Gaucher disease type 1 (non-neuronopathic) results from glucocerebrosidase (acid beta-glucosidase) deficiency with accumulation of glucocerebroside in macrophages/Kupffer cells. Enzyme replacement therapy (imiglucerase, velaglucerase) is available. Substrate reduction therapy with eliglustat inhibits which enzyme?

• A Glucocerebrosidase directly, reducing substrate accumulation
• B Sphingomyelin synthase, diverting ceramide away from glucocerebroside synthesis
• C Sphingosine kinase, reducing ceramide conversion to glucocerebroside precursors
• D UDP-glucose:ceramide glucosyltransferase (glucosylceramide synthase), reducing glucocerebroside synthesis ✓

Explanation

Eliglustat (Cerdelga) is a substrate reduction therapy for Gaucher disease type 1 that inhibits UDP-glucose:ceramide glucosyltransferase (also called glucosylceramide synthase, GCS), the enzyme that synthesizes glucosylceramide (glucocerebroside) by adding glucose to ceramide. By reducing the rate of glucocerebroside synthesis, eliglustat decreases the substrate load reaching lysosomes, partially compensating for the deficient glucocerebrosidase. Miglustat (an older SRT) inhibits the same enzyme but has lower selectivity and more side effects. Eliglustat is orally administered and metabolized by CYP2D6 (dose adjustment needed in poor/ultra-rapid metabolizers), making it an important pharmacogenomics example.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.