TMEM5-associated dystroglycanopathy presenting with CMD and mild limb-girdle muscle involvement

Abstract

The dystroglycanopathies, which are caused by reduced glycosylation of alpha-dystroglycan, are a heterogeneous group of neurodegenerative disorders characterized by variable brain and skeletal muscle involvement. Recently, mutations in TMEM5 have been described in severe dystroglycanopathies. We present the clinical, molecular and neuroimaging features of an Italian boy who had delayed developmental milestones with mild limb-girdle muscle involvement, bilateral frontotemporal polymicrogyria, moderate intellectual disability, and no cerebellar involvement. He also presented a cochlear dysplasia and harbored a reported mutation (p.A47Rfs*42) in TMEM5, detected using targeted next-generation sequencing. The relatively milder muscular phenotype and associated structural brain abnormalities distinguish this case from previously reported patients with severe dystroglycanopathies and expand the spectrum of TMEM5-associated disorders.

Keywords: Cochlear dysplasia; Congenital muscular dystrophy; Limb-girdle muscle weakness; Polymicrogyria; TMEM5.

Fig. 1

Brain MRI in a patient with CMD carrying a mutation in TMEM5. (A–C) Coronal, axial and sagittal FSE T₂-weighted images showing bilateral frontotemporal polymicrogyria (white arrow). (D, E) Axial FLAIR and (F) coronal FSE T2-weighted images revealing patchy, confluent frontoparietal white matter hyperintensities, bilaterally distributed (white arrow). In F as well as in G (axial T2-weighted image) cerebellar anomalies are evident. The latter include abnormal orientation of the cerebellar folia, an irregular gray matter-white matter junction (black arrows) and multiple small subcortical cysts in both cerebellar hemispheres (white arrow heads). In G the cleft in the ventral pons (note the black arrow head) and an enlarged and dysmorphic fourth ventricle (star) are also evident. (H) Sagittal T1-weighted image demonstrating hypoplasia of the pons (white arrow) and a mildly enlarged tectum (white arrow head). (I) Reconstruction of MIP 3D FIESTA image showing bilateral cochlear dysplasia, with fusion of the middle and apical cochlear turns, suggestive of Mondini-type deformity (white arrow). R, right; L, left.