke D, et al. The glucuronyltransferase B4GAT1 is required for initiation of LARGE-mediated α-dystroglycan functional glycosylation. Elife 2014; 3: 3941
Cormand B, Pihko H, Bayés M, et al. Clinical and genetic distinction between Walker-Warburg syndrome and muscle-eye-brain disease. Neurology 2001; 56: 1059–1069
Beltran-Valero De Bernabé D, Voit T, Longman C, et al. Mutations in the FKRP gene can cause muscle-eye-brain disease and Walker-Warburg syndrome. J Med Genet 2004; 41: e61
Van Reeuwijk J, Olderode-Berends MJW, Van Den Elzen C, et al. A homozygous FKRP start codon mutation is associated with Walker-Warburg syndrome, the severe end of the clinical spectrum. Clin Genet 2010; 78: 275–281
Francisco R, Pascoal C, Marques-da-Silva D, et al. Keeping an eye on congenital disorders of O-glycosylation: A systematic literature review. J Inherit Metab Dis. 2019;42(1):29-48

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Updated on November 30, 2020

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