Prospective study of neurological responses to treatment with macrophage-targeted glucocerebrosidase in patients with type 3 Gaucher's disease.
We prospectively evaluated the clinical and biochemical responses to enzyme-replacement therapy (ERT) with macrophage-targeted glucocerebrosidase (Ceredase) infusions in 5 patients (age, 3.5-8.5 years) with type 3 Gaucher's disease. The patients were followed for up to 5 years. Enzyme dosage ranged from 120 to 480 U/kg of body weight/month. Systemic manifestations of the disease regressed in all patients. Neurological deficits remained stable in 3 patients and slightly improved in 1. One patient developed myoclonic encephalopathy. Cognitive deterioration occurred in 1 patient and electroencephalographic deterioration in 2. Sequential cerebrospinal fluid (CSF) samples were obtained during the first 3 years of treatment in 3 patients and were analyzed for biochemical markers of disease burden. Glucocerebroside and psychosine levels were not elevated in these specimens, whereas chitotriosidase and quinolinic acid were elevated in 2 patients. Progressive decrease in the CSF levels of these latter macrophage markers during 3 years of treatment implies a decreased number of Gaucher cells in the cerebral perivascular space. Similar changes were not observed in the patient who had a poor neurological outcome. In conclusion, ERT reverses systemic manifestations of type 3 Gaucher's disease and appears to reduce the burden of Gaucher cells in the brain-CSF compartment in some patients.
Schiffmann
R
R
Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health Bethesda, MD 20892-1260, USA.
Heyes
M P
MP
Aerts
J M
JM
Dambrosia
J M
JM
Patterson
M C
MC
DeGraba
T
T
Parker
C C
CC
Zirzow
G C
GC
Oliver
K
K
Tedeschi
G
G
Brady
R O
RO
Barton
N W
NW
D000906:Antibodies / Q000097:blood; D015415:Biomarkers; D002648:Child; D002675:Child, Preschool; D004569:Electroencephalography; D016057:Evoked Potentials, Auditory, Brain Stem; D005260:Female; D005776:Gaucher Disease / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D005962:Glucosylceramidase / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D006596:Hexosaminidases / Q000097:blood / Q000134:cerebrospinal fluid; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000097:blood / Q000134:cerebrospinal fluid; D008264:Macrophages / Q000201:enzymology*; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009460:Neurologic Examination; D009483:Neuropsychological Tests; D009573:Nitrites / Q000097:blood / Q000134:cerebrospinal fluid; D011446:Prospective Studies; D011609:Psychosine / Q000097:blood / Q000134:cerebrospinal fluid; D017378:Quinolinic Acid / Q000097:blood / Q000134:cerebrospinal fluid; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors; D012795:Sialoglycoproteins / Q000097:blood / Q000134:cerebrospinal fluid; D016212:Transforming Growth Factor beta / Q000097:blood / Q000134:cerebrospinal fluid
D000906:Antibodies; D015415:Biomarkers; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D009573:Nitrites; D017472:Receptors, Interleukin-1; D012795:Sialoglycoproteins; D016212:Transforming Growth Factor beta; D011609:Psychosine; D006596:Hexosaminidases; C086400:chitotriosidase; D005962:Glucosylceramidase; D017378:Quinolinic Acid