May 4-6, 2017 Hyatt Regency Montreal

Montreal, Quebec

Garrod Symposium
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Scientific Program

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Thursday, May 4

Friday, May 5

Saturday, May 6


 

Thursday, May 4
Dietitians’ Webinar

 

Moderators: Manon Bouchard Dt.P., CHU Sainte-Justine, génétique médicale and Marie Lefrançois Dt.P. / R.D., McGill University Health Center, Montreal Children’s Hospital

 

Mitochondrial Disease: A Dietary and Nutritional Perspective

Mark Korson, Genetic Metabolic Center for Education, Salem

 

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

  • Discuss mitochondrial autonomic dysfunction and how it impacts the gut.
  • Develop an approach for managing the nutritional needs of patients with GI dysmotility.
  • Describe the unique nutritional approach for select mitochondrial diseases, e.g., PDHC deficiency.

“Mitochondrial disease” is a term representing hundreds of defects in oxidative phosphorylation that often show multi-systemic involvement. When the GI tract is involved, the issue is usually GI dysmotility due to autonomic dysregulation. Symptoms of altered motility can occur at any level of the gut in any combination, causing symptoms such as gastroesophageal reflux, vomiting, bloating, abdominal pain, and/or constipation. At its most severe, intestinal pseudo-obstruction can occur. The energy status of the patient can impact her/his GI function; furthermore, autonomic functions are interdependent and one aspect of the autonomic nervous system can positively or negatively impact another. A dietary approach must take into account a patient’s variable GI motility. In some cases of mitochondrial disease (e.g., pyruvate dehydrogenase complex deficiency), a specialized diet is recommended to optimize cellular energy production and minimize metabolic instability.

 

Dietary Treatment of Cobalamin C Deficiency

Can Ficicioglu, The Childeren’s Hospital of Philadelphia

 

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

  • Recognize: Biochemistry, Genetics, Clinical manifestations, Diagnosis, Basic principles of Treatment of Cobalamin C disease.
  • Discuss: If there is a relationship between initial or long-term metabolic control and neurocognitive outcomes.
  • Discuss: If dietary protein composition affects long-term metabolic control or amino acid imbalances.
  • Discuss: If the long-term protein composition of the diet affects growth or neurocognitive outcomes.

Combined methylmalonic acidemia and hyperhomocysteinemia, cobalamin C subtype (or cobalamin C deficiency (cblC), is the most common disorder of vitamin B12 metabolism. Clinical features of cblC can vary. Some patients manifest with an early-onset phenotype that includes intrauterine growth restriction, feeding difficulties, microcephaly, developmental delay, seizures, retinopathy, hemolytic uremic syndrome, cytopenias. A later-onset form of cblC presents with neurologic and thromboembolic complications. Newborn screening (NBS) for cblC through detection of elevated propionylcarnitine (C3) on tandem mass spectrometry analysis of dried blood spots has been widely implemented in the United States for over a decade.

Despite implementation of newborn screening (NBS), outcomes in Cobalamin C disease (cblC) remain poor. Therapy with hydroxycobalamin and betaine is widely employed, but dietary recommendations vary among metabolic centers. I will present a longitudinal analysis of the relationship between metabolic control, diet, and outcomes in a cohort of cblC patients.

 

Click here to register for this webinar

 

Friday, May 5
Bone Involvement in Metabolic Diseases

 

Moderator: Philippe Campeau, Université de Montréal

 

Skeletal Manifestations of Inborn Errors of Metabolism: Lessons form Congenital Disorders of Glycosilation

Roberto Mendoza, University of Toronto, The Hospital for Sick Children

 

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

  • Discuss the basic elements of bone formation and maintenance .
  • List the common clinical and radiological features of skeletal dysplasias.
  • Identify the specific skeletal changes that can be seen in Congenital Disorders of Glycosylation.
  • Compare the skeletal manifestations of the most common forms of inborn errors of metabolism.

This session will outline the basis of normal bone development and explain how inborn errors of metabolism (IEM) alter that processes in different ways (changing signaling pathways, leading to abnormal storage or abnormal reabsortion or bone components). The session will outline the main skeletal manifestations of common metabolic disorders and make particular emphasis on the skeletal manifestations of congenital disorders of glycosylation. This session will be of value to medical geneticists, paediatricians and health care professionals that provide direct patient care and are at the front line of making these diagnosis and managing patients with IEM.

 

Bone mineralization gone wrong: Defective enzymatic processing of mineralization inhibitors in osteomalacia (hypophosphatasia and X-linked hypophosphatemia)

Marc McKee, McGill University, Shriners Hospital for Children

 

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

  • List several molecular determinants of skeletal and dental mineralization that act directly on the mineral phase.
  • Explain how pyrophosphate and tissue-nonspecific alkaline phosphatase function in hypophosphatasia.
  • Explain how osteopontin and PHEX functions in X-linked hypophosphatemia.
  • Discuss the balance between mineralization inhibitor action and the enzymes that degrade them.

Reconciliation of the evolving interplay between organic moieties and inorganic crystals lies at the heart of modern biomineralization inquiry. Recent mineralization research performed primarily in mouse models has described mineral-binding functions for key noncollagenous extracellular matrix proteins, and small molecules, in regulating crystal growth in the skeleton and dentition. Gene mutations affecting mineral-regulating proteins can lead to bone and tooth nanocrystallites being defective in number, size, shape and/or orientation, and can even potentially lead to changes in mineral type, such that these otherwise hard tissues become diseased, soft and/or brittle. Importantly, a key step in regulating the actions of mineralization inhibitors appears to be their removal by enzymes, thus allowing mineralization to proceed. The effects of inactivating mutations in two such enzymes ‒ TNAP and PHEX, whose substrates are inhibitory pyrophosphate and the protein osteopontin, respectively ‒ will be presented in mouse models and in human studies for the rare bone and tooth osteomalacia diseases hypophosphatasia and X-linked hypophosphatemia. This work was funded by CIHR. This presentation will be of value to clinicians and basic scientists interested in rare bone and tooth diseases, and biomineralization.

 

Everything is Metabolism – Also in the Skeleton

Andrea Superti-Furga, University Hospital of Lausanne

 

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

  • Identify metabolic processes associated with the skeleton as an organ.
  • Identify examples of bone disease associated with metabolic disorders.
  • Identify bone disorders associated with metabolic processes intrinsic to the skeletal system.

The presentation will review some aspects of skeletal disease associated with systemic metabolic disorders and the review some of the many metabolic processes intrinsic to cartilage and bone that, if perturbed, results in genetic skeletal disorders.

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Friday, May 5
Treatment of Metabolic Disorders

 

Moderators: Catherine Brunel-Guitton and Grant Mitchell, Université de Montréal, CHU Sainte-Justine

 

Metabolic Pathway Reprogramming: A Novel Therapeutic Approach for Tyrosinemia Type I

Karl-Dimiter Bissig, Baylor College of Medicine, Houston

 

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

  • Explain current therapy of tyrosinemia type I.
  • Compare current therapy to experimental therapy.
  • Summarize metabolic pathway reprogramming.

We recently developed a new therapeutic concept called metabolic pathway reprogramming, which couples the power of CRISPR/Cas9 technology with a strategy from pharmacology, namely, to inhibit a metabolic pathway rather than directly edit a disease-causing gene. We demonstrate the efficacy of this approach by using CRISPR/Cas9 to convert lethal type I tyrosinemia into benign type III tyrosinemia by somatic genome engineering. In contrast to small molecule drugs, genome editing is sequence specific and neither its therapeutic potential nor its side effects can be evaluated properly in conventional animal models. To this end, we developed novel xenograft models for metabolic liver disease, which should allow us to properly validate this therapy in the context of primary human cells. I will present the xenograft platform and ongoing research applying metabolic pathway reprogramming in vivo.

The session will be valuable to medical geneticists, translational scientists and metabolic disease physicians.

 

Clinical diagnosis and treatment of disorders of cobalamin metabolism

Carlo Dionisi Vici, Bambino Gesù Children’s Hospital, Rome

 

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

  • Recognize the clinical signs of cblC and other defects of cobalamin metabolism.
  • Diagnose a patient with cblC and other defects of cobalamin metabolism.
  • Discuss about treatment in patients with cblC and other defects of cobalamin metabolism.

The clinical signs of cobalamin metabolism disorders reveal no specific, distinct signs and symptoms but rather highlight that these conditions affect multiple systems. A few patterns of clinical presentations can be identified. Most prominently the central and peripheral nervous system and the bone marrow are affected. Developmental and neurocognitive impairment, feeding problems, neurological symptoms including seizures, movement disorders, abnormal muscle tone, visual impairment, neuropathy, and haematological abnormalities are present in the majority of patients. In many patients, renal manifestations, e.g. atypical haemolytic uraemic syndrome (HUS) or glomerulopathy, mostly related to microangiopathy, have been identified. Clinical presentations may vary considerably but the combination of neurological and haematological symptoms, often in the presence of renal signs, failure to thrive or feeding difficulties should raise suspicion of a cobalamin metabolism disorder. Treatment, based on parenteral hydroxocobalamin and oral betaine, should be initiated without delay in any suspected remethylation disorder.
This session will be of value to pediatricians, neonatologists, medical geneticists, and medical biochemists to improve diagnosis and treatment of cobalamin metabolism disorders.

 

Surprises from the study of patients with inherited disorders of one-carbon metabolism

David Rosenblatt, McGill University

 

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

  • List two disorders that are phenocopies of cblC.
  • Compare disorders of cobalamin metabolism.
  • Explain how mutations in transcription factors can result in an inborn error of cobalamin metabolism.

The study of cultured cells from patients referred because of elevations of homocysteine, methylmalonic acid, or both in blood and/or urine has allowed the characterization of genes responsible for the inherited disorders of cobalamin transport and metabolism. Recently there have been surprising discoveries implicating regulatory mechanisms in disease. One of the biggest is that some patients who have a cellular phenotype identical to that of patients with the cblC disorder actually have mutations in genes leading to down regulation of MMACHC expression. What is particularly surprising is that cells from these patients fail to correct those from cblC patients in somatic cell complementation analysis. One set of patients has mutations in the HCFC1 gene, which is on the X chromosome. For this reason, their disease has been called “cblX” even though it does do not represent a true new complementation class. In addition, a single patient is known with a homozygous mutation in the THAP11 gene; this patient has a similar clinical and cellular phenotype to the cblX patients. We have recently described another patient in whose cells there is down regulation of MMACHC, but in whom the cellular phenotype differs from that of the cblC disorder. Transcobalamin (TC)-cobalamin is taken up normally but does not dissociate within cells, suggesting a block in cobalamin uptake at an earlier step than that affected by the cblC disorder, prior to the dissociation of cobalamin from TC in lysosomes. Compound heterozygous mutations were identified in ZNF143, which codes for a transcription factor known to form a complex with HCFC1 and THAP11. We suggested that the defect in cobalamin metabolism in this patient is the result of altered expression of an unidentified gene specifically regulated by ZNF143, independent of HCFC1 and THAP11. This session will be of value to biochemical geneticists. (The above material will be presented at an international meeting in Aarhus so please do not publish this summary in a citable source).

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Saturday, May 6
Leukodystrophies

 

Moderators: Geneviève Bernard and John Mitchell, McGill University, Montreal Children’s Hospital

 

POLR3-related leukodystrophy: from gene identification and phenotypic description to understanding of disease mechanisms

Geneviève Bernard, McGill University, Montreal Children’s Hospital

 

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

  • List the clinical manifestations of POLR3-related leukodystrophy.
  • Summarize the MRI characteristics of the disease.
  • Discuss the genetic causes of the disease, and what is known on the pathophysiology.

Leukodystrophies are a group of genetic disorders characterized by abnormal cerebral white matter. They are divided between hypomyelinating and non-hypomyelinating (HLD) according to MRI characteristics and whether the primary pathophysiological problem is thought to be lack of myelin deposition during development or abnormal myelin homeostasis, respectively. RNA polymerase III-related leukodystrophy (POLR3-HLD) is a recently described disorder now recognized as the second most common HLD. It was found by our group to be caused by recessive mutations in POLR3A, POLR3B or POLR1C. POLR3-HLD is characterized by an expanding spectrum of clinical and radiological features, including neurological and non-neurological features. Patients with POLR3-HLD experience a progressive course with increasing disabilities, including progressive gait ataxia leading to loss of ambulation, dysarthria leading to anarthria, dysphagia leading to the inability to eat, etc. POLR3A and POLR3B encode for the two largest subunits of the RNA polymerase III and together, they form its catalytic core. POLR1C, on the other hand, encodes for a common subunit of POLR1 and POLR3. POLR3 is responsible for the transcription of small non-coding RNAs primordial for cell homeostasis. Our recent work led to the first insight into the pathogenesis of the disease. Indeed, mutations in these 3 genes lead to either (1) abnormal assembly of the 17-subunits complex POLR3, (2) abnormal nuclear import of POLR3, and/or (3) abnormal interaction of POLR3 with the DNA to allow normal transcription. In sum, our work on the clinical and imaging characterization of the disease, combined with the discovery of the causal genes and study of the pathophysiology of the disease has allowed families to have a molecular diagnosis, genetic counselling and improved supportive care, and most importantly, has opened the door for the development of therapeutic strategies.

The session will be of value to Medical Geneticists.

 

Metachromatic leukodystrophy: New insights into treatment

Nicole Wolf, VU University Medical Center, Amsterdam

 

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

  • List the different forms of MLD and their respective symptoms.
  • Discuss indications for hematopoietic cell transplantation.
  • Summarize supportive treatment options for MLD patients.

Metachromatic leukodystrophy (MLD) is one of the most frequent inherited white matter disorder. Onset is mostly in (early) childhood and adolescence, but adult onset is not infrequent either. When diagnosed early enough, hematopoietic cell transplantation (HCT) can halt the disease. For about two thirds of all patients, diagnosis, however, comes too late, and HCT is no longer an option. By compiling and comparing results of HCT for MLD during the last decade, criteria for this treatment are now emerging. Findings at quantitative imaging can support the decision for or against HCT. When MLD patients do not qualify for HCT, adequate supportive treatment is important, as spasticity, vomiting and irritability greatly impair quality of life.

This presentation will be of value to: medical geneticists, child neurologists, paediatricians and metabolic paediatricians.

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