Restricted ketogenic diet enhances the therapeutic action of N-butyldeoxynojirimycin towards brain GM2 accumulation in adult Sandhoff disease mice

J Neurochem. 2010 Jun;113(6):1525-35. doi: 10.1111/j.1471-4159.2010.06733.x. Epub 2010 Apr 3.


Sandhoff disease is an autosomal recessive, neurodegenerative disease involving the storage of brain ganglioside GM2 and asialo-GM2. Previous studies showed that caloric restriction, which augments longevity, and N-butyldeoxynojirimycin (NB-DNJ, Miglustat), an imino sugar that hinders the glucosyltransferase catalyzing the first step in glycosphingolipid biosynthesis, both increase longevity and improve motor behavior in the beta-hexosaminidase (Hexb) knockout (-/-) murine model of Sandhoff disease. In this study, we used a restricted ketogenic diet (KD-R) and NB-DNJ to combat ganglioside accumulation. Adult Hexb-/- mice were placed into one of the following groups: (i) a standard diet (SD), (ii) a SD with NB-DNJ (SD + NB-DNJ), (iii) a KD-R, and (iv) a KD-R with NB-DNJ (KD-R + NB-DNJ). Forebrain GM2 content (mug sialic acid/100 mg dry wt) in the four groups was 375 +/- 15, 312 +/- 8, 340 +/- 28, and 279 +/- 26, respectively, indicating an additive interaction between NB-DNJ and the KD-R. Most interestingly, brain NB-DNJ content was 3.5-fold greater in the KD-R + NB-DNJ mice than in the SD + NB-DNJ mice. These data suggest that the KD-R and NB-DNJ may be a potential combinatorial therapy for Sandhoff disease by enhancing NB-DNJ delivery to the brain and may allow lower dosing to achieve the same degree of efficacy as high dose monotherapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Deoxynojirimycin / analogs & derivatives*
  • 1-Deoxynojirimycin / therapeutic use
  • 3-Hydroxybutyric Acid / blood
  • Analysis of Variance
  • Animals
  • Blood Glucose / drug effects
  • Body Weight / drug effects
  • Brain / cytology
  • Brain / drug effects*
  • Brain / metabolism
  • Chromatography, High Pressure Liquid / methods
  • Chromatography, Thin Layer / methods
  • Diet, Ketogenic / methods*
  • Eating / drug effects
  • G(M2) Ganglioside / metabolism*
  • Lipid Metabolism / drug effects
  • Mice
  • Mice, Knockout
  • Myelin Sheath / metabolism
  • Purkinje Cells / metabolism
  • Purkinje Cells / pathology
  • Sandhoff Disease* / diet therapy
  • Sandhoff Disease* / drug therapy
  • Sandhoff Disease* / pathology
  • beta-N-Acetylhexosaminidases / deficiency
  • beta-N-Acetylhexosaminidases / genetics


  • Blood Glucose
  • 1-Deoxynojirimycin
  • G(M2) Ganglioside
  • migalastat
  • beta-N-Acetylhexosaminidases
  • 3-Hydroxybutyric Acid