Identification of a novel mutation in a Korean patient with oculopharyngeal muscular dystrophy.

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset muscle disorder characterized by progressive dysphagia and bilateral ptosis. Mutations in the polyadenylate binding protein nuclear 1 (PABPN1) gene have been found to cause OPMD. The typical mutation is a stable trinucleotide repeat expansion in the first exon of the PABPN1 gene, in which (GCG)(6) is the normal repeat length. We investigated a Korean patient with OPMD and identified a novel mutation: a heterozygous insertion of a 9-bp sequence [(GCG)(GCA)(GCA); c.27_28insGCGGCAGCA] instead of the (GCG) repeat expansion, resulting in an in-frame insertion of three alanines (p.A10insAAA). To the best of our knowledge, this is the first report of a genetically confirmed case of OPMD in Korea.     

眼咽型肌营养不良汉族六家系的临床和遗传学特点

目的 初步总结我国汉族眼咽型肌营养不良(OPMD)患者的临床和多腺苷酸结合蛋白核1(PABPN1)基因改变特点.方法 6个OPMD家系共28例患者,男性13例,女性15例,发病年龄32～70岁,平均发病年龄49.7岁.在可确定首发症状的患者中,以吞咽困难或构音障碍首发的13例、眼睑下垂首发的4例、双下肢无力首发的1例.经过3～20年均出现眼睑下垂、吞咽困难和构音障碍,其中7例出现四肢近端无力.对6例先证者做肌肉活体组织检查,标本进行常规组织病理和电镜检查.对6个家系的先证者以及部分家庭成员进行PABPN1基因检查,并对6例先证者进行单体型分析.结果 6例先证者的肌肉活体组织检查均发现肌纤维直径轻度变异加大伴随肌纤维内镶边空泡形成,4例患者经电镜检查发现OPMD典型的核内栅栏样丝状包涵体.3个家系的PABPN1基因型为(GCG)9,另外3个家系的基因型分别为(GCG)6(GCA)1(GCG)3、(GCG)10和(GCG)8.2个携带(GCG)9突变的家系存在rs2239579(C)-(GCG)9-SNP2622(C)的单倍体型.结论 吞咽异常和眼睑下垂均是我国汉族OPMD患者的首发症状.肌纤维出现镶边空泡以及核内包涵体是我国患者的常见病理改变.PABPN1基因的(GCG)异常扩增和(GCA)插入突变均出现在我国患者,起源具有多源性.携带(GCG)9突变的部分家系可能来自共同祖先.     

Progress in understanding the pathogenesis of oculopharyngeal muscular dystrophy

Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disorder characterized by progressive eyelid drooping (ptosis), swallowing difficulties (dysphagia), and proximal limb weakness. The autosomal dominant form of this disease is caused by expansions of a (GCG)6 repeat to (GCG)8-13 in the PABPN1 gene. These mutations lead to the expansion of a polyalanine stretch from 10 to 12-17 alanines in the N-terminal domain of PABPN1. Mutated PABPN1 (mPABPN1) induces the formation of muscle intranuclear inclusions that are thought to be the hallmark of this disease. In this review, we discuss: 1) OPMD genetics and PABPN I function studies; 2) diseases caused by polyalanine expansions and cellular polyalanine toxicity; 3) mPABPN1-induced intranuclear inclusion toxicity; 4) role of oligomerization of mPABPNI in the formation and toxicity of OPMD intranuclear inclusions and; 5) recruitment of subcellular components to the OPMD inclusions. We present a potential molecular mechanism for OPMD pathogenesis that accounts for these observations.     

HnRNP A1 and A/B interaction with PABPN1 in oculopharyngeal muscular dystrophy

BACKGROUND: Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disorder characterized by progressive ptosis, dysphagia and proximal limb weakness. The autosomal dominant form of this disease is caused by short expansions of a (GCG)6 repeat to (GCG) in the PABPN1 gene. The mutations lead to the expansion of a polyalanine stretch from 10 to 12-17 alanines in the N-terminus of PABPN1. The mutated PABPN1 (mPABPN1) induces the formation of intranuclear filamentous inclusions that sequester poly(A) RNA and are associated with cell death. METHODS: Human fetal brain cDNA library was used to look for PABPNI binding proteins using yeast two-hybrid screen. The protein interaction was confirmed by GST pull-down and co-immunoprecipitation assays. Oculopharyngeal muscular dystrophy cellular model and OPMD patient muscle tissue were used to check whether the PABPN1 binding proteins were involved in the formation of OPMD intranuclear inclusions. RESULTS: We identify two PABPNI interacting proteins, hnRNP A1 and hnRNP A/B. When co-expressed with mPABPN1 in COS-7 cells, predominantly nuclear protein hnRNP A1 and A/B co-localize with mPABPN1 in the insoluble intranuclear aggregates. Patient studies showed that hnRNP A1 is sequestered in OPMD nuclear inclusions. CONCLUSIONS: The hnRNP proteins are involved in mRNA processing and mRNA nucleocytoplasmic export, sequestering of hnRNPs in OPMD intranuclear aggregates supports the view that OPMD intranuclear inclusions are "poly(A) RNA traps", which would interfere with RNA export, and cause muscle cell death.     

Oculopharyngeal muscular dystrophy

Autosomal dominant oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disease with worldwide distribution. It usually presents in the fifth or sixth decades with progressive dysphagia, eyelid ptosis, and proximal limb weakness. Unique intranuclear filament inclusions in skeletal muscle fibers are its morphological hallmark. Surgical correction of the ptosis and cricopharyngeal myotomy are the only therapies available. Autosomal dominant OPMD is caused by short (GCG)8-13 riplet-repeat expansions in the polyadenylation binding protein 2 (PABP2) gene, which is localized in chromosome 14q11. Autosomal recessive OPMD is caused by a double dose of a (GCG)7 PABP2 allele. The GCG expansions cause lengthening of a predicted polyalanine tract in the protein. The expanded polyalanine domains may cause polyalanine nuclear toxicity by accumulating as nondegradable nuclear filaments.     

Preferential distal muscle involvement in case of oculopharyngeal muscular dystrophy with (GCG) 13 expansion]

We reported a 52-year-old woman with oculopharyngeal muscular dystrophy (OPMD) harboring expanded (GCG) 13 mutation of the poly (A) binding protein 2 gene. She presented not only ptosis and dysphagia but distal dominant muscle atrophy in four extremities. CT demonstrated distal muscle atrophy with marked fat replacement in the biceps femoris, semitendinosus, membraneous, soleus, and gastrocnemius muscles. Although OPMD is considered to be a muscle disease, this patient showed even neurogenic features in the electrophysiological and pathological findings. Although previous reports indicate that OPMD is genetically homogeneous disease, some cases with OPMD may show some atypical features associated with neurogenic involvement.     

Okulopharyngeale Muskeldystrophie Genetische Diagnostik einer Familie in Deutschland

Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant myopathy with almost benign course. Its clinical features include ptosis, dysphagia, and proximal limb muscle weakness. The OPMD gene has been localized to chromosome 14, causing expansions of GCG triplets. Scattered families with OPMD belonging to different ethnic groups have been described worldwide. We describe one from northern Germany. In genetic diagnosis, expansion of GCG triplets to 11 was observed, which proved that myopathy, which is very rare in Germany.     

Mutation analysis of oculopharyngeal muscular dystrophy in Hispanic American families.

BACKGROUND: Oculopharyngeal muscular dystrophy (OPMD) is a late-onset autosomal dominant muscular dystrophy characterized by progressive ptosis, swallowing difficulties, and proximal limb weakness. Recently, the genetic basis of this disease has been characterized by mutations in the PABP2 gene that involve short expansions of the trinucleotide repeat GCG. OBJECTIVES: To independently confirm the presence and study the meiotic stability of the GCG expansion mutations in a distinct ethnic population with OPMD. SETTINGS: Hospital and university research laboratories in Los Angeles, Calif. SUBJECTS AND METHODS: Three unrelated families of Hispanic American descent were identified in whom OPMD was transmitted in an autosomal dominant pattern. All of these families can trace affected ancestors to the southwestern United States or to the bordering states of Mexico. In these families, 14 persons with OPMD were identified and studied. RESULTS: Our results confirm that in these families, expansion mutations characterized by a gain of 3 GCG repeats in the wild-type allele result in an abnormal nucleotide length of 9 GCG repeats in the PABP2 gene. In these families, these mutations are associated with the OPMD phenotype. The identical repeat mutation ([GCG]9) is found in all affected members of these unrelated families and shows relative meiotic stability. CONCLUSIONS: These results support and extend our study of haplotype analysis and suggest that a founder effect may have occurred for OPMD in this Hispanic American population.     

A late-onset case of oculopharyngeal muscular dystrophy carrying a (GCG)8 repeat expansion in the PAPBN1 gene]

We report a sporadic case of a female patient with oculopharyngeal muscular dystrophy (OPMD). Her father died at age 86 and mother at age 74. There was no familial occurrence of the disease. The patient initially developed a nasal voice at age 66. Neurological examinations on admission at age 72 revealed bilateral ptosis, a limitation of ocular movement without diplopia, dysphagia, and proximal muscle weakness. Serum creatine kinase level was slightly increased. Biopsied muscle specimens showed variation in fiber size as well as the occasional presence of rimmed vacuoles. On the basis of these clinical and laboratory findings, we suspected a diagnosis of OPMD, although a family history was absent. To confirm the diagnosis of OPMD, we performed a gene analysis for poly A binding protein, nuclear 1 (PABPN1; PABP2), which revealed a mild expansion of GCG repeat (8 repeats) as a heterozygous state. Clinical features of the patient were consistent with those in a previous literature reporting that patients carrying (GCG)8 repeat as a heterozygous state show a relatively late onset and a mild phenotype. The case of this patient emphasizes the importance of the PABPN1 gene analysis for patients showing muscular weakness involving oculopharyngeal and proximal limb muscles even when a familial occurrence of the disease is not apparent.     

Homozygotes for oculopharyngeal muscular dystrophy have a severe form of the disease.

Autosomal dominant oculopharyngeal muscular dystrophy (OPMD) usually begins with ptosis or dysphagia during the fifth or sixth decade of life. We studied 7 patients with OPMD symptoms starting before the age of 36 years. All were found to be homozygotes for the dominant (GCG)9 OPMD mutation. On average, disease onset was 18 years earlier than in heterozygotes, and patients had a significantly larger number of muscle nuclei containing intranuclear inclusions (INIs) (9.4 vs 4.9%).     

Quantitative vs qualitative muscle MRI: Imaging biomarker in patients with Oculopharyngeal Muscular Dystrophy (OPMD)

Oculopharyngeal muscular dystrophy (OPMD) is a genetic muscle disease causing ptosis, severe swallowing difficulties and progressive limb weakness, although atypical presentations may be difficult to diagnose. Sensitive biomarkers of disease progression in OPMD are needed to enable more effective clinical trials. This study was designed to test the feasibility of using MRI to aid OPMD diagnosis and monitor OPMD progression. Twenty-five subjects with Dixon whole-body muscle MRI were enrolled: 10 patients with genetically confirmed OPMD, 10 patients with non-OPMD muscular dystrophies, and 5 controls. Using the MRI Dixon technique, muscle fat replacement was evaluated in the tongue, serratus anterior, lumbar paraspinal, adductor magnus, and soleus muscles using quantitative and semi-quantitative rating methods. Changes were compared with muscle strength testing, dysphagia severity, use of gait aids, and presence of dysarthria. Quantitative MRI scores of muscle fat replacement in the tongue could differentiate OPMD from other muscular dystrophies and from controls. Moreover, fat fraction in the tongue correlated with clinical severity of dysphagia. This study provides preliminary support for the use of Dixon-based quantitative MRI images as outcome measures for monitoring disease progression in clinical trials and provides rationale for future prospective studies aimed at methodological refinement and covariate identification.     

GCG genetic expansions in Italian patients with oculopharyngeal muscular dystrophy

OBJECTIVE: To screen Italian patients with oculopharyngeal muscular dystrophy (OPMD) for GCG repeat expansions in the Poly(A) binding-protein 2 (PABP2) gene. BACKGROUND: Oculopharyngeal muscular dystrophy is an adult-onset autosomal dominant muscle disease linked to 14q11 pathologically characterized by unique 8.5 nm intranuclear filaments in skeletal muscle fibers. Short expansions of a (GCG)6 repeat located in exon 1 of the newly isolated PABP2 gene have been demonstrated in a large number of OPMD families. METHODS: We studied 18 patients diagnosed with OPMD. A muscle biopsy was performed in 16 patients. Screening for the pathologic expansion was performed on a PCR amplified DNA fragment encompassing the GCG repeat. RESULTS: Heterozygous (GCG)-repeat expansions were detected in 13 patients in association with (GCG)6 normal allele or (GCG)7 polymorphic allele. All the patients whose muscle biopsy showed typical 8.5 nm intranuclear filaments had a mutated PABP2 allele. Five patients with no intranuclear filaments were homozygous for the normal (GCG)6 allele. The pathologic expansion appeared to be stable with no variation among family members and between different tissues as blood and skeletal muscle in the same individual. CONCLUSIONS: These data 1) further confirm PABP2 gene analysis as a valuable tool in OPMD diagnosis; 2) indicate that PABP2 gene mutations are always present among Italian patients with morphologically proven OPMD, suggesting genetic homogeneity of the disease; and 3) strengthen the putative role of mutated PABP2 protein in filamentous inclusions accumulation.     

眼咽型肌营养不良一家系临床、电生理、病理及基因分析

目的 报道1个出现神经源性骨骼肌损害的眼咽型肌营养不良(OPMD)家系的临床、骨骼肌病理和基因改变特点.方法 先证者为60岁男性,50岁时出现双下肢近端无力,53岁出现吞咽困难和构音障碍,57岁出现双眼睑下垂和眼球突出.肌酸激酶轻度增加,四肢肌电图为神经源性损伤,周围神经传导速度下降20%～43%.家系3代中除先证者外尚有5例在45岁后出现吞咽困难,4～20年后出现眼睑下垂,其中3例有肢体无力.对先证者左肱二头肌做肌肉活体组织检查,标本进行组织学、酶组织化学以及免疫组织化学染色(以抗结蛋白和泛素蛋白抗体作为一抗)和超微病理检查.对先证者和家系中另外18人进行多腺苷酸结合蛋白(PABPN1)基因检查.结果 先证者肌纤维内出现镶边空泡伴泛素阳性沉积物和成组分布的小角状萎缩肌纤维,个别肌纤维出现再生改变伴随结蛋白沉积,可见细胞色素C氧化酶阴性肌纤维.电镜检查发现约3%的肌纤维核内存在栅栏样细丝包涵体.先证者和另外11名家系成员的PABPN1基因存在(GCG)9异常扩增.结论 杂合(GCG).异常扩增性OPMD可先出现咽喉肌无力,伴随脱髓鞘性神经病.我国患者也存在肌纤维核内包涵体.     

Mutation and haplotype analysis of oculopharyngeal muscular dystrophy in Thai patients

Oculopharyngeal muscular dystrophy (OPMD) is an inherited neuromuscular disease associated with a short trinucleotide repeat expansion in Exon 1 of the PABPN1 gene. OPMD is uncommon in East Asian populations, and there have been no previous reports of Thai patients. We studied clinical and molecular genetic features of six unrelated Thai patients with autosomal dominant OPMD. All patients had expansions of the guanine-cytosine-guanine (GCG) repeat ranging from three to seven additional repeats in the PABPN1 gene. Haplotype analysis showed that these mutations might have originated independently. Analysis of the size of the GCG repeat in the PABPN1 gene in 200 Thai control patients showed that 0.5% of the control subjects possessed (GCG)₇, thereby suggesting that the prevalence of autosomal recessive OPMD in the Thai population was approximately 1 in 160,000. In conclusion, our data suggest that OPMD in Thailand may be more common than previously thought.     

Muscular involvement assessed by MRI correlates to motor function measurement values in oculopharyngeal muscular dystrophy

Oculopharyngeal muscular dystrophy (OPMD) is a progressive skeletal muscle dystrophy characterized by ptosis, dysphagia, and upper and lower extremity weakness. We examined eight genetically confirmed OPMD patients to detect a MRI pattern and correlate muscle involvement, with validated clinical evaluation methods. Physical assessment was performed using the Motor Function Measurement (MFM) scale. We imaged the lower extremities on a 1.5 T scanner. Fatty replacement was graded on a 4-point visual scale. We found prominent affection of the adductor and hamstring muscles in the thigh, and soleus and gastrocnemius muscles in the lower leg. The MFM assessment showed relative mild clinical impairment, mostly affecting standing and transfers, while distal motor capacity was hardly affected. We observed a high (negative) correlation between the validated clinical scores and our visual imaging scores suggesting that quantitative and more objective muscle MRI might serve as outcome measure for clinical trials in muscular dystrophies.     

Unequal crossing-over in unique PABP2 mutations in Japanese patients: a possible cause of oculopharyngeal muscular dystrophy

BACKGROUND: Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset autosomal dominant muscle disease with a worldwide distribution. Recent findings reveal the genetic basis of this disease to be mutations in the polyA binding-protein 2 (PABP2) gene that involve short expansions of the GCG trinucleotide repeat encoding a polyalanine tract. The underlying mechanism causing the triplet-expansion mutation in PABP2 remains to be elucidated, although the DNA slippage model is thought to be a plausible explanation of that. METHODS AND RESULTS: We analyzed PABP2 using polymerase chain reaction analysis and DNA sequencing in Japanese patients with pathologically confirmed OPMD, and found mutated (GCG)(6)GCA(GCG)(3)(GCA)(3)GCG and (GCG)(6)(GCA)(3)(GCG)(2)(GCA)(3)GCG alleles instead of the normal (GCG)(6)(GCA)(3)GCG allele. These mutated alleles could be explained by the insertions or duplications of (GCG)(3)GCA and (GCG)(2)(GCA)(3), respectively, but not by the simple expansion of GCG repeats. The clinical features of our patients were compatible with those of other Japanese patients carrying PABP2 that encodes a polyalanine tract of the same length, but were not compatible with those of Italian patients. CONCLUSIONS: The mutated alleles identified in our Japanese patients with OPMD were most likely due to duplications of (GCG)(3)GCA and (GCG)(2)(GCA)(3) but not simple expansions of the GCG repeats. Therefore, unequal crossing-over of 2 PABP2 alleles, rather than DNA slippage, is probably the causative mechanism of OPMD mutations. All mutations that have been reported in patients with OPMD so far can be explained with the mechanism of unequal crossing-over. On the other hand, comparison of the clinical features of our patients with those of other patients in previous reports suggests that specific clinical features cannot be attributed to the length of the polyalanine tract per se.     

Siblings with recessive oculopharyngeal muscular dystrophy

Oculopharyngeal muscular dystrophy (OPMD) is a late onset myopathy usually presenting in the 5th or 6th decade of life with progressive ptosis, dysphagia and proximal muscle weakness. It is usually dominantly inherited; however, a rare recessive form has also been described although documentation of such cases in the literature is very sparse. Here we report two siblings with recessive OPMD, in one of whom the clinical picture is complicated by ankylosing spondilitis and pneumonia. They exhibit later onset and milder symptoms than is typical for patients with dominantly inherited OPMD. This and the possibility that OPMD may be masked by symptoms of other diseases of the elderly may account for the paucity of cases of recessive OPMD reported in the literature.     

Variability of the recessive oculopharyngeal muscular dystrophy phenotype

Oculopharyngeal muscular dystrophy (OPMD) is usually transmitted as an autosomal-dominant trait and characterized by an expansion from 6 to 8 or more GCG/GCA repeats in the poly-(A) binding protein nuclear 1 (PABPN1) gene on chromosome 14q11. Autosomal-recessive OPMD with a homozygous (GCG)7 expansion of PABPN1 has only been described in two Canadian patients, who showed a comparably mild phenotype, suggesting that it is less severe than the dominant form. We clinically and genetically characterized the first two reported cases of autosomal-recessive OPMD in Europe. Remarkably, both patients revealed severe and diverse phenotypes, with an unusual onset and atypical clinical course in one patient. Former studies found a 1%-2% frequency of the (GCG)7 allele, which theoretically produces an incidence of 1:10,000 of autosomal-recessive OPMD in the general population. We conclude that the apparent rarity of the autosomal-recessive form of OPMD may be due to the fact that genetic testing is generally administered only to patients with typical clinical features or a positive family history.     

GCG repeats and phenotype in oculopharyngeal muscular dystrophy

Short GCG repeat expansions in the PABP2 gene were recently shown to cause oculopharyngeal muscular dystrophy (OPMD) in French-Canadian and Italian pedigrees. We diagnosed OPMD in 16 German patients by the detection of GCG repeat expansions, confirming genetic homogeneity. Myopathic and neurogenic changes were found in skeletal muscle biopsies. Age of onset and severity of disease were not correlated with the number of repeats.     

Clinical and electrophysiologic features of oculopharyngeal muscular dystrophy: Lack of evidence for an associated peripheral neuropathy

ObjectiveTo describe the clinical and electrophysiologic features of an unselected population of patients diagnosed clinically or genetically with oculopharyngeal muscular dystrophy (OPMD), and to discern any association with a peripheral neuropathy.MethodsPatients with a clinical or genetic diagnosis of OPMD were retrospectively identified and characterized in terms of clinical and electrophysiologic features.ResultsFourteen patients who met the design criteria were identified and included. All had progressive ptosis and dysphagia, and most had ophthalmoparesis and proximal limb weakness. The electromyographic findings were similar to findings in other dystrophic diseases. Nine out of 10 patients had normal sural sensory nerve action potentials (mean amplitude 14.2 μV, range 0–22 μV).ConclusionsThe electrophysiologic findings associated with OPMD are similar to changes noted in other dystrophic diseases. These findings argue against an association between OPMD and peripheral neuropathy.SignificanceOPMD may not be associated with a peripheral neuropathy, as has been previously suggested.