Brain MRI abnormalities in muscular dystrophy due to FKRP mutations

Abstract

Introduction: FKRP mutations cause a muscular dystrophy which may present in the neonatal period (MDC1C) or later in life (LGMD2I). Intelligence and brain imaging have been previously reported as being normal in FKRP-associated muscular dystrophy, except in rare cases presenting with mental retardation associated with structural brain abnormalities. Patients and methods: We studied cerebral MRIs in twelve patients with FKRP-associated muscular dystrophy presenting in infancy or early childhood, at ages between 14 months and 43 years. Two patients had severe cognitive deficits, four had mild-moderate mental retardation and the rest were considered to have normal intelligence. All, but one were wheelchair-bound and 7 were mechanically ventilated. Results: Brain MRI was abnormal in 9 of 12 patients. Brain atrophy was seen in 8 patients. One child had isolated ventricular enlargement at 4 years. Cortical atrophy involved predominantly temporal and frontal lobes and was most important at later ages. In two cases with serial images this atrophy seemed progressive. Three patients, two with severe and one with moderate mental retardation, showed structural abnormalities of the posterior fossa with hypoplasia of the vermis and pons, and cerebellar hemispheric cysts. These abnormalities were stable with time. Two of these three patients also showed diffuse white matter abnormalities in early childhood, which regressed with time. Conclusions: MRI abnormalities are common in patients with FKRP-associated muscular dystrophy presenting at birth or in early childhood. Progressive brain atrophy is the most frequent finding. Posterior fossa malformations and transient white matter changes may be seen in patients with associated mental retardation.

Introduction

Mutations in the FKRP (fukutin-related protein) gene were first identified in 2001 in a series of children with congenital muscular dystrophy (CMD), very high CK levels, progressive weakness and muscle hypertrophy [1], [2]. Soon after, mutations in the same gene were also found in a number of patients with a milder, later-onset form of limb-girdle muscular dystrophy [3], previously known as LGMD2I and linked to the FKRP locus on chromosome 19q13.3 [4] and in an intermediate phenotype with a Duchenne-like picture [5].

The CMDs have autosomal recessive inheritance and are clinically very heterogeneous. In Western countries, most patients show clinical features derived from the muscle involvement and are classified as ‘classical’ CMDs, to distinguish them from rare forms of CMD-associated with severe mental retardation and structural malformations of the central nervous system (CNS). In Europe, more than one third of patients with a classical form of CMD are due to mutations in the LAMA2 (laminin alpha-2 chain of merosin) gene, resulting in a primary defect of merosin (MDC1A in the international classification of CMDs). Intelligence is usually considered normal in these patients, although diffuse white matter signal abnormalities are observed on the brain MRI [6], [7], [8], [9], [10]. Other well defined classical forms of CMD include RSMD1 (rigid spine muscular dystrophy type 1) due to mutations in the selenoprotein N1 [11], UCMD (Ullrich CMD) due to mutations in collagen VI subunits [12], [13], and MDC1C (muscular dystrophy, congenital type 1C) due to FKRP mutations [1], [2].

The group of CMD syndromes associated with severe CNS malformations and mental retardation includes Fukuyama congenital muscular dystrophy (FCMD), the Muscle–Eye–Brain Syndrome (MEB), the Walker Warburg syndrome (WWS), and a recently identified form, designated as MDC1D [14]. These disorders are associated with a wide spectrum of brain malformations and variable eye involvement. Immunocytochemical studies in all of these disorders show a reduction in the immunolabeling of alpha-dystroglycan (alpha-DG), but not of beta-DG [15], [16], [17], and therefore, they are now classified as secondary dystroglycanopathies. Their underlying genetic defects are mutations in genes coding for known or putative glycosyltransferases (fukutin, POMGnT1, POMT1 and LARGE, respectively) [14], [18], [19], [20], suggesting that abnormal protein glycosylation may underlie muscle and CNS involvement in these entities. Patients with muscular dystrophy due to FKRP mutations (MDC1C and LGMD2I) show also reduced alpha-DG glycosylation in muscle. This is not surprising, since FKRP is a fukutin-like enzyme which is also considered to be involved in protein-glycosylation processes [1].

Although intelligence and brain imaging in FKRP patients were initially thought to be normal, we previously reported cognitive impairment and brain atrophy in several cases with MDC1C [2]. More recently, mutations in the FKRP gene have been identified in a number of mentally retarded children with posterior fossa malformations [21], [22], and a smaller number of cases with severe structural brain involvement typical of MEB or WWS [23]. To better address this issue, we systematically investigated for abnormalities on cerebral MRI in twelve FKRP mutated patients with muscular dystrophy presenting in infancy or early childhood, with or without clinical cognitive impairment, and found that CNS involvement is much more frequent than expected in such cases.