Disclaimer: The views expressed here are the views of the presenting physicians. The content presented in this report is not reviewed, approved or endorsed by the International Congress of Inborn Errors of Metabolism (ICIEM), or any of its employees, agents or contractors. No speakers or staff were interviewed directly or involved in the development of this report. Unofficial content. Official content is available only to registered attendees of ICIEM 2021.
The 14th ICIEM 2021 meeting, entitled “Transforming Rare Disorders”, was held as a virtual and in-person meeting this year and brought together key opinion leaders from the field of lysosomal disorders and rare diseases. Below is a summary of the presentations that were relevant to Fabry disease.
Professor Edwin Kirk (Sydney Children’s Hospital, New South Wales Health Pathology Randwick Genomic Laboratory, Sydney, New South Wales, Australia) primarily focused his presentation on Mackenzie’s Mission – the Australian Reproductive Genetic Carrier screening project.1 Professor Kirk explained the background and origin of Mackenzie’s Mission and that the aim of this project was to screen ~10,000 couples for carrier status for ~1300 autosomal and X-linked recessive genes, pre- or early in pregnancy. He briefly outlined the criteria for selecting genes for inclusion in this project: the condition should be life-limiting or disabling, with childhood onset, such that couples would be likely to take steps to avoid having an affected child, and/or be a condition for which early diagnosis and intervention would substantially change the outcome. Strong evidence for genotype–phenotype relationship was required.1
In Mackenzie’s Mission, individual carrier results are not provided.1 Professor Kirk explained, from experience, that >50% of couples are expected to be carriers of ≥1 condition and therefore time for genetic counselling is high: a median time of 64 minutes has been reported.2 In addition, he highlighted that individual gene variant analysis and reporting of carrier status for 1300 genes would provide an extensive laboratory burden compared with couple screening, which only analyses genes that pass the initial filtering, thereby resulting in reduced workload and laboratory burden.1
Professor Kirk discussed the reasoning behind the extensive gene list of ~1300 genes used in Mackenzie’s Mission and provided examples, from his perspective, of the challenges faced when generating the list for this study, including issues associated with the GBA1 gene and the wide spectrum of severity associated with Gaucher disease. A recently published practice resource from The American College of Medical Genetics and Genomics (ACMG) includes a suggested list of genes to be included when screening for autosomal recessive and X-linked conditions.3 Professor Kirk highlighted that this list was mainly based upon results provided by Guo et al., which utilised an exome sequencing database (n=123,136) to estimate carrier rates across six major ancestries for 415 genes associated with severe recessive conditions.4 However, Professor Kirk then noted that the ACMG list excluded several genes he considered to be important in the diagnosis of rare diseases.
In conclusion, Professor Kirk stated that, in his opinion, carrier screening is here to stay. However, he also noted that he thinks there is no real consensus on which genes should be screened, and that the reporting of gene variants of uncertain significance creates challenges for clinicians. He finished by stating that he thinks there is an important role for the field in providing guidance on these issues as well as the follow-up for couples who are identified through carrier screening.
Professor Stefan Kölker (Heidelberg University Hospital, Heidelberg, Germany) began his presentation by stating that, in his opinion, newborn screening may shift the paradigm of medicine by enabling secondary prevention through early diagnosis. He continued with a brief discussion around the complexity of inherited metabolic disorders and how the genotypes and biochemical phenotypes do not necessarily predict the clinical phenotype.5
Professor Kölker then presented results from a recent study by Mütze et al., which studied the clinical outcomes of patients with inherited metabolic disorders identified through newborn screening between 1999 and 2016.6 He highlighted that for the majority of patients and diseases in newborn screening programmes included in this study, there was a very good outcome in terms of prevention of chronic permanent disease manifestation until the last study visit, which is often during adolescence or adulthood. However, he went on to explain that there are some ‘tricky’ diseases where, from his perspective, treatment is not optimal and therefore the manifestation of disease-specific symptoms cannot be prevented (e.g. maple syrup urine disease, long-chain 3-hydroxyacyl-coenzyme A dehydrogenase and mitochondrial trifunctional protein deficiency, and glutaric aciduria type 1).6
Professor Kölker stated that in his opinion, the quality of diagnostic processes in newborn screening must be optimised to aid reliable and fast diagnoses of patients with inherited metabolic diseases. Professor Kölker continued this line of discussion by listing the three main factors that can affect newborn screening process quality, which included age at dry blood spot sampling (sender), age at first report to sender (laboratory) and transport interval (carrier).6 He then emphasised that from his perspective, all three must work together effectively to provide maximum newborn screening process quality.
Professor Kölker concluded his presentation by stating that, in his opinion, newborn screening is the prerequisite of favourable clinical outcome. However, he followed this up by clarifying that long-term health benefits of patients identified by newborn screening depended on various factors, such as optimal diagnostic process quality and development of evidence-based clinical care guidelines. In addition, his final words emphasised that optimisation and continuous improvement of international newborn screening programmes require transnational collaborative collection of interoperable outcome data.
Dr David Dimmock (Rady Children’s Institute for Genomic Medicine, San Diego, CA, USA) discussed rapid precision medicine with a focus on whole-genome sequencing (WGS). He firstly discussed the initial study published on rapid WGS (rWGS), which was conducted in 35 infants from newborn intensive care units who were selected to receive genome sequencing based upon the suggestion that a genetic disease was present.7 All 35 patients received rWGS, of whom 32 had standard genetic testing. Genetic disease diagnosis was made in 20 out of 35 patients (57%) as a result of rWGS, compared with three out of 32 patients (9%) with standard tests (p=0.0002). As a result of rWGS, four patients (20%) had diagnoses with strong favourable effects on management and six patients (30%) initiated palliative care.7
Dr Dimmock then presented results from a subsequent randomised controlled trial (NSIGHT1) in which 32 infants received rWGS plus standard tests and 33 received standard tests alone (5 out of 33 infants crossed over to receive rWGS).8 He emphasised that, in this study, rWGS was associated with a dramatically increased diagnostic yield (approximately double the number of infants diagnosed with standard testing alone), as well as a dramatic reduction in the time to diagnosis in those children who were diagnosed.8 He also briefly discussed a third study demonstrating that rWGS decreased infant morbidity and the cost of hospitalisation.9
Dr Dimmock highlighted four historical physician concerns regarding WGS including: (1) differing opinions about whether and how genomic results could be clinically useful; (2) potential harms of genomic testing; (3) uncertainty about the interpretation of results; and (4) parental consents and limits on their right to know genomic information.10 Dr Dimmock did not explain in detail the key studies looking at WGS in the intensive care unit; however, he emphasised that, in his opinion, the evidence suggests this should become standard of care.
When comparing genome versus panel screening, Dr Dimmock briefly discussed a study by Maron et al., in which 113 infants were tested and all received both rWGS and panel screening of 1722 genes. As a result, diagnostic and/or variants of unknown significance were returned for 51 patients.11 Continuing with the comparisons of screening methods, Dr Dimmock compared genome versus exome screening and highlighted a study by Splinter et al., in which 53% of patients (n=17/32) with previous exome sequencing had a diagnosis made by WGS.12 Additionally, he included data from The UK 100,000 Genomes Project reporting 13% of the diseases diagnosed by genome sequencing were caused by mutations in non-coding sequences or mitochondrial genomes, tandem repeat expansions in patients with Huntington’s disease, and a wide range of structural variants with nucleotide resolution of breakpoints. Additionally, 2% of the diagnoses involved coding variants in regions of low coverage on exome sequencing.13
Dr Dimmock concluded his presentation with an overview of what he believes the future may look like for WGS, including emphasis on the results of NSIGHT1, which demonstrated that clinicians may miss the diagnosis in around two-thirds of children who could benefit from WGS.8
Associate Professor Curtis Coughlin (University of Colorado School of Medicine, Aurora, CO, USA) discussed the Consent and Disclosure Recommendations (CADRe) framework in the final presentation of this session. He explained that the framework for genetic testing was developed by the CADRe Workgroup in response to genetic testing being widely ordered by non-genetics clinicians. He emphasised that it provides guidance to facilitate communication about genetic testing, ultimately leading to improved patient experience.14 Professor Coughlin listed the following four factors, which are recommended to be taken into consideration when evaluating the degree of communication required by a patient14:
- Complexity of the testing
- Increased risk of adverse psychological impact of genetic testing process
- Significant risk for near-term mortality
- Clinically complex management.
The CADRe recommendations provide clinicians ordering genetic testing for patients with a framework to determine the appropriate level of communication regarding informed consent with different patients15:
- In patient cases where there is a decreased complexity of decision making, testing for a known diagnosis or familial gene variant, and quality education materials are available, the CADRe framework recommends brief communication supported by educational materials.15
- In patient cases where there is increased complexity of decision making, a medically burdensome condition, uncertain gene–disease validity and evidence of adverse psychological outcomes related to genetic testing, the CADRe framework recommends traditional genetic counselling and pre-test education.
Application of the CADRe framework in the context of the American College of Medical Genetics secondary findings v2.0 conditions, neurodegenerative disorders and exome sequencing suggested that most conditions required a brief or a targeted consent process.16 However, traditional genetic counselling was recommended for indications that present more complex and uncertain situations, such as neurodegenerative disorders.16
Associate Professor Steven Gray (Departments of Pediatrics, Neurology & Neurotherapeutics, and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA) provided an overview of research into gene therapy for lysosomal storage diseases, primarily featuring adeno-associated virus (AAV) as a gene therapy vector. He described favourable characteristics of AAV as a vector, including how it is naturally non-pathogenic, able to transduce non-dividing cells and confer long-term transgene expression.17 Research supporting the use of AAV9 as a treatment approach for central nervous system (CNS) diseases has demonstrated a dose-responsive manner for delivery of the gene to the CNS, but with limited biodistribution in peripheral tissues, following transduction of the green fluorescent protein (GFP) reporter gene with AAV9 injected into the tail vein of mice.18 Delivery of the vector into adult mice by lumbar intrathecal injection instead has shown widespread distribution of GFP expression, including in brain regions (0.5 copies of GFP per mouse genome in the olfactory bulb).19 Professor Gray concluded from this that intravenous injection results in more peripheral distribution of the vector, whereas injection into the cerebrospinal fluid resulted in CNS-targeted distribution.
Next, Professor Gray presented research that has demonstrated the translation of this approach into other animal models including non-human primates. One study showed that intrathecal administration of AAV9 leads to widespread vector distribution and transgene expression to the CNS, overcoming barriers associated with intravenous administration such as a lower dose, avoidance of neutralising antibodies and reduced peripheral organ biodistribution.20 Professor Gray concluded that AAV9, administered intravenously or intrathecally, has been validated across numerous labs for effective, disease-modifying CNS gene transfer across several species. He added that, in his opinion, AAV9 can mediate transformative benefit for many diseases, but it is likely not efficient enough to rescue others and is still limited to one dosing event, due to the development of persistent antibodies against the vector.
Symposium sponsored by Avrobio Therapeutics
Dr Michel Tchan (Westmead Hospital and University of Sydney, Sydney, New South Wales, Australia) opened the symposium by introducing the multisystemic nature of Fabry disease. In his opinion, the focus in Fabry disease tends to be on the neurological, renal and cardiac manifestations of the disease; however, he stated that Fabry disease is a multisystem disease that can also affect ophthalmological, dermatological and gastrointestinal systems. He then highlighted the current treatment options for Fabry disease: enzyme replacement therapy (agalsidase alfa or agalsidase beta)21,22 and chaperone therapy (migalastat).23 Dr Tchan concluded his presentation by describing the mechanism of action of migalastat, which was to be the focus of this satellite symposium.
The second presentation of the symposium by Professor Daniel Bichet (University of Montreal, Montreal, Quebec, Canada) focused on the long-term effects of migalastat on renal function. He described results from a post hoc integrated analysis which evaluated long-term changes in renal function in patients with Fabry disease and amenable GLA variants who received migalastat for ≥2 years in the FACETS and ATTRACT long-term open-label extension Phase III trials (NCT01458119 and NCT02194985).24 Patients in FACETS had never received prior enzyme replacement therapy or had not received enzyme replacement for ≥6 months (enzyme replacement therapy-naïve); patients in ATTRACT were enzyme replacement therapy-experienced (enzyme replacement therapy ≥12 months before study entry).
In FACETS, patients were split across a double-blind period to receive either migalastat 123 mg every other day (n=28) or placebo (n=22), before all patients received open-label migalastat 123 mg (n=47) after 6 months. In ATTRACT, patients received either open-label migalastat 123 mg every other day (n=34) or open-label enzyme replacement therapy 123 mg every other day (n=19). Both trials included a long-term open-label expansion element, in which patients from both trials received migalastat 123 mg (n=84).24
The overall median (range) duration of migalastat exposure was 7.0 (2.0–8.6) years in enzyme replacement therapy-naïve patients and 5.1 (2.1–7.2) years in enzyme replacement therapy-experienced patients. Professor Bichet summarised that results from this post hoc analysis suggest that patients with Fabry disease and amenable GLA variants had stable renal function (for up to 8.6 years), irrespective of treatment status (naïve and experienced), sex or phenotype.24 Professor Bichet also noted that migalastat was generally well tolerated, and that the most common adverse reaction was headache, which was experienced by 10% of patients receiving migalastat.25
Professor Roser Torra (Fundació Piugvert, Barcelona, Spain) then discussed real-world evidence for migalastat in Fabry disease. She highlighted results from a study at a hospital in Naples, Italy, where patients (n=7; all male) who had previously received enzyme replacement therapy for 12 months (n=6, agalsidase alfa; n=1, agalsidase beta) switched to migalastat for 1 year.26 She noted that the most common reason for switching was the patients’ own personal choice.26 Results showed that a significant improvement was observed between baseline and end of migalastat treatment in left ventricular mass index (p=0.016) and in median proteinuria (p=0.048); and no safety concerns were raised.26 Regarding the case report of a 56-year-old patient presenting with left ventricular hypertrophy at the Lisbon North Hospital, Lisbon, Portugal, Professor Torra summarised that left ventricular mass decreased following treatment with migalastat from baseline (148.3 g/m2) to 6 months (144.5 g/m2).27 She then moved on to data on the real-world experience of 78 patients (54 male; average age 53 years) with Fabry disease treated with migalastat at Salford Hospital, Salford, UK. After a follow-up of 1.6 years, mean left ventricular mass index improved (118.9 at baseline to 115.8 g/m2).28
Next, Professor Torra presented results of the German FAMOUS 24-month, observational, multicentre study of patients (n=54) with Fabry disease treated with oral migalastat 123 mg every other day, and followed for 24 months.29 The primary endpoint of left ventricular mass index decreased significantly from baseline at 12 (10.4 g/m2; p=0.0004) and 24 months (7.5 g/m2; p=0.0118), while also remaining stable for males and females without left ventricular hypertrophy and decreased towards normalisation in patients with left ventricular hypertrophy. Professor Torra concluded that this study showed how treatment with migalastat decreased left ventricular mass index over time, with the largest decrease observed in those patients with previous left ventricular hypertrophy. Estimated glomerular filtration rate (GFR) declined in both males and females and was associated with certain situations, such as those treated with angiotensin-converting enzyme, angiotensin II type 1 or aldosterone receptor blockers. Overall, no safety concerns were raised and migalastat was generally well tolerated.29
Professor Torra explained how another study in Germany at the Wurzburg Hospital demonstrated that with 1 year of treatment with migalastat, α-Gal A activity increased significantly (p=0.001) alongside significant changes in left ventricular myocardial mass index (p=0.037).30 She went on to describe a case study report of two unrelated male patients with Fabry disease from France who also showed decreased left ventricular mass and increased α-Gal A activity when treated with migalastat.31 In another study in Switzerland, α-Gal A activity was again shown to increase in most patients receiving migalastat.32 Professor Torra concluded that these real-world studies suggest that migalastat is generally well tolerated and that it may decrease cardiac hypertrophy, while not significantly increasing proteinuria, and may possibly preserve estimated GFR; however, further clinical trials are needed to confirm these observations.
Symposium sponsored by Takeda
Professor Kathy Nicholls chaired the Takeda symposium and began by detailing the objectives of the symposium which were to:
- Provide an overview of the evolution of Fabry disease outcomes after the introduction of enzyme replacement therapies.
- Review the importance of heart and renal protection and the impact on survival for patients with Fabry disease.
- Share clinical insights and best practice on the management of patients with Fabry disease.
Professor Aleš Linhart (Charles University and General University Hospital, Prague, Czech Republic) opened the symposium with an insight into the cardiovascular complications associated with Fabry disease and the effects of enzyme replacement therapies.
Professor Linhart stated that Fabry disease is complex, and went on to describe the progressive and irreversible nature of organ damage in Fabry disease, highlighting the profound functional impairment that leads to energy depletion33 and inflammation,34 which then activates compensatory mechanisms that inevitably lead to cardiac hypertrophy and also to apoptosis and fibrosis.35
He presented data showing Fabry disease is associated with rapid progression of left ventricular hypertrophy in both male and female patients and noted that, in female patients, the age of onset is delayed, and the rate of progression is slower compared with male patients.36 Professor Linhart then posed the questions of when should treatment be initiated and what degree of left ventricular hypertrophy is still reversible?
Based on his own expertise, Professor Linhart explained that many patients with Fabry disease present with extensive fibrosis and akinesia of the posterolateral wall and at this level any treatment such as enzyme replacement therapy or substrate reduction therapy may not effectively enhance the prognosis. Professor Linhart presented evidence that better cardiovascular (p<0.0001) and renal (p=0.0007) outcomes were obtained when enzyme replacement therapy (agalsidase alfa) was initiated in patients without left ventricular hypertrophy compared with patients that presented with left ventricular hypertrophy at treatment initiation.37 Similarly, low estimated glomerular filtration rate (eGFR) at initiation of enzyme replacement therapy was associated with worse cardiovascular and renal outcomes compared with patients with normal eGFR at baseline (both p<0.0001).37
The multitude of pathogenic variants associated with Fabry disease,38 which may make clinical decision making difficult, was highlighted by Professor Linhart. He then explained that while males are usually more severely affected, the clinical presentation of Fabry disease in females is normally more variable. He discussed data showing that X-chromosome inactivation significantly impacts the phenotype and natural history of Fabry disease in female patients.39
Data presented by Professor Linhart from a study by Hughes et al. also highlighted that prompt (<24 months) enzyme replacement therapy initiation after symptom onset was associated with a significantly lower risk of cardiovascular and renal events compared with delayed (≥24 months) treatment initiation (both p<0.001).40 In addition to this, 10-year data from the Fabry Outcome Survey (FOS) reported that early initiation of enzyme replacement therapy was associated with greater improvements in left ventricular mass index compared with delayed initiation of enzyme replacement therapy: patients who received treatment aged ≤30 years showed a more stable disease compared with patients who received treatment aged >30 years.41
Five-year FOS data reporting event rates (cardiac, renal, stroke or death) in patients treated with agalsidase alfa compared with untreated patients showed that treatment with enzyme replacement therapy slowed the progression of renal impairment and cardiomyopathy, and delayed the onset of morbidity and mortality.42
Professor Linhart concluded his presentation by emphasising that, in his opinion, early treatment is vital in order to effectively prevent irreversible organ damage in patients with Fabry disease.
Professor Kathy Nicholls (Royal Melbourne Hospital, Melbourne, Victoria, Australia) furthered the discussion of the importance of organ protection in Fabry disease by providing an insight into the renal complications associated with the disease.
Professor Nicholls highlighted the proposed relationship between age and podocyte parameters in untreated male patients with Fabry disease compared with normal controls – in patients with untreated Fabry disease the rate of loss of podocytes is accelerated and leads to progression of the disease.43 She then went on to emphasise that, from her own clinical experience, renal involvement is strongly correlated with morbidity and mortality in Fabry disease.
Data presented by Professor Nicholls from the Fabry Registry showed that patients with rapid renal disease progression experienced clinical events (stroke or cardiovascular event) before the initiation of agalsidase beta enzyme replacement therapy.44 The 10-year FOS data demonstrated that in agalsidase alfa-treated patients, eGFR was stable over time in female patients but a slow decline in eGFR was observed in male patients.45 However, later in the presentation, and based on her own knowledge, Professor Nicholls explained that enzyme replacement therapy alone does not fully protect from eGFR decline. Professor Nicholls then went on to present the 5-year FOS data, which showed that male patients treated with agalsidase alfa reported slower decline in eGFR, lesser increase in left ventricular mass, fewer composite morbidity events, and a higher estimated median survival compared with untreated male patients.42 Furthermore, she highlighted that the incidence rate of severe clinical events (renal or cardiac event, stroke or death) declined following initiation of agalsidase beta.46
At the beginning of the presentation, and based on her own experience, Professor Nicholls highlighted that proteinuria is present in over 50% of male patients with Fabry disease by the age of 35 years, leading to all male patients presenting with proteinuria by the age of 60 years. She then discussed the results from a study reporting the safety and efficacy of antiproteinuric therapy with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) in patients with Fabry disease who were receiving recombinant agalsidase beta therapy.47 A preservation of kidney function was observed in patients that initiated agalsidase beta treatment at a younger age and maintained urine protein/creatinine ratio (≤0.5 g/g) with antiproteinuric therapy.47 Hyperkalaemia occurred in seven patients and was managed with dietary modification and reduction in ACE inhibitor or ARB dose. Hypotension occurred in eight patients and was managed with dosing modification. No serious outcomes were attributed to hyperkalaemia or hypotension.47
Professor Nicholls discussed the importance of early treatment in relation to Fabry nephropathy. The 10-year FOS data in which patients with Fabry disease who began treatment with algalsidase alfa at a younger age were shown to maintain their GFR more effectively than those patients who initiated treatment at an older age. She then presented the results looking at the effect of early treatment on proteinuria level over time – slower increase in the levels of proteinuria was observed in patients who initiated enzyme replacement therapy at a younger age compared with patients who initiated treatment at an older age.41
Professor Christoph Kampmann (University Medical Centre, University of Mainz, Mainz, Germany) opened his presentation on the evolution of Fabry disease in the era of enzyme replacement therapy by presenting 10-year data from the FOS.42 He described how the estimated survival of patients receiving agalsidase alfa (n=677) was 77.5 years42 in males compared with untreated patients in the original Fabry disease trials (n=279) which was 60 years.42,48 Professor Kampmann explained that in the 2001 FOS data (n=181), the major cause of death in affected male relatives was renal failure (42%) while for affected female relatives it was cerebrovascular disease (25%).49 However, in the 5-year FOS data (n=42), cardiac disease was the most frequent cause of death in both males (34%) and females (57%), while only 7% died from renal disease.49 He further explained how in the 10-year FOS data, slowing and stabilisation of cardiomyopathy was observed with enzyme replacement therapy, versus data from a published study.36,42
Next, Professor Kampmann reported on the observed improvements in quality of life and pain scores following 1 and 2 years of treatment with enzyme replacement therapy, as reported in the FOS. The 5-dimension European Quality of Life questionnaire and Brief Pain Inventory (BPI) scores of patients receiving enzyme replacement therapy significantly improved after 1 and/or 2 years of treatment (p<0.05 for all comparisons).50 He noted that this improvement continued into the 5-year data for the average BPI score.51 Professor Kampmann highlighted the wide range of symptoms patients with Fabry disease receiving enzyme replacement therapy can experience to emphasise that patient well-being is recommended to be a management focus during treatment. He presented a published case study of a 28-year-old male with Fabry disease who received enzyme replacement therapy and demonstrated stabilised glomerular filtration rate and urine albumin during long-term follow-up.52 However, the patient continued to report complaints of panic attacks, gastrointestinal problems, tinnitus, mild attacks of chest pain, and fatigue.52 Professor Kampmann’s concluded that, in his opinion, improvements in survival and management of Fabry disease symptoms, and initial improvements in cardiac and renal events and quality of life are observed with enzyme replacement therapy. However, these should be taken into consideration with the adverse events of treatment, as well as the missing data on the long-term effects of treatment and impacts of Fabry disease.
Nicole Millis (Chief Executive Officer, Rare Voices Australia, Auchenflower, Queensland, Australia) presented her experience of patient advocacy, which began when her son was diagnosed with Hunter syndrome 20 years ago. She successfully campaigned towards having enzyme replacement therapy available in Australia, 9 months sooner than she was originally told, and learnt the power of patient advocacy to effect change. Nicole’s presentation focused on Rare Voices Australia (https://rarevoices.org.au/), the National peak body organisation advocating for people living with a rare disease, formed in 2012. Rare Voices Australia work in partnership with over 90 rare disease organisations, researchers, clinicians, government and industry to advocate for policy and systems that work for people.
Rare Voices Australia have launched a national strategic action plan, following a call for a national plan for rare diseases by Australian academics in 2010. Nicole described the three inter-related pillars of this action plan: awareness and education, care and support, and research and data. The aim is to provide a framework and policy direction from which the whole rare diseases sector can advocate on issues that are important to them. She explained how the action plan is a powerful tool in rare disease advocacy, due to it being collaboratively developed by the rare disease sector, having a government policy framework, bi-partisan support, politician and bureaucrat awareness, applying to a very broad range of rare disease issues, using shared language and a common voice, and with a strong evidence base.
Next, Nicole outlined the strategies of patient advocacy that should be avoided, due to limited effectiveness in the long term, including aggressive, adversarial or dismissive approaches, unlikely simplistic solutions and exaggerated messages. Instead, the more effective approaches included polite persistence and pragmatic, collaborative, independent, credible, measured engagement, targeted to decision makers and with a patient-centred approach that engages with all stakeholders and shows an understanding of policy and systems. She then explained patient advocacy involvement in government programmes such as the Life Saving Drugs Program53 and newborn bloodspot screening.54 Nicole concluded her presentation by saying that there are many ways people can be involved in patient advocacy and it is a shared responsibility to effect this type of change.
Dr Terry Derks (University of Groningen, Beatrix Children’s Hospital, Groningen, The Netherlands) described the care continuum model in rare diseases which he summarised as focusing on three concepts: telehealth, integration of care and research, and improving patient–clinician research collaborations.55 He further explained the different values that can be considered in value-based healthcare, which include personal value (appropriate care to achieve patients’ personal goals), technical value (achievement of best possible outcomes with available resources), societal value (contribution of healthcare to social participation and connectedness) and allocative value (equitable resource distribution across all patient groups).56 Dr Derks stated that the essence of value-based healthcare is to investigate whether added value can be achieved for the patient and to cut aspects where this is not the case. However, he also explained that there is no single definition of value-based healthcare or even what value is in a healthcare context. What a patient or family considers valuable may not be the same as what a physician or stakeholder considers valuable. Furthermore, in Dr Derks’s opinion, researchers and investors normally decide what gets researched and the priorities of people who use healthcare services and those of healthcare providers who treat and care for them can be very different.
Dr Derks then described a research initiative aiming to change this, the International Liver Glycogen Storage Disease (GSD) Priority Setting Partnership, which planned to find the unanswered questions of patients with liver GSD, their families and healthcare professionals to establish the top research priorities in this area.57 The top-ranked priority identified was to find out “what are the best options for achieving sufficient amount of working enzymes in patients with liver GSD?” and the rest of the identified priorities had a similar focus on issues surrounding treatment. Furthermore, the majority of top research priorities identified here were concluded to be relevant healthcare topics for many other inborn errors of metabolism and rare diseases in general. Dr Derks’s closing remark was that activities of the academic rare diseases community will benefit more from better organised multi-stakeholder collaborations between patients, healthcare providers, policy makers and private companies. He added that healthcare has developed into multidisciplinary networks to deliver the right care at the right time for patients, and that their role is becoming increasingly professionalising, given the high level of self-monitoring and self-management required of them today.
Dr Callum Wilson’s (National Metabolic Service, Starship Children’s Hospital, Auckland, New Zealand) presentation highlighted equitable healthcare for Indigenous people, from his experiences working in the New Zealand National Metabolic Service to deliver quaternary care at various centres around the country to Indigenous people. He described the Treaty of Waitangi (1840): “Tino Rangatiratanga – guarantees Māori self-determination and design, delivery and monitoring of health”, with the “aim to achieve equitable health outcomes” and ensure “services are culturally appropriate”. Dr Wilson explained that consultation with Indigenous people can include culturally appropriate aspects such as meeting with extended family, meeting at their home or tribal centre and with support workers, extensive use of Indigenous language, protocol (e.g. prayer) and understanding of Māori Health and its aspects. Dr Wilson then explained lessons he has learned from his clinical experiences, including that Indigenous metabolic disease may have a different phenotype, that different Indigenous people should not be lumped together and that regional screening practices need to adapt to local disease prevalence. Additionally, international molecular databases are not as reliable for Indigenous peoples, and the discovery rate for Indigenous Mendelian diseases is still steep.
C-ANPROM/INT/FAB/0145; Date of preparation: November 2021
- Kirk EP, Ong R, Boggs K, et al. Gene selection for the Australian Reproductive Genetic Carrier Screening Project ("Mackenzie's Mission"). Eur J Hum Genet 2021; 29: 79-87.
- Lynch FL, Himes P, Gilmore MJ, et al. Time costs for genetic counseling in preconception carrier screening with genome sequencing. J Genet Couns 2018; 27: 823-833.
- Gregg AR, Aarabi M, Klugman S, et al. Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med 2021; 23: 1793-1806.
- Guo MH, Gregg AR. Estimating yields of prenatal carrier screening and implications for design of expanded carrier screening panels. Genet Med 2019; 21: 1940-1947.
- Lanpher B, Brunetti-Pierri N, Lee B. Inborn errors of metabolism: the flux from Mendelian to complex diseases. Nat Rev Genet 2006; 7: 449-460.
- Mütze U, Garbade SF, Gramer G, et al. Long-term outcomes of individuals with metabolic diseases identified through newborn screening. Pediatrics 2020; 146.
- Willig LK, Petrikin JE, Smith LD, et al. Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of diagnostic and clinical findings. Lancet Respir Med 2015; 3: 377-387.
- Petrikin JE, Cakici JA, Clark MM, et al. The NSIGHT1-randomized controlled trial: rapid whole-genome sequencing for accelerated etiologic diagnosis in critically ill infants. NPJ Genom Med 2018; 3: 6.
- Farnaes L, Hildreth A, Sweeney NM, et al. Rapid whole-genome sequencing decreases infant morbidity and cost of hospitalization. NPJ Genom Med 2018; 3: 10.
- Knapp B, Decker C, Lantos JD. Neonatologists' attitudes about diagnostic whole-genome sequencing in the NICU. Pediatrics 2019; 143: S54-s57.
- Maron JL, Kingsmore SF, Wigby K, et al. Novel variant findings and challenges associated with the clinical integration of genomic testing: an interim report of the Genomic Medicine for Ill Neonates and Infants (GEMINI) study. JAMA Pediatrics 2021; 175: e205906-e205906.
- Splinter K, Adams DR, Bacino CA, et al. Effect of genetic diagnosis on patients with previously undiagnosed disease. N Engl J Med 2018; 379: 2131-2139.
- The 100,000 Genomes Pilot Investigators. 100,000 Genomes Pilot on rare-disease diagnosis in health care – preliminary report. N Engl J Med 2021; 385: 1868-1880.
- Ormond KE, Hallquist MLG, Buchanan AH, et al. Developing a conceptual, reproducible, rubric-based approach to consent and result disclosure for genetic testing by clinicians with minimal genetics background. Genet Med 2019; 21: 727-735.
- Faucett WA, Peay H, Coughlin CR, 2nd. Genetic testing: consent and result disclosure for primary care providers. Med Clin North Am 2019; 103: 967-976.
- Hallquist MLG, Tricou EP, Ormond KE, et al. Application of a framework to guide genetic testing communication across clinical indications. Genome Med 2021; 13: 71.
- Atchison RW, Casto BC, Hammon WM. Adenovirus-associated defective virus particles. Science 1965; 149: 754-756.
- Gray SJ, Matagne V, Bachaboina L, et al. Preclinical differences of intravascular AAV9 delivery to neurons and glia: a comparative study of adult mice and nonhuman primates. Mol Ther 2011; 19: 1058-1069.
- Bailey RM, Rozenberg A, Gray SJ. Comparison of high-dose intracisterna magna and lumbar puncture intrathecal delivery of AAV9 in mice to treat neuropathies. Brain Res 2020; 1739: 146832.
- Gray SJ, Nagabhushan Kalburgi S, McCown TJ, et al. Global CNS gene delivery and evasion of anti-AAV-neutralizing antibodies by intrathecal AAV administration in non-human primates. Gene Ther 2013; 20: 450-459.
- Eng CM, Guffon N, Wilcox WR, et al. Safety and efficacy of recombinant human α-galactosidase A replacement therapy in Fabry's disease. N Engl J Med 2001; 345: 9-16.
- Schiffmann R, Kopp JB, Austin HA, 3rd, et al. Enzyme replacement therapy in Fabry disease: a randomized controlled trial. JAMA 2001; 285: 2743-2749.
- Germain DP, Hughes DA, Nicholls K, et al. Treatment of Fabry’s disease with the pharmacologic chaperone migalastat. N Engl J Med 2016; 375: 545-555.
- Bichet DG, Torra R, Wallace E, et al. Long-term follow-up of renal function in patients treated with migalastat for Fabry disease. Mol Genet Metab Rep 2021; 28: 100786.
- Amicus Therapeutics Europe Ltd. Galafold® EU Summary of Product Characteristics. Last updated August 2021.
- Riccio E, Zanfardino M, Ferreri L, et al. Switch from enzyme replacement therapy to oral chaperone migalastat for treating fabry disease: real-life data. Eur J Hum Genet 2020; 28: 1662-1668.
- Aguiar P, Jancar N, Gonçalves F, et al. Short term effects of migalastat in cardiac structure: a case report. Mol Genet Genomic Med 2019; 129: S18.
- Orsborne C, Thompson L, Jovanovic A. A retrospective outcome analysis of chaperone therapy in Fabry disease: Clinical outcomes after the first year of therapy - a single centre experience. Mol Genet Genomic Med 2019; 129: S123.
- Lenders M, Nordbeck P, Kurschat C, et al. Treatment of Fabry disease with migalastat-outcome from a prospective 24 months observational multicenter study (FAMOUS). Eur Heart J Cardiovasc Pharmacother 2021; Epub ahead of print.
- Müntze J, Gensler D, Maniuc O, et al. Oral chaperone therapy migalastat for treating Fabry disease: enzymatic response and serum biomarker changes after 1 year. Clin Pharmacol Ther 2019; 105: 1224-1233.
- Lamari F, Mauhin W, Koraichi F, et al. Strong increase of leukocyte apha-galactosidase A activity in two male patients with Fabry disease following oral chaperone therapy. Mol Genet Genomic Med 2019; 7: e894.
- Nowak A, Huynh-Do U, Krayenbuehl PA, et al. Fabry disease genotype, phenotype, and migalastat amenability: Insights from a national cohort. J Inherit Metab Dis 2020; 43: 326-333.
- Machann W, Breunig F, Weidemann F, et al. Cardiac energy metabolism is disturbed in Fabry disease and improves with enzyme replacement therapy using recombinant human galactosidase A. Eur J Heart Fail 2011; 13: 278-283.
- Nappi C, Altiero M, Imbriaco M, et al. First experience of simultaneous PET/MRI for the early detection of cardiac involvement in patients with Anderson-Fabry disease. Eur J Nucl Med Mol Imaging 2015; 42: 1025-1031.
- Linhart A, Paleček T. Narrative review on Morbus Fabry: diagnosis and management of cardiac manifestations. Cardiovasc Diagn Ther 2021; 11: 650-660.
- Kampmann C, Linhart A, Baehner F, et al. Onset and progression of the Anderson-Fabry disease related cardiomyopathy. Int J Cardiol 2008; 130: 367-373.
- Feriozzi S, Linhart A, Ramaswami U, et al. Effects of baseline left ventricular hypertrophy and decreased renal function on cardiovascular and renal outcomes in patients with Fabry disease treated with agalsidase alfa: a Fabry Outcome Survey study. Clin Ther 2020; 42: 2321-2330.e0.
- Ortiz A, Germain DP, Desnick RJ, et al. Fabry disease revisited: management and treatment recommendations for adult patients. Mol Genet Metab 2018; 123: 416-427.
- Echevarria L, Benistan K, Toussaint A, et al. X-chromosome inactivation in female patients with Fabry disease. Clin Genet 2016; 89: 44-54.
- Hughes D, Linhart A, Gurevich A, et al. Prompt agalsidase alfa therapy initiation is associated with improved renal and cardiovascular outcomes in a Fabry Outcome Survey analysis. Drug Des Devel Ther 2021; 15: 3561-3572.
- Parini R, Pintos-Morell G, Hennermann JB, et al. Analysis of renal and cardiac outcomes in male participants in the Fabry Outcome Survey starting agalsidase alfa enzyme replacement therapy before and after 18 years of age. Drug Des Devel Ther 2020; 14: 2149-2158.
- Beck M, Hughes D, Kampmann C, et al. Long-term effectiveness of agalsidase alfa enzyme replacement in Fabry disease: a Fabry Outcome Survey analysis. Mol Genet Metab Rep 2015; 3: 21-27.
- Najafian B, Tøndel C, Svarstad E, et al. Accumulation of globotriaosylceramide in podocytes in fabry nephropathy is associated with progressive podocyte loss. J Am Soc Nephrol 2020; 31: 865-875.
- Warnock DG, Ortiz A, Mauer M, et al. Renal outcomes of agalsidase beta treatment for Fabry disease: role of proteinuria and timing of treatment initiation. Nephrol Dial Transplant 2012; 27: 1042-1049.
- Ramaswami U, Beck M, Hughes D, et al. Cardio-renal outcomes with long- term agalsidase alfa enzyme replacement therapy: a 10-year Fabry Outcome Survey (FOS) analysis. Drug Des Devel Ther 2019; 13: 3705-3715.
- Ortiz A, Abiose A, Bichet DG, et al. Time to treatment benefit for adult patients with Fabry disease receiving agalsidase β: data from the Fabry Registry. J Med Genet 2016; 53: 495-502.
- Warnock DG, Thomas CP, Vujkovac B, et al. Antiproteinuric therapy and Fabry nephropathy: factors associated with preserved kidney function during agalsidase-beta therapy. J Med Genet 2015; 52: 860-866.
- Schiffmann R, Warnock DG, Banikazemi M, et al. Fabry disease: progression of nephropathy, and prevalence of cardiac and cerebrovascular events before enzyme replacement therapy. Nephrol Dial Transplant 2009; 24: 2102-2111.
- Mehta A, Clarke JTR, Giugliani R, et al. Natural course of Fabry disease: changing pattern of causes of death in FOS – Fabry Outcome Survey. J Med Genet 2009; 46: 548-552.
- Hoffmann B, Garcia de Lorenzo A, Mehta A, et al. Effects of enzyme replacement therapy on pain and health related quality of life in patients with Fabry disease: data from FOS (Fabry Outcome Survey). J Med Genet 2005; 42: 247-252.
- Mehta A, Beck M, Elliott P, et al. Enzyme replacement therapy with agalsidase alfa in patients with Fabry's disease: an analysis of registry data. Lancet 2009; 374: 1986-1996.
- Kampmann C, Kalkum G, Beck M, et al. Successful long-term enzyme replacement therapy in a young adult with Fabry disease. Clin Genet 2013; 83: 395-396.
- Australian Government Department of Health. Life Saving Drugs Program. February 2021. Available at: https://www.health.gov.au/initiatives-and-programs/life-saving-drugs-program. Accessed November 2021.
- Australian Health Ministers' Advisory Council. Newborn Bloodspot Screening: National Policy Framework. May 2018. Available at: https://www.health.gov.au/sites/default/files/documents/2020/10/newborn-bloodspot-screening-national-policy-framework.pdf. Accessed November 2021.
- Augustine EF, Dorsey ER, Saltonstall PL. The care continuum: an evolving model for care and research in rare diseases. Pediatrics 2017; 140: e20170108.
- European Commission. Expert Panel on effective ways of investing in Health: Defining value in "value-based healthcare". 2019. Available at: https://ec.europa.eu/health/sites/default/files/expert_panel/docs/024_defining-value-vbhc_en.pdf. Accessed November 2021.
- Peeks F, Boonstra WF, de Baere L, et al. Research priorities for liver glycogen storage disease: an international priority setting partnership with the James Lind Alliance. J Inherit Metab Dis 2020; 43: 279-289.