Of the seventeen patients included, most were of White British descent (47%). Other ethnicities comprised of Pakistani (17%), Iraqi (6%), Romanian (6%), Syrian (6%) and Mixed (6%). All patients’ current ages ranged from 7 months – 20 years. The geographical locations of the samples varied from all parts of the UK, with many patients residing in the northern parts of the UK. Patients were also seen from Scotland and Wales (Fig. 2).
Timeline of diagnosis
Subsequently, we interpreted waiting time in relation to the time from first symptom onset to diagnosis. In most cases, retinopathy starts in infancy. 41% of patients did not receive a diagnosis until 5–20 + years after initial symptom presentation. 29% were diagnosed between the ages of 1–5 years, while only 18% received a diagnosis in the between three months to a year (Fig. 3).
Route to diagnosis and symptom onset
As well as this establishing key determinants of successful AS diagnosis as part of the patient pathway was observed. The most common route of diagnosis was through ophthalmology referral (Fig. 4). Other individuals involved were GPs, paediatricians, clinicians dealing with weight management and cardiac geneticists. Cardiac gene panels provided 12% of the patients a diagnosis following the onset of cardiovascular symptoms in early life (< 1 year). In terms of symptoms obesity, visual impairment and cardiovascular disease were the most reported (Fig. 5). A combination of early onset cardiomyopathy and visual impairment seems to lead to quicker diagnosis, compared with patients in which these symptoms are absent or late onset.
Cardiovascular disease
Dilated cardiomyopathy is one of the most common first AS symptoms with over half (58%) presenting with cardiovascular disease as 1 of the 3 first symptoms. The onset of cardiomyopathy can vary from infancy to late childhood and adulthood (7). Those with early symptoms are seen earlier.
Obesity
Obesity is a relatively consistent feature and important early symptom of AS. The majority of patients experienced rapid weight gain in the first year of life. This condition was formally recorded as clinical obesity after paediatric clinic evaluation. More than half of our sample presented with excessive weight gain (Fig. 6). Patient 17 of this study was identified through such a clinic, and with input from ASUK a direct sibling and another family member were also diagnosed. Access to such clinics proved to be a significant factor in confirming AS in this case.
Visual Impairment
Visual impairment was 1 of the 3 first symptoms reported in 88% of patients included. Again more than half displayed rod-cone dystrophy before the age of 1, resulting in photophobia and nystagmus (8). Nevertheless, if this was an isolated symptom patients waited longer for diagnosis in comparison to a cluster of symptoms mentioned above.
Genetic Tests
Of all the patients 3/17 were successfully identified with genetic panel testing before the age of 1. Unfortunately, in some cases while testing provides closure, not all experiences are positive. Letters use complex terminology and are somewhat lacking in information about AS. Similarly, little emphasis is placed on signposting to highly specialised services, leading carers and families needing to seek alternative sources of knowledge to facilitate understanding of the care pathway.
Establishing a diagnosis
Previously we documented the average time to diagnosis, but the age of patients is equally as important. There can be significant delays in accessing this. Only 29% of AS cases are diagnosed in the first year of life following the onset of AS symptoms. 35% were diagnosed between 2–6 years, 24% between the age of 10–17 years (Fig. 7). A total of 2/17 patients in our study received an incorrect diagnosis of Bardet Biedl Syndrome and Leber Congenital Amaurosis before further genetic tests confirming AS. Research from ASUK underlined the fact that families attend numerous GP and hospital appointments before AS is diagnosed. Due to inconsistencies in healthcare practitioners, they saw that the lack of continuity of care meant effective holistic review of the patient was not taking place. Patients are frequently diagnosed in institutions far from home.
Barriers to diagnosis
Specifically, a barrier noted is the distinct lack of awareness among healthcare professionals concerning referral to appropriate specialists. In some cases patients were not referred at all. Providing training on dealing with unusual symptoms and making sources available that describe the referral process may offer a solution. ASUK is regularly the first point of contact; but this is dependent on independent research.
Health inequalities are growing in the UK. A report published by the NHS Race and Health Observatory gathered evidence to illustrate ethnic inequalities in healthcare (10). The most diverse and marginalised communities tend to be at most disadvantage in accessing healthcare. Often education plays a part too with people from a lower socioeconomic background falling behind. Being from an isolated, rural location has given patients with AS limited resources, with diagnostic capabilities available only at large hospitals.
Stigma surrounding certain cultural practices can make families rapport with healthcare professionals is strained. Certainly, in consanguineous relationships, parents can attach blame to themselves and opt out of genetic testing due to fear of judgement. Cultural competence is increasing amongst clinicians, and more so than ever they are aware of the different practices and worldviews individuals may have.
More recently the COVID-19 pandemic has affected multiple families. Even after the lockdown many face to face consultations were cancelled, compounding feelings of worry, anxiety and isolation. A byproduct being the missed opportunity for diagnosis and counselling of patients in person. The ability to communicate directly with healthcare professionals was diminished. On the other hand, some positives have come about as a result. The burgeoning area of telemedicine has enabled families to negate long-distance travel, and be seen in a comfortable environment (9). Acceleration in this area should prevent the troubles associated with getting to appointments due to mobility and vision issues.
Recommendations
Targeted education and training are critical for increasing awareness of AS and rare conditions can encourage clinicians to always consider such disorders as part of their differential diagnoses. Continually evaluating and updating current AS clinical guidelines can disseminate information linked to key criteria, which should raise suspicion for referral and genetic testing. Standardised protocols level out the differences that can contribute to health inequalities. When it comes to genetics, there needs to be a clear structure on what type of tests should be ordered depending on the circumstances. Adopting a multidisciplinary approach improves collaboration involving various specialists in charge of patient care (11, 12).
Additionally in this digital age lack of access can no longer be an excuse. The usage of virtual consultations can bridge this gap between symptom onset to diagnosis; especially in areas with scarce access to specialist services. Comprehensive assessments can minimise error and avoid incorrect conclusions (13). A rapport of trust and openness between families and clinicians can alert doctors to certain concerns and observations enriching the patient experience. Examining the holistic aspects can ascertain more facets such as the social, mental and physical effects of AS.
What is more is that growing interest can prompt more research in this area to advance treatments, and open access to clinical trials of therapies (14). A synthesis of the instances where cardiac transplantation has been successful can provide scientific evidence that can build for the future. NHS England can endorse charities such as ASUK to drive clinicians to signpost resources for newly diagnosed patients and families. Mandatory training on cultural competence and humility is a practical solution to ameliorate understanding of patients’ background (15). The Breaking Down Barriers Experts by Experience Advisory Group provides individuals from diverse backgrounds to give input when developing services.
Notably the symptoms identified should be added with extra weight placed on the first key features to present. Liasing with paediatric clinics can expedite the finding of potential AS cases. Ultimately exploring the possibility of AS being included in newborn screening would be the gold-standard for accelerating diagnosis (16). Lessons learned from the past should be reflected on going forward to present the best chances for all AS patients. Hopefully, new ideas and concepts can be designed in the coming years revolutionising the outlook on outcomes in ultra-rare conditions.