Oculopharyngeal Muscular Dystrophy: Phenotypic and Genotypic Studies in a Chinese Population

Jiang, Shan; Chen, Bin; Lin, Pengfei; Li, Duoling; Luo, Yue‐Bei; Ji, Kunqian; Zheng, Jieyun; Yuan, Yun; Yan, Chuanzhu

doi:10.1007/s12017-014-8327-5

Cited by 15 publications

(15 citation statements)

References 17 publications

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“…Prior to this study, this important issue had not been confirmed, probably due to the relatively small size of genotyped cohorts ranging from 17 to 86 patients. 4 – 11 Nevertheless, it seemed that phenotypes including early onset, severe ptosis and dysphagia, proximal muscle weakness, and loss of ambulation were observed in patients with the largest PABPN1 heterozygous expansion repeats, as well as in compound heterozygous and homozygous patients. 2 , 13 , 15 , 16 Cognitive decline and psychological disorders were described in homozygous patients 17 and in 2 heterozygous patients harboring 18 expansions.…”

Section: Discussionmentioning

confidence: 99%

“… 2 , 3 OPMD shows a large worldwide distribution (described in more than 30 countries) and several studies describing the distribution of PABPN1 alleles on a large cohort have been published. 4 – 11 In these studies, no correlation between the size of the expansion and the severity of the phenotype could clearly be evidenced, probably due to the relatively small size of genotyped patient cohorts. Here we performed a retrospective analysis on the French cohort diagnosed in neuromuscular reference centers between 1999 and 2014.…”

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confidence: 83%

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Correlation between PABPN1 genotype and disease severity in oculopharyngeal muscular dystrophy

et al. 2017

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Objective:Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant adult-onset disease characterized by progressive ptosis, dysphagia, and proximal limb weakness. The genetic cause is an expanded (GCN)n mutation in the PABPN1 gene encoding for the polyadenylate-binding protein nuclear 1. We hypothesized a potential correlation between the size of the (GCN)n expansion and the severity of the phenotype. To do this, we characterized the distribution of the genotypes as well as their correlation with age at diagnosis and phenotypical features in a large cohort of heterozygous and homozygous patients with OPMD in France with a confirmed molecular diagnosis of PABPN1.Methods:We explored 354 unrelated index cases recruited between 1999 and 2014 in several neuromuscular centers in France.Results:This cohort allowed us to characterize the frequency of mutated alleles in the French population and to demonstrate a statistical correlation between the size of the expansion and the mean age at diagnosis. We also confirmed that homozygous patients present with a more severe disease.Conclusions:It has been difficult to establish phenotype–genotype correlations because of the rare nature of this disease. Our work demonstrates that patients with OPMD with longer PABPN1 expansion are on average diagnosed at an earlier age than patients with a shorter expansion, confirming that polyalanine expansion size plays a role in OPMD, with an effect on disease severity and progression.

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Section: Discussionmentioning

confidence: 99%

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confidence: 83%

Correlation between PABPN1 genotype and disease severity in oculopharyngeal muscular dystrophy

et al. 2017

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“…All patients were analyzed for (GCN) expansion in exon 1 of PABPN1 by polymerase chain reaction (PCR) followed by direct sequencing to exclude OPMD [ 17 ]. The CTG repeat in the 3′ region of the DMPK gene, which is causative for DM1, was assessed by triplet repeat primed PCR.…”

Section: Methodsmentioning

confidence: 99%

Clinical and Muscle Imaging Findings in 14 Mainland Chinese Patients with Oculopharyngodistal Myopathy

et al. 2015

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Oculopharyngodistal myopathy (OPDM) is an extremely rare, adult-onset hereditary muscular disease characterized by progressive external ocular, pharyngeal, and distal muscle weakness and myopathological rimmed vacuole changes. The causative gene is currently unknown; therefore, diagnosis of OPDM is based on clinical and histopathological features and genetic exclusion of similar conditions. Moreover, variable manifestations of this disorder are reported in terms of muscle involvement and severity. We present the clinical profile and magnetic resonance imaging (MRI) changes of lower limb muscles in 14 mainland Chinese patients with OPDM, emphasizing the role of muscle MRI in disease identification and differential diagnosis. The patients came from 10 unrelated families and presented with progressive external ocular, laryngopharyngeal, facial, distal limb muscle weakness that had been present since early adulthood. Serum creatine kinase was mildly to moderately elevated. Electromyography revealed myogenic changes with inconsistent myotonic discharge. The respiratory function test revealed subclinical respiratory muscle involvement. Myopathological findings showed rimmed vacuoles with varying degrees of muscular dystrophic changes. All known genes responsible for distal and myofibrillar myopathies, vacuolar myopathies, and muscular dystrophies were excluded by PCR or targeted next-generation sequencing. Muscle MRI revealed that the distal lower legs had more severe fatty replacement than the thigh muscles. Serious involvement of the soleus and long head of the biceps femoris was observed in all patients, whereas the popliteus, gracilis and short head of biceps femoris were almost completely spared, even in advanced stages. Not only does our study widen the spectrum of OPDM in China, but it also demonstrates that OPDM has a specific pattern of muscle involvement that may provide valuable information for its differential diagnosis and show further evidence supporting the conclusion that OPDM is a unique disease phenotype.

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“…It is yet obscure whether in OPMD, alanine expansion length affects muscle weakness severity. Recent studies suggested that additional factors, other than the known genotype, could modulate disease severity [29]. Our previous studies suggested that aging factors could affect symptom initiation [27].…”

Section: Resultsmentioning

confidence: 99%

Diagnostics of short tandem repeat expansion variants using massively parallel sequencing and componential tools

et al. 2018

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Short tandem repeats (STRs) are scattered throughout the human genome. Some STRs, like trinucleotide repeat expansion (TRE) variants, cause hereditable disorders. Unambiguous molecular diagnostics of TRE disorders is hampered by current technical limitations imposed by traditional PCR and DNA sequencing methods. Here we report a novel pipeline for TRE variant diagnosis employing the massively parallel sequencing (MPS) combined with an opensource software package (FDSTools), which together are designed to distinguish true STR sequences from STR sequencing artifacts. We show that this approach can improve TRE diagnosis, such as Oculopharyngeal muscular dystrophy (OPMD). OPMD is caused by a trinucleotide expansion in the PABPN1 gene. A short GCN expansion, (GCN[10]), coding for a 10 alanine repeat is not pathogenic, but an alanine expansion is pathogenic. Applying this novel procedure in a Dutch OPMD patient cohort, we found expansion variants from GCN[11] to GCN[16], with the GCN[16] as the most abundant variant. The repeat expansion length did not correlate with clinical features. However, symptom severity was found to correlate with age and with the initial affected muscles, suggesting that aging and muscle-specific factors can play a role in modulating OPMD.

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Oculopharyngeal Muscular Dystrophy: Phenotypic and Genotypic Studies in a Chinese Population

Cited by 15 publications

References 17 publications

Correlation between PABPN1 genotype and disease severity in oculopharyngeal muscular dystrophy

Correlation between PABPN1 genotype and disease severity in oculopharyngeal muscular dystrophy

Clinical and Muscle Imaging Findings in 14 Mainland Chinese Patients with Oculopharyngodistal Myopathy

Diagnostics of short tandem repeat expansion variants using massively parallel sequencing and componential tools

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