Stabilizing Membranes in Lipid Storage Disorders by Addressing Epigenetics with Phospholipids

Subjects with rare lipid storage disorders have a characteristic accumulation of very long chain fatty acids (VLCFAs) revealing cell membrane derangement per disturbance in peroxisomal respiration which interrupts cell membrane integrity and neurometabolic function (Kane and Cartaxo, 2009), (Cutler et al, 2002), (Moser et al, 1999). Accumulating evidence suggests that even subtle perturbations in the lipid content of neurons and myelin can disrupt their function and architecture (Rapoport,1999 ), (Borjesson et al, 2008), (Cui and Houweling, 2002). The brain is 60% lipid. Stabilizing cellular and organelle membranes, particularly cardiolipin located exclusively in the inner lipid membranes of mitochondria and myelin (Kann and Kovacs, 2007), may be primary therapeutic targets in neurometabolic abnormalities such as those with lipid storage disorders. Recent research has revealed that in the brain myelin acts as one enormous mitochondrion (Ravera et al, 2011), as cardiolipin and ATP have been found embedded in myelin. Restoring the lipid content of the inner membrane of mitochondria to support its primary phospholipid cardiolipin with omega 6 linoleic acid and phosphatidylethanolamine are major contributors towards optimizing mitochondrial and neural function. Subjects with rare lipid storage disorders and neurological disease often have membrane phospholipid abnormalities with elevation of VLCFAs that may be indicative of exposure to neurotoxins resulting in suppressed peroxisomal beta oxidation of VLCFAs (Kane and Cartaxo, 2009). In addition to disturbed peroxisomal and membrane function they also often have mitochondrial translocator and nuclear DNA adducts (induced by toxic insult) that further compromise gene expression due to epigenetic factors which may begin to elucidate the reason some carriers have a more aggressive course of the disease than others. In capturing visual images of distorted phospholipid membranes we have linked the impact of the DNA adducts (toxins) altering gene expression to aberrations in lipid metabolism, cellular dysfunction and alteration of the structure of phospholipids in the cell membranes (Greenwood et al, 2007) characteristic to the presenting diagnosis and symptoms. To optimize organelle and cellular membrane architecture we address appropriate balance, fluidity (Schachter D et al, 1983) and content of phospholipids which is crucial towards normal cellular processes to optimize metabolic function. Therapeutic intervention includes a membrane stabilizing modified ketogenic-type diet to suppress phospholipase A2 (Farooqui et al, 2004), (Veech RL, 2004) which acts as a lipid scissors that compromises membrane integrity. In addition, a targeted lipid therapy is administered orally, in some cases intravenously, of phosphatidylcholine, phosphatidylethanolamine, balanced essential fatty acids as Yehuda’s SR3 oil or Specific Ratio 3 (Yehuda et al, 1998), evening primrose oil, butyrate/ phenylbutyrate (Vinolo et al, 2011), (Iannitti and Palmieri, 2011), IV Glutathione (Dentico et al, 1995) and co-factors to clear DNA adducts, stimulate methylation, control inflammation with the stimulation of anti-inflammatory lipid mediators resolvins and lipoxins, and stabilize cellular architecture. Our phospholipid protocol has yielded marked clinical neurological improvement in our subjects