Cases Of Oculopharyngeal Muscular Dystrophy Research Articles

Two Cases of Oculopharyngeal Muscular Dystrophy in Brothers with Ptosis and Eye Movement Disorder

ëª©ì  만성 진행성 외안근마비병증 의심 하에 경과 관찰 중이던 í˜•ì œì—ì„œ, 이후 조기 발병된 눈인두근육퇴행위축병증으로 진단된 2예를 경험하였기에 이를 ë³´ê³ í•˜ê³ ìž 한다. 증례요약 í˜•ì œ 관계인 15세, 13세 남자 환자가 6ë „ ì „ë¶€í„° 지속된 복시 증상을 주소로 내원하였다. 형의 경우 내원 당시 êµì •ì‹œë ¥ì€ 양안 0.6이었으며, 프리즘교대가림검사상 25프리즘디옵터의 외편위를 보였다. ì „ 방향의 ì•ˆêµ¬ìš´ë™ì œí•œê³¼ 함께 양안의 눈꺼풀처짐이 관찰되었으며, ì•ˆì €ê²€ì‚¬ìƒ 양안 í™©ë°˜ë¶€ì¢ ì´ 관찰되었다. 동생은 내원 당시 êµì •ì‹œë ¥ 좌안 1.0ì´ì—ˆê³ , 프리즘교대가림검사상 45프리즘디옵터의 외편위를 보였다. 형과 마찬가지로 ì „ 방향으로 ì•ˆêµ¬ìš´ë™ì œí•œê³¼ 양안 눈꺼풀처짐 소견이 관찰되었다. 두 환자 모두 만성 진행성 외안근마비병증 의증으로 ì§„ë‹¨í•˜ê³ ê·¼ìƒê²€ 및 ì‹ ê²½í•™ì  평가를 위해 ì‹ ê²½ê³¼ë¡œ 의뢰되었다. ì‹ ê²½ê³¼ì—ì„œ 시행한 근생검 ê²°ê³¼, í˜•ì œ 모두 눈인두근육퇴행위축병증으로 진단되었다. ê²°ë¡ ëˆˆêº¼í’€ 및 ëˆˆìš´ë™ì œí•œ 증상을 가진 ì Šì€ 환자에서, 기존의 ì „í˜•ì  양상이 아닌 조기 발병 눈인두근육퇴행위축병증의 사례를 국내에서 처음으로 ë³´ê³ í•¨ì— ê·¸ 의미가 있다. Keywords: Blepharoptosis, Chronic progressive external ophthalmoplegia, Oculopharyngeal muscular dystrophy

Value of insoluble PABPN1 accumulation in the diagnosis of oculopharyngeal muscular dystrophy.

The aim was to assess the value of insoluble PABPN1 muscle fibre nuclei accumulation in the diagnosis of atypical cases of oculopharyngeal muscular dystrophy (OPMD). Muscle biopsies from a selected cohort of 423 adult patients from several Italian neuromuscular centres were analysed by immunofluorescence: 30 muscle biopsies of genetically proven OPMD, 30 biopsies from patients not affected by neuromuscular disorders, 220 from genetically undiagnosed patients presenting ptosis or swallowing disturbances, progressive lower proximal weakness and/or isolated rimmed vacuoles at muscle biopsy and 143 muscle biopsies of patients affected by other neuromuscular diseases. The detection of insoluble nuclear PABPN1 accumulation is rapid, sensitive (100%) and specific (96%). The revision of our cohort allowed us to discover 23 new OPMD cases out of 220 patients affected with nonspecific muscle diseases. Oculopharyngeal muscular dystrophy is often misdiagnosed leading to diagnosis delay, causing waste of time and resources. A great number of these cases present symptoms and histological findings frequently overlapping with other muscle diseases, i.e. inclusion body myositis and progressive external ophthalmoplegia. PABPN1 nuclear accumulation is a reliable method for diagnostic purposes and it is safe and useful in helping pathologists and clinicians to direct genetic analysis in the case of suspected OPMD, even when clinical and histological clues are deceptive.

Advances in imaging of brain abnormalities in neuromuscular disease.

Brain atrophy, white matter abnormalities, and ventricular enlargement have been described in different neuromuscular diseases (NMDs). We aimed to provide a comprehensive overview of the substantial advancement of brain imaging in neuromuscular diseases by consulting the main libraries (Pubmed, Scopus and Google Scholar) including the more common forms of muscular dystrophies such as dystrophinopathies, dystroglycanopathies, myotonic dystrophies, facioscapulohumeral dystrophy, limb-girdle muscular dystrophy, congenital myotonia, and congenital myopathies. A consistent, widespread cortical and subcortical involvement of grey and white matter was found. Abnormalities in the functional connectivity in brain networks and metabolic alterations were observed with positron emission tomography (PET) and single photon emission computed tomography (SPECT). Pathological brain changes with cognitive dysfunction seemed to be frequently associated in NMDs. In particular, in congenital muscular dystrophies (CMDs), skeletal muscular weakness, severe hypotonia, WM abnormalities, ventricular dilatation and abnormalities in cerebral gyration were observed.In dystroglycanopathy 2I subtype (LGMD2I), adult patients showed subcortical atrophy and a WM periventricular involvement, moderate ventriculomegaly, and enlargement of subarachnoid spaces. Correlations with clinical features have been observed with brain imaging characteristics and alterations were prominent in congenital or childhood onset cases. In myotonic dystrophy type 2 (DM2) symptoms seem to be less severe than in type 1 (DM1).In Duchenne and Becker muscular dystrophies (DMD, BMD) cortical atrophy is associated with minimal ventricular dilatation and WM abnormalities.Late-onset glycogenosis type II (GSD II) or Pompe infantile forms are characterized by delayed myelination. Only in a few cases of oculopharyngeal muscular dystrophy (OPMD) central nervous system involvement has been described and associated with executive functions impairment.

Miogenic ptosis in oculopharyngeal muscular dystrophy

The authors report a case of oculopharyngeal muscular dystrophy, an autosomal dominant genetic disease, which leads to miogenic ptosis. This patient presented bilateral palpebral ptosis and dysphagia and underwent ptosis surgical treatment, with a good functional and aesthetic result. Miogenic ptosis in oculopharyngeal muscular dystrophy

G.P.6: Oculopharyngeal Muscular Dystrophy with PABPN1 mutation in two Chinese Singaporean families

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset autosomal dominant disorder presenting with progressive ptosis and dysphagia, due to GCN trinucleotide repeat in PABPN1 . OPMD is rarely seen in the Far East and genetically confirmed case has not been reported in Singapore. We describe two unrelated Chinese Singaporean families with autosomal dominant OPMD. The first patient, a 67-year-old Chinese, presented with progressive ptosis since age 30 and dysphagia for 5 years. He was initially thought to have a mitochondrial myopathy and muscle biopsy performed did show subtle mitochondrial abnormalities—few ragged red and COX negative fibres—but no rimmed vacuoles. However, in view of possible positive family history of similar condition in his father and paternal grandfather (both diseased), OPMD was suspected and genetic screening was performed, which showed heterozygous expansion of GCN in PABPN1 (13 repeats). The second patient, a 52-year-old Chinese man, had bilateral asymmetrical ptosis for about 10 years and progressive dysphagia for 6 years. He was initially diagnosed to have seronegative myasthenia gravis (MG) based on positive single fibre EMG study. His father, at the age of 75, had also similar presentation and was also diagnosed to have seronegative MG, based on single fibre EMG study. However, his condition did not improve with immunosuppressant and plasmapheresis. Genetic screening for OPMD performed on the proband showed 13 GCN repeats in PABPN1 . This is the first report of Singaporean families of Chinese descent with genetically confirmed OPMD, which may be under diagnosed in Singapore. OPMD can mimic other conditions such as mitochondrial myopathy or MG and hence often misdiagnosed, resulting in unnecessary treatment or procedure. It should be considered in any patient who present with late-onset progressive ptosis and dysphagia. Molecular genetic testing of PABPN1 is recommended for suspected case of OPMD.

Delayed diagnosis of oculopharyngeal muscular dystrophy in Denmark: from initial ptosis to genetic testing

Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset dominantly inherited myopathy. Its genetic basis has been identified as a trinucleotide repeat expansion ranging from (GCG)8 to (GCG)13 in the N-terminus polyalanine domain of the PABPN1 gene on chromosome 14q11. Affected members present with progressive ptosis and ophthalmoplegia, swallowing difficulties and proximal limb weakness in a context of a family history with dominant transmission (Brais et al. 1999). This condition is commonly described in French and Canadian families, but some sporadic cases have been reported in various countries (Müller et al. 2006; Rodriguez et al. 2005, Hill et al. 2001). There does not appear to be differences in the clinical course of OPMD based on regions; however, delay in the diagnosis may occur because of the slow progression of symptoms, low prevalence and lack of awareness among ophthalmologists. Our cross-sectional study reports the clinical presentations and treatment of 14 patients from 8 unrelated Danish families with genetically confirmed OPMD. The study was conducted in accordance with the International Conference of Harmonization Good Clinical Practice guidelines and the declaration of Helsinki. The study protocol was approved by the ethics committee for the Capital Region. Written informed consent was obtained for all subjects. Patients were followed at the reference centre for neuromuscular diseases at Rigshospitalet in Copenhagen. Demographic data about sequence of symptoms, diagnosis and treatment were collected. A complete oculo-palpebral examination was performed. DNA was isolated from an EDTA blood sample by standard methods. The GCG repeats were determined by PCR. Onset of symptoms occurred at a mean age of 51 years (range 37–60). Only six patients could report a family history of ptosis and/or other neurological symptoms. A pathogenic trinucleotide expansion was identified and sequenced in all eight families. In 10 patients (77%), ptosis was the initial symptom, occurring at a mean age of 52 years (range 41–64). In three patients, limb weakness was the initial symptom, followed by ptosis. The frequency of ptosis-associated dysphagia, dysarthria and ophthalmoplegia increased with age and disease duration. Table 1 summarizes the clinical findings at inclusion. The mean delay between the presenting signs and genetic confirmation was 8 years (range 5–15). Thirteen patients were operated for ptosis, with an average of 3.5 procedures per patient. Among those, 9 (69%) were operated several times, before referral for genetic testing. As a first procedure, 11 patients underwent aponeurosis surgery and 2 had brow suspension. Six patients (55%), who underwent aponeurosis surgery with immediate insufficient results, had the procedure repeated at least once (range 1–3) before being diagnosed with OPMD. Frontal brow suspension always resulted in good functional and cosmetic results. Sporadic and familial cases of OPMD have been reported in many countries (Hill et al. 2001; Müller et al. 2006; Mihaylova et al. 2008). However, the disease has been poorly investigated in Northern Europe and has never been described in Denmark. The clinical evolution of OPMD is slow, its treatment is symptomatic, and life span is usually normal. In our series, an appropriate OPMD diagnosis at presentation was often missed, and patients were offered an aponeurotic surgery without further investigations. Repeated ptosis interventions were therefore not uncommon. Subsequent success was obtained by frontal brow suspension, which is the appropriate surgery for myopathic ptosis, in which levator palpebrae muscle function is poor (Wong et al. 2002). In conclusion, ptosis is the most common presenting sign of OPMD. An appropriate work-up of bilateral and progressive ptosis in middle-aged adults with dysphagia and/or limb weakness should include genetic screening for OPMD, especially if there is a first-degree family history of similar symptoms.

191st ENMC International Workshop: Recent advances in oculopharyngeal muscular dystrophy research: From bench to bedside 8-10 June 2012, Naarden, The Netherlands

This workshop hosted a group of 19 clinicians and basic scientist from 5 countries (France, USA, Canada, Denmark and The Netherlands). Recent research developments and possible collaboration in advancing therapies for oculopharyngeal muscular dystrophy (OPMD), a late onset, rare and progressive neurodegeneration disorder were discussed in this meeting. The disease is caused by alanine expansion mutations in the gene encoding for poly(A)-binding protein nuclear 1 (PABPN1), resulting in accumulation of mutant PABPN1 in the cell nucleus and the formation of insoluble aggregates. Therefore, OPMD is categorized together with neurodegenerative disorders that are caused by single amino acid repeats. While the genetic cause for those disorders is often recognized, the molecular basis for symptoms is still obscure. PABPN1 is ubiquitously expressed and it is not known why symptoms develop only after midlife and initially only in subsets of skeletal muscles [1,2]. While the genetic cause for OPMD was reported in 1998 and good surgical treatments exist for major early symptoms, there are currently no medical options for the more general skeletal muscle involvement, no validated biomarkers and no clinical severity scale.

Oculopharyngeal muscular dystrophy: A polyalanine myopathy

It has been 10 years since the identification of the first PABPN1 gene (GCN)(n)/polyalanine mutations responsible for oculopharyngeal muscular dystrophy (OPMD). These mutations have been found in most cases of OPMD diagnosed in more than 35 countries. Sequence analyses have shown that such mutations have occurred numerous times in human history. Although PABPN1 was found early on to be a component of the classic filamentous intranuclear inclusions (INIs), mRNA and other proteins also have been found to coaggregate in the INIs. It is still unclear if the INIs play a pathologic or a protective role. The generation of numerous cell and animal models of OPMD has led to greater insight into its complex molecular pathophysiology and identified the first candidate therapeutic molecules. This paper reviews basic and clinical research on OPMD, with special emphasis on recent developments in the understanding of its pathophysiology.

An apparently sporadic case of oculopharyngeal muscular dystrophy: the first Italian report

An apparently sporadic case of oculopharyngeal muscular dystrophy: the first Italian report

An apparently sporadic case of oculopharyngeal muscular dystrophy: the first Italian report

Here we report the case of a 73-year-old Italian woman affected by genetically confirmed oculopharyngeal muscular dystrophy (OPMD) with a negative family history. As OPMD is usually transmitted as an autosomal-dominant meiotically stable trait, this case allows us to suggest that putative de novo OPMD mutations might occur more frequently than previously thought; moreover, when compatible with a proper clinical phenotype, OPMD might be included in the differential diagnosis even in the absence of a positive family history.

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.

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.

The mitotic clock in skeletal muscle regeneration, disease and cell mediated gene therapy

The regenerative capacity of skeletal muscle will depend on the number of available satellite cells and their proliferative capacity. We have measured both parameters in ageing, and have shown that although the proliferative capacity of satellite cells is decreasing during muscle growth, it then stabilizes in the adult, whereas the number of satellite cells decreases during ageing. We have also developed a model to evaluate the regenerative capacity of human satellite cells by implantation into regenerating muscles of immunodeficient mice. Using telomere measurements, we have shown that the proliferative capacity of satellite cells is dramatically decreased in muscle dystrophies, thus hampering the possibilities of autologous cell therapy. Immortalization by telomerase was unsuccessful, and we currently investigate the factors involved in cell cycle exits in human myoblasts. We have also observed that insulin-like growth factor-1 (IGF-1), a factor known to provoke hypertrophy, does not increase the proliferative potential of satellite cells, which suggests that hypertrophy is provoked by increasing the number of satellite cells engaged in differentiation, thus possibly decreasing the compartment of reserve cells. We conclude that autologous cell therapy can be applied to specific targets when there is a source of satellite cells which is not yet exhausted. This is the case of Oculo-Pharyngeal Muscular Dystrophy (OPMD), a late onset muscular dystrophy, and we participate to a clinical trial using autologous satellite cells isolated from muscles spared by the disease.

Oculopharyngeal Muscular Dystrophy Complicating Airway Management

Oculopharyngeal muscular dystrophy (OPMD) is an uncommon autosomal dominant disorder characterized by late onset and slow progression. Complications of OPMD include ptosis and progressive dysphagia leading to eventual malnutrition and aspiration. We report a rare case of OPMD complicating mechanical ventilator management following emergent surgery. OPMD and the resulting dysphagia contributed to multiple intubations, tracheostomy, aspiration pneumonia, and a prolonged hospital course. Awareness of the possibility of OPMD in intubated patients with a history of dysphagia is crucial for avoidance of complications.

Oculopharyngeal muscular dystrophy in Hispanic New Mexicans.

Oculopharyngeal muscular dystrophy (OPMD) is a rare myopathy caused by polyalanine triplet repeat expansion in the gene for poly(A) binding protein 2 (PABP2) and is found in isolated cohorts throughout the world. We have observed numerous cases of OPMD in New Mexico. To characterize the clinical, genetic, and demographic features of the OPMD population in New Mexico. Cohort study with analysis of outpatient clinic medical records from 1965 to 2001 at the University of New Mexico Hospital and the New Mexico VA Health Care System in Albuquerque, which serve the entire state. Clinical phenotype, supplemented with genetic confirmation (n = 10 patients) and in-depth clinical evaluations (n = 49 patients). We identified 216 cases of OPMD (99 women and 117 men) from 39 kindreds of New Mexicans spanning up to 4 generations. All patients were Hispanic, and the majority of probands came from northern New Mexico. In patients who had both ocular and pharyngeal muscle weakness, ptosis was just as likely to occur before or concurrent with dysphagia. Proximal limb muscle weakness and gait abnormalities were common and occurred later than ocular or pharyngeal weakness. The clinical expression of OPMD caused marked debility, although life-table analysis showed no decrease in life expectancy compared with unaffected family members (P =.81). Ten individuals from different kindreds were found to have an identical polyalanine triplet repeat expansion ([GCG](9)) in the PABP2 gene. Individuals in this cohort had clinical and genetic characteristics of classic OPMD. Longevity was not affected, but patients experienced considerable morbidity. The origin of the PABP2 mutation in New Mexican OPMD patients is unclear, although the geographic and genetic isolation of northern New Mexicans with a long ancestry in this region may have contributed to the development of this cohort. This disease cohort represents a large and previously unrecognized health care issue in the state of New Mexico and should serve to raise the awareness of this disorder among clinicians who treat Hispanics in the Southwest and throughout the United States.

Oculopharyngeal MD among Bukhara Jews is due to a founder (GCG)9 mutation in the PABP2 gene.

To determine whether all cases of oculopharyngeal muscular dystrophy (OPMD) among Bukhara Jews share the same founder mutation. Autosomal dominant OPMD is caused by a (GCG)8-13 repeat expansion in the polyadenylation binding protein 2 (PABP2) gene. The disease has a worldwide distribution but is particularly prevalent in Bukhara Jews and in French Canadians, in whom it was introduced by three sisters in 1648. We established the size of the PABP2 mutation in 23 Bukhara Jewish patients belonging to eight unrelated families. In all families, we constructed haplotypes for the carrying chromosomes composed of the alleles for eight chromosome 14q polymorphic markers. All patients share a (GCG)9 PABP2 mutation and a four-marker haplotype. Furthermore, a shared intron single nucleotide polymorphism (SNP) in the PABP2 gene 2.6Kb from the mutation was not observed in 22 families with (GCG)9 mutations from nine different countries. The smaller size of the chromosomal region in linkage disequilibrium around the mutation in Bukhara Jews, as compared with French Canadians, suggests a founder effect that occurred more than 350 years ago. Based on the Luria-Delbrück corrected "genetic clock," we estimate that the mutation appeared or was introduced once in the Bukhara Jewish population between AD 872 and 1512 (mean, AD 1243). OPMD among Bukhara Jews is the result of a shared, historically distinct, PABP2 (GCG)9 mutation that likely arose or was introduced in this population at the time they first settled in Bukhara and Samarkand during the 13th or 14th centuries.

Unique PABP2 mutations in ?Cajuns? suggest multiple founders of oculopharyngeal muscular dystrophy in populations with French ancestry

Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset autosomal dominant myopathy found world-wide, but with the highest incidence in French-Canadians. Short GCG expansions in the poly(A) binding protein 2 (PABP2) gene were identified recently as the molecular basis for OPMD in French-Canadians. All French-Canadian cases of OPMD have been traced to a single founder couple [Bouchard, 1997: Neuromuscul Disord 7(Suppl):S5-S11]. Cultural links between French-Canadians and Cajuns suggest that this same founder couple may have transmitted the OPMD mutation to Cajuns as well. To determine if OPMD patients from Louisiana share a founder effect with French-Canadian families, we collected blood samples and muscle biopsies from several Cajuns with OPMD for mutation and linkage studies. We found a unique 'GCA GCG GCG' insertion mutation in Cajuns. Consistent with these sequence data, we identified a disease haplotype in our Cajun families that is different from the ancestral haplotype defined in French-Canadians. These data prove that different founders introduced the PABP2 mutation to Cajuns and French-Canadians and lend support to emerging genealogical data suggesting that French-Canadians and Cajuns represent distinct immigrant groups from France.

Oculopharyngeal muscular dystrophy in France

The clinical, histopathological, ultrastructural and geographical data on 29 cases of oculopharyngeal muscular dystrophy (OPMD) identified by the authors in France in briefly presented. The mean age of the patients was 53.8 ± 8.1 years. Onset symptoms were ptosis ( 14 29 ), dysphagia ( 12 29 ) and limb girdle weakness ( 3 29 ). The evolution of the disease was always progressive and followed different clinical patterns. The main histological changes in muscle biopsies were atrophic angulated fibers ( 29 29 ) and rimmed vacuoles ( 25 29 ); muscle fiber necrosis was very rare ( 1 29 ). The characteristic nuclear inclusions made of 8.5-nm filaments were observed in all cases, and found in 2–5% of the nuclei in a given ultrathin section. They are the morphological marker of the disease.

Morphological changes in muscle fibers in oculopharyngeal muscular dystrophy

The study of muscle biopsies of 29 cases of oculopharyngeal muscular dystrophy (OPMD) showed the two main morphological features of this disease: rimmed vacuoles (in 26 cases) and intranuclear inclusions (in all cases). These inclusions are made of 8.5 nm tubular filaments and the areas occupied by them are lighter than the surrounded nucleoplasm. This can be seen by light microscopy, facilitating the detection of the tubulo-filamentous inclusions which can only be identified with certitude by electron microscopy. In a given ultrathin section the area occupied by these inclusions varied from 2% to 5% of the nuclei. The intranuclear inclusions are the morphological marker of OPMD and their finding in a muscle biopsy allows the exact diagnosis of this disease. The origin and biochemical nature of the intranuclear inclusions is unknown.