Combination therapy in a patient with chronic neuronopathic Gaucher disease: a case report

Abstract

BackgroundThe variants of neuronopathic Gaucher disease may be viewed as a clinical phenotypic continuum divided into acute and chronic forms. The chronic neuronopathic form of Gaucher disease is characterized by a later onset of neurological symptoms and protracted neurological and visceral involvement. The first-choice treatment for nonneuronopathic Gaucher disease is enzyme replacement therapy with recombinant analogues of the deficient human enzyme glucocerebrosidase. Enzyme replacement therapy has been shown to improve hematological and bone manifestations associated with Gaucher disease, but, as with most proteins, recombinant enzymes cannot cross the blood–brain barrier, which prevents effects on neurological manifestations. Substrate reduction therapy with miglustat (N-butyldeoxynojirimycin) inhibits glucosylceramide synthase, which catalyzes the first step in glycosphingolipid synthesis. Because miglustat can cross the blood–brain barrier, it has been suggested that, combined with enzyme replacement therapy, it might be effective in treating neurological symptoms in patients with neuronopathic Gaucher disease.Case presentationWe report observed effects of combined enzyme replacement therapy and substrate reduction therapy in a 7-year-old Caucasian boy with neuronopathic Gaucher disease who was homozygous for L444P mutations. He had received enzyme replacement therapy from the age of 18 months, and concomitant miglustat treatment was commenced, with dosing according to body surface area uptitrated over 1 month with dietary modifications when he reached the age of 30 months. He experienced mild diarrhea after commencing miglustat therapy, which decreased in frequency/severity over time. His splenomegaly was reduced, and his hematological values and plasma angiotensin-converting enzyme activity normalized. Plasma chitotriosidase also showed substantial and sustained decreases. After 5 years of combination therapy, the patient showed no signs of neurological impairment.ConclusionsThis case supports the concept that oral miglustat in combination with intravenous enzyme replacement therapy may be beneficial in preventing neurological signs in patients with chronic neuronopathic Gaucher disease. The importance of dietary modifications has also been confirmed. Further follow-up studies are needed to better define the therapeutic effect of combined treatment in this Gaucher disease subtype.

Liver transplantation for Gaucher disease presenting as neonatal cholestasis: Case report and literature review

“…Generally, treatment consists of ERT which has been found to improve the visceral manifestations of GD but is unable to cross the blood‐brain barrier so does not have an impact on the neurological sequelae. Newer substrate reduction therapy is able to cross the blood‐brain barrier and has the potential to improve neurologic outcomes 5,6 . Another treatment option is liver transplantation (LT).…”

Effect of Substrate Reduction Therapy in Comparison to Enzyme Replacement Therapy on Immune Aspects and Bone Involvement in Gaucher Disease

“…While certain components of bone disease see improvement with SRT, it is not possible to conclude with certainty as to superiority of SRT over ERT regarding bone complications [15][16][17][22][23][24]. Recent case reports demonstrate that judicious use of the SRT-ERT combination therapy may benefit in certain GD patients [25,26].…”

Combined miglustat and enzyme replacement therapy in two patients with type 1 Gaucher disease: two case reports

“…The third sibling, who received combination treatment from the age of 5 months, showed improvement/stabilization of neurological manifestations and normal psychomotor development. Most recently an Italian group treated a male Italian L444P homozygous infant with imiglucerase (60 U/kg every 2 weeks started at age 18 months) and miglustat (added at age 30 months) [ 20 ]. While the patient’s genotype predicted early-onset neurological manifestations, no neurological manifestations were observed throughout follow-up.…”

“…While SRTs and ERTs are generally used as monotherapies in GD, one previous study has been reported in which combination therapy was used for a short time in GD1 patients [ 17 ]. There are also anecdotal reports of combinations of different agents being used in individual patients with neuronopathic GD (GD3) [ 18 – 20 ].…”