NORD OCTOBER 21ST – 22ND, 2014
Stabilizing Membranes in Lipid Storage Disorders
by Addressing Epigenetics with Phospholipids
Patricia C. Kane, Ph.D.1, Shideh Pouria, MD2,3, Annette L. Cartaxo, MD2,4, Mark O’Neal Speight, MD2,5,
Damien Downing, MD2,6, Sheryl L. Leventhal, MD2,7, John McLaren-Howard, Ph.D.2,8, Ralph Holsworth,
DO2,9, Katrin Bieber, MD2,10, Meinrad Milz, MD2,10, Kristine Gedroic, MD2,11
ABSTRACT
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 ), (Börjesson 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
Director, NeuroLipid Research Foundation, Millville, New Jersey, USA www.neurolipid.org, 2NeuroLipid Research Foundation, Millville, New Jersey, USA www.neurolipid.
org, 3Kings College; The Grace Clinic, London, UK, 4Atlantic / Morristown Hospital, Morristown, New Jersey, USA, 5Private Practice, North Carolina, USA, 6Private Practice,
London, UK, 7Private Practice, Valley Cottage, New York, USA, 8Acumen Laboratory, Devon, UK, 9Southeast Colorado Hospital, Springfield, Colorado, USA, 10Medical Clinic Villa
Thal, Bad Groenbach Thal, Germany, 11Private Practice and Atlantic / Morristown Hospital, Morristown, New Jersey, USA
1
1
NORD OCTOBER 21ST – 22ND, 2014
following six months of a targeted treatment regime corresponding with significant normalization in red cell lipid
analysis, cardiolipin studies, epigenetic status, cellular structure and function, viewed in images of the subjects
membrane phospholipid leaflets and mitochondria membranes.
Addressing epigenetic aspects by clearing DNA adducts with oral or intravenous phospholipids further enhances
treatment outcomes. We have documented significant clinical neurological improvement in our subjects, including
cessation of seizures, along with marked normalization of cellular architecture following six months of a targeted
phospholipid dietary regime. Stabilization of cardiolipin, therefore myelin, and the cell/organelle membranes are
new targets to consider in neurometabolic disease and the administration of a balanced phospholipid membrane
stabilizing diet and phospholipid regime may offer a new therapeutic strategy for lipid storage disorders.
CASE STUDY 1: AUTISTIC SPECTRUM, SEIZURES AND CARNITINE
PALMITOYLTRANSFERASE DEFICIENCY
Seven year old male with diagnosis of ASD (autistic spectrum disorder) and seizure presentation unmedicated.
Nonverbal, learning difficulties, poor concentration/focus, eczema, anxiety, incontinence. Diet high in natural
carbohydrates (fruit, grains) with supplementation daily of 6 capsules of fish oil. Testing with Acumen revealed
epigenetic blockage associated with the gene for carnitine palmitoyltransferase and poor methylation patterns on
several chromosomes. Red cell fatty acid and blood examination showed gross elevation of very long chain fatty
acids indicative of impaired peroxisomal respiration, blocked conversion of eicosanoids into prostaglandins, low
structural lipids, very low cholesterol and a state of hyperammonemia. Patient began aggressive administration of
oral PC followed by intravenous Essentiale PC with improvement in presentation. After the diagnosis of Carnitine
Palmitoyltransferase deficiency patient’s diet was altered to predominately coconut oil and phospholipids (PC,
PE) along with egg yolk, meat fat, primrose oil, seeds. Patient’s seizures are now controlled for 1 year without
medication and patient continues to improve in cognitive skills and speech.
Figure 1: Gross elevation of very long chain fatty acids which impaired membrane and cellular function. After one year of oral balanced
lipids and six months of IV Phosphatidylcholine note marked improvement in the status of aberrant fatty acids which coincided with
improvement in the patient’s clinical picture.
2
NORD OCTOBER 21ST – 22ND, 2014
Post Stroke Seizures Male / Age: 5
Red Cell Lipid Biomarkers
Specimen Draw Date: 8/10/2010
The % Status is the weighted deviation of the lab result and will show no graph when the research does not support negative values.
-100
-50
0
50
100
LA
ALA
GLA
DGLA
AA
EPA
DHA
-25
25
16 DMA
18:0 DMA
18:1 DMA
C10:0 Capric
C14:0 Myristic
C14:1w5 Myristoleic
C15:0 Pentadecanoic
C16:0 Palmitic
C16:1w7 Palmitoleic
C16:1w9 Hexadecanoic
C17:0 Heptadecanoic
C17:1 Heptadecaenoic
C18:0 Stearic
C18:1w5 Octadecanoic
C18:1w7 Vaccenic
C18:1w9 Oleic
C18:2w6 Linoleic
C18:2w6 Conj Rumenic
C18:3w3 Alpha Linolenic
C18:3w6 Gamma Linolenic
C20:0 Arachidic
C20:2w6 Eicosadienoic
C20:3w6 Dihomo-y Lino.
C20:3w9 Mead
C20:4w6 Arachidonic
C20:5w3 Eicosapenta.
C22:0 Behenic
C22:1w9 Erucic
C22:2w6 Docosadienoic
C22:4w6 Adrenic
C22:5w3 Docosapenta.
C22:5w6 Osbond
C22:6w3 Docosahexa.
C23:0 Tricosanoic
C24:0 Lignoceric
C24:1w9 Nervonic
C24:2w6 Tetracosadienoic
C25:0 Pentacosanoic
C26:0 Hexacosanoic
C26:1 Lumequic
C26:2 Hexacosadienoic
C28:0 Octacosanoic
C30:0 Triacontanoic
Phytanic
Pristanic
Sum C16:1 Trans FAs
Sum C18:1 Trans FAs
Sum C18:2 Trans FAs
Total Lipid Content
Total Saturates
Total w3's
Total w6's
Figure 2: Full panel of fatty acid analysis for Case Study 1 subject
3
% Status
-9.03
43.98
-28.12
2600.00
91.84
50.00
96.30
7.02
223.61
50.00
336.87
503.85
65.69
-41.80
81.54
58.61
-288.85
159.09
35.51
-69.05
-30.92
-120.00
-79.83
121.43
-96.71
433.63
-87.59
-79.41
-122.97
-101.82
173.15
-80.63
129.98
-98.04
-19.48
131.31
-57.72
6.00
95.87
81.53
-52.02
50.00
0.00
150.00
-50.00
-27.50
-2.06
-37.50
-6.50
31.66
261.71
-294.28
H
L
H
H
H
H
H
H
H
H
H
L
H
H
L
H
H
L
L
L
L
H
L
H
L
L
L
L
H
L
H
L
H
L
H
H
L
H
H
L
L
L
H
H
L
Result
Low
1.62
1.40
1.93
3.46
2.63
3.51
High
0.79
0.69
1.14
0.0550
0.002
0.004
0.39
0.19
0.34
0.0030
0.001
0.003
0.16
0.08
0.14
19.75
17.80
21.22
0.29
0.09
0.16
0.07
0.05
0.07
0.67
0.29
0.39
0.09
0.02
0.03
17.04
14.38
16.68
0.07
0.05
0.24
0.92
0.55
0.83
12.13
10.10
11.97
3.45
8.43
10.51
0.10
0.03
0.07
0.12
0.06
0.13
0.02
0.02
0.04
0.39
0.36
0.49
0.12
0.19
0.29
0.96
1.12
1.64
0.07
0.03
0.05
9.91
11.16
13.82
2.33
0.17
0.62
1.35
1.58
2.16
0.04
0.05
0.07
0.02
0.05
0.08
1.36
2.06
3.40
3.45
1.28
2.25
0.31
0.47
0.97
6.03
2.32
4.38
0.23
0.28
0.38
5.08
4.74
5.87
4.78
3.06
4.01
0.35
0.37
0.66
0.12
0.09
0.14
0.36
0.20
0.31
0.29
0.14
0.25
0.06
0.06
0.16
0.0070
0.002
0.007
0.0010
0.000
0.002
0.0060
0.002
0.004
0.0000
0.000
0.000
0.05
0.04
0.08
0.74
0.41
1.09
0.08
0.07
0.13
1586.21
1403.05
1824.10
45.64
41.59
46.55
11.93
4.26
6.72
16.67
25.85
29.61
NORD OCTOBER 21ST – 22ND, 2014
Plasma surface of cell
membrane
Image of cell membrane
phospholipids
Mitochondria with closeup
of outer membrane
revealing damage Image of
cell membrane phospholipids
Figure 3: Note before and after treatment in cell membrane and mitochondrial images. Case Study 1 patient was responsive to oral and IV
phosphatidylcholine. Oral lipids needed to be adjusted to patient’s metabolic defect thus PC and coconut oil (MCT) were administered as
primary lipids in the diet.
4
NORD OCTOBER 21ST – 22ND, 2014
CASE STUDY 2: IMPAIRED PEROXISOMAL RESPIRATION, POST STROKE,
GLOBAL DEVELOPMENTAL DELAY, UNCONTROLLED SEIZURES
Five year old male with history of in utero stroke presented with uncontrolled daily seizures, onset at 7 months.
Non-verbal, unable to walk, autistic features, excessive drooling, poor cognitive skills. Meds include daily Klonopin
and Carnitor (carnitine). Delayed linear growth secondary to 4:1 Ketogenic Diet started at 18 months of age
with formula containing hydrogenated vegetable oil. Patient presented with no source of omega 6 linoleic fatty
acid in his diet, rather the oils in the diet consisted of MCT oil, fish oil, and fat contained in pork/chicken/beef/
egg. Note gross deprivation of linoleic acid with -288% red cell fatty acid status (normal Linoleic acid range is
8.43 -10.51%, patient’s result was 3.45% of total RBC lipids). Imaging of patient’s cellular phospholipids reveal
gross abnormalities. After one month of aggressive balanced lipid therapy with organic high linoleic sunflower oil
(replaced MCT oil and fish oil completely), oral Phosphatidylcholine/ Phosphatidylethanolamine, egg yolk (supplies
arachidonic acid) patient returned to the clinic with marked improvement – able to walk short distances unassisted,
attempting to communicate, seizure activity controlled.
Figure 4: Note DNA adducts depicting alteration of
genes expressing for Manganese dependent SOD2,
Tyrosine-3-monooxygenase and Isocitrate dehydrogenase
Figure 5: Poor methylation of PE into PC (Phosphatidylethanolamine into Phosphatidylcholine), poor
expression of cardiolipin synthase, low normal level
of cardiolipin, calcium replacing some of the cardiolipin synthase manganese binding sites, and impaired
ion gating
5
NORD OCTOBER 21ST – 22ND, 2014
Figure 6: Images from probe of the plasma membrane surface (top image), phospholipids within lipid membrane (middle image), and
mitochondrion (bottom image) of Case Study 2 subject’s cells.
6
NORD OCTOBER 21ST – 22ND, 2014
Red Cell Lipid Biopsy
Post Stroke Seizures Male / Age: 5
ABERRANT FATTY ACIDS
TRANS ISOMERS
SATURATED ODD
Pentadecanoic
96.30
Heptadecanoic
336.87
VLCFA'S
Lumequic
Hexacosanoic
H
H
RENEGADES
Vaccenic
Mead
Eicosanoic
Phytanic
Specimen Draw Date: 8/10/2010
MEMBRANE & MYELIN MARKERS
81.53
95.87
MYELINATION
18:1 DMA
H
H
SUMMATION
Total w6
81.54
121.43
121.43
150.00
-28.12
L
-294.28
L
STRUCTURAL
H
H
H
H
ESSENTIAL FATTY ACID
OMEGA 6
Linoleic
Gamma Linolenic
Dihomo-y Linolenic
Arachidonic
Adrenic
-288.85
-69.05
-79.83
-96.71
-101.82
OMEGA 3
Alpha Linolenic
Eicosapentaenoic
Docosapentaenoic
Docosahexaenoic
L
L
L
L
L
35.51
433.63
173.15
129.98
H
H
H
H
-5.70
0.00
239.69
H
INDEXES
Fluidity Index
MR Index
PR Index
-115.00
41.43
207.26
Myelination Index
Trans Isomer Index
Odd Chain Index
L
H
H
Figure 7: Disturbance in peroxisomal respiration is indicated with an accumulation of very long chain fatty acids is depicted
in upper left panel of Case Study 2 subject.
Note in the lower EFA panel gross imbalance of omega 6 and omega 3 due to inappropriate dietary lipids from a ketogenic
infant formula that contained trans fatty acids, overdose of fish oil supplementation, and an inadequate source of linoleic
acid for an extended period which is crucial for cardiolipin located in the inner membrane of the mitochondria.
7
NORD OCTOBER 21ST – 22ND, 2014
Post Stroke Seizures Male / Age: 5
Lipid Bio Systems Analysis
Specimen Draw Date: 8/10/2010
The % Status is the weighted deviation of the lab result and will show no graph when the research does not support negative values.
Omega 6 EFAs
The w6 EFA’s are the primary EFA’s with the highest concentration in mammals. They include Linoleic acid (LA),
gamma-Linolenic Acid (GLA), Dihomo-gamma-Linolenic Acid, ( DGLA) and Arachidonic Acid (AA). Together with Adrenic Acid
they comprise approximately 30% of red blood cell fatty acid membrane lipids. All are vital for structure and fluidity and as second
messengers (17-19,73,75). DGLA and AA are precursors to PGE1 and PGE2 series prostaglandins, which act as local controllers
and circuitry for cell to cell communication (75-77). The metabolic functions that w6 PG’s control ( literally endless ) are gradually
surfacing in the medical literature. To mention a few: growth of tissues and transcription, uterine contraction, heart rate, UV skin
response, inflammation, child birth and cyclic functions such as sleep, temperature control, GI functions, regulate fever, mucous
control, regulate nerve transmission, trigger cell division, steroid production, etc.etc.
Comments: The w6 eicosanoids AA and DGLA control / initiate a vast, actually indeterminable array of metabolic control
including inflammation. The use of NSAID’s as well as steroids are specifically designed to block these processes and in so
VLCFA'S
doing produce disturbing side-effects. Through the use of MYELINATION
RBC fatty acid analysis and the availability of highSTRUCTURAL
quality dietary lipids
as phosphatidylcholine (PC),81.53
Balanced 4:1
primrose
and Kirunal
Lumequic
H w6 to w3 oil, evening
18:1
DMAoil, egg yolk/butter
-28.12
L it is possible, to get to
the root of the inflammatory condition: Essential Fatty Acid imbalance.
Hexacosanoic
95.87 H
EFA Index --- w3 / w6 Range…….18 - 30
Red Cell Lipid Biopsy
ost Stroke Seizures Male / Age: 5
ABERRANT FATTY ACIDS
TRANS ISOMERS
Specimen Draw Date: 8/10/2
MEMBRANE & MYELIN MARKERS
• AA -- Major w6 FA Suppressed * Increase Eggs * Add Sun oil & OA * Retest in 1 Yr
• w6 FA -- Suppressed * Avoid Marine Oils * Follow AA Diet recommendations * Retest in 6 months
C18:2w6 Linoleic
C18:3w6 Gamma Linolenic
C20:3w6 Dihomo-y Lino.
SATURATED
ODD
C20:4w6 Arachidonic
Pentadecanoic
96.30 H
C22:4w6 Adrenic
Total w6's
Heptadecanoic
336.87 H
% Status
Result
-288.85
3.45
-69.05
0.02
-79.83
0.96
RENEGADES
-96.71
9.91
Vaccenic 1.36
-101.82
-294.28
16.67
Mead
Low
High
8.43
0.02
1.12
11.16
81.54
2.06
25.85
121.43
10.51
0.04
1.64
13.82
3.40
29.61
-100
-50
SUMMATION
Total w6
0
50
-294.28
100
L
H
H
Eicosanoic
121.43 H
Figure 8: Note deep supression of
omega 6 linoleic acid
due to very
Phytanic
150.00
H limited dietary sources in Case Study 2 subject. Further, the other omega 6
fatty acid levels are compromised due to competitive inhibition from fish oil overdose and inappropriate dietary lipid sources.
ESSENTIAL FATTY ACID
OMEGA 6
Linoleic
Gamma Linolenic
Dihomo-y Linolenic
Arachidonic
Adrenic
-288.85
-69.05
-79.83
-96.71
-101.82
OMEGA 3
Alpha Linolenic
Eicosapentaenoic
Docosapentaenoic
Docosahexaenoic
L
L
L
L
L
35.51
433.63
173.15
129.98
H
H
H
H
-5.70
0.00
239.69
H
INDEXES
Fluidity Index
MR Index
PR Index
-115.00
41.43
207.26
Myelination Index
Trans Isomer Index
Odd Chain Index
L
H
H
8
NORD OCTOBER 21ST – 22ND, 2014
CASE STUDY 3: NIEMANN PICK TYPE C, TONIC CLONIC SEIZURES
Nine year old female presents with Niemann Pick Type C, symptoms of developmental delay at 2.5 years, diagnosis
at age 6. Patient is wheelchair-bound and presents with generalized tonic clonic seizures and staring spells,
cervical dystonia and marked dystonia of hands/feet, fatigue, hyperreflexia in lower extremities with positive
Babinski sign, posturing of hands/feet, vertical gaze palsy, enlarged liver and spleen, sustained clonus bilaterally,
nonverbal, drooling, constipation, facial fasciculations, ptosis, hearing loss, tremor, incontinence of bladder and
bowel, aggressive behavior, global regression, recurrent illness with high dosing of antibiotics (mitochondrial toxin).
Patient tube fed diet of rice, fruit, poultry, meat, vegetables, juice, high dose flax oil and fish oil. Patient’s red cell
fatty acid analysis from the Peroxisomal Diseases laboratory at Kennedy Krieger Institute indicated gross overdose
of EPA (+ 758%) which showed deep suppression of arachidonic acid (-131%) due to competitive inhibition.
Elevation of very long chain fatty acids (VLCFAs) and blocked conversion of DGLA into PG1 was found (from steroid
use) along with marked elevation of myelin precursor dimethyl acetyl or DMA 18:1 (+225%) indicative of a gross
increase of the phospholipid sphingomyelin in cell membranes indicative of membrane architecture instability
and low membrane phosphatidylcholine. Patient’s diet was adjusted a membrane stabilizing diet via tube feeding
and supplemented with SR3 oil (Yehuda’s 4:1 omega 6 to omega 3 oil), phosphatidylcholine, evening primrose oil,
butyrate, carnosine and adjustment of supplementation as catalysts per cellular and lipid analysis. Intravenous
therapy was initiated with Essentiale phosphatidylcholine, leucovorin and glutathione, then phenylbutyrate was
added to the regime with marked positive response. Therapeutic response was documented by patient’s pediatric
neurologist after 6 months intravenous (3 days monthly) and oral phospholipid therapy with reduction in seizure
activity, faciculations, tremors, hyper reflexia, posturing and dystonia. Neurologist noted patient’s liver and spleen
were no longer enlarged, and that patient was starting to walk, attempting to talk, and that there was cognitive
improvement and mood stabilization.
Figure 9: Note suppressed beta oxidation reflected in the accumulation of very long chain fatty acids in upper panel and
gross elevation of EPA due to an overdose of fish oil.
9
MEMBRANE STABILIZING DIET
Table 1: The Membrane Stabilizing Diet is suggested for optimizing patients nutritional status
10
LIPID DATA
COMPARISON OF STARTING DOSE OF MACRONUTRIENT
PRESCRIPTION OF DIETARY TREATMENTS
Fat
Protein
Carbohydrate
Classical ketogenic
diet at 4:1 ratio
90% of energy,
long chain
MCT ketogenic diet
30–60% of energy
from MCT,
11–45% of energy
from long chain
10% of energy
15–19% of energy
Modified Atkins diet
Not measured – high fat
foods encouraged
Not limited
10 g daily (15 g in adults)
Low glycemic
index treatment
60% of energy
20–30% of energy
40–60 g daily, low glycemic index only
Membrane Stabilizing
Diet
Essential Fatty Acids,
PC, Butyrate or PB
Not Limited
80 g daily, low glycemic index only,
no grains, no fruit other than berries
10% of energy from protein and carbohydrate combined
MCT - Medium Chain Triglycerides PC - Phosphatidylcholine
PB - Phenylbutyrate
Table 2: The Membrane Stabilizing Diet utilities targeted phospholipids (PC, PE), SR3 oil, High linoleic Safflower oil, Evening
primrose oil, egg yolk predominantly rather than saturated or unessential fatty acids.
PUFAs, HUFAs and EFAs
Lower order essential fatty acids (EFAs), or polyunsaturated fatty acids (PUFAs)
•
linoleic acid (LA), omega 6, found in high linoleic sunflower and safflower oil
•
alpha linolenic acid (ALA), omega 3, found in flax, walnut, and soy oil
Higher order EFAs, or highly unsaturated fatty acids (HUFAs)
Omega 6
•
gamma linolenic acid (GLA) found in evening primrose oil
•
dihomo gamma linolenic acid (DGLA)
•
arachidonic acid (AA) found in meat fat, butter, dairy, egg yolk
Omega 3
•
eicosapentaenoic acid (EPA) found in cold water fish and fish oil
•
docosahexaenoic acid (DHA) found in cold water fish and fish oil
Table 3: List of essential fatty acids, lower and higher order.
THE AMOUNT OF PC REQUIRED TO CLEAR DNA ADDUCTS
AND STABILIZE PATIENT
#"
"
0.5 to 1.2 grams or PC per kg of body weight
is the quantity of PC required to clear DNA adducts,
11 normalize cell membranes and stabilize patient
Bieber K and Milz M 2010
TREATMENT REGIMES
Table 4: A more specific targeted mitochondrial cocktail is utilized as a Cardiolipin Cocktail along with the Synapse Cocktail
as determined by the patient’s test results and presentation
Table 5: Intravenous therapy is utilized per patients test results, clinical presentation and availability from local physician.
12
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