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 Gaucher disease.

Transforming rare disorders

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. One challenge being 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, which reported that 13% of the diseases diagnosed by genome sequencing were caused by variants 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

Symposium sponsored by Sanofi Genzyme

The symposium was introduced by Professor Pramod Mistry (Yale School of Medicine, New Haven, CT, USA), who highlighted that, in his opinion, there is diagnostic confusion between Gaucher disease and acid sphingomyelinase deficiency (ASMD). He believes the two disorders can greatly enrich the scientific understanding of each other.

Professor Mistry’s presentation reported ‘the science’ in this symposium, which focused on insights from inflammation in Gaucher disease and applied them to ASMD. ASMD is a rare progressive genetic disorder with highly variable clinical presentation. ASMD includes Niemann-Pick disease Types A and B, and results from a deficiency of the enzyme acid sphingomyelinase, which is required to metabolise sphingomyelin.17 Professor Mistry went on to explain that within the spectrum of clinical manifestations of Gaucher disease, there are specific hallmarks of metabolic disorder such as weight loss,18 fatigue,19 hypermetabolic state,18 decreased high-density lipoprotein cholesterol,19 increased risk of cholesterol gallstones,19,20 insulin resistance19,20 and increased cancer risk.21 He further added to this by presenting the risk of multiple myeloma (relative risk [RR] 25; 95% confidence interval [CI] 9.17–54.40) and haematological malignancies (RR 3.45; 95% CI 1.49–6.79) in patients with Gaucher disease.21

As glucosylceramide and glucosylsphingosine (lyso-Gb1) most prominently build up within macrophages in patients with Gaucher disease,22 Professor Mistry indicated that the macrophages present these lipids via the CD1d+ molecule to Type II natural killer T cells, which promotes B-cell proliferation and ultimately the production of anti-lipid antibodies. Delineation of this pathway highlights that Gaucher disease is not just macrophage lipid accumulation.23-25 He then continued to explain that the accumulation of glucosylceramide results in complement activation and increased glucosylceramide synthase and glucosylceramide synthesis, which accelerates the development of Gaucher disease pathophysiology.26

Professor Mistry briefly highlighted the partial overlap with symptoms of Gaucher disease and the symptoms described in patients with ASMD and stated that, similar to Gaucher disease, indicators of metabolic inflammation are present in ASMD.27 Furthermore, increased levels of chitotriosidase (a biomarker of macrophage activation) have been observed in both Gaucher disease and ASMD.28

Professor Mistry concluded his presentation by stating that the mechanisms he discussed are, in his opinion, highly relevant beyond Gaucher disease and could provide useful information in other lipid metabolic storage disorders, such as ASMD, non-alcoholic fatty liver disease and sporadic multiple myeloma.

Dr Michel Tchan (Westmead Hospital and University of Sydney, Sydney, New South Wales, Australia) followed on from Professor Mistry with a presentation focused on ‘the clinic’, in which he discussed major disease manifestations and the approach to diagnosis in ASMD. He briefly introduced the history of ASMD and explained that deficient acid sphingomyelinase activity leads to an accumulation of sphingomyelin in the cells of patients with ASMD.17 He emphasised the challenges in diagnosing ASMD due to clinical manifestations overlapping with other conditions.29 However, Dr Tchan highlighted that, in his opinion, from a genetics perspective, the primary differential diagnosis of ASMD is Gaucher disease. Due to the overlapping symptomatology, differential diagnosis of ASMD is recommended to include Gaucher disease.29

Professor Maurizio Scarpa (University Hospital Udine, Udine, Italy) concluded the symposium with a presentation focused on ‘the practice’, in which he discussed pulmonary manifestations as key features of ASMD. He explained that pulmonary disease is a common clinical manifestation in patients with ASMD.30 Furthermore, he stated that pulmonary dysfunction is a leading cause of death in patients with ASMD.31,32

He continued by highlighting that pulmonary manifestations have been reported in some patients with Gaucher disease.33-35 Pulmonary manifestations in Gaucher disease result from infiltration of either alveoli, interstitium, bronchi or pulmonary vasculature by Gaucher cells.36 Interstitial lung disease (ILD) is infrequently reported in Gaucher disease Type 1 and Type 2; however, pulmonary manifestations and ILD are more common in Gaucher disease Type 3.34

Professor Scarpa outlined results published in a study of 95 patients with Gaucher disease Type 1 highlighting that 68% of patients had pulmonary function abnormalities. The most common were reduced functional residual capacity, reduced lung diffusion capacity for carbon monoxide and reduced total lung capacity (observed in 45%, 42% and 22% of patients, respectively).33

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.37 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 AAV type 9 (AAV9) injected into the tail vein of mice.38 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).39 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.40 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.

Dr Merve Koç Yekedüz (Ankara University Faculty of Medicine, Department of Pediatric Metabolism, Ankara, Turkey) opened her presentation by discussing the relationship between Parkinson’s disease and lysosomal storage disorders (LSDs). She stated that the autophagic system works defectively in LSDs and the degradation of α-synuclein is disrupted, resulting in accumulation of α-synuclein and the death of dopaminergic neurons in the substantia nigra, potentially leading to the development of Parkinson’s disease.41 She then noted that Parkinson’s disease was observed in patients with Gaucher disease42 and Fabry disease,43 and went on to present early results from a study investigating the role of GLA variants in Parkinson’s disease.

Dr Koç Yekedüz highlighted the potential association between Parkinson’s disease and Fabry disease by presenting data from Mosejova et al. 2019, which showed a possible relationship between Parkinson’s disease and Fabry disease in a small cohort of patients diagnosed with Parkinson’s disease.44 However, the GLA variant found in this cohort was classified as a variant of unknown significance, and it was concluded that its pathogenic causative role in the context of Parkinson’s disease should be further elucidated and that these findings should be interpreted with caution.44

Dr Koç Yekedüz concluded her presentation by stating that further research is required to fully understand the pathogenic causative role of GLA variants in Parkinson’s 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 (, 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 Program45 and newborn bloodspot screening.46 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.47 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).48 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.49 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.


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.

C-ANPROM/INT/GAUD/0122; Date of preparation: November 2021



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