Design, set-up and utility of the UK facioscapulohumeral muscular dystrophy patient registry

The registry was launched at a patient information day in the UK, and presented to around 90 delegates. Two months after the launch 225 people had registered. Over the first 2 years (25 months) period an average of 21 people have registered per month. Thirty-four doctors have agreed to take part in the registry and provide genetic data. Two hundred and twenty-six patients have selected a clinician to provide additional details. Of the 518 people registered, 260 have logged into update their data, 121 have not logged in after an annual reminder and 137 have not yet been registered for 12 months (Online Supplementary Material Fig. 1: Rate of patient enrolment; May 2013 to May 2015.)

The additional outcomes (pain, scapular fixation and quality of life) have been completed by the majority of people. Of the 518 people registered in total 425 (82 %) provided answers to InQoL, 479 (92 %) answered the McGill pain questionnaire and 468 (90 %) answered the FSHD specific pain questionnaire. Within the core questionnaire 46 people report having had scapular fixation, of which 40 have completed the additional questionnaire.

In its first 2 years, the registry has helped recruitment into an international natural history study for infantile onset FSHD “A multicentre collaborative study on the clinical features, expression profiling, and quality of life of infantile onset facioscapulohumeral muscular dystrophy.” (ClinicalTrials.gov Identifier; NCT01437345). Interrogation of the registry database identified 33 patients meeting some or all of the inclusion criteria. All patients were contacted and five were included in the study. This made up 42 % of the total participant requirement for the UK study site (John Walton Muscular Dystrophy Research Centre); the remaining participants were identified from the local clinic population.

Between May 2013 and May 2015 a total of 518 patients registered with the UK FSHD Patient Registry, an average of 21 patients per month from all across the UK (Fig. 1). Most patients live in the south of England with the major clustering around London. Other clusters surround the areas of Liverpool/Manchester, Newcastle and Edinburgh. These clusters represent most probably a higher population density and the existence of centres with neuromuscular specialists. Of these 475 reported being affected by FSHD 1 (91.7 %), 9 reported FSHD2 (1.7 %) and 34 (6.6 %) reported that they had a yet to be confirmed diagnosis. Excluding the patients with unconfirmed diagnosis, 98.14 % of patients were reported as FSHD1 and 1.9 % as FSHD2. Those with an unknown diagnosis have been excluded from further analysis. All data mentioned has been reported by patient themselves with the exception of genetic confirmation which has been provided by the treating neuromuscular specialist or central diagnostic lab.

The self-reported diagnosis was checked against the result of the genetic testing when available. FSHD1 is genetically confirmed in 307 cases, 286 of which had identified as having FSHD1, three misreported having FSHD2, and 18 reported an unknown diagnosis or left this question blank. We have a genetically confirmed diagnosis for two FSHD2 patients, matching the self-report in both cases.

The mean age of all patients included in the registry is 47.82 ± 16.08; (range 6–83) years. There are 243 (50.20 %) males and 241 (49.79 %) females registered with a slight non-significant predominance of females in the younger age groups (0–19). Considering only the 475 FSHD1 patients, there is also an even distribution across genders (239 Males, 236 Females) and the current age ranges from 4 to 83 years old (mean 47.7 ± 16.13), 60.21 % (286) of patients are between the ages of 40 and 70 years old (Fig. 2). The age range of the nine FSHD2 patients is from 19 to 67 with a mean of 50 (±13.85) years, with an even distribution between genders (5 males; 4 females). Detailed family history is not collected; however, the majority of patients are aware of at least one additional family member being affected (father 79, mother 131, sibling 145, and other family member 157) (Table in online supplementary material).

The ethnic origin of all FSHD patients is predominantly Caucasian, in FSHD1 this makes up to 89.9 % (427) of those registered, [Asian 20 (4.2 %), black African 1 (0.2 %), mixed 4 (0.84 %), declined 13 (2.7 %), other 10 (2.1 %)] and in FSHD2 8 of the 9 (88.9 %) patients reported Caucasian ethnicity with the remaining patients of unknown ethnic origin. Comparison with the ethnic distribution in the 2011 Census the different ethnic groups are evenly distributed apart from the black African group that are at a lower percentage than the general population, although applying a two-sample test of proportions the difference is non-significant (Table 2).

Fourteen records were excluded from this analysis, 12 FSHD1 and two FSHD2, these records have been excluded due to incomplete patient reported data. Excluded records had one or more of the following data items missing; to current motor function, hearing loss, wheelchair use, facial weakness, foot drop, hip girdle weakness and periscapular weakness. The analysis of the results showed that of the FSHD1 patients 82.5 % (n = 382) are ambulant although 45.1 % (n = 171) of these report that they require some assistance (e.g., using a cane or wheelchair part time). All of the FSHD2 patients remain ambulant with three requiring assistance. Muscle weakness is often reported to begin in multiple areas most commonly including facial muscles (59.18 %), with shoulder girdle weakness reported first in 53.33 % of cases, foot dorsiflexion weakness in 22.45 % and hip-girdle in 14.79 % (Table 3).

Additional symptomatic information is available for 463 FSHD1 patients registered, 17.28 % (n = 80) reported hearing loss, evenly split across genders (46.25 % female; 53.75 % male) with 38.57 % (n = 27/70) reporting hearing loss before the age of 40 years. Retinal vascular disease is reported in just 10 patients 6 males and 4 females, with a mean age of 45.6 years (range 25–69).

Thirty-seven (7.9 %) patients 22 males and 15 females, with a mean age of 50.96 years (range 20–76) reported the use of ventilation, with five (13.5 %) describing this as full time ventilation. Thirty-three of these (89.2 %) describe their current best motor function as requiring at least some assistance when walking.

A more in depth analysis of the clinical data will be discussed in a subsequent study.

The UK FSHD patient registry contains information on over 518 FSHD patients, 475 of whom are confirmed to have FSHD1. Given the published FSHD1 prevalence of 3.95 FSHD1 patients per 100,000 in North East England [1] and based on a population of 64.1 million in UK in 2014, this would equal 31 % of population coverage. The primary goal of the registry is not to capture all patients within the UK but rather to identify patients who are interested in participating in research. This should be considered when drawing clinical conclusions as the registry is likely to represent a biased sample of the more able and willing patients or arguably could also represent the more severely affected that are more engaged to enrol. FSHD1 is the most common form of the disease with approximately 95 % of patients falling into this category, and this is similar in the UK registry population (91.7 %). The remaining 5 % are considered as FSHD2 patients [16] similar to the 8.3 % of the UK registry population. It will be interesting to assess whether there will be an increase of FSHD2 diagnosis and registration following the relatively recent development of confirmatory genetic testing for FSHD2.

Most of the patients registered are ambulant and although this could be due to a recruitment bias, when we compare our data with population based collected data the percentage of ambulant patients is similar, we therefore believe this self-reported data transmits and accurate snapshot of the general FSHD population [17‐19]. The same is true when we look at the first location of muscle weakness, with facial and shoulder girdle being the most common locations. As already reported in the literature, distal or proximal lower limb involvement as the first manifestation is not unusual. In a previous report the frequency was 13 % for foot drop and 7 % for proximal lower limbs [20], the percentage is lower than in our population as they were considered as isolated manifestations and while in our cases the patients reported simultaneous locations for the beginning of the symptoms. An interesting aspect is the high incidence of hearing loss either under or above the age of 40. Further study is needed to determine whether this self-reported problem is in fact associated with any greater degree of hearing loss within the general population. From the recently published evidence-based guidelines from the American Academy of Neurology (AAN) [21] the recommendation regarding hearing loss is to screen patients with childhood onset as the prevalence of clinically relevant hearing loss is not clear in the general population. Respiratory involvement in FSHD is considered rare. From the literature and according to the guidelines of the AAN evidence from 2 studies suggests that respiratory involvement with an estimated frequency from 1.25 to 13 % and once more the self-reported respiratory status in our population is in accordance with this.

In asking the patients to provide the majority of the data through electronic communication, it has been possible to identify a large number of patients with FSHD in the UK in a short time frame and limited resources. A large amount of accurate and complete data now exists within the registry and is available to support the research community. In addition, there is a cohort of patients interested and able to participate in future clinical research. However, it should be noted the data provided are subjective and are not a substitute for data collected in a natural history study or clinical trial collected under GCP guidelines.

The input of detailed genetic data was delayed by the limited time and resources available to consultants within the NHS. This has been greatly increased through collaboration with diagnostic laboratories in the UK (Northern Genetics Service and Bristol Genetics Laboratory) that are able to provide details directly to the registry, as covered by the informed consent. In order to increase the coverage of genetic diagnosis further we will explore ways to receive this data directly from patients.

The registry has achieved its primary aim of helping to facilitate and accelerate recruitment into trials, evidenced by the infantile onset study mentioned above. The use of the registry led to the UK site (John Walton Muscular Dystrophy Research Centre) recruiting 70 % more patients than would have been available through local contacts alone. This significant increase is particularly important in rare diseases. Furthermore the response rates (>80 %) to the additional research questionnaires show that the utility of the registry goes above and beyond its primary purpose. The registry continues to consult with researchers in the UK and globally to ensure its use in clinical research, furthermore it could be utilised to develop and disseminate standards of care.

For the last few years, the European Union policy on Rare Diseases has stressed the need for an active collaboration in and between Member States as a way to promote equal access to care and to make the maximum use of the resources available for rare disease patients. The tools developed for this were at the level of the Member States the creation of National Plans for Rare Diseases and the nomination of Centres of Reference/Expertise; at a European level the future constitution of European Reference Networks are meant to help to fulfil that aim. For these instruments to be of use; data sharing and accurate, well established registries like the present one are an upmost requirement.

The registry has a mean recruitment rate of 21 registrations per month. A number of other registries utilise the same dual reporting system and have achieved similar rates, when taking into account different disease prevalence rates. The UK myotonic dystrophy registry (http://​www.​dm-registry.​org/​uk) has a mean rate of 16 per month while the incidence of myotonic dystrophy in the UK is thought to be higher than that of FSHD [1]. The Global FKRP registry (http://​www.​fkrp-registry.​org/​uk) collecting information about people with mutations in the FKRP gene has a lower rate of recruitment at an average of seven people joining per month, this is a much rarer condition (about 1 in 100,000 [1, 22]) however has global coverage. The persistent rate of inclusion seen in the UK FSHD registry suggests that there is an engaged and motivated FSHD population in the UK interested in participating and being informed about research.

The registry now contains a wealth of data on a subset of the UK FSHD population; the next steps are to carry out an in depth analysis on this data, in particular looking at the progression of the condition. The registry allows for the collection and analysis of longitudinal data, and that analysis, particularly in relation to pain and quality of life may provide an interesting resource to improve care of FSHD patients in the UK. The registry will also be able to inform on genotype phenotype correlation for FSHD1 and FSHD2.

A sub study is planned using the information collected on scapular fixation, contacting the surgeons who performed the procedure to create a more in depth picture of how this operation is carried out in the UK. We hope this coupled with the detailed patient experience could help clinicians better inform patients considering this procedure in the future. Further analysis will also be carried out on the remaining clinical data to generate hypothesis for future research which may improve standards of care.

The UK FSHD patient registry contains all of the mandatory and highly encouraged items outlined in an internationally agreed dataset [13]. This data set is known to be collected by 15 registries either established or in the setup stage (Italy, Croatia, Netherlands, Ukraine, Spain, Argentina, Chine, Czech Republic, Georgia, UK, USA, Canada, Australia, Egypt and New Zealand) under the TREAT-NMD umbrella. This comparability could allow the creation of a Global FSHD registry, something TREAT-NMD has achieved successfully for paediatric neuromuscular diseases Duchenne muscular dystrophy and spinal muscular atrophy [23, 24]. The UK FSHD Registry would welcome any efforts of this kind from TREAT-NMD and would hope to be at the forefront of such developments. Furthermore there is an increased movement towards harmonisation of data among the wider rare disease community, not only with registries but also considering biobank, omics and imaging information. The UK FSHD registry has been working with RD-Connect as it pilots a number of initiatives working towards this goal [17‐20].