The National Israeli Registry for Oculo-Pharyngeal Muscular Dystrophy (IsrO-PMD): rationale and design

Oculo-pharyngeal muscular dystrophy (OPMD) is a rare disease, caused by trinucleotide repeat expansion in the PABPN1 gene, inherited in an autosomal dominant (AD) manner. Its main features are eyelid ptosis and dysphagia, which manifest at the end of the fifth decade of life. Other symptoms include proximal muscle weakness and bulbar muscle weakness. Although OPMD is prevalent worldwide, a higher prevalence has been reported in the Jewish population from Bukhara. Currently, no specific drugs are available for OPMD. Our National Israeli Registry for Oculo-Pharyngeal Muscular Dystrophy (IsrO-PMD) study aims to provide a framework for the assessment and documentation of the natural history of the diseases as we as a multi-disciplinary management of patients with OPMD. The IsrO-PMD may be the cornerstone of future clinical trials for novel therapies for OPMD. The IsrO-PMD is a national prospective registry that involves non-interventional data collection based on the Global Rare Diseases Patient Registry (GRDPR) and data repository standard. Inclusion criteria are clinical diagnosis of OPMD and positive genetic testing. Patients who meet inclusion criteria will be examined using a series of multi-disciplinary investigations and questionnaires including periodic follow-up examinations. Specific attention is given to comprehensive neurological, swallowing, and ophthalmological evaluations. The establishment of this national registry will enhance our understanding of the natural history of OPMD, establish quality care benchmarks, and develop treatment strategies in addressing the multi-system pathophysiology of the disease and associated comorbidities. Our registry provides a foundation for the use of new cutting-edge treatments as they become available.


Introduction
Oculo-pharyngeal muscular dystrophy (OPMD) is a rare, late-onset, progressive degenerative muscle disease that leads to dysphagia and eyelid, skeletal muscle weakness.Other neurological manifestations, such as fronto-temporal dementia, executive function deficits, peripheral neuropathy, fatigue, and pain [1].
OPMD is caused by short tandem trinucleotide GCN repeat (coding for Alanine) expansion in exon 1 of the polyadenylate-binding protein, nuclear 1 (PABPN1) gene (MIM 164300).The normal PABPN1 protein contains 10 alanine repeats, while the mutant PABPN1 protein has 11-18 repeats.OPMD is inherited most in an autosomal dominant (AD) pattern implying that carriers of the gene mutation are asymptomatic until late adulthood and the disease may not be fully expressed until later in life.The occurrence of homozygous biallelic mutations is extremely rare but might be more prevalent in Israel [2,3].The underlying mechanisms of OPMD have not been completely elucidated and may include toxicity of intranuclear aggregates, sequestration of various substances within the intranuclear aggregates that undermine cell maintenance processes; reduced levels of wild-type PABPN1 or suppression of its normal function by the mutant protein [1].
While OPMD is a rare disease worldwide, it is disproportionally prevalent among several populations, including Bukharian Jews, French Canadians, and Hispanic New Mexicans [3].The rarity of OPMD imposes a significant challenge for adequate research and development of effective treatment options.The Bukharian Jewish population is a Jewish diaspora originating from what is today Uzbekistan.The prevalence of OPMD is particularly high among the Bukhara Jewish community, in which a founder mutation occurred approximately 800 years ago [4].The estimated prevalence of OPMD among this population is 1:600 [4] implying that there are a few hundreds of patients in Israel.
The primary aim of this report is to describe the design and rationale of the national registry of Israeli patients with OPMD.Due to the rarity of OPMD, there are significant challenges to conducting research and developing effective treatments.Therefore, the registry is expected to facilitate research and provide a better understanding of the disease's epidemiology, natural history, and clinical characteristics, which may guide the development of more effective diagnostic and therapeutic strategies.Furthermore, the registry will allow for the identification of eligible patients for clinical trials and enable the evaluation of the effectiveness of new treatments [1].

Study design and aims
The IsrO-PMD registry aims to investigate the clinical features and natural history of OPMD in patients from Israel.This is an open, prospective, non-randomized multi-disciplinary study that involves adult individuals affected by OPMD.The study was designed according to the Consolidated Standards of Reporting Trials (CONSORT) extension criteria for pilot trials [5] and was approved by the institutional review board of Sheba Medical Center (SMC), Israel.The primary objective of the study is to describe the clinical manifestations of OPMD in Israeli patients, including dysphagia, eyelid and skeletal muscle weakness, and other neurological manifestations.In addition, the study aims to determine the natural history of the disease in 1-2-year intervals and investigate potential predictors of disease progression.The IsrO-PMD study will provide valuable insights into the clinical features and natural history of OPMD in the Israeli population and may aid in the development of more effective diagnostic and therapeutic strategies for this rare disease [6].The IsrO-PMD committee comprises representatives of various sub-specialties involved in the management of OPMD, including clinical genetics, neurology, laryngology, ophthalmology, oral health, psychology, and psychiatry.In addition, a representative from a patient's organization is included in the committee.The multi-disciplinary nature of the steering committee ensures a comprehensive approach to the study design and implementation, and ensures that the study accounts for the diverse clinical manifestations and patient perspectives of OPMD.

Participant recruitment
All participants will sign informed consent.The recruitment process will consist of several routes of awareness promotion among laymen and healthcare professionals: 1.An awareness campaign, led by a national charity dedicated to the promotion of health and cure in patients with OPMD.This includes publications on electronic social media, publications in journals distributed among high-risk populations, meetings with community leaders in high-risk populations, and outreach activities among close relatives of identified affected individuals.2.An awareness campaign among primary care and family physicians.This consists of lectures within post-graduate education programs for family physicians in all national HMOs and publications in national medical journals.In addition, health providers in relevant subspecialties (e.g., neurology, clinical genetics, ENT, and ophthalmology) are also approached to raise attention to OPMD and options for diagnosis and treatment.

Eligibility
Both men and women aged over 18 years are eligible for recruitment if they have signs or symptoms suggestive of OPMD, and/or have confirmed genetic diagnosis of OPMD.Individuals with suspected OPMD, with or without relevant family history, are encouraged to seek genetic counseling and molecular testing.
All available medical records of the patients will be reviewed to identify the initial onset of OPMD manifestations.The investigators will maintain an enrollment log with confidential identifying information that corresponds to the subject numbers and initials of each study participant.The log will be kept secure and confidential to ensure patient privacy and data protection.The rigorous eligibility criteria and the confidentiality measures employed in the IsrO-PMD study will ensure the integrity and reliability of the study's findings.

Demographics, disease history, data storage, and collection
Prior to enrollment, each participant will be required to provide informed consent and complete an intake questionnaire.The questionnaire includes the Common Data Elements (CDEs) of the Global Rare Diseases Patient Registry and Data Repository (GRDR) Standard as recommended by the European Union Committee of Experts on Rare Diseases (EUCERD) and the National Institutes of Health (NIH).The CDEs are standardized data elements that allow for the collection and comparison of data across different studies and research sites, promoting data quality and consistency.
By using the GRDR Standard, the IsrO-PMD study ensures that its data collection is comprehensive, standardized, and aligned with international best practices for rare disease research.The informed consent process ensures that the participants are fully informed about the study and their rights as research subjects, and that their privacy and confidentiality are protected.The use of CDEs and informed consent is essential to ensuring the ethical conduct of research and the trust of participants and the broader public in the research enterprise [7,8].
The questionnaire consists of 74 items pertaining to contact information, socio-demographic information, history of diagnosis, family history, anthropometrics, medications, devices, and health services, clinical research, participation and biospecimens, and communication preferences.Patient data will be collected from electronic medical records and registered in a de-identified electronic database developed specifically for the registry.The database is designed to ensure that patient privacy and confidentiality are protected while allowing for comprehensive data collection and analysis.Data elements will be entered into the registry according to the parameters described below.

Registry design
All patients are periodically evaluated by the multi-disciplinary team of specialists: neuromuscular, ophthalmologic, laryngology and respiratory rehabilitation, oral health, and rehabilitation clinical psychology.

Neuromuscular evaluation
Each patient will be examined by a neuromuscular specialist.Aside from ptosis and dysphagia, a variety of OPMD manifestations can be evaluated upon physical examination, such as upward gaze limitation, tongue weakness or atrophy, facial muscle paresis, and proximal muscle weakness.Proximal muscle weakness is a characteristic feature of OPMD that may lead to major disability.Subjects will be assessed for skeletal muscle strength according to the Medical Research Council (MRC) grading system.The grading scale is ranked from 0 to 5 with 0 indicating muscle paralysis and 5 indicating normal strength [9].
To ensure a comprehensive evaluation of functional status, walking speed will be measured as part of the clinical assessments.Walking speed is a valid and reliable measure of functional and overall health, and it has been shown to be a useful tool for assessing disease progression and response to treatment in various neuromuscular disorders [10].During the clinical assessments, patients will be asked to walk a predetermined distance at their usual pace, and the time to complete the distance will be recorded.This measure will be repeated multiple times to ensure accuracy and reliability.The average score will be entered into the registry database, and they will be used to evaluate changes in functional status over time and to assess the effectiveness of therapeutic interventions.A 14-m walkway will be used for testing, with two-meter acceleration and deceleration phases included in the walking speed measurements.
Nerve conduction studies (NCS) and electromyography (EMG) will be performed as previously described [11].Motor NCSs included one or more of the following median, ulnar, tibial, and peroneal nerves.Sensory NCSs included median, ulnar, radial, sural, and superficial peroneal nerves.Bilateral upper limbs were tested in all but one case.Orthodromic median mixed-nerve studies across the wrist were performed when the median sensory study was normal.In the lower limbs, motor studies were conducted on one side and sensory studies bilaterally.The sympathetic skin response (SSR) was tested in the palm and foot on one side when the sural study was normal or near normal [12].EMG was performed on one lower or upper extremity and included but was not limited to the tibialis anterior, medial gastrocnemius, and quadriceps vastus medialis).

Laboratory parameters
In addition to CK screening, patients with OPMD will undergo several laboratory tests as part of their routine evaluation.These tests may include a complete blood count (CBC), liver function tests (LFTs), renal function tests (RFTs), electrolyte panel, thyroid function tests (TFTs), and fasting glucose levels.CBC provides information about the number and type of blood cells, including red blood cells, white blood cells, and platelets.LFTs and RFTs evaluate liver and kidney function, respectively.The electrolyte panel measures the levels of various ions, such as sodium, potassium, and calcium, which are important for normal bodily function.TFTs assess thyroid gland function, which can affect muscle strength and overall health.Fasting glucose levels are used to screen for diabetes.

Respiratory and pulmonological evaluations
Weakness of respiratory muscles in OPMD results in impaired cough and increased risk for infection, atelectasis, and respiratory failure, and may present as a feature of OPMD [1,13].To assess the effectiveness of a cough reflex, spirometry, mean inspiratory (MIP) and expiratory (MEP) pressures, forced vital capacity (FVC), as well as functional independence measure are performed [1,14].MEP is one of the most used assessments of cough impairment and values above 60 cm H 2 O are considered as an effective cough [15].A peak cough flow (PCF) > 360 L/min would be expected in normal subjects, while a PCF < 160 L/min would be classified as inadequate airway clearance [15].

Genetic testing
To promote availability and facilitate genetic testing, the registry team refers subjects with clinical symptoms of OPMD to the Danek Gertner Institute of Human Genetics at SMC.A board-certified physician in medical genetics provides genetic counseling to the subjects prior to testing, which is offered and performed at the SMC genetic laboratory.In cases where positive results are obtained, options for future family planning are discussed.This may include screening of unaffected family members (such as adult offspring) for the mutation, in order to offer prenatal testing and preimplantation genetic diagnosis.It should be noted that some participants may have already undergone genetic counseling and testing elsewhere, and will only be included in the registry if their results are compatible with an OPMD diagnosis.

Swallow studies
All participants are requested to complete the Swallowing Disturbance Questionnaire (SDQ) self-reporting questionnaire [16,17].SDQ consists of 15 questions on swallowing disturbances, 5 questions are related to the oral phase of swallowing, and 10 questions are related to the pharyngeal phase.Fourteen questions are rated by a four-point (0-3) scale (0 for no disturbance and 3 for severe disturbance), and one is a "yes/no" question (yes was scored 2.5 and no was scored 0.5).SDQ score of 12.5 or more is considered pathological.
Functional oral intake is determined by the Functional Oral Intake Scale (FOIS) [18].The FOIS is a 7-item scale that rates the degree of oral and non-oral food consumption and considers diet modifications and patient compensations.
A fiber-optic video-endoscopic swallow study (FEES) is performed to evaluate the participants' swallowing functions.Following the FEES examination the Penetration Aspiration Scale (PAS) [19] and Yale Pharyngeal Residue Severity Rating Scale (Yale-PRSRS) [20] are recorded.PAS represents the degree of bolus invasion into the airway, whether there was a cough reflex and the effectiveness of the cough in clearing the bolus.This is an eight-point scale, 1 represents normal swallowing and 8 represents the finding of aspiration with no cough reflex at all.
The Yale-PRSRS quantifies the degree of residues from 1 (normal) to 5 (maximum residue) separately for the valeculae and for the pyriform sinuses.The nutritional status of the participants is evaluated by a nutritionist and rated according to the Subjective Global Assessment (SGA) tool [21,22].SGA is determined on changes in nutrients intake, weight loss, symptoms affecting oral intake (diarrhea, vomiting, nausea, dysphagia, oral problems), functional capacity (fatigue and progressive loss of function), and on physical examination findings-subcutaneous fat, muscle wasting, and presence of edema and ascites.Scoring of A represents normal nutrition, B for moderate malnutrition and C represents severe malnutrition.

Ophthalmologic examination
Each patient will undergo clinical assessment: clinical photography, visual acuity, intraocular pressure, examination of the anterior chamber, fundoscopy, palpebral oculogyric reflex (Bell's reflex), computerized examination of the visual field, upper and lower margin reflex distance (MRD1 and MRD2), assessment of the levator palpebrae superioris muscle strength, and orthoptic examination [23].Eyelid ptosis is a cardinal feature of OPMD that can be assessed using facial photographs.By photographing our participants at both initial evaluation and follow-up screening, we may be able to assess clinical stage and disease progression after 1 year.Clinical photographs will be analyzed by software algorithms to obtain accurate measurements of MRD1 and MRD2 [24].MRD1 is defined as the distance between the central pupillary light reflex and the central margin of the upper eyelid, while MRD2 is defined as the distance between the central pupillary light reflex to the lower eyelid margin [25].These measurements provide data about the severity of ptosis as it results in a narrowing of the palpebral fissures.Each participant will be assessed for these metrics by measuring MRD1 and MRD2 in centimeters, with the participant's eyes in the primary gaze position.
Our study participants will undergo visual acuity testing at both the initial and follow-up screening visits to assess the impact of ptosis on vision and to track the progression of the disease over time.This will involve using standard eye charts to measure the clarity of vision and detect any changes or deterioration in visual acuity.This information will be important for understanding the full impact of OPMD on patients' quality of life and identifying any potential treatments or interventions that could help preserve or improve their vision.

Oral health assessment
Oropharyngeal dysphagia inevitably results in continuous presence of food remnants in oral cavity that may adversely affect teeth and oral health.Oral examinations will be performed by a periodontist and include number of decayed, missing, and filled teeth (DMFT) [32] and plaque index [33].Reportedly, majority of patients almost always or often complain on "having thick saliva" [34]therefore, unstimulated and stimulated sialometry [35] will be included in oral health assessment.

Discussion
OPMD is a rare disease with limited awareness among primary care physicians in Israel, leading to delayed diagnosis and appropriate management.A recent survey of patients referred to the SMC revealed significant gaps in access to appropriate healthcare, with most patients not receiving any evaluation for dysphagia and/or eyelid ptosis, and a third of referred patients having their OPMD diagnosis overlooked or dismissed.Furthermore, only a third of patients with dysphagia were evaluated by an ENT specialist and less than 20% by a speech therapist.Additionally, only about 20% of children of OPMD patients were referred for diagnostic evaluation, despite a 50% risk of inheriting the disease from their parents (unpublished data, the non-profit organization for promotion of health and cure of OPMD, https:// opmd.health/ en/ 2021/ 07/ 10/ recent-publi catio ns/).This survey suggests that primary care physicians in Israel may have limited to awareness of OPMD, which might lead to delayed diagnosis and management.
Currently, there is no FDA-approved curative treatment for OPMD.Symptom management consists of instructive training to facilitate swallowing and prevent food aspiration, physiotherapy to preserve muscle strength of the head, neck, chest, and proximal limb muscles, non-surgical or surgical procedures on the eyelids and pharyngeal muscles to correct ptosis and reduce swallowing difficulties, respectively [1].
Developing effective treatments for rare diseases such as OPMD requires a strong research infrastructure, and patient registries are a key component of this infrastructure.In this study, we established the Israeli registry for OPMD, IsrO-PMD, and our multi-disciplinary OPMD service has been recognized as the national specialized medical service for OPMD, ensuring that patients are referred to us for appropriate evaluation and management.We anticipate that within 3 years, the registry will include the majority of OPMD patients in Israel, providing a standardized dataset that can be used for multinational research projects.The registry will include adult patients of varying ages and disease severity levels with periodic follow-ups to reflect the natural progression of the disease.
The "silence and replace" gene therapy has been shown to restore muscle strength and mass in mouse and canine models of OPMD [36,37].These results highlight the need for a robust research infrastructure to support clinical trials for new treatments.Patient registries, like the IsrO-PMD, can play an important role in the development of curative therapies for OPMD.
The comprehensive multi-disciplinary protocol of the national registry launched in February 2022 will provide a better understanding of OPMD's natural history and identification of subtypes of OPMD.Follow-up of a large cohort of OPMD patients in 1-2 year intervals may identify factors that affect treatment response and disease progression.The registry can serve as a platform for collaboration and knowledge exchange between healthcare providers, researchers, and patient advocacy groups, leading to new insights on pathogenetic mechanisms and lead to the development of targeted therapies for specific genetic abnormalities associated with OPMD.