title: Combination therapy in a patient with chronic neuronopathic Gaucher disease: a case report.
abstract: BACKGROUND
  The 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.
  
  
  METHODS
  We 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.
  
  
  CONCLUSIONS
  This 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.
authors.affiliation: Pediatrics Unit, Department of Medical and Surgical Science, University "Magna Graecia", Catanzaro, Italy. geneticacatanzaro@gmail.com.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Ceravolo
authors.affiliation: Pediatrics Unit, Department of Medical and Surgical Science, University "Magna Graecia", Catanzaro, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Grisolia
authors.affiliation: Pediatrics Unit, Department of Medical and Surgical Science, University "Magna Graecia", Catanzaro, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Sestito
authors.affiliation: Pediatrics Unit, Department of Medical and Surgical Science, University "Magna Graecia", Catanzaro, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Falvo
authors.affiliation: Pediatrics Unit, Department of Medical and Surgical Science, University "Magna Graecia", Catanzaro, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Moricca
authors.affiliation: Pediatrics Unit, Department of Medical and Surgical Science, University "Magna Graecia", Catanzaro, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Concolino
mesh_terms: D017485:1-Deoxynojirimycin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D061605:Administration, Intravenous; D001812:Blood-Brain Barrier / Q000503:physiopathology; D002648:Child; D002908:Chronic Disease; D003131:Combined Modality Therapy; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D056947:Enzyme Replacement Therapy; D005776:Gaucher Disease / Q000628:therapy*; D005962:Glucosylceramidase / Q000172:deficiency; D006596:Hexosaminidases / Q000097:blood; D006801:Humans; D008297:Male
chemical_list: D004791:Enzyme Inhibitors; D017485:1-Deoxynojirimycin; C059896:miglustat; D006596:Hexosaminidases; C086400:chitotriosidase; D005962:Glucosylceramidase
keywords: Combination therapy; Enzyme replacement therapy (ERT); Miglustat; Neurological symptoms; Neuronopathic Gaucher disease (NGD); Substrate reduction therapy (SRT)