Seminar: Distal myopathies – elucidation of mechanism and development of therapy

MDUK OXFORD NEUROMUSCULAR CENTRE SEMINAR SERIES

ATTENDANCE

This seminar is intended for the personnel and students at the University of Oxford and the Oxford University Hospitals Foundation Trust.

Hybrid seminar at the George Pickering Education Centre on Floor 3 of the JR Hospital. For the online link, please email chelsea.larabee@idrm.ox.ac.uk.

Students, postdoctoral researchers, and other trainees will be invited to have lunch with Dr. Nishino following the talk. To attend the lunch, please sign up here.

ABSTRACT

I will focus on two (non-dystrophic) distal myopathies which are relatively frequent in Japan: GNE myopathy and oculopharyngodistal myopathy (OPDM).

GNE myopathy is an autosomal recessive muscle disease characterized clinically by preferential involvement of tibialis anterior muscle and relative sparing of quadriceps, and pathologically by the presence of rimmed vacuoles, which is caused mostly by missense mutations in the GNE gene that encodes a protein with the activity of two enzymes in sialic acid biosynthesis, UDP-GlcNAC 2-epimerase and ManNAc kinase, resulting in the reduction of the sialic acid levels in serum and skeletal muscles. So far, 103 different mutations have been identified among 345 Japanese unrelated families. We treated our model mice, which showed a phenotype clinicopathologically similar to human patients, with ManNAc, NeuAc, and sialic acid conjugate, sialyllactose from around 15 weeks of age and continued to around 55 weeks. Phenotypic manifestations were almost completely suppressed, indicating that sialic acid deficiency is the cause of GNE myopathy and that the disease can be suppressed by sialic acid supplementation.

OPDM is an autosomal dominant muscle disease which is characterized by ocular and bulbar symptoms, including ptosis, ophtalmoparesis, and dysphagia, in addition to preferential distal limb muscle involvement. It is clinicopathologically similar to oculopharyngeal muscular dystrophy (OPMD) which is caused by alanine codon expansions in PABPN1. Recently, it was identified to be due to the expansion of the CGG repeats in the 5’ UTR of LRP12. Soon after that, similar 5’ UTR CGG repeat expansions in GIPC1 and NOTCH2NLC were found to be associated with OPDM. In Japan, majority of OPDM patients seem to have expansions in LRP12 while Chinese OPDM patients those in GIPC1. I will discuss detailed clinicopathological features of OPDM_LRP12 and pathological differentiation between OPDM and OPMD.

SPEAKER

Dr. Ichizo Nishino is Director of Department of Neuromuscular Research, National Institute of Neuroscience (NIN), National Center of Neurology and Psychiatry (NCNP). He is also appointed to Director of two departments in Medical Genome Center in NCNP. Currently, he is a Guest/Visiting Professor at 6 universities: University of Yamanashi, Shinshu University, Nara Medical University, Kaohsiung Medical University (Taiwan), Peking University First Hospital (China) and Siriraj Hospital, Mahidol University (Thailand).

Dr. Nishino obtained his M.D. in 1989 from Kyoto University. After 5 years of neurology training, he started muscle disease research in NCNP in 1994 and further continued research for 2 years in Columbia University in New York. He was appointed to his current position in 2001. By now, he has published more than 680 PubMed-listed papers in the field.

His laboratory functions as a nationwide referral center for muscle disease in Japan, providing diagnostic service for muscle pathology and genetic analysis. His lab collects around 80% of muscle biopsies performed in Japan (1119 cases in 2022) and he reads and signs out all cases. As a result, his muscle repository has more than 23,000 frozen muscle biopsy samples, which is one of the largest collections of the patient’s muscles.

LOCATION

The talk will be in the George Pickering Education Centre on Floor 3 of the John Radcliffe Hospital. Once entering the Main Entrance (with Marks & Spencer and WHSmith), go to the lifts (immediately past the pharmacy on the right side). Go up one floor to Floor 3 and follow the signs for the Education Centre. The George Pickering Lecture Hall is inside the cafe.