Ichizo Nishino

Sialyllactose ameliorates myopathic phenotypes in symptomatic GNE myopathy model mice

Patients with GNE myopathy, a progressive and debilitating disease caused by a genetic defect in sialic acid biosynthesis, rely on supportive care and eventually become wheelchair-bound. To elucidate whether GNE myopathy is treatable at a progressive stage of the disease, we examined the efficacy of sialic acid supplementation on symptomatic old GNE myopathy mice that have ongoing, active muscle degeneration. We examined the therapeutic effect of a less metabolized sialic acid compound (6-sialyllactose) or free sialic acid (N-acetylneuraminic acid) by oral, continuous administration to 50-week-old GNE myopathy mice for 30 weeks. To evaluate effects on their motor performance in living mice, spontaneous locomotion activity on a running wheel was measured chronologically at 50, 65, 72 and 80 weeks of age. The size, force production, and pathology of isolated gastrocnemius muscle were analysed at the end point. Sialic acid level in skeletal muscle was also measured. Spontaneous locomotion activity was recovered in 6-sialyllactose-treated mice, while NeuAc-treated mice slowed the disease progression. Treatment with 6-sialyllactose led to marked restoration of hyposialylation in muscle and consequently to robust improvement in the muscle size, contractile parameters, and pathology as compared to NeuAc. This is due to the fact that 6-sialyllactose is longer working as it is further metabolized to free sialic acid after initial absorption. 6-sialyllactose ameliorated muscle atrophy and degeneration in symptomatic GNE myopathy mice. Our results provide evidence that GNE myopathy can be treated even at a progressive stage and 6-sialyllactose has more remarkable advantage than free sialic acid, providing a conceptual proof for clinical use in patients.

Two cases of nemaline myopathy presenting with hypertrophy of distal limbs with prominent asymmetry

Nemaline myopathy commonly presents with symmetrical proximal weakness. Here we report two cases of nemaline myopathy presenting with distal dominant involvement with prominent asymmetry. Case 1 was a 37-year-old man who recalled frequently falling down and had right calf atrophy since he was 3-years-old. He had right calf muscle atrophy and weakness and steppage gait; his cardiopulmonary function was normal. Case 2 was a 35-year-old man with right calf muscle atrophy and weakness since childhood. He had right dominant distal leg weakness and atrophy together with respiratory failure and started noninvasive positive pressure ventilation. He also developed cardiomyopathy and died from acute respiratory failure due to pneumonia at age 39. Both cases harbored compound heterozygous nebulin (NEB) mutations with c.20131 C>T:p.Arg6711Trp and a nonsense mutation. Nemaline myopathy associated with NEB mutations can present as distal dominant myopathy with prominent asymmetry.

Childhood-onset anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) necrotizing myopathy needs to be distinguished from muscular dystrophy: A case study

A 24-year-old woman visited our hospital with a complaint of walking disability. She had no family history of consanguineous marriage, and her developmental history was unremarkable, with good physical performance just before the onset. At the age of 13, she developed difficulty in walking and visited a pediatrician. Her serum CK level was 10,000u2005IU/l and she was diagnosed with muscular dystrophy by muscle biopsy. At the age of 16, she became wheelchair dependent and was admitted to our hospital. Physical examination revealed diffuse muscle atrophy and proximal weakness, with no calf hypertrophy or selectivity of muscle involvement. Needle EMG and MR images indicated inflammatory myopathy. Muscle biopsy revealed necrotic and regenerating fibers and lymphocyte infiltration. She was re-diagnosed with inflammatory myopathy and recovered walking capacity after immunotherapy. Subsequently, she was tested positive for anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies. To distinguish treatable inflammatory myopathy from muscular dystrophy, a comprehensive assessment of patient history, family history, selectivity of muscle involvement, findings suggestive of inflammation in EMG and CT/MR imaging, and muscle pathology is necessary.