Rochelle Hirschhorn, MD

Research Professor, Department of Medicine

Professor Emerita of Medicine, Cell Biology and Pediatrics, Department of Medicine

Keywords
molecular pathology of inherited diseases
Summary

Our laboratory investigates the pathophysiology, therapy and molecular basis of inherited diseases, primarily focussing on two "inborn errors of metabolism", adenosine deaminase (ADA) deficiency and acid alpha-glucosidase deficiency, including studies of correlation of the molecular defect and the clinical picture (genotype-phenotype).

ADA deficiency, when severe, causes a lethal immunodeficiency in children. We have also shown that a less severe deficiency can cause a later onset immunodeficiency, including onset in adult life. We found that absence of this enzyme activity in lymphocytes causes accumulation of deoxy-ATP and deoxyadenosine, which are toxic to these cells and reduces their number and function. We also demonstrated that a form of enzyme therapy reduces the concentrations of these toxic metabolites and can ameliorate the disease, leading to current use of a modified enzyme replacement as a standard form of therapy. We have defined a large variety of mutations, but most frequently missense mutations at hot spots for mutation associated with CpG dinucleotides. Generally,l the ability of mutant ADA enzymes to code for residual activity correlates inversely with accumulation of the toxic metabolites and severity of the immunodeficiency. In cases where this correlation does not hold, we have shown that these children are mosaics carrying both normal and mutant cells in their body. In one case we discovered that the mosaicism occurred by the remarkable "reversion to normal" of a specific inherited mutation, by mechanisms that we currently are trying to elucidate.

Deficiency of acid alpha glucosidase, whose gene we cloned, leads to accumulation of glycogen in lysosomes (Glycogen Storage Disease Type II; GSDII) and a resulting spectrum of muscle disease, ranging from a lethal infantile onset disorder affecting both heart and skeletal muscle to a slowly progressive disorder with onset as late as the sixth decade and pathology only in skeletal muscle. In this disorder we have also defined multiple different mutations but with a predominance of mutations that alter mRNA. We have shown that one splice site mutation is the molecular defect in the majority of adult onset patients and additionally identified specific mutations that are found frequently in limited ethnic groups. In contrast to our studies with ADA deficiency, we have found discordance between specific mutations and clinical features (genotype/phenotype). We are currently cloning a gene that is a candidate for acting as a modifier to explain the discrepancy between phenotype and genotype.

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Research Professor, Department of Medicine

Professor Emerita of Medicine, Cell Biology and Pediatrics, Department of Medicine

MD from New York University

Hirschhorn, Kurt; Hirschhorn, Rochelle; Hirschhorn, Joel N

Annual review of genomics & human genetics. 2017 Jan 26; ?-?

Hirschhorn, Kurt; Hirschhorn, Rochelle

American journal of human genetics. 2014 Mar 06; 94(3):336-337

Foreword

Hirschhorn, Kurt; Hirschhorn, Rochelle

Primary Immunodeficiency Diseases: A Molecular and Genetic Approach. Oxford : Oxford University Press, 2014. 3rd ed. p.?-?. (997972)

Immunodeficiency due to defects of purine metabolism

Hirschhorn, Rochelle; Grunebaum, Eyal; Roifman, Chaim; Candotti, Fabio

Primary Immunodeficiency Diseases: A Molecular and Genetic Approach. Oxford : Oxford University Press, 2014. 3rd ed. p.?-?. (997982)

Hershfield, Michael S; Meuwissen, Hilaire J; Hirschhorn, Rochelle

Primary immunodeficiency disorders : a historic and scientific perspective. Oxford : Elsevier Academic Press, [2014]. p.255-266. (2256342)

Biobanks and the human microbiome

Schwab, Abraham P; Brenner, Barbara; Goldfarb, Joseph; Hirschhorn, Rochelle; Philpott, Sean

The human microbiome : ethical, legal and social concerns. Oxford ; New York : Oxford University Press, 2013. p.?-?. (988692)

Rhodes, Rosamond; Azzouni, Jody; Baumrin, Stefan Bernard; Benkov, Keith; Blaser, Martin J; Brenner, Barbara; Dauben, Joseph W; Earle, William J; Frank, Lily; Gligorov, Nada; Goldfarb, Joseph; Hirschhorn, Kurt; Hirschhorn, Rochelle; Holzman, Ian; Indyk, Debbie; Jabs, Ethylin Wang; Lackey, Douglas P; Moros, Daniel A; Philpott, Sean; Rhodes, Matthew E; Richardson, Lynne D; Sacks, Henry S; Schwab, Abraham; Sperling, Rhoda; Trusko, Brett; Zweig, Arnulf

American journal of bioethics : AJOB. 2011 Nov; 11(11):1-7

Immunodeficiency due to defects of purine metabolism

Hirschhorn, Rochelle; Candotti, Fabio

Primary immunodeficiency diseases : a molecular and genetic approach. New York : Oxford University Press, 2007. 2nd ed. p.?-?. (997962)