Scientific Sessions

Friday, May 22 2015

Saturday, May 23 2015

 


Friday, May 22 2015

0830-0835 Welcome

 

Clara van Karnebeek, MD PhD, Chair Garrod 2015 Committee

 

Friday, May 22 2015

0835-1030 Neuro-Metabolic Movement Disorders

 

Moderators:
Clara van Karnebeek, MD PhD, University of British Columbia
Ramona Salvarinova, MD, University of British Columbia

 

Birgit Assmann, MD, University Children’s Hospital Heidelberg
Nenad Blau, PhD, University Children’s Hospital Heidelberg

 

These two experts will provide a comprehensive overview of the clinical spectrum and biochemical / genetic basis of neurometabolic movement disorders.

 

0835-0915 Movement Disorders in Neurometabolic Diseases

Birgit Assmann, MD, University Children’s Hospital Heidelberg

 

Click here to download the handout for this session

 

Objectives:

At the end of this session, participants will be able to:

  • Diagnose a pyramidal movement pattern.
  • Diagnose a dystonic movement pattern.
  • Diagnose a choreatic movement pattern.
  • Diagnose a cerebellar movement pattern.
  • Evaluate some treatment options.

The target audience are clinicians working in the field of metabolic disorders. The key features of different movement disorders will be explained and demonstrated by patient’s video Clips. The movement disorders of some metabolic disorders will be shown in Video Clips. Some Treatment Options will be outlined.

 

0915-0945 Neuro-Metabolic Movement Disorders

Nenad Blau, PhD, University Children’s Hospital Heidelberg

 

Objectives:

At the end of this session, participants will be able to:

  • Discuss biochemical pathways of biogenic amine.
  • Explain differences in biochemical patterns.
  • Interpret biochemical laboratory data.

Laboratory diagnosis of biogenic amine metabolism disorders is generally conducted in patients in which initial diagnostic testing for genetically-determined metabolic diseases (by analyzing commonly accessible metabolites like amino acids and organic acids in plasma or urine) result in no diagnosis. These tests are, however, invaluable tolls, together with clinical signs and symptoms, for the initiation of more specific tests in CSF and for the final diagnosis of biogenic amine metabolism disorders. There is a growing group of disorders that affect specifically CNS and the only way to demonstrate abnormalities is to investigate CSF in patients with suspected disease. Many of clinical signs and symptoms described in patients with biogenic amine metabolism disorders overlap with neurological conditions seen in other metabolic disorder and thus initial CSF investigation should include amino acids, lactate, and glucose (e.g. serin and glycine pathway defects and GLUT1). More specific tests in CSF are indicated for disorder of dopamine and serotonin metabolism, including tetrahydrobiopterin (BH4) deficiencies and Segawa disease (5HIAA, HVA, 3OMD, and pterins), folate metabolism and transport (5MTHF), and B6 metabolism (PLP). Some of these tests may also detect other less common disorder like Aicardi-Goutieres syndrome (high neopterin and biopterin). Strategy in the diagnosis of biogenic amine metabolism disorders, incl. TH, AADC, MAO-A/B, DAT, VMAT2, and BH4 deficiencies will be discussed.

 

0945-1030 3 Platform Presentations of selected abstracts

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1100-1230 Adult Metabolic Diseases & Transitions

 

1100-1130 Adult Metabolic Diseases & Transitions

 

Moderator:
Lorne Clarke, MD, PhD, University of British Columbia

 

Sandra Sirrs, MD, University of British Columbia

 

Objectives:

At the end of this session, participants will be able to:

  • Define transition as it applies to patients with metabolic diseases.
  • List elements of a successful transition process.
  • Describe barriers to transition as they apply to patients with metabolic diseases.
  • List potential resources to enhance transition planning.

This session will provide information on the process of transition to adult health care and will describe some barriers to this process for patients with metabolic diseases. The session will be of value to physicians and allied health professionals caring for patients with metabolic diseases.

 

1130-1230 4 Platform Presentations of selected abstracts

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1345-1600 New Discoveries/New Approaches

 

Moderators:
Sylvia Stockler, MD, PhD, MBA, University of British Columbia
André Mattmann, MD, University of British Columbia

 

Elizabeth Conibear, PhD, University of British Columbia

Silvia Corvera, MD, University of Massachusetts Medical School

 

Together with the TIDEX group at UBC, these two scientists investigated and reported a novel inborn error of endosomal trafficking, Rabenosyn-5 deficiency, in a girl with intractable epilepsy and complex medical and biochemical features.

 

1345-1400 A personal introduction to Rabenoysn-5 deficiency

Sylvia Stockler, MD PhD, University of British Columbia & the Davis Family

 

1400-1430 Metabolic Medicine in Motion

Silvia Corvera, University of Massachusetts Medical School, USA

 

Objectives:

At the end of this session, participants will be able to:

  • List the major proteins that participate in early endosome trafficking.
  • List the five different functional motifs in the protein Rabenosyn-5.
  • Compare the functional motifs of the proteins Rabenosyn-5 and EEA1.
  • Discuss the possible consequences to the cell of disruption of Rabenosyn-5 function.

This presentation will include a) background information on mechanisms of internalization and sorting of receptors and membrane proteins in the endosomal pathway of mammalian cells; b) description of the functional motifs of the protein Rabenosyn-5 and its role in endocytosis and recycling; c) description of clinical phenotypes associated with point mutations in Rabenosyn-5 d) description of changes in protein structure elicited by point mutations in Rabonosyn-5 associated with clinical phenotypes e) description of cellular consequences of point mutations in Rabonosyn-5 associated with clinical phenotypes f) discussion on how alterations at the cellular level are manifested as clinical phenotypes; g) discussion on potential therapeutic approaches. The session will be valuable to molecular geneticists, biochemists, clinicians.

 

1430-1500 Endosomal Trafficking & Recycling in Health and Genetic Disease

Elizabeth Conibear, University of British Columbia

 

Objectives:

At the end of this session, participants will be able to:

  • Name at least three neurological diseases linked to endosomal defects.
  • Discuss how a systems biology approach can be used to prioritize gene variants.
  • Describe how model organisms such as budding yeast can be used for the identification and functional validation of candidate disease genes.

An increasing number of mutations that compromise membrane trafficking within the endosomal system have been found to cause severe neurological and neurodegenerative disease including Parkinson’s, Niemann–Pick type C and Charcot–Marie–Tooth disease. Endosomes are major sorting centers in the cell, and proteins that are delivered to endosomes can be recycled and directed to the plasma membrane or Golgi, or targeted for degradation in the lysosome. The emerging relationship between endosome dysfunction and neurodegenerative disorders motivates further investigations to define the full set of genes that coordinate these processes, and determine the molecular basis of endosomal sorting. We have carried out a global analysis of endosomal transport in the yeast model system to identify and characterize new components of the trafficking machinery relevant to human disease. Because membrane transport is highly conserved in eukaryotes, large-scale integrative approaches to define the gene networks that regulate endosomal dynamics in model organisms may help us understand the underlying basis of these diseases.

 

 

1500-1600 4 Platform Presentations of selected abstracts

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Saturday, May 23 2015

0900-1215 Collaborative Discovery, Emerging Therapies, More Evidence

 

Moderators:
Graham Sinclair, PhD, University of British Columbia
Hilary Vallance, MD, University of British Columbia

 

Philip Hieter, PhD, University of British Columbia

Alex MacKenzie, MD, PhD, CHEO Research Institute

Marc Patterson, MD, Mayo Clinic

 

The advent of –omics technologies has accelerated the discovery of novel diseases genes and potential treatment targets. These 3 eminent speakers will focus on the process from bench to bedside for inborn errors of metabolism, addressing topics such as model organism research, high throughput drug screening, pre-/clinical trials, and the challenges of relevant outcomes and evidence in rare diseases.

 

0900-0930 Understanding Rare Disease Pathogenesis: A Grand Challenge for Model Organisms

Philip Hieter, PhD, University of British Columbia

 

Objectives:

At the end of this session, participants will be able to:

  • Highlight the variety of strategies and power of model organisms to elucidate human disease mechanisms.
  • Highlight the value of model organisms for discovering and evaluating novel treatment approaches for genetic disease.
  • Highlight the value of collaboration between clinicians, clinician scientists, and basic researchers.

The application of next-generation DNA sequencing (NGS) technology has brought an unprecedented era of rare disease gene discovery. However, the discovery of a disease-causing, human variant is inherently a descriptive, hypothesis-generating milestone that requires subsequent studies on the basic function of the gene and the functional consequences of specific gene mutations in a biological context. If the disease mutation mapping discoveries are to lead to novel therapies, mechanistic understanding of the disease gene’s function, and experimental platforms that provide rational approaches to the identification of therapeutic targets, will be required.

Fundamental aspects of most human disorders can be informed through analysis of orthologous genes and pathways in experimentally tractable organisms (yeast, fly, worm, zebrafish, mouse) by using sophisticated experimental toolboxes developed for each model organism. This allows researchers to determine biological mechanisms at the levels of genes, pathways and networks through an analysis of the equivalent (orthologous) genes in model organisms. Therefore, model organisms provide powerful tools to investigate the mechanistic basis of rare genetic diseases and their etiology and to identify and explore potential therapeutic interventions.

We have established a national network to mobilize the Canadian biomedical community of model organism researchers and clinician scientists to: communicate and connect; integrate and share their resources and expertise; and, work together to provide functional insights into newly discovered rare disease genes. The Canadian “Rare Diseases: Models and Mechanisms” (RDMM) network is expediting collaboration between scientists and clinicians in model-based functional studies of rare disease genes. The over-arching goal is to facilitate investigation of the molecular mechanisms of rare disease early in the process of disease gene mutation discovery by catalyzing connections when resources and expertise are pre-existing in a Canadian research laboratory.

The session will be of value to: clinicians, clinician scientists and basic researchers.

 

0930-1000 Novel Therapeutic Approaches for Rare Genetic Disease; After the Deluge

Alex MacKenzie, MD, PhD, CHEO Research Institute

 

Objectives:

At the end of this session, participants will be able to:

  • Appreciate unmet medical need of rare diseases.
  • Develop understanding of generalizable approaches for rare diseases.
  • Understand pharmacologic modulation of gene expression.

The recent rapid (and accelerating) genetic pathophysiologic delineation of monogenic disorders has resulted in the identification of 1000’s of transcripts and proteins which either cause or impact these conditions. The modulation of these transcripts and proteins might be anticipated to have therapeutic utility, either by their upregulation (e.g. of mutated recessive disease genes encoding proteins with residual enzymatic activity, of genes that are sequentially similar to, and that functionally recapitulate, mutated recessive disease genes or of genes that cause disease when haploinsufficient) or downregulation (e.g. of mutated dominant genes which confer a gain of pathologic function or of genes which, when present in increased number, cause disease). Moreover, it is known that small molecules can affect a substantial proportion of the human transcriptome. Given the number of genes that cause or effect inherited human conditions and the substantial subset of the transcriptome that is impacted by drugs, it is a virtual certainty that there are genes which are both modifiers of human disease and responsive to pharmacologic modulation. The identification of the genes which populate this overlapping subset of the transcriptome is a goal of our laboratory. We have performed in silico screens of full-transcriptome gene-expression data sets produced by the effects of many hundreds of FDA-approved drugs and drug-like small molecules on a range of in vitro cell systems. We have identified clinic-ready molecules (e.g. isotretinoin, celecoxib, deferoxamine) that modulate a number of such disease associated genes (e.g. SMAD3, SMN2, ITPR1) which shall be discussed.

 

1000-1030 2 Platform Presentations of selected abstracts

 

1100-1130 Discovery in IEMs: Translation into Clinical Care

Marc Patterson, MD, Mayo Clinic

 

Objectives:

At the end of this session, participants will be able to:

  • Discuss challenges in designing clinical trials in IEMs.
  • Summarize the basics of regulatory requirements for drug approval.
  • Explain why standard clinical trial designs may not be appropriate for IEMs.
  • Explain the importance of natural history studies and validated biomarkers in clinical trials in IEMs.

Funding agencies, regulators and industry have shown unprecedented interest in rare diseases, including IEMs, in the last decade. In addition, investigators have exploited the power of ‘omics’ technologies to enhance understanding of these disorders, and to identify druggable targets. Despite this favorable climate, and the approval of a number of therapies for IEMs, most patients do not have access to disease-modifying therapies. A critical element in translating potential therapies into practice is the availability of well characterized cohorts of patients, whose clinical features have been prospectively characterized, and for whom validated biomarkers have been identified. Such data is lacking in many IEMs.

Regulatory agencies generally require one or more positive randomized controlled trials before drugs are approved for marketing. The statistical standards are generally attainable for common diseases, where the power of a study may be readily increased by recruiting more subjects. This approach is generally not applicable in IEMs, where the pool of potential trial participants is usually small, and where interindividual variation is often pronounced – even within kindreds. These challenges can be addressed by developing national and international networks to ensure that all eligible subjects are identified and can be offered the opportunity to participate in natural history and therapeutic studies. Investigators must partner with support groups and be prepared to use novel approaches to data gathering, including social networks and video technology to enable isolated subjects to participate in trials to which they would otherwise be denied access. Even if every patient with a rare IEM can be recruited to a study, the use of traditional statistical methods is likely to lead to underpowered studies and type II errors. Novel approaches, including N=1 designs, self-controls and crossover designs may be helpful in addressing the statistical and ethical challenges inherent in translating discoveries in the basic science of IEMs into approved and accessible therapies.

The session will be of value to: medical and biochemical geneticists and all pediatric practitioners caring for patients with IEMs.

 

1130-1215 3 Platform Presentations of selected abstracts

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1215 Closing Scientific Symposium

 

Clara van Karnebeek, MD, PhD, University of British Columbia