O.14B3GNT4 deficiency: a new α-dystroglycanopathy causing late-onset progressive brain atrophy and muscular dystrophy

Abstract

Defects of α-dystroglycan glycosylation (dystroglycanopathies) account for 20 disorders presenting with either early onset brain and muscular dystrophy phenotype, or late onset purer muscular dystrophy. Here, we report a new dystroglycanopathy with an atypical phenotype of late-onset, progressive brain atrophy and muscular dystrophy. The proband is a 46-year-old man with consanguineous parents of Pakistani origin. He was born at term and had normal motor and cognitive milestones until age 8, when he started to fall and develop involuntary movements and spastic paresis of limbs. He was wheelchair bound by age 13 and speech deteriorated from age 25, until loss of language and cognitive skills at age 32. Cerebral MRI at age 16 showed mild changes of corpus callosum smallness and leukoencephalopathy, which at age 44 had developed into profound atrophy of the entire cerebrum. At age 38, CK was 620 U/l. The muscle biopsy showed severe dystrophic changes, upregulated glycosylation (IIH6 and VIA4 antibodies) in regenerating fibers, but loss of glycosylation in mature fibers. Muscle MRI showed fatty replacement, preferentially of hamstring muscles. No candidate genes were found in large NGS gene panels. Exome sequencing, specifically looking at glycosylation genes, revealed a homozygous p.G160W variant in the B3GNT4 gene, an acetylglucosaminyltransferase highly expressed in brain. Unaffected parents and a brother were heterozygous for this change. We developed a knock-in mouse model of the p.G160W variant. Homozygous mice showed muscle weakness and atrophy at 4 months. At age 6 months, muscle histology showed similar changes as seen in the patient. Brain abnormalities had not developed at this stage. The study demonstrates a new dystroglycanopathy, which unlike other forms has late-onset progressive brain involvement and muscular dystrophy. The muscular dystrophy was replicated in the knock-in mouse model, supporting the pathogenicity of the variant in this new disease gene.