Abstract
Background: Gaucher disease type 1 (GD1) is an inherited lysosomal storage disorder caused by a deficiency of glucocerebrosidase, and is characterised by haematological, visceral and bone manifestations that vary widely in terms of severity and age at onset. In particular, the bone manifestations of GD1 can restrict physical activity and impact heavily on patient quality of life (QoL). Here, we describe three GD1 patients who showed remarkable improvements in bone-related outcomes during treatment with oral miglustat, two of whom had previously failed to respond to relatively high doses of enzyme replacement therapy (ERT). In the third, needle phobia led to oral miglustat being used as the initial treatment.
 Case presentation: Case 1 is a 39 year-old female diagnosed aged 4 years (genotype N370S/L444P) and underwent ERT (alglucerase then imiglucerase) since 1994. In 2013 she discontinued ERT (treatment duration 19 years) due to ongoing and debilitating bone pain and fatigue, and switched to miglustat therapy. She has since experienced substantial reductions in bone pain and improved physical function. Case 2 is a 59 year-old female diagnosed aged 17 years (genotype N370S/H162P). She commenced ERT treatment in 2002, with a brief interruption in 2007, and continued on ERT (imiglucerase followed by velaglucerase) up to 2014: total ERT monotherapy duration 12 years. She subsequently received combination therapy (velaglucerase plus miglustat) for 2 years but finally switched to miglustat monotherapy in 2016 due to ongoing bone manifestations. Her bone pain has since improved a great deal, alongside improvements in QoL parameters. Case 3 is a 48 year-old male diagnosed aged 11 years (genotype R463C/L105R). Having not received any previous treatment he avoided ERT due to life-long needle phobia. He therefore started miglustat therapy in late-2017, and has received it for approximately 1 year. During this time he experienced vast improvements in QoL due to decreased bone pain. Interestingly in all three cases, there were little or no observed changes in objective bone parameters (bone marrow burden, bone mineral density).
 Conclusions: These three GD1 cases illustrate the potential to achieve substantial reductions in bone pain and improvements in QoL, even in patients who have failed to respond to long-term ERT with regard to bone status.
Highlights
Gaucher disease type 1 (GD1) is an inherited lysosomal storage disorder caused by a deficiency of glucocerebrosidase, and is characterised by haematological, visceral and bone manifestations that vary widely in terms of severity and age at onset
quality of life (QoL), even in patients who have failed to respond to long-term enzyme replacement therapy (ERT) regarding bone status
All patients reported substantial effects on key quality of life aspects. These findings should be considered alongside the prevailing focus on patient-centric outcomes data, which are important at the clinical practice level as well as in clinical trials, in rare diseases such as GD1 where study patient numbers tend to be low [25]
Summary
Gaucher disease (GD) is an inherited lysosomal storage disorder caused by a deficiency of the enzyme glucocerebrosidase. Left femur and lumbar spine dual X-Ray absorptiometry (DXA), bone mineral density (BMD) measurements and skeletal MRI assessments showed little change during miglustat therapy (Table 2). The patient was lost to follow-up for several years, but re-presented aged 28 years with easy bruising, left hip pain, mild splenomegaly and a platelet count of 68 x 109/l. As the patient has a lifelong extreme aversion to needles, he was started on oral miglustat therapy in late-2017, with doses increased gradually from 100 mg o.d. to 100 mg t.i.d. over a period of 6 weeks He experienced mild bloating and flatulence during the first month of miglustat therapy, but no gastrointestinal or other adverse effects have been reported since . BMB, bone marrow burden score; BMD, bone mineral density; DXA, dual X-ray absorptiometry; EF, Erlenmeyer-flask deformity; LF, left femur; LS, lumbar spine; MI, marrow infiltration; MRI, magnetic resonance imaging; ND, not determined
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