Mutations in the FKRP gene can cause muscle-eye-brain disease and Walker–Warburg syndrome

The hypoglycosylation of α-dystroglycan is a new disease mechanism recently identified in four congenital muscular dystrophies (CMDs): Walker–Warburg syndrome (WWS), muscle-eye-brain disease (MEB), Fukuyama CMD (FCMD), and CMD type 1C (MDC1C).1 The underlying genetic defects in these disorders are mutations in known or putative glycosyltransferase enzymes, which among their targets probably include α-dystroglycan. FCMD (MIM: 253800) is caused by mutations in fukutin2; MEB (MEB [MIM 236670]) is due to mutations in POMGnT13; and in WWS (WWS [MIM: 236670]) POMT1 is mutated.4 In addition to the brain abnormalities, both MEB and WWS have structural eye involvement. In FCMD, eye involvement is more variable, ranging from myopia to retinal detachment, persistent primary vitreous body, persistent hyaloid artery, or microphthalmos.5 WWS, MEB, and FCMD display type II or cobblestone lissencephaly, in which the main abnormality is different degrees of brain malformation secondary at least in part to the overmigration of heterotopic neurones into the leptominenges through gaps in the external (pial) basement membrane.6,7 Whereas there are broad similarities between WWS and MEB, clear diagnostic criteria differentiating between these two conditions have been proposed8 and are shown as clinical features in table 1. A similar combination of muscular dystrophy and cobblestone lissencephaly is also found in the myodystrophy mouse (myd, renamed Largemyd), in which the Large gene is mutated.6,9,10 Our group has very recently identified mutations in the human LARGE gene in a patient with a novel form of CMD (MDC1D).11 View this table: Table 1 Clinical features of patients 1 and 2, compared with MEB and WWS patients with confirmed mutations in POGnT1 and POMT1, respectively The gene encoding the fukutin related protein (FKRP, [MIM 606612]) is mutated in a severe form of CMD (MDC1C, [OMIM 606612]).12 Clinical features of MDC1C are …