Screening for Lysosomal Storage Disorders in African Americans
Recently, Dr. Marjorie Gondré-Lewis, Director of the Developmental Neuropsychopharmacology Laboratory at the Howard University College of Medicine, won the Senior Faculty Research Award for best oral presentation during Howard University's Research Week, held April 9-13.
Dr. Gondré-Lewis discusses her award-winning presentation titled "Screening for lysosomal storage disorders in African-Americans shows higher incidence rates - A possible link to ancestry-specific genetic variation" in the interview below with Dr. Gwendolyn S. Bethea, editor.
Abstract: Variations in genomics and biochemical cascades contribute to health and disease and can be ancestry-specific. Here, we investigate the incidence of four lysosomal storage disorders (LSDs) in a cohort of urban-dwelling African Americans (AAs). LSDs are inherited genetic disorders caused by the functional absence of lysosomal enzymes and result in varied clinical symptoms. To date, studies of LSDs in AAs are few or non-existent with ambiguous clinical manifestations, that cause diagnostic challenges. We initiated a large scale screening for 'treatable forms' of LSDs in 5000 patients: 85% African American, 10% Hispanic, and 5% Caucasian or other. Under IRB approved protocols (NCT02120235 and HUIRB-14-MED-09), dried blood spots were prepared from peripheral blood samples and fluorometric enzyme assays performed using 4-methylumbelliferyl (4-MU) substrates specific for b-glucosidase (Gaucher disease), a-galactosidase (Fabry disease), a-glucosidase (Pompe disease), and b-galactosidase (MPS IV B) enzymes. After two rounds of screening, we confirmed undetectable activity for b-glucocerebrosidase in 1 subject; a-galactosidase in 3 subjects and a-glucosidase in 1 subject. Approximately 0.05-0.1% showed significantly reduced enzyme activity, likely indicating carrier status. NextGen Sequencing of the b-glucocerebrosidase gene in subjects with low enzymatic activity revealed a heterozygous c.1342G>C (D448H) and a homozygous missense mutation c.476G>A, R119Q(R159Q). Interestingly, a significant cohort had enzymatic activities several-fold higher than the reference. These findings highlight higher incidence rates for abnormal enzyme levels in this population and shows the importance of such large-scale screenings in minority groups traditionally not associated with a high incidence of LSDs, but who may have ancestry-based genotype variations that confer risk or resilience.
Q: What or who first sparked your interest in researching this subject?
Gondré-Lewis: My interest in Lysosomal Storage Diseases (LSDs) goes back to when I was a graduate student at Albert Einstein College of Medicine (Bronx, NY). There, I used animal models of health and disease to study the role of gangliosides and other lipids in neuronal development and in the sprouting and maturation of dendrites, one of the structures that allows one neuron of the brain to receive information from another. Importantly, I investigated pathology in diseased brains that resulted from defects in cellular trafficking due to lysosomal enzymes that do not function properly. In the lysosome, which is the breakdown and recycling center of the cell, when a molecule cannot be broken down; this molecule, along with all its precursors are accumulated in the lysosomes and other cellular compartments. The cells enlarge with the stored material, and the entire cellular machinery is impacted, such that these cells (neurons, liver, kidney, etc.,) eventually die. I used LSD animal models, but especially the Niemann-Pick Disease type C models. It had always struck me that there were no African American populations included in clinical studies of lysosomal storage disorders. Recently, there may be a case report here and there that involves a minority group, but no large-scale study to determine incidence. It had been long determined that the most affected groups are the Ashkenazi Jews; however, outside of this population, most clinical studies of these rare disorders were conducted on individuals of European descent and were not really ethnically diverse. It was suggested that because LSDs are rare diseases, they are likely not found in African Americans. A few years ago, I met an investigator, Dr. Ozlem Goker-Alpan, an MD with similar background in storage diseases, who treats LSDs at her research facility in Virginia. I voiced my concern that these studies often exclude African Americans, and that Howard University is a rich resource to study certain LSDs in African Americans. Given that heart disease, respiratory, kidney and liver disease are common in African Americans, and are primary features of many LSDs, we chose to investigate 'treatable' forms of LSDs involving these organs ... LSDs that could be common in African Americans. Thus, this work focuses on Gaucher Disease, Fabry Disease, and Pompe Disease. We are also testing other LSDs.
Q: Were you at all surprised by your findings?
Gondré-Lewis: We absolutely were! When we identified the first patient with low enzyme values and potentially an LSD after surveying just 1,000 patients, we were quite shocked because we expected to have needed DNA from at least 20,000 patients for a possible 1 positive ... if we were lucky. We now have more than 5,200 patients, and have identified potentially 2-3 cases of Pompe, 1 case of Gaucher, and 5 cases of Fabry disease. In addition, we've identified carriers and compound heterozygotes. We are still conducting the genetic work to fully characterize the population, but the results thus far are encouraging in that we can present a large screening study to establish that we have a significant occurrence in our population, to offer treatment, and to educate providers to recognize symptoms associated with these rare disorders, with which they may not be familiar.
Quite surprisingly, we found a cohort of individuals with high enzymatic values, not previously reported in controls or disease states. It is not clear what the significance of high enzymatic values are for disease states in our populations, or whether they confer protective properties, or even if they are correlated with LSDs in specific.
Q: What is most significant -- ancestral or environmental factors?
Gondré-Lewis: In this case, genetic factors are prominent, and very significant in that these are genetic trafficking disorders involving the brain in the most severe cases, and peripheral organs in the later onset forms of these diseases. However, it is not fully known what/if environmental triggers can induce disease phenotype in the late onset cases. Late onset cases can be severe disease states, but do not necessarily result in death in infancy, childhood, or adolescence.
Q: I noticed that you mention resiliency; would you elaborate?
Gondré-Lewis: Well we have not fully evaluated all of the meanings that could be extrapolated from our study cohort or the meaning of the various single nucleotide polymorphisms (SNPs) identified. The significance of the high enzymatic values is being investigated, and in the future, we will determine whether they are associated with protective SNPs, or certain health conditions. It is well known that certain SNPs could confer resilience to disease phenotype and we certainly are mindful as we mine the data.
Q: What impact does your laboratory have in your research, and what is the broader impact of your research?
Gondré-Lewis: Well, in general, we are primarily a neuropsychopharmacology laboratory conducting drug abuse research, and have heavily published on the mechanisms associated with addiction, prenatal nicotine exposure, early life stress and excessive alcohol drinking. In recent years, we have developed a clinical translational arm to the laboratory where we investigate genetic variations that contribute to disease in humans, with the mindset of searching for ancestry-specific SNPs that confer specific phenotypes in terms of drug metabolism, reward deficiency, or associated neuropsychiatric disorders. The overarching goal is to use scientific data in implementing Precision Genomic Medicine at Howard University, for a targeted approach to health problems in individuals. The LSD project uses precision medicine based on individual genetics to evaluate LSDs and treatment in African-American and minority patients at the HU Hospital. A major aim is to build awareness among physicians and make available new treatment strategies to our patients. We are also conducting NIH-funded research to study the genetics of opioid use disorder in African Americans and the impact of chronic opioid use and ecopsychosocial status on brain health. Entwined in these projects are evaluations of psychosocial determinants of health and genetics of substance use disorders to make available and deliver precision addiction medicine to our patient population. Perhaps next year I can share this work with the HU community. Here are some publications generated by my research team in the past five years.
View pdf listing - (opens in a new window).
Q: How are students involved in your research? Who are other faculty members involved in your research?
Gondré-Lewis: For many students, coming to my laboratory is their first exposure to a hands-on research experience, and to an active laboratory where they must participate daily, present findings, analyze data, and critically evaluate the literature. We have had many graduate, medical, dental, and undergraduate students, and even students from the Nursing Program, and the Nutrition Program at HU work with us. It is our pleasure to train passionate individuals in the proper conduct of research, to see them learn about mechanisms of disease and to partake in the inquiry. In addition to the Department of Anatomy, this work could not have been possible without the support of the Department of Pathology, and especially Dr. Marie N. Fidelia-Lambert, who provides a clinical perspective.
Q: What are your goals for the future?
Gondré-Lewis: For this project, my hope is to work with internal medicine physicians to launch a registry, to capture LSD patients coming through our doors at HUH, and to refer them to receive treatment entailing enzyme replacement therapy. For the forms that are treatable, it seems urgent to do this, because based on our data on three separate LSDs, there are patients who are in need in our community right now.
Q: Have you found any resistance to your findings among the general public, the medical community, the educational community, particularly pertaining to diagnosed disorders, such as Attention Deficit Deficiency, and other diagnoses among African Americans, other populations?
Gondré-Lewis: We have not yet experienced resistance. We don't anticipate push-back among the general public or the medical community. In fact, shedding light on a different potential diagnosis for an ailment previously thought to have a different source, may be welcome. This particular project or the associated symptoms and diagnoses are not as stigmatized as some other conditions.
Q: What barriers, if any, have you found in your quest to disseminate this research?
Gondré-Lewis: Well, the barriers to disseminating the research is internal, not external. By this, I mean that before making a claim about incidence of a rare disorder within our population, there had to have been a greater degree of due diligence in terms of 1) acquiring a strong number of samples to examine; 2) confirming the findings by repeating biochemical assays, and 3) confirming the findings at a genetic level. Thus, the study has taken several years, and is still not complete. We plan to publish findings for at least one of the LSDs soon.
Q: Do you see any political or social ramifications pertaining to your research?
Gondré-Lewis: As we continue, should we maintain the incidence rates that we have found in the current study, and identify individuals to receive treatment, this could prove highly impactful to the health of our community. In fact, the knowledge of a potentially higher incidence in those seeking healthcare is indeed already very impactful. It demonstrates that there needs to be a greater number of studies specifically to address more fully, African-American health in this society. Because of the traditional exclusion of African-American and minority groups from studies that offer novel treatment, it isn't always known what the occurrence and benefits of state-of-the-art care could be to our population. This study addresses a previously unknown health disparity that can and must be addressed and will allow the use of Precision Medicine to do so.
Q: Was there any resistance in collecting the data among the screened populations? Why or why not?
Gondré-Lewis: For this screening study, we assayed already collected blood samples to survey incidence. Now that we have the data to support that LSDs are an important consideration to minority and African Americans, we have justification for approaching communities directly in developing the registry.
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