Phenotypic stratification and genotype–phenotype correlation in a heterogeneous, international cohort of GNE myopathy patients: First report from the GNE myopathy Disease Monitoring Program, registry portion

Pogoryelova, Oksana; Cammish, P.; Mansbach, Hank; Argov, Zohar; Nishino, Ichizo; Skrinar, Alison; Chan, Yiu-mo; Nafissi, Shahriar; Shamshiri, Hosein; Kakkis, Emil; Lochmüller, Hanns

doi:10.1016/j.nmd.2017.11.001

Cited by 38 publications

(47 citation statements)

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“…The global prevalence estimate for GNE myopathy is lower at 0.4-2.1 per 100,000. 13 However, our prevalence estimates are comparable with those for the Persian Jewish cluster of GNE myopathy caused by the same Middle Eastern mutation. 6 From our data, we extrapolated the carrier frequency for the p.M743T mutation in the Bedouin community to be 1 in 43.…”

Section: Discussionsupporting

confidence: 68%

“…We estimated the minimum prevalence of GNE myopathy caused by the p.M743T mutation in the Bedouin population of Kuwait to be 14 per 100,000. The global prevalence estimate for GNE myopathy is lower at 0.4–2.1 per 100,000 . However, our prevalence estimates are comparable with those for the Persian Jewish cluster of GNE myopathy caused by the same Middle Eastern mutation …”

Section: Discussionsupporting

confidence: 48%

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GNE myopathy in the bedouin population of Kuwait: Genetics, prevalence, and clinical description

et al. 2018

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Section: Discussionsupporting

confidence: 68%

Section: Discussionsupporting

confidence: 48%

GNE myopathy in the bedouin population of Kuwait: Genetics, prevalence, and clinical description

et al. 2018

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“…Generally, inflammation is not associated with HIBM, in which quadriceps muscles are relatively spared of any rimmed vacuolar pathology compared with other muscle types, as seen in studies of smaller numbers of individuals with inclusion‐body myositis (IBM) and in larger study cohorts . The presence of both inflammation and rimmed vacuoles in the quadriceps muscle of this patient is not characteristic of either primary inflammatory or rimmed vacuolar myopathies.…”

Section: Discussionmentioning

confidence: 61%

“…We report here a family having a patient with a novel upstream promoter-region large deletion in the GNE gene, which abolishes expression of the respective allele. Previous reports showed that patients with compound heterozygous variants in both epimerase and kinase GNE mdomains manifest more severe phenotypes than those with both variants in 1 domain, 25 suggesting that mild pathogenicity of missense variants in each domain needed for more disease severity. Although V727M pathogenicity is uncertain given its relatively high prevalence in South Asians, the most parsimonious conclusion given many other similar reports is that this compound heterozygous state contributes to the pathology.…”

Section: Discussionmentioning

confidence: 99%

Clinical utility of RNA sequencing to resolve unusual GNE myopathy with a novel promoter deletion

et al. 2019

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Introduction: UDP N‐acetylglucosamine2‐epimerase/N‐acetylmannosamine‐kinase (GNE) gene mutations can cause mostly autosomal‐recessive myopathy with juvenile‐onset known as hereditary inclusion‐body myopathy (HIBM). Methods: We describe a family of a patient showing an unusual HIBM with both vacuolar myopathy and myositis without quadriceps‐sparing, hindering diagnosis. We show how genetic testing with functional assays, clinical transcriptome sequencing (RNA‐seq) in particular, helped facilitate both the diagnosis and a better understanding of the genotype‐phenotype relationship. Results: We identified a novel 7.08 kb pathogenic deletion upstream of GNE using array comparative genomic hybridization (aCGH) and a common Val727Met variant. Using RNA‐seq, we found only monoallelic (Val727Met‐allele) expression, leading to ~50% GNE reduction in muscle. Importantly, α‐dystroglycan is hypoglycosylated in the patient muscle, suggesting HIBM could be a “dystroglycanopathy.” Conclusions: Our study shows the importance of considering aCGH for GNE‐myopathies, and the potential of RNA‐seq for faster, definitive molecular diagnosis of unusual myopathies. Muscle Nerve, 2019

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“…Patients with GNE myopathy typically present in early adulthood, between 20 and 40 years of age [9,10] with manifestations of anterior tibialis weakness, such as tripping, gait disturbance, inability to lift toes, or foot drop [9][10][11], although some patients present to medical attention at later stages of the disease.…”

Section: Clinical Manifestations Of Gne Myopathymentioning

confidence: 99%

GNE Myopathy: Etiology, Diagnosis, and Therapeutic Challenges

2018

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GNE myopathy, previously known as hereditary inclusion body myopathy (HIBM), or Nonaka myopathy, is a rare autosomal recessive muscle disease characterized by progressive skeletal muscle atrophy. It has an estimated prevalence of 1 to 9:1,000,000. GNE myopathy is caused by mutations in the GNE gene which encodes the rate-limiting enzyme of sialic acid biosynthesis. The pathophysiology of the disease is not entirely understood, but hyposialylation of muscle glycans is thought to play an essential role. The typical presentation is bilateral foot drop caused by weakness of the anterior tibialis muscles with onset in early adulthood. The disease slowly progresses over the next decades to involve skeletal muscles throughout the body, with relative sparing of the quadriceps until late stages of the disease. The diagnosis of GNE myopathy should be considered in young adults presenting with bilateral foot drop. Histopathologic findings on muscle biopsies include fiber size variation, atrophic fibers, lack of inflammation, and the characteristic Brimmed^vacuoles on modified Gomori trichome staining. The diagnosis is confirmed by the presence of pathogenic (mostly missense) mutations in both alleles of the GNE gene. Although there is no approved therapy for this disease, preclinical and clinical studies of several potential therapies are underway, including substrate replacement and gene therapy-based strategies. However, developing therapies for GNE myopathy is complicated by several factors, including the rare incidence of disease, limited preclinical models, lack of reliable biomarkers, and slow disease progression.

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Phenotypic stratification and genotype–phenotype correlation in a heterogeneous, international cohort of GNE myopathy patients: First report from the GNE myopathy Disease Monitoring Program, registry portion

Cited by 38 publications

References 29 publications

GNE myopathy in the bedouin population of Kuwait: Genetics, prevalence, and clinical description

GNE myopathy in the bedouin population of Kuwait: Genetics, prevalence, and clinical description

Clinical utility of RNA sequencing to resolve unusual GNE myopathy with a novel promoter deletion

GNE Myopathy: Etiology, Diagnosis, and Therapeutic Challenges

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