Extra-muscular manifestations in GNE myopathy patients: A nationwide repository questionnaire survey in Japan

Yoshioka, Wakako; Shimizu, Reiko; Takahashi, Yūji; Oda, Yuriko; Yoshida, Sumiko; Ishihara, Nahoko; Nishino, Ichizo; Nakamura, Harumasa; Mori‐Yoshimura, Madoka

doi:10.1016/j.clineuro.2021.107057

Cited by 11 publications

(13 citation statements)

References 25 publications

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“…Extramuscular manifestations of GNE myopathy were described recently [7 ▪ ,8 ▪▪ ] (Fig. 1), and may provide important insights into the pathomechanisms underlying the disease.…”

Section: Extramuscular Manifestationsmentioning

confidence: 80%

“…Sleep apnea syndrome (SAS), which is known to greatly increase risk of death [11], was recently reported to occur at high frequency in Japanese patients with GNE myopathy [7 ▪ ,8 ▪▪ ]. Obstructive SAS, rather than central apnea [8 ▪▪ ], was detected, but there was no correlation with respiratory function or disease duration [8 ▪▪ ].…”

Section: Extramuscular Manifestationsmentioning

confidence: 99%

“…Thrombocytopenia has been reported in 13 families with pathogenic GNE variants, including eight families with myopathy and five families without myopathy [1 ▪▪ ,13 ▪ –15 ▪ ]. In a survey of Japanese patients, 4% were previously or currently diagnosed with idiopathic thrombocytopenia, which is higher than the rate in the general population [7 ▪ ]. Platelets expressing desialylated glycans are removed by a hepatic-based system, resulting in thrombocytopenia [16].…”

Section: Extramuscular Manifestationsmentioning

confidence: 99%

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Recent advances in establishing a cure for GNE myopathy

Yoshioka

Nishino

Noguchi

2022

Current Opinion in Neurology

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Purpose of review GNE myopathy is a rare autosomal recessive disease caused by biallelic variants in the GNE gene, which encodes an enzyme involved in sialic acid biosynthesis. No drugs are approved for the treatment of GNE myopathy. Following proof-of-concept of sialic acid supplementation efficacy in mouse models, multiple clinical trials have been conducted. Here, we review clinical trials of sialic acid supplementation therapies and provide new insights into the additional clinical features of GNE myopathy. Recent findingsClinical trials of sialic acid supplementation have been conducted in Europe, the USA, Japan, and South Korea. Some clinical trials of NeuAc-extended release tablets demonstrated amelioration of decline in upper extremity muscle strength; however, no significant improvement was observed in phase 3 trials in Europe and USA. A phase 2 trial of ManNAc showed slowed decline of both upper and lower extremity strength. GNE myopathy patient registries have been established in Europe and Japan, and have provided information on extramuscular manifestations such as thrombocytopenia, respiratory dysfunction, and sleep apnea syndrome. Sensitive and reliable biomarkers, and a disease-specific functional activity scale, have also been investigated.

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“…Extramuscular manifestations of GNE myopathy were described recently [7 ▪ ,8 ▪▪ ] (Fig. 1), and may provide important insights into the pathomechanisms underlying the disease.…”

Section: Extramuscular Manifestationsmentioning

confidence: 80%

Section: Extramuscular Manifestationsmentioning

confidence: 99%

Section: Extramuscular Manifestationsmentioning

confidence: 99%

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Recent advances in establishing a cure for GNE myopathy

Yoshioka

Nishino

Noguchi

2022

Current Opinion in Neurology

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“…Initial symptoms, complications, and disease progression have been reported for 121 Japanese patients with GNE myopathy 3 . Surveys have also been conducted, including for pregnancies in patients with GNE myopathy, including 28 post‐onset pregnancies, 47 and for extra‐muscular manifestations in 126 patients 36 . The newsletter is distributed to the participants and their clinicians including the latest news of the disease.…”

Section: Patient Registriesmentioning

confidence: 99%

Advances in understanding of the natural history, mechanism, extra‐muscular manifestations and treatment of GNE myopathy

Yoshioka

Noguchi

Mori

et al. 2022

Neurology & Clinical Neurosc

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GNE myopathy has an estimated worldwide prevalence of 1/1 000 000 (Orphanet; https://www.orpha.net/conso r/cgi-bin/index.php) but is more common in Persian and Japanese populations. 1 It is an adultonset progressive myopathy which typically starts with foot drop and uniquely spares quadriceps until the late stage. [2][3][4][5] Rimmed vacuoles are frequently be found in atrophic fibers of affected muscles. 1 Model mice studies have led to the better understanding of molecular mechanism and multiple clinical trials. At the same time, natural history studies and patient registries have contributed much for the comprehension of GNE myopathy including extra-muscular manifestations. In this review, we summarize the evolving research on GNE myopathy and introduce more recently identified features.

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“…Recent studies have found that GNE mutations affect both muscles and nerves, and multiple patients have evidence of axonal motor nerve involvement [ 10 , 11 ]. Patients with GNE myopathy have extramuscular manifestations of idiopathic thrombocytopenia, cardiac damage, sleep apnea syndrome, and respiratory dysfunction, the etiologies of which are unknown [ 12 ]. The diversity of clinical phenotypes reminds us that we must investigate other GNE enzymes’ roles.…”

Section: Introductionmentioning

confidence: 99%

The role of amyloid β in the pathological mechanism of GNE myopathy

2022

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GNE myopathy is a hereditary muscle disorder characterized by muscle atrophy and weakness initially involving the lower distal extremities. The treatment of GNE myopathy mainly focuses on a sialic acid deficiency caused by a mutation in the GNE gene, but it has not achieved the expected effect. The main pathological features of GNE myopathy are myofiber atrophy and rimmed vacuoles, including accumulation of amyloid β, which is mainly found in atrophic muscle fibers. Although the role of amyloid β and other misfolded proteins on the nervous system has been widely recognized, the cause and process of the formation of amyloid β in the pathological process of GNE myopathy are unclear. In addition, amyloid β has been reported to be linked to quality control mechanisms of proteins, such as molecular chaperones, the ubiquitin–proteasome system, and the autophagy-lysosome system. Herein, we summarize the possible reasons for amyloid β deposition and illustrate amyloid β-mediated events in the cells and their role in muscle atrophy in GNE myopathy. This review represents an overview of amyloid β and GNE myopathy that could help identify a potential mechanism and thereby a plausible therapeutic for the disease.

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Extra-muscular manifestations in GNE myopathy patients: A nationwide repository questionnaire survey in Japan

Cited by 11 publications

References 25 publications

Recent advances in establishing a cure for GNE myopathy

Recent advances in establishing a cure for GNE myopathy

Advances in understanding of the natural history, mechanism, extra‐muscular manifestations and treatment of GNE myopathy

The role of amyloid β in the pathological mechanism of GNE myopathy

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