PracticeUpdate Conference Series_WORLDSymposium 2019

Enzyme Therapy Reduces ParaproteinLevels inType 1 Gaucher Disease Patients with Gaucher disease 1 may respond to enzyme replacement therapy. F urther evidence has been provided that altering levels of lysolipid accumulation in patients with Gaucher disease 1 and monoclonal gammopathy of undeter- mined significance may attenuate malignancy risk. This outcome of a retrospective chart reviewwas reported at theWORLDSymposium 2019. Graeme A.M. Nimmo, MD, MBBS, MSc, MPH, of the Hospital for Sick Children in Toronto, Ontario, Canada, reviewed the charts of 85 patients with Gaucher disease 1. A total of 12 patients harboredmonoclonal gammopathy of undetermined significance (incidence 14%), including 4 patients who received enzyme replacement therapy. Enzyme replacement therapy resulted in an improvement in markers of disease activity (including chitotriosidase, ferritin, glucosylsphingosine) and in reduction of the monoclonal protein. The response was sustained in the majority of patients. One patient demonstrated a transient reduction in paraprotein with enzyme replace- ment therapy but progressed to smoldering myeloma with an immunoglobulin G-κ monoclonal component. Dr. Nimmo explained that individuals with Gaucher disease I are at a 25- to 50-fold increased risk of developing monoclonal gammopathy of undetermined significance and its postcursor, multiple myeloma vs the general population. Multiple myeloma is a major contributor to morbidity and mortality in patients with Gaucher disease with up to 8.0% of patients progressing to a malignant gammopathy. Chronic immune activation and pathogenic accumulation of lysolipids in Gaucher disease are hypothesized to contribute to this increased risk. The response of monoclonal gammopathy of undetermined significance to enzyme replacement therapy and/or an alteration in the risk of progression to multiple myeloma on treatment is not clear, however. Gaucher disease is an autosomal-recessive lysosomal storage disorder caused by deficient activity of β-glucocerebrosidase. Glucocerebroside accumulates in cells and certain organs. The disorder is char- acterized by bruising, fatigue, anemia, low platelet count, and liver and spleen enlargement. Glucocerebroside accumulates, particularly in leukocytes and espe- cially in macrophages. Glucocerebroside can collect in the spleen, liver, kidneys, lungs, brain, and bone marrow. Skeletal disorders and bone lesions may be painful. Severe neurological compli- cations, swelling of the lymph nodes, and (occasionally) adjacent joints, distended abdomen, a brownish tint to the skin, anemia, and yellow fatty deposits on the sclera are also features. Patients affected seriously may also bemore susceptible to infection. Both clinical features and response to treatment are heterogeneous. Skeletal dis- ease is complex, and a proportion of patients do not respond or progress despite Gaucher-specific therapy. Determinants of skeletal response are not known. The disease is characterized by polyclonal gammopathy and monoclonal gammopathy of undetermined significance. Dr. Nimmo concluded that monoclonal gammopathy of undetermined significance may respond to enzyme replacement therapy. Further evidence has been provided that altering levels of lysolipid accumulation in patients with Gaucher disease I with monoclonal gammopathy of undetermined significance may attenuate the risk of progression to malignancy.

First pre-hematopoietic stem cell trans- plant echocardiography was performed at MEDRNG 45 (range 0–88) days of life. Hematopoietic stem cell transplantation (n=6 cord blood, n=1 related) occurred at MEDRNG 131 (range 105–183) days of life with most recent echocardiography at MEDRNG 408 (range 10–1897) days after hematopoietic stem cell transplantation. Mitral regurgitation occurred in 2 infants before hematopoietic stem cell transplan- tation and remained present thereafter. Patent foramen ovale was common. Left ventricular hypertrophy occurred after hematopoietic stem cell transplantation. One infant suffered from severely decreased function at initial echocardiog- raphy and requiredmanagement in the ICU. One infant died unexpectedly 69 days after hematopoietic stem cell transplantation. Dr. Braunlin explained that hematopoietic cell transplantation is accepted therapy for severe MPS I-H. Newborns and young infants with severe MPS I presenting for hematopoietic stem cell transplantation suffer from unique medical issues related to their age. Dr. Braunlin concluded that early cardiac evaluation will identify cardiac features; however, increased awareness of the anatomic and functional differences of all organ systems related to young age will be necessary for optimal outcomes in patients with MPS I-H.

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WORLDSymposium 2019 • PRACTICEUPDATE CONFERENCE SERIES 7