TY - JOUR
T1 - Substrate reduction therapy in juvenile GM2 gangliosidosis
AU - Maegawa, Gustavo H.B.
AU - Banwell, Brenda L.
AU - Blaser, Susan
AU - Sorge, Geoffrey
AU - Toplak, Maggie
AU - Ackerley, Cameron
AU - Hawkins, Cynthia
AU - Hayes, Jason
AU - Clarke, Joe T.R.
N1 - Funding Information:
We thank Vivian Cruz RN, Lynn MacMillian, RN, Margaret Mackrell RN and Barbara Chapman RN, all from Hospital for Sick Children (HSC), Toronto, ON, Canada, who assisted in the clinical assessments. We also thank the initial work done by Jody Levenbach psychologist at Toronto Western Hospital, University Health Network, Toronto, ON, Canada. We are also in dept with Derek Stephens from Biostatistics, Design and Analysis, Research Institute, HSC. We thank Ms. Ania Tulips, Yew Meng Heng and Richard Leung from Electron Microcospy, Div. of Pathology, Dept. of Paediatric Laboratory Medicine, HSC, who provided equipments and crucial assistance for sample processing and analysis. Life for Luke Foundation supported the fellowship of GHBM. This study was supported in partially by Actelion Pharmaceuticals Inc., Allschwil, Switzerland.
PY - 2009/10
Y1 - 2009/10
N2 - Substrate reduction therapy (SRT) is considered to be a potential therapeutic option for juvenile GM2 gangliosidosis (jGM2g). We evaluated the efficacy of SRT in jGM2g, assessing neurological, neuropsychological and brain magnetic resonance imaging (MRI) outcomes over a 24-month period of treatment. In an open-label and single-center study, five jGM2g patients (mean age 14.6 ± 4.5 years) received oral miglustat at doses of 100-200 mg t.i.d. adjusted to body surface area. Patients underwent general and neurological examinations, neuropsychological, electrophysiological, and brain MRI studies. All patients showed neurological deterioration over the period of the study, with particularly notable worsening of gait, speech and coordination. One patient experienced acute psychosis, and another showed worsening of pre-existing epilepsy. Some neuropsychological tests showed no evidence of deterioration in the three patients with high enough cognitive functioning for reliable assessment. Profound cognitive impairment in two children precluded neuropsychological evaluation. In four patients, evaluation of brain MRI showed no changes in white matter signal abnormalities and cerebellar atrophy noted at baseline, while one patient showed progression of cerebellar and supratentorial brain atrophy. Transmission electron microscopy analysis of peripheral mononuclear cells showed reduction of intracytoplasmatic inclusions with treatment. SRT with miglustat of patients with jGM2g failed to ameliorate progressive neurological deterioration, but apparently no worsening of some areas of cognitive function tested and brain MRI lesions was noted over 24 months of treatment. The results must be interpreted with care owing to the small sample of patients and the lack of a control-arm.
AB - Substrate reduction therapy (SRT) is considered to be a potential therapeutic option for juvenile GM2 gangliosidosis (jGM2g). We evaluated the efficacy of SRT in jGM2g, assessing neurological, neuropsychological and brain magnetic resonance imaging (MRI) outcomes over a 24-month period of treatment. In an open-label and single-center study, five jGM2g patients (mean age 14.6 ± 4.5 years) received oral miglustat at doses of 100-200 mg t.i.d. adjusted to body surface area. Patients underwent general and neurological examinations, neuropsychological, electrophysiological, and brain MRI studies. All patients showed neurological deterioration over the period of the study, with particularly notable worsening of gait, speech and coordination. One patient experienced acute psychosis, and another showed worsening of pre-existing epilepsy. Some neuropsychological tests showed no evidence of deterioration in the three patients with high enough cognitive functioning for reliable assessment. Profound cognitive impairment in two children precluded neuropsychological evaluation. In four patients, evaluation of brain MRI showed no changes in white matter signal abnormalities and cerebellar atrophy noted at baseline, while one patient showed progression of cerebellar and supratentorial brain atrophy. Transmission electron microscopy analysis of peripheral mononuclear cells showed reduction of intracytoplasmatic inclusions with treatment. SRT with miglustat of patients with jGM2g failed to ameliorate progressive neurological deterioration, but apparently no worsening of some areas of cognitive function tested and brain MRI lesions was noted over 24 months of treatment. The results must be interpreted with care owing to the small sample of patients and the lack of a control-arm.
KW - Juvenile GM2 gangliosidosis
KW - Miglustat
KW - Sandhoff disease
KW - Substrate reduction therapy
KW - Tay-Sachs disease
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U2 - 10.1016/j.ymgme.2009.06.005
DO - 10.1016/j.ymgme.2009.06.005
M3 - Article
C2 - 19595619
AN - SCOPUS:67651232532
SN - 1096-7192
VL - 98
SP - 215
EP - 224
JO - Biochemical Medicine and Metabolic Biology
JF - Biochemical Medicine and Metabolic Biology
IS - 1-2
ER -