Clinical and genetic features of a large homogeneous cohort of oculopharyngeal muscular dystrophy patients from the Canary Islands.

BACKGROUND: Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant, late-onset myopathy characterized by ptosis, dysphagia, and progressive proximal limb muscle weakness. The disease is produced by a short expansion of the (GCN)n triplet in the PABPN1 gene. The size of expansion has been correlated to the disease onset and severity. We report the clinical features of a large cohort of OPMD patients harboring the (GCN)15 allele from the Canary Islands. METHODS: A retrospective observational study was performed analyzing the clinical, demographic, and genetic data of 123 OPMD patients. Clinical data from this cohort were compared with clinical data collected in a large European study including 139 OPMD patients. RESULTS: A total of 113 patients (94.2%) carried the (GCN)15 expanded PABN1 allele. Age of symptoms' onset was 45.1 years. The most frequent symptom at onset was ptosis (85.2%) followed by dysphagia (12%). The severity of the disease was milder in the Canary cohort compared to European patients as limb weakness (35.1% vs. 50.4%), the proportion of patients that require assistance for walking or use a wheelchair (9.3% vs. 27.4%), and needed of surgery because of severe dysphagia (4.6% vs. 22.8%) was higher in the European cohort. CONCLUSIONS: Nearly 95% of patients with OPMD from the Canary Islands harbored the (GCN)15 expanded allele supporting a potential founder effect. Disease progression seemed to be milder in the (GCN)15 OPMD Canary cohort than in other cohorts with shorter expansions suggesting that other factors, apart from the expansion size, could be involved in the progression of the disease.

A Japanese case of oculopharyngeal muscular dystrophy (OPMD) with PABPN1 c.35G > C; p.Gly12Ala point mutation.

BACKGROUND: Oculopharyngeal muscular dystrophy (OPMD) is a late-onset muscular dystrophy characterised by slowly progressive ptosis, dysphagia, and proximal limb muscle weakness. A common cause of OPMD is the short expansion of a GCG or GCA trinucleotide repeat in PABPN1 gene. CASE PRESENTATION: A 78-year-old woman presented with ptosis and gradually progressive dysphagia. Her son had the same symptoms. A physical examination and muscle imaging (MRI and ultrasound) showed impairment of the tongue, proximal muscles of the upper limbs, and flexor muscles of the lower limbs. Needle-electromyography (EMG) of bulbar and facial muscles revealed a myopathic pattern. Based on the characteristic muscle involvement pattern and needle-EMG findings, we suspected that the patient had OPMD. Gene analysis revealed PABPN1 c.35G > C point mutation, which mimicked the effect of a common causative repeat expansion mutation of OPMD. CONCLUSION: We herein describe the first reported Japanese case of OPMD with PABPN1 point mutation, suggesting that this mutation is causative in Asians as well as in Europeans, in whom it was originally reported.

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

BACKGROUND AND PURPOSE: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Cytokine genes as potential biomarkers for muscle weakness in OPMD.

Molecular biomarkers emerge as an accurate diagnostic tool, but are scarce for myopathies. Lack of outcome measures sensitive to disease onset and symptom severity hamper evaluation of therapeutic developments. Cytokines are circulating immunogenic molecules, and their potential as biomarkers has been exploited in the last decade. Cytokines are released from many tissues, including skeletal muscles, but their application to monitor muscle pathology is sparse. We report that the cytokine functional group is altered in the transcriptome of oculopharyngeal muscular dystrophy (OPMD). OPMD is a dominant, late-onset myopathy, caused by an alanine-expansion mutation in the gene encoding for poly(A) binding protein nuclear 1 (expPABPN1). Here, we investigated the hypothesis that cytokines could mark OPMD disease state. We determined cytokines levels the vastus lateralis muscle from genetically confirmed expPABPN1 carriers at a symptomatic or a presymptomatic stage. We identified cytokine-related genes candidates from a transcriptome study in a mouse overexpressing exp PABPN1 Six cytokines were found to be consistently down-regulated in OPMD vastus lateralis muscles. Expression levels of these cytokines were highly correlated in controls, but this correlation pattern was disrupted in OPMD. The levels of these 6 cytokines were not altered in expPABPN1 carriers at a pre-symptomatic stage, suggesting that this group of cytokines is a potential biomarker for muscle weakness in OPMD. Correlation pattern of expression levels could be a novel measurer for disease state.

Orthoptic and video-oculographic analyses in oculopharyngeal muscular dystrophy.

INTRODUCTION: Mild ophthalmoparesis can be seen in oculopharyngeal muscular dystrophy (OPMD). METHODS: Orthoptic analysis included assessment of phoria/tropia, eye excursion, saccades, pursuit, stereoacuity, and Hess-Lancaster screen test. Video-oculography included fixation, horizontal and vertical saccades, and pursuit. RESULTS: Orthoptic abnormalities were: tropia (4 of 6); abnormal eye excursion (4 of 6, 78% involved lateral or superior rectus muscles); abnormal horizontal or vertical saccades (2 of 6); abnormal pursuit (0 of 6); abnormal stereoacuity (2 of 6); and pathological Hess-Lancaster screen (4 of 6). Video-oculographic abnormalities were present for: fixation (1 of 6); saccade latency (1 of 6); horizontal pursuit (3 of 6); and vertical pursuit (0 of 6). For horizontal saccades, mean velocity, peak velocity, and gain were pathological in 5 of 6, 5 of 6 (61% of pathological mean and peak velocities involved abducting eye movements), and 3 of 6, respectively. For vertical saccades, mean velocity, peak velocity, and gain were pathological in 4 of 6, 4 of 6 (53% involved upward movements), and 3 of 6, respectively. CONCLUSION: The data indicate preferential involvement of lateral and (to a lesser degree) superior rectus muscles in OPMD.

Autologous myoblast transplantation for oculopharyngeal muscular dystrophy: a phase I/IIa clinical study.

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset autosomal dominant genetic disease mainly characterized by ptosis and dysphagia. We conducted a phase I/IIa clinical study (ClinicalTrials.gov NCT00773227) using autologous myoblast transplantation following myotomy in adult OPMD patients. This study included 12 patients with clinical diagnosis of OPMD, indication for cricopharyngeal myotomy, and confirmed genetic diagnosis. The feasibility and safety end points of both autologous myoblast transplantation and the surgical procedure were assessed by videoendoscopy in addition to physical examinations. Potential therapeutic benefit was also assessed through videoendoscopy and videofluoroscopy of swallowing, quality of life score, dysphagia grade, and a drink test. Patients were injected with a median of 178 million myoblasts following myotomy. Short and long-term (2 years) safety and tolerability were observed in all the patients, with no adverse effects. There was an improvement in the quality of life score for all 12 patients, and no functional degradation in swallowing was observed for 10 patients. A cell dose-dependant improvement in swallowing was even observed in this study. This trial supports the hypothesis that a local injection of autologous myoblasts in the pharyngeal muscles is a safe and efficient procedure for OPMD patients.

HNRNPA2B1 myopathy presenting in a family with an early onset oculopharyngeal muscular dystrophy-like phenotype.

Genetic variation at HNRNPA2B1 is associated with inclusion body myopathy, Paget's disease and paediatric onset oculopharyngeal muscular dystrophy. We present a pedigree where a mother and two daughters presented with adolescent to early-adulthood onset of symptoms reminiscent of oculopharyngeal muscular dystrophy or chronic progressive external ophthalmoplegia, with a later limb-girdle pattern of weakness. Creatine Kinase was ∼1000 U/L. Myoimaging identified fatty replacement of sartorius, adductors longus and magnus, biceps femoris, semitendinosus and gastrocnemii. Muscle biopsies showed a variation of fibre size, occasional rimmed vacuoles and increased internalised myonuclei. Cases were heterozygous for a frameshift variant at HNRNPA2B1, consistent with a dominant and fully-penetrant mode of inheritance. Genetic variation at HNRNPA2B1 should be considered in adults with an oculopharyngeal muscular dystrophy-like or chronic progressive external ophthalmoplegia-like myopathy where initial testing fails to identify a cause.

Oculopharyngeal muscular dystrophy: underdiagnosed disease in Hong Kong.

Despite the advances in the understanding of the molecular basis for oculopharyngeal muscular dystrophy in the last decade, it remains an underdiagnosed disease, especially among the Chinese. In the presence of a positive family history and late-onset ptosis, dysphagia, and proximal muscle weakness (its cardinal features), we suggest that PABPN1 gene analysis should be the first-line investigation to rule out this condition. Muscle biopsy can be reserved for atypical cases. Non-specific mitochondrial changes in the muscle specimens of these patients should be appreciated, so as to avoid diagnostic confusion. It is hoped that greater awareness among medical professionals and judicious use of PABPN1 gene analysis will lead to earlier diagnosis, better management, and avoidance of unnecessary invasive investigations of affected patients.

Distal myopathies.

The distal myopathies are a heterogeneous group of genetic disorders defined by a predominant distal weakness at onset or throughout the evolution of the disease and by pathological data supporting a myopathic process. The number of genes associated with distal myopathies continues to increase. Fourteen distinct distal myopathies are currently defined by their gene and causative mutations, compared to just five entities delineated on clinical grounds two decades ago. The known proteins affected in the distal myopathies are of many types and include a significant number of sarcomeric proteins. The useful indicators for clinicians to direct towards a correct molecular diagnosis are the mode of inheritance, the age at onset, the pattern of muscle involvement, the serum creatine kinase level and the muscle pathology findings. This review gives an overview of the clinical and genetic characteristics of the currently identified distal myopathies with emphasis on some recent findings.

Eyelid surgery in ocular myopathies.

OBJECTIVE: To retrospectively analyse surgical outcome and complications in patients with ocular myopathy undergoing ptosis correction and to introduce preoperative prophylactic lower lid elevation in this group. METHODS: The medical records of all ocular myopathy patients who had undergone oculoplastic surgery between June 1995 and May 2006 were obtained. Patients' demographics, surgical details and measurements, and complications were recorded. RESULTS: 29 patients were identified; 21 with chronic progressive external ophthalmoplegia (CPEO), 7 with myotonic dystrophy (MD) and 1 with oculopharyngeal muscular dystrophy (OPMD). Then, 61 procedures to adjust eyelid height were performed, comprising levator resection, brow suspension, anterior lamellar repositioning, lower lid elevation and upper lid lowering. Palpebral aperture was significantly increased in all patient groups, by procedure and diagnosis, more significantly following brow suspension compared with levator resection. The patients' feedback was very positive. Post-operative complications were few, included corneal exposure and ulceration, ptosis recurrence, arched brow, and sling infection, all of which were successfully treated. CONCLUSION: Our results demonstrate subjective and objective benefit following surgery in these patients, with a low complication rate. The use of pre-operative prophylactic lower lid elevation procedures is a promising modality.

Introducing the Dysphagiameter: a novel patient-reported outcome measure for evaluating dysphagia in oculopharyngeal muscular dystrophy - from conceptual framework to initial development.

Oculopharyngeal muscular dystrophy (OPMD) is a rare late-onset muscle disease associated with progressive dysphagia. As there was no patient-reported outcome measure specific for the assessment of dysphagia in OPMD, the Dysphagiameter was developed. The Food and Drug Administration guidance was followed. In Phase 1, a systematic literature review and an expert consultation were conducted to identify the concepts of interest. It was decided that the instrument should assess difficulty swallowing using pictures of foods of various textures (part A) and impact of dysphagia on activities and participation (part B), as defined by the International Classification of Functioning, Disability and Health. In Phase 2, focus groups (n = 3) and online surveys (n = 55) were conducted to generate the items. Then, the food items for part A were selected and grouped into 17 textures by a panel of registered dietitians. Cognitive interviews were conducted (n = 23) to refine the instrument and assess its clarity and comprehensiveness. The final draft included 82 food items assessing the capacity to swallow foods and drinks (part A) and 10 items assessing the impact of dysphagia on activities and participation (part B). Item reduction and assessment of psychometrics properties, using Rasch analysis, are ongoing as part of Phase 3.

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.

Oculopharyngeal muscular dystrophy --an under-diagnosed disease in China? Report a China-born Chinese with PABPN1 mutation and epidemiology review of the literature.

BACKGROUND/PURPOSE: Most reports about oculopharyngeal muscular dystrophy (OPMD) have been contributed by occidental countries, and most of the victims of this disease are racially white. In contrast, this disorder is rarely seen in Asians and has only one African report. Consequently, OPMD has been regarded as a disease of the Western world. The purpose of this paper is to challenge the accuracy of this concept. METHODS: In a Chinese immigrant family, 3 patients manifesting signs related to OPMD were examined. Electromyography, nerve conduction studies, muscle biopsy and genetic analysis were performed on the proband. All the 322 papers about OPMD were reviewed and their country of origin was labeled to perceive the approximate prevalence of OPMD. Countries were categorized into groups according to the continents to which they belonged. RESULTS: The proband's muscle histopathology showed small angulated fiber with rimmed vacuoles, ultrastructural pathology exposed filamentous intranuclear inclusions, and genetic analysis of the polyadenylate binding protein nuclear 1(PABPN1) gene revealed 13 GCG trinucleotide repeats in one allele (GCG)13 while being normal in the other. The survey of the country of origin of OPMD reports showed that 80% of these papers were contributed by occidental countries and that the number of publications of OPMD among countries of Americas and Asia were unequal, when compared to those of European countries, which were fairly proportioned. An epidemiologic review of the literature is presented and the prevalence of OPMD is discussed. CONCLUSION: This is a China-born Chinese patient with both morphologically and genetically proven of OPMD. The very low OPMD report rate in developing countries of East Asia is due to the unfamiliarity of medical workers to OPMD and the unavailability of medical supplies to confirm the diagnosis. In addition, the present and previous reports provide clear evidence that OPMD in these areas is underdiagnosed.

Intranuclear inclusions in muscle biopsy can differentiate oculopharyngodistal myopathy and oculopharyngeal muscular dystrophy.

Oculopharyngodistal myopathy (OPDM) and oculopharyngeal muscular dystrophy (OPMD) are similar and even believed to be indistinguishable in terms of their myopathological features. To address the diagnostic gap, we evaluated the muscle biopsy samples for p62 expression by immunohistochemistry and compared the occurrence and the frequency of intranuclear inclusions among the individuals with OPDM (harboring CGG repeat expansion in LRP12 (n = 19), GIPC1 (n = 6), or NOTCH2NLC (n = 7)), OPMD (n = 15), and other rimmed vacuolar myopathies. We found that myonuclei with p62-positive intra-nuclear inclusions (myo-INIs) were significantly more frequent in OPMD (11.9 ± 1.1%, range 5.9-18.6%) than in OPDM and other rimmed vacuolar myopathies (RVMs) (0.9-1.5% on average, range 0.0-2.8%, p < 0.0001). In contrast, INIs in non-muscle cells such as blood vessels, peripheral nerve bundles, and muscle spindles (non-muscle-INIs) were present in OPDM, but absent in OPMD. These results indicate that OPMD can be differentiated from OPDM and other RVMs by the frequent presence of myo-INIs; and in OPDM, the presence of non-muscle-INIs in muscle pathology should be a diagnostic hallmark.

Mitochondrial neurogastrointestinal encephalomyopathy in a Pakistani female: a case report.

BACKGROUND: Mitochondrial neurogastrointestinal encephalopathy is a rare multisystem autosomal recessive disease caused by mutations in the TYMP gene, that encodes for thymidine phosphorylase. Mitochondrial neurogastrointestinal encephalopathy is a progressive degenerative disease characterized by a distinctive tetrad of gastrointestinal dysmotility, peripheral neuropathy, ophthalmoplegia with ptosis, and asymptomatic leukoencephalopathy. It provides a diagnostic dilemma to physicians in regions like Pakistan because of a lack of genetic study availability and associated financial constraints of the population. However, with careful examination and a few basic investigations, mitochondrial neurogastrointestinal encephalopathy can be diagnosed by ruling out most of the close differentials. CASE PRESENTATION: We report the case of a 23-year-old Asian female whose chief complaints were epigastric pain, bilious emesis, weight loss for 3 months, and bilateral lower limb weakness for 20 days. All clinical signs and symptoms along with relevant investigations including nerve conduction studies, electromyography, and magnetic resonance imaging of the brain were highly suggestive of mitochondrial neurogastrointestinal encephalopathy syndrome. Because of financial constraints, genetic studies could not be performed. The patient was managed with a multidisciplinary approach involving gastroenterology, physiotherapy, and nutrition departments. Currently, therapeutic options for the disease include allogeneic hematopoietic stem cell transplant and carrier erythrocyte entrapped thymidine phosphorylase; however, these could not be provided to the patient owing to certain limitations. CONCLUSIONS: As misdiagnosis and delayed diagnosis are quite common in this disease, the prime objective of this case report is to increase the basic understanding of this disease, especially its signs and symptoms, and address the limitations regarding the diagnostic investigations and management of patients with mitochondrial neurogastrointestinal encephalopathy.

Behavioural Impairment and Frontotemporal Dementia in Oculopharyngeal Muscular Dystrophy.

Some patients with Oculopharyngeal Muscular Dystrophy (OPMD) develop frontotemporal dementia (FTD). The prevalence and clinical correlates of behavioural impairment, including FTD, is unknown in OPMD.24 OPMD patients and their proxies completed a questionnaire concerning behavioural impairment (ALS-FTD-Q). We examined proportions with mild or severe behavioural changes, according to validated cut-off proxy scores. We examined correlations with the Hospital Anxiety and Depression Scale (HADS), the Short Form Health Survey (SF-36), motor symptoms, genotype and disease duration.In this small patient sample, behavioural impairment was present in 29%of OPMD patients; in 17%the severity of symptoms was compatible with bvFTD. Correlations were small to medium.

A GCG expansion (GCG)11 in polyadenylate-binding protein nuclear 1 gene caused oculopharyngeal muscular dystrophy in a Chinese family.

PURPOSE: To identify the mutation in polyadenylate-binding protein nuclear 1 gene (PABPN1, previously termed PABP2) in a Chinese family with autosomal, dominantly inherited oculopharyngeal muscular dystrophy (OPMD). METHODS: Clinical and ophthalmologic examinations were conducted on available living family members from three generations. Genomic DNA was extracted from peripheral blood leukocytes of every available family member, and the fragment flanking the (GCG)(n) of the PABPN1 gene was amplified by PCR. Mutations were screened by DNA sequencing. Photographs of deceased family members were examined for signs of OPMD. RESULTS: Clinical features of OPMD were found in all patients in generation II except the youngest sister, and no clinical manifestations were found in generation III. Mutation sequencing demonstrated that (GCG)6 in the wild PABPN1 gene was expanded to heterozygous (GCG)11 in all affected family members and in some but not all unaffected members. CONCLUSIONS: In a Chinese family with autosomal dominantly inherited OPMD, a heterozygous (GCG)11 expansion was identified in all affected family members and in several young unaffected members.

Gene diagnosis of oculopharyngeal muscular dystrophy in a Chinese family by a GeneScan method.

This study aims to perform gene diagnosis for Chinese family patients with Oculopharyngeal muscular dystrophy (OPMD). Genomic DNAs were extracted from the pedigrees' members. Gene diagnosis was performed for these pedigrees' members by approaches, such as DNA sequencing and GeneScan. Sequence analysis and PABPN1 genotyping showed that the mutated allele in affected members of this family has nine trinucleotide repeats of GCG (GCG)(9), whereas the normal allele contains six trinucleotide repeats of GCG (GCG)(6). The above results suggest that mutated GCG repeats in PABPN1 gene may cause OPMD in this family, and PABPN1 genotyping could be used as a convenient, highly effective, and reliable gene diagnostic test for OPMD patients.

Polyneuropathy Reveals Origins of Decade-long Gastrointestinal Symptoms in a Patient With Undiagnosed Mitochondrial Neurogastrointestinal Encephalopathy Caused by a Novel Mutation.

Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is a rare autosomal recessive disease that manifests with multiorgan presentation characterized by gastrointestinal, extraocular, and both peripheral and central nervous system involvement. MNGIE is caused by mutation in the TYMP (thymidine phosphorylase) gene, resulting in loss of thymidine phosphorylase enzyme activity. This causes its substrates, thymidine and deoxyuridine, to accumulate in tissues and plasma, while also causing secondary alterations in mitochondrial DNA. To date, more than 80 mutations have been reported in this gene. We present herein the clinical, neuroimaging, electrodiagnostic, and molecular findings of a patient with MNGIE caused by a novel homozygous missense mutation (C1175T > G) of the TYMP gene.