Anne Marie Laberge

Population history and its impact on medical genetics in Quebec

Knowledge of the genetic demography of Quebec is useful for gene mapping, diagnosis, treatment, community genetics and public health. The French‐Canadian population of Quebec, currently about 6 million people, descends from about 8500 French settlers who arrived in Nouvelle‐France between 1608 and 1759. The migrations of those settlers and their descendants led to a series of regional founder effects, reflected in the geographical distribution of genetic diseases in Quebec. This review describes elements of population history and clinical genetics pertinent to the treatment of French Canadians and other population groups from Quebec and summarizes the cardinal features of over 30 conditions reported in French Canadians. Some were discovered in French Canadians, such as autosomal recessive ataxia of the Charlevoix–Saguenay (MIM 270550), agenesis of corpus callosum and peripheral neuropathy (MIM 218000) and French‐Canadian‐type Leigh syndrome (MIM 220111). Other conditions are particularly frequent or have special genetic characteristics in French Canadians, including oculopharyngeal muscular dystrophy, hepatorenal tyrosinaemia, cystic fibrosis, Leber hereditary optic neuropathy and familial hypercholesterolaemia. Three genetic diseases of Quebec First Nations children are also discussed: Cree encephalitis (MIM 608505), Cree leukoencephalopathy (MIM 603896) and North American Indian childhood cirrhosis (MIM 604901).

Genetics in Health Care: An Overview of Current and Emerging Models

Background: With advances in genetic and genomic medicine, the optimal integration of genetic services into the health care system remains of major concern in many countries. Objectives: To review the current organisation of genetic services, mostly in Europe, North America and Australia, explore emerging service delivery models, and probe challenges inherent in the transition process. Methods: We conducted a literature review of genetics in clinical practice: testing, diagnosis, counselling, and treatment. We examined the basic structures of genetic services, examples of integrated networks, and existing professional resources. We investigated services belonging traditionally in medical genetics as well as those developed for more common diseases. Results: Multidisciplinary specialist clinics and coordinated services appeared to be key to delivering proper care in rare genetic disorders. For oncogenetics, neurogenetics and cardiogenetics, interprofessional collaboration between geneticists and other specialists seemed to be favoured. On the other hand, there was also a tendency toward the integration of genetic services directly into primary care. Among the most pressing challenges was the morphing of paediatric care into adult care. Conclusion: The coordination of activities between professionals in first-, second-, and third-line medical care is a primary objective calling for the reconfiguration of professional roles and responsibilities. This entails the forging of new relationships as well as an enhanced sharing of expertise and genetic information, including information regarding services. Barriers to overcome include the redistribution of roles, sharing of data and databases, and the lack of preparedness of non-genetics professionals and of the health care system in general.

Debating clinical utility.

The clinical utility of genetic tests is determined by the outcomes following test use. Like other measures of value, it is often contested. Stakeholders may have different views about benefits and risks and about the importance of social versus health outcomes. They also commonly disagree about the evidence needed to determine whether a test is effective in achieving a specific outcome. Questions may be presented as factual disagreements, when they are actually debates about what information matters or how facts should be interpreted and used in clinical decision-making. Defining the different issues at stake is therefore an important element of policy-making. Key issues include evidence standards for test use, and in particular, the circumstances under which prospective controlled data should be required, as well as evidence on feasibility, cost and equitable delivery of testing; the goals of population-based screening programs, and in particular, the role of social outcomes in evaluating test value; and the appropriate uses and funding of tests that inform non-medical actions. Addressing each of these issues requires attention to stakeholder values and methods for effective deliberation that incorporate consumer as well as health professional perspectives.

Motivating Factors for Physician Ordering of Factor V Leiden Genetic Tests

BACKGROUNDnThe factor V Leiden (FVL) genetic test is used by many physicians despite its uncertain clinical utility.nnnMETHODSnWe investigate whether self-reported motivations and behaviors concerning FVL genetic testing differ between 2 groups of primary care physicians defined by frequency of previous FVL test use. In January 2007, 112 physicians (60 frequent and 52 infrequent FVL test users) at Group Health, a large health care delivery system, were surveyed. Survey content areas included primary reasons and motivating factors for ordering the FVL test, the likelihood of ordering the FVL test for hypothetical patients, potential barriers to genetic testing, and practices and skills regarding FVL test ordering.nnnRESULTSnResponses between groups agreed concerning most clinical- and patient-related factors. Frequent-FVL physicians were more likely than infrequent-FVL physicians to report ordering the FVL test for hypothetical patients with mesenteric venous thrombosis (adjusted odds ratio, 4.57; 95% confidence interval, 1.55-13.53) or venous thrombosis after hospital discharge (adjusted odds ratio, 3.42; 95% confidence interval, 1.30-8.95). Frequent-FVL physicians were also less likely to identify several items on the survey as barriers to genetic testing and were more likely to report high confidence in interpreting and explaining FVL test results.nnnCONCLUSIONSnGenerally, both physician groups reported similar motivating factors for ordering FVL tests, and reported behaviors were consistent with existing guidelines. More striking differences were observed for measures such as barriers to and confidence in using genetic tests. Although additional research is necessary to evaluate the impact of these results, they inform several knowledge-to-practice translation issues that are important for the successful integration of genetic testing into primary care.

Long‐term follow‐up of a new case of liver glycogen synthase deficiency

We report a new case of hereditary hepatic glycogen synthase (GS) deficiency (MIM 240600) in a French Canadian girl referred at 7 years of age for a family history of hyperlipidemia. Her initial evaluation incidentally revealed fasting hypoglycemia and ketonuria after a 10‐hr fast with normal growth, development, and physical examination. Additional biochemical findings included fasting hypoalaninemia with elevated plasma branched chain amino acids and postprandial hyperlactatemia. Liver glycogen synthase activity was reduced. Unlike most other reported patients, we observed on three different occasions an increase in fasting plasma glucose levels after glucagon administration during episodes of hypoglycemia. At 13 years of age, her growth and intellect are normal; however, she still has hypoglycemia after 18 hr of fasting. From our patients course and a review of the literature, we conclude: (A) Usual modes of presentation of GS deficiency are non‐specific symptoms after overnight fasting (7/17), incidental findings (3/17), or positive family history (7/17); (B) Most patients maintain normal growth (8/11) and intellectual abilities (12/15); (C) Fasting hypoglycemia (17/17) and reduced liver glycogen content (9/9) are constant features; (D) Biochemical findings also include postprandial hyperlactatemia (13/13), fasting hyperketonemia (12/12), and fasting hypoalaninemia (8/9); (E) Glucagon response following fasting hypoglycemia is usually reduced or absent (7/8) but can be repeatedly present (1/8); (F) Liver steatosis is frequent (6/6). Although rare, GS deficiency results in a characteristic biochemical profile that, if recognized, should lead promptly to its diagnosis.

Use of Factor v Leiden genetic testing in practice and impact on management

Purpose: To assess the use of the genetic test for Factor V Leiden in clinical practice, physician adherence to national and local guidelines, and impacts of test results on patient management.Methods: Chart review of all patients tested for Factor V Leiden during a 1-year period (2003) in a large nonprofit health care system (group health) (n = 272).Results: The test for Factor V Leiden was most often used in nonacute outpatient settings by primary care practitioners, in combination with other tests for procoagulant disorders. Testing was performed more broadly than recommended: 61% of tests met American College of Medical Genetics guidelines, 46% of tests met CAP guidelines, and 37% of tests met group health internal guidelines. The most common rationale for testing was to explain a clinical event (58%). Patient management was modified more often in heterozygotes (54%) than in those with normal results (13%) (P < 0.0001).Conclusions: The uptake of the test for Factor V Leiden has not followed existing recommendations. Genetic risk information was used to influence patient management in the absence of supporting evidence related to health outcomes. These results underscore the importance of further research concerning effective prevention and treatment strategies for patients with genetic risk to help translate genetic risk information into improved health outcomes.

Assessing the potential success of cystic fibrosis carrier screening: lessons learned from Tay-Sachs disease and β-thalassemia.

Objective: The objective of this study was to identify factors involved in the success of 2 well-established population-based carrier screening programs – Tay-Sachs disease (TSD) in Ashkenazi Jews and β-thalassemia in Sardinia and Cyprus – and to assess the potential for success of a population-based cystic fibrosis (CF) carrier screening strategy using these factors. Methods: We performed a literature review and key informant interviews. Results: Factors involved in the success of TSD and β-thalassemia carrier screening programs include disease characteristics (well-defined population at risk, severe disease with predictable course, availability of effective treatment), test characteristics (high sensitivity, straightforward interpretation of results), and community characteristics (involvement of community, support of families and advocacy groups, consensus in favor of avoiding affected births). Current CF screening strategies include few of the factors listed above. Unlike TSD and β-thalassemia, the purpose of current CF carrier screening strategies is informed reproductive decision-making, without an explicit goal of reducing disease incidence. Conclusion: When compared to TSD and β-thalassemia, CF is a less favorable candidate for population-based carrier screening. Because of its different purpose, CF carrier screening will require different measures of success than those used for TSD and β-thalassemia carrier screening, and a consensus on the value or success of CF carrier screening may be difficult to achieve.

The CANadian Pediatric Weight Management Registry (CANPWR): Study protocol

BackgroundOver recent decades, the prevalence of pediatric obesity has increased markedly in developed and developing countries, and the impact of obesity on health throughout the lifespan has led to urgent calls for action. Family-based weight management interventions that emphasize healthy lifestyle changes can lead to modest improvements in weight status of children with obesity. However, these interventions are generally short in duration, reported in the context of randomized controlled trials and there are few reports of outcomes of these treatment approaches in the clinical setting. Answering these questions is critical for improving the care of children with obesity accessing outpatient health services for weight management. In response, the CANadian Pediatric Weight management Registry (CANPWR) was designed with the following three primary aims:1. Document changes in anthropometric, lifestyle, behavioural, and obesity-related co-morbidities in children enrolled in Canadian pediatric weight management programs over a three-year period;2. Characterize the individual-, family-, and program-level determinants of change in anthropometric and obesity-related co-morbidities;3. Examine the individual-, family-, and program-level determinants of program attrition.Methods/DesignThis prospective cohort, multi-centre study will include children (2–17xa0years old; body mass index ≥85th percentile) enrolled in one of eight Canadian pediatric weight management centres. We will recruit 1,600 study participants over a three-year period. Data collection will occur at presentation and 6-, 12-, 24-, and 36-months follow-up. The primary study outcomes are BMI z-score and change in BMI z-score over time. Secondary outcomes include anthropometric (e.g., height, waist circumference,), cardiometabolic (e.g., blood pressure, lipid profile, glycemia), lifestyle (e.g., dietary intake, physical activity, sedentary activity), and psychosocial (e.g., health-related quality of life) variables. Potential determinants of change and program attrition will include individual-, family-, and program-level variables.DiscussionThis study will enable our interdisciplinary team of clinicians, researchers, and trainees to address foundational issues regarding the management of pediatric obesity in Canada. It will also serve as a harmonized, evidence-based registry and platform for conducting future intervention research, which will ultimately enhance the weight management care provided to children with obesity and their families.

Pre-implantation Genetic Diagnosis: The Road Forward in Canada

The use of pre-implantation genetic diagnosis (PGD) is increasing as the list of indications it can test for constantly expands. This raises new challenges for clinicians and prospective parents regarding possible uses and calls for guidance. Policy approaches towards PGD vary greatly worldwide. The 2004 Canadian Assisted Human Reproduction Act does not provide guidance, except for prohibiting non-medical sex selection. Criminal legislation is an unsuitable policy instrument to regulate human genetics and reproductive medicine. We call for professional societies to issue guidelines regarding the uses of PGD that would establish the standard of care and legal norms. Such guidelines should be based on a patient-centered approach and respect individual autonomy in reproductive decision-making. Canadian approaches to PGD should also consider issues related to equity of access. Moreover, since PGD often raises concerns about eugenic uses, guidelines should also consider its societal impact and its implementation should be accompanied by policies that maintain or increase social support for people with disabilities. Finally, public engagement could provide an evidence-base regarding Canadian societal values and concerns that should guide regulatory reform, for example, the regulation of non-medical sex selection through PGD.

A new caw of hepatic glycogen snthase deficiency. biochemical findings and comparison with reported cases

Hepatic glycogen synthase deficiency (GSD-0) is an autosomal recessive disorder first described in 1963. Fifteen cases in seven different families have been reported. Mutations in GYS2, the gene coding for liver glycogen synthase, were found in the four families studied. We report a new case of GSD-0 in a female patient born to healthy non-consanguineous French Canadian parents. She was referred for a family-history of hyperlipidemia at 7 years of age. In addition to increased plasma total cholesterol and triglyceride levels, workup revealed fasting hypoglycemia and ketonuria. Her only complaint was morning headaches. Growth and development were normal Physical exam including neurological exam was normal. Cerebral MRI and EEC were normal Biochemical findings consistent with the diagnosis included fasting hypoglycemia, ketonemia and hypoalaninemia, and postprandial hyperlactatemia and elevated plasma branched chain amino acid levels. Liver biopsy confirmed reduced glycogcn synthase activity. Ratio of active to inactive form of glycogen synthase was normal, suggesting reduced enzyme synthesis rather than synthesis of an inactive protein. Low hepatic glycogen content and mild to moderate liver stealosis were present. Plasma free carnitine concentrations decreased during fasting while esterified carnitine levels remained unchanged. In contrast to other cases, we twice observed an increase in blood glucose levels after administration of glucagon following 15 and 18 hours of fasting respectively (from 2.2 to 3.4 and 2.7 to 4.0 mmol/L respectively) Since her hepatic glycogen content was reduced, this might come from gluconcogenesis At 13 years of age, our patient still has fasting hypoglycemia although to a lesser degree. Her growth and intellectual development remain normal From our patients clinical course and a review of the literature, we draw the following conclusions (1) non specific symptoms after overnight fasting were the presenting complaint in 6/16, 3 cases were brought to medical attention because of incidental findings, family history led to the diagnosis in 7 cases. (2) fasting hypoglycemia (16/16) and reduced liver glycogen content (8/8) are constant features, (3) other frequent biochemical findings include hyperlactatemia with feeding (13/16) and fasting hyperketonemia (9/16) and hypoalaninemia (8/16); (4) glucagon response after feeding is usually absent (4/6) but can be observed (2/6); (5) liver steatosis was observed in 5/8 cases. (6) growth and development are usually normal (12/16 and 13/16 respectively).