Predicting cross-reactive immunological material (CRIM) status in Pompe disease using GAA mutations: Lessons learned from 10 years of clinical laboratory testing experience

Authors

  • Deeksha S. Bali,

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    • Duke Biochemical Genetics Laboratory, 801 Capitola Drive, Ste 6, Durham, NC 27713.
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    • Deeksha Bali is Director of the Duke Glycogen Storage Disease laboratory and has been highly involved in laboratory diagnosis and research on Pompe disease and other glycogen storage diseases for the past 15 years. New methods for non-invasive diagnosis of lysosomal storage diseases have been developed so that patients can benefit from early diagnosis and initiation of treatment.

  • Jennifer L. Goldstein,

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    • Jennifer L. Goldstein is a Clinical Research Coordinator at Duke Medicine with a strong interest in laboratory diagnosis of glycogen storage diseases. Other interests are creatine deficiency syndromes, molybdenum cofactor disorders, newborn screening, and autism research.

  • Suhrad Banugaria,

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    • Suhrad Banugaria is actively involved in Clinical and Pre-Clinical Research involving Pompe disease at Duke Medicine. He is involved in projects working towards improvement of GAA enzyme delivery into muscle tissue of patients with Pompe disease using mouse models. CRIM status and associated immune modulation in CRIM-negative patients is one of his keen interests.

  • Jian Dai,

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    • Jian Dai is a Laboratory Technician at Duke Medicine who has vast experience in performing Western blots to determine CRIM status in patients with Pompe disease. She has been involved in pre-clinical and clinical work involving Pompe disease using GAA knock out and GAA-muscle M6PR double knock out mouse models.

  • Joanne Mackey,

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    • Joanne Mackey is a Nurse Practitioner who has worked in the Duke Medical Genetics Program taking care of patients with Pompe disease and their families for the past 15 years. She has been involved in enzyme replacement therapy clinical trials for Pompe disease since the first trial was performed at Duke. Her other interests are Down syndrome and various treatment modalities for metabolic diseases.

  • Catherine Rehder,

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    • Catherine Rehder is Director of the Molecular Diagnostics and Cytogenetics Laboratories at Duke. She has been involved with genotyping patients with Pompe disease and other metabolic diseases for the past 5 years through gene sequencing.

  • Priya S. Kishnani

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    • Priya S. Kishnani is Chief of Medical Genetics, Professor of Pediatrics, and a clinician scientist who is dedicated to the care and treatment of individuals with Pompe disease and other metabolic disorders. She has been involved in numerous clinical trials for the treatment of Pompe disease, Down syndrome, and many other conditions. She continues to research new therapies for Pompe disease, Down syndrome, and other glycogen storage diseases.


  • How to cite this article: Bali DS, Goldstein JL, Banugaria S, Dai J, Mackey J, Rehder C, Kishnani PS. 2012. Predicting cross-reactive immunological material (CRIM) status in Pompe disease using GAA mutations: Lessons learned from 10 years of clinical laboratory testing experience. Am J Med Genet Part C Semin Med Genet 160C:40–49.

Abstract

Enzyme replacement therapy (ERT) for Pompe disease using recombinant acid alpha-glucosidase (rhGAA) has resulted in increased survival although the clinical response is variable. Cross-reactive immunological material (CRIM)-negative status has been recognized as a poor prognostic factor. CRIM-negative patients make no GAA protein and develop sustained high antibody titers to ERT that render the treatment ineffective. Antibody titers are generally low for the majority of CRIM-positive patients and there is typically a better clinical outcome. Because immunomodulation has been found to be most effective in CRIM-negative patients prior to, or shortly after, initiation of ERT, knowledge of CRIM status is important before ERT is begun. We have analyzed 243 patients with infantile Pompe disease using a Western blot method for determining CRIM status and using cultured skin fibroblasts. Sixty-one out of 243 (25.1%) patients tested from various ethnic backgrounds were found to be CRIM-negative. We then correlated the CRIM results with GAA gene mutations where available (52 CRIM-negative and 88 CRIM-positive patients). We found that, in most cases, CRIM status can be predicted from GAA mutations, potentially circumventing the need for invasive skin biopsy and time wasted in culturing cells in the future. Continued studies in this area will help to increase the power of GAA gene mutations in predicting CRIM status as well as possibly identifying CRIM-positive patients who are at risk for developing high antibody titers. © 2012 Wiley Periodicals, Inc.

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