A favorable outcome in an infantile-onset Pompe patient with cross reactive immunological material (CRIM) negative disease with high dose enzyme replacement therapy and adjusted immunomodulation

Molecular Genetics and Metabolism Reports

Priya S. Kishnani¹  Yoav Zehavi²  Shiri Curelaru²  Ronen Spiegel³  Ankit K. Desai³  Daniel Fink⁴ 

[1] Rappaport School of Medicine, Technion, Haifa, Israel;Department of Pediatrics B, Emek Medical Center, Afula, Israel;Division of Medical Genetics, Department of Pediatrics, Duke University Health System, Durham, NC, United States;Pediatric Cardiology Unit, Emek Medical Center, Afula, Israel;

关键词: Infantile-onset Pompe disease;    Enzyme replacement therapy;    Immunomodulation;    Cross reactive immunological material (CRIM);    GAA gene;   

DOI  :  

来源: DOAJ

【 摘 要 】

Infantile onset Pompe disease (IOPD) is a rare devastating disease that presents in early infancy with rapidly progressive hypertrophic cardiomyopathy, severe generalized myopathy and death within the first year of life. The emergence of enzyme replacement therapy (ERT) with recombinant human acid alpha glucosidase (rhGAA) has improved the natural course of IOPD with a significant impact on cardiomyopathy but has a more limited effect on the progression of myopathy and consequently the later deterioration of the disease. Possible reasons for reduced ERT efficacy include insufficient enzyme, partial targeting of skeletal muscle and the development of IgG rhGAA antibodies especially in patients who are cross-reactive immunological material (CRIM) negative. We report a CRIM-negative IOPD female patient who started treatment upon diagnosis at 4.5 months with ERT at 20 mg/kg every other week and a course of combined immunomodulation with rituximab, methotrexate and IVIG according to the published Duke protocol and increased ERT within a month to 40 mg/kg/week. Despite initial good clinical response to ERT and immunomodulation, monthly monitoring identified a gradual increase of serum antibody titers to rhGAA necessitating a second course of immunomodulation with bortezomib and maintenance rituximab and methotrexate. A gradual reduction in frequency of immunotherapy was instituted and over a period of 14 months was discontinued. Serum anti-rhGAA antibody titers remained negative for 5 months since cessation of immunomodulation and the patient is now immune tolerant with recovery of CD19. At the age of 30 months the patient is walking independently and has normal cardiac function and anatomy. We recommend initiating ERT at 40 mg/kg/week in CRIM-negative IOPD patients, concomitant with immunomodulation and monthly monitoring of serum anti-rhGAA IgG titers upon confirmation of the diagnosis.

【 授权许可】

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