Showing posts with label Regressive autism. Show all posts
Showing posts with label Regressive autism. Show all posts

Monday, 20 January 2020

Sulfarlem / Anethole trithione (AOL) for Autism secondary to Mitochondrial Dysfunction (AMD)? Not to mention Metastasis

Sulfarlem has been used to treat dry mouths for half a century
By -, CC BY-SA 4.0,

Sulfarlem is a drug containing a chemical called Anethole trithione. Anethole is an organic compound used as a flavouring, it contributes a large component of the odour and flavour of anise and fennel.

Anise seed, or aniseed, contains a large amount of Anethole. The popular Greek drink Ouzo turns cloudy when diluted with water because of the Anethole. For the French it is called Pastis.   

Ouzo has been used to treat dry Greek mouths for seven centuries, particularly after a good meal.

For Anethole without the alcohol, a good source would include aniseed or fennel.


Today's post was prompted by a comment made before Christmas by our reader Claudia; she highlighted some recent French research that repurposes a drug developed by Solvay half a century ago.  The drug is Sulfarlem / Anethole trithione and it is used to treat people with a dry mouth, mainly in French speaking countries (including Canada) and in China, particularly Taiwan.

Sulfarlem appears to have secondary effects that include inhibiting oxidative stress in mitochondria which might benefit a long list of diseases, though they do not mention autism secondary to mitochondrial disease.

The other effect is a reduction in metastasis in people with cancer. This effect was written about in 2002 in the mass media.

Here, we demonstrate that OP2113 (5-(4-Methoxyphenyl)-3H-1,2-dithiole-3-thione, CAS 532-11-6), synthesized and used as a drug since 1696, does not act as an unspecific antioxidant molecule (i.e., as a radical scavenger) but unexpectedly decreases mitochondrial reactive oxygen species (ROS/H2O2) production by acting as a specific inhibitor of ROS production at the IQ site of complex I of the mitochondrial respiratory chain. Studies performed on isolated rat heart mitochondria also showed that OP2113 does not affect oxidative phosphorylation driven by complex I or complex II substrates. We assessed the effect of OP2113 on an infarct model of ex vivo rat heart in which mitochondrial ROS production is highly involved and showed that OP2113 protects heart tissue as well as the recovery of heart contractile activity. 

Conclusion / Significance This work represents the first demonstration of a drug authorized for use in humans that can prevent mitochondria from producing ROS/H2O2. OP2113 therefore appears to be a member of the new class of mitochondrial ROS blockers (S1QELs) and could protect mitochondrial function in numerous diseases in which ROS-induced mitochondrial dysfunction occurs. These applications include but are not limited to aging, Parkinson’s and Alzheimer’s diseases, cardiac atrial fibrillation, and ischemia-reperfusion injury.

Here is the associated patent:-


The present invention relates to an inhibitor of production of reactive oxygen species (ROS) for treating or for use in the treatment of free oxygen-radicals related diseases. In one embodiment, said inhibitor is anethole trithione (AOL). In one embodiment, said inhibitor inhibits mitochondrial production of ROS. In a preferred embodiment, said inhibitor inhibits mitochondrial production of ROS at site IQ of complex I of mitochondria

In one embodiment, said free oxygen-radicals related diseases are selected from the group comprising: age-related macular degeneration, Parkinson's disease, Alzheimer's disease, ischemic and reperfusion injury, pulmonary arterial hypertension, scleroderma, atherosclerosis, heart failure, myocardial infarction, arthritis, pulmonary toxicity, cardiopulmonary diseases, inflammatory diseases, cancer, metastasis, cardiac toxicity of anthracyclines, heart failure regardless of origin, ischemia, heart attack, stroke, thrombosis and embolism, asthma, allergic/inflammatory conditions, bronchial asthma, rheumatoid arthritis, Inflammatory Bowel Disease, Huntington's disease, cognitive disorders, Progeria, progeroid syndromes, epileptic dementia, presenile dementia, post traumatic dementia, senile dementia, vascular dementia, HIV-1-associated dementia, post-stroke dementia, Down's syndrome, motor neuron disease, amyloidosis, amyloid associated with type 11 diabetes, Creutzfelt-Jakob disease, necrotic cell death, Gerstmann-Straussler syndrome, kuru and animal scrapie, amyloid associated with longterm hemodialysis, senile cardiac amyloid and Familial Amyloidotic Polyneuropathy, cerebropathy, neurospanchnic disorders, memory loss, aluminum intoxication, reducing the level of iron in the cells of living subjects, reducing free transition metal ion levels in mammals, patients having toxic amounts of metal in the body or in certain body compartments, multiple sclerosis, amyotrophic lateral sclerosis, cataract, diabetes, cancer, liver diseases, skin ageing, transplantation, ototoxic secondary effects of aminoglycosides, neoplasms and toxicity of anti-neoplastic or immunosuppressive agents and chemicals, innate immune responses, and, Friedreich's Ataxia.

In one embodiment, said inhibitor is for preventing or for use in the prevention of metastasis.

From way back in 2002: -

Dry-Mouth Drug Joins Cancer Fight

Stephen Lam, director of the lung cancer prevention program at the British Columbia Cancer Research Center in Vancouver, British Columbia, found that one of Solvay's drugs, marketed as Sialor or Sulfarlem, also significantly reduces the spread of lung-cancer tumors.

Lam's study completed the second phase of trials necessary for the FDA's consideration. Over six months, 101 smokers and former smokers took the dry-mouth drug. It reduced the progression of their lung cancer tumors by an average of 22 percent.
To participate in the study, the smokers had to have smoked at least a pack a day for 30 years, or two packs a day for 15 years.
Those who took a placebo had 53 percent more new lesions or lesions that got worse than those who took the drug.
The billion-dollar question is, who will pay for more clinical trials? Lam's study was paid for with grants from the National Cancer Institute, and the money has run out. The final stage of clinical trials can cost hundreds of millions of dollars.

The French have recently followed up :-

Mitochondria ROS blocker OP2-113 downregulates the insulin receptor substrate-2 (IRS-2) and inhibits lung tumor growth

They go further in their patent and propose Sulfarlem as a blocker of metastasis.

A recent Chinese paper sets out the mechanism of action.

CXCR4 and PTEN are involved in the anti-metastatic regulation of anethole in DU145 prostate cancer cells

Taken together, anethole demonstrated to act as the CXCR4 antagonist and as the PTEN activator which resulted to PI3K/AKT-mediated inhibition of the metastatic prostate cancer progressions.

Regular readers will know that PTEN is both a cancer gene and an autism gene.

PTEN is best known as a tumor suppressor affecting RAS-dependent cancer, like much prostate cancer. Activating PTEN is good for slowing cancer growth. As I mentioned in a recent comment to Roger, many substances are known to activate PTEN; a good example being I3C (indole-3-carbindol) which is found in those cruciferous vegetables (broccoli, Brussels sprouts, cabbage etc) that many people choose not to eat.

Activating PTEN should also help some types of autism.

A recent Japanese study has a different take on the anti-metastatic mode of action.

Anethole is known to possess anti-inflammatory and anti-tumor activities and to be a main constituent of fennel, anise, and camphor. In the present study, we evaluated anti-metastatic and apoptotic effects of anethole on highly-metastatic HT-1080 human fibrosarcoma tumor cells. Despite weak cytotoxicity against HT-1080 cells, anethole inhibited the adhesion to Matrigel and invasion of HT-1080 cells in a dose-dependent manner. Anethole was also able to down-regulate the expression of matrix metalloproteinase (MMP)-2 and -9 and up-regulate the gene expression of tissue inhibitor of metalloproteinase (TIMP)-1. The similar inhibitory effect of anethole on MMP-2 and -9 activities was confirmed by zymography assay. Furthermore, anethole significantly decreased mRNA expression of urokinase plasminogen activator (uPA), but not uPA receptor (uPAR). In addition, anethole suppressed the phosphorylation of AKT, extracellular signal-regulated kinase (ERK), p38 and nuclear transcription factor kappa B (NF-kB) in HT-1080 cells. Taken together, our findings indicate that anethole is a potent anti-metastatic drug that functions through inhibiting MMP-2/9 and AKT/mitogen-activated protein kinase (MAPK)/NF-kB signal transducers.


There is quite a lot in this blog about cancer, due to the overlapping signalling pathways with autism, so follows a little digression about metastasis.

Metastasis is a pathogenic agent's spread from an initial/primary site to a different/secondary site within the host's body.

Often it is the metastasis that ultimately kills people; indeed this just happened to the mother of one of Monty's friends with autism.

Metastasis involves a complex series of steps in which cancer cells leave the original tumor site and migrate to other parts of the body via the bloodstream, via the lymphatic system, or by direct extension.

Source: Mikael Häggström 

If a cheap substance could reduce metastasis that would be a big deal.  Cancer is currently the second most common cause of death.  If you can take cheap/safe chemoprotective agents to reduce cancer’s occurrence and a cheap substance to reduce its spread/metastasis you would be pretty smart.

Cheap Cancer Drugs

Numerous cheap drugs have known anti-cancer properties (Metformin, Aspirin, Statins, plus many more) but absolutely no serious interest is shown to apply any of them.  Instead, some hugely expensive drugs have been developed that often extend life by a matter of months.

Sulfarlem certainly is cheap, costing 3 euros (USD 3.3) a pack in France, where it seems to be sold OTC.

It looks like the world of cancer research is as dysfunctional as the world of autism research, when it comes to translating existing knowledge into beneficial therapies.  Nobody wants a cheap cancer drug and I think nobody wants a cheap autism drug.  

Most people still believe autism cannot be treated and some even think it should not be treated. 


Sulfarlem has been around for 50 years and so there is plenty of safety data regarding its use.

It does look like a significant number of people with autism have a problem with Complex 1 in their mitochondria.  This subject has been covered extensively in this blog in regard to regressive autism and what Dr Kelley, from Johns Hopkins, termed autism secondary to mitochondrial disease (AMD).  Unfortunately for us, he has retired.

Dr Kelley’s mito-cocktail of antioxidants is used by many, but even he makes clear that it is far from perfect and it is not so cheap. 

Sulfarlem looks like an interesting potential add-on, or even a potential replacement.

The fact that Sulfarlem also activates PTEN means that an entirely different group with autism might see a benefit.

Who might carry out a trial of Sulfarlem in autism?  I think the one likely group are those irrepressible autism researchers in Iran, who have trialed so many off-label drugs.  Since Sulfarlem is already licensed in Canada, one of those more enlightened researchers in Toronto might like to investigate.

If you live in France you can skip your early morning expresso and go down to the pharmacy with your three euros and then make your own trial.

Sulfarlem, or just plain anethole, seems a cheap/safe way to potentially reduce metastasis once cancer has been identified. Probably not worth waiting another 20 years for any possible further clinical trials.

Friday, 7 April 2017

Treating Mitochondrial Disease/Dysfunction in Autism

In my book I will be covering the science behind hopefully almost all autism, which then naturally leads to translating it into therapy.  In the ideal world you would just skip straight to the therapy and the final section of the book will be just that.  Clearly it would make sense to read the science first, so that you know what are the dysfunctions that you might need to treat.

Hopefully there will also be some case studies from people who have applied a science-based approach to identify and implement effective therapies.

Roger would clearly make a very good example of a reversible in-born metabolic-caused type of autism.

I will be posting on my blog some drafts from the Part III - Translating Science to Treat Autism.  This is of course just one person's collection of other people's ideas and some of his one.  The reader and his/her medical medical team ultimately decide what to implement and must monitor its ongoing implementation.

 * * *

Mitochondrial disease is managed rather than cured. It seems to be present in autism in widely varying degrees of severity.  Extreme cases result in very severe regressive autism with MR/ID.

It is either diagnosed based on detailed analysis of numerous blood tests, or more recently via a sample taken from inside the cheek. These tests cannot be perfect, because mitochondrial disease can be organ-specific.

Someone with body-wide mitochondrial disease will have poor exercise endurance and this will be very noticeable compared to siblings and peers.

Dr Kelley, from Johns Hopkins, has published his therapy for autism secondary to mitochondrial disease (AMD):-

1.      Augment residual mitochondrial enzyme complex I activity

2.      Enhance natural systems for protection of mitochondria from reactive oxygen species

3.      Avoid conditions known to impair mitochondrial function or increase energy demands, such  as prolonged fasting, inflammation, and the use of drugs that inhibit complex I.

Combining the first and second parts of the treatment plan, the following is a typical prescription for treating AMD:

L-Carnitine 50 mg/kg/d                Alpha Lipoic acid 10 mg/kg/d

Coenzyme Q10 10 mg/kg/d          Pantothenate 10 mg/kg/d

Vitamin C 30 mg/kg/d                  Nicotinamide 7.5 mg/kg/d (optional)

Vitamin E 25 IU/kg/d                   Thiamine 15 mg/kg/d (optional)

There are actually five stages in the OXPHOS process in mitochondria and there are five enzyme complexes. Dr Kelley's plan above is for the most common dysfunction, complex 1.

Different clinicians have different treatments.

Also appearing elsewhere are :-

Calcium folinate (2 x 25 mg), but not because of peroxynitrite

Biotin 5-10 mg/day


Methylcobalamin B12


On the basis that peroxynitrite, from nitrosative stress, damages the mitochondria, you might consider:

·         Calcium folinate (leucoverin) in very high doses like 25mg twice a day.

·         Xanthine oxidase inhibitors, typically used to lower uric acid to treat gout. A good example is Allopurinol. It will both lower uric acid and peroxynitrite. Uric acid is itself a potent scavenger of peroxynitrite; this may look odd given the previous sentence. If someone has low uric acid and wants to reduce peroxynitrite then uric acid itself should be therapeutic. The purine metabolism may play a key role in some types of autism, as proposed by Professor Robert Naviaux.

·         Rosmarinic acid, a natural scavenger of peroxynitrite.

There are many anomalies in autism and one is uric acid.  Some people have low levels and some have high levels. Uric acid is itself a scavenger of peroxynitrite.  People with high levels of uric acid do get gout, but almost never MS (multiple sclerosis) and it has been suggested that scavenging peroxynitrite is neuroprotective.

Special, electrically charged, antioxidants have been developed to target the mitochondria.  MitoE is a charged version of vitamin E and MitoQ is a charged version of coenzyme Q10.

Based on the research, you might  also seek to activate PGC-1α, the master regulator of mitochondrial biogenesis. This can potentially be achieved via:-

·         Exercise  (gradual endurance training)

·         Activate PPARγ and perhaps  PPARα (e.g. Bezafibrate  and Rosiglitazone)

·         Activate AMPK (Metformin)

·         Activate Sirt-1 (resveratrol and other polyphenolic ‎compounds)

Carnitine-like analogs may also help in theory.  The standard L-Carnitine, widely used as a supplement, is very poorly absorbed even at high doses. An analog is a modified version of a molecule that keeps the therapeutic beneficial effect, but overcomes a drawback, bioavailability in the case of carnitine. There is some basis in the literature to believe that the Latvian drug Mildronate might be useful to treat complex 1 mitochondrial dysfunction.

more detail at

Wednesday, 15 October 2014

Regressive Autism and Mitochondria - Part 1

This blog is mainly about classic early-onset autism and the biology underlying it.

There are many other disorders that also result in autistic behaviours, some of which are much better understood than classic autism.  Today’s post is about Mitochondrial Disease which appears to be the precursor to most cases of regressive autism, according to Dr Richard Kelley, at Johns Hopkins and the Kennedy Krieger Institute.

In well-resourced centers for autism, by which I mean large teaching hospitals in the US, cases of autism are often fully investigated.  First they rule out mitochondrial disease and common known single gene causes like Fragile X.  Next comes the chromosome microarray. The microarray (often referred to as CMA) may identify a genetic cause in 15-20% of individuals with an ASD. 

In the rest of the world no such testing takes place, unless you are very lucky.

If the supplement Carnitine makes you feel better, read on, because you quite likely have some mitochondrial dysfunction and have Asperger’s secondary to Mitochondrial Disease.

If you are interested in regressive autism and particularly if you live outside the US, this post could be very relevant.

In short, medical testing can establish whether mitochondrial disease is present.  If it is present, it may be the underlying cause of the regressive autism, or perhaps just an aggravating factor.  If steps are taken quickly, further damage can be limited and the final outcome much improved.

Some of the therapies are the same as for classic autism, like anti-oxidants but some are the opposite.

Certain common drugs should be avoided like types of painkiller (Tylenol/ acetaminophen/paracetamol and aspirin), statins, steroids, valproic acid, risperidone (Risperdal), haloperidol, and some SSRIs; all are inhibitors of complex I / toxic to mitochondria.

There is at least one emerging drug therapy to treat the mitochondria, as opposed to just limit further damage.

The following extensive extracts are all from a paper by Dr Richard Kelley, at the Kennedy Krieger Institute and the neighboring Johns Hopkins Hospital.  I suggest reading the full original paper.  It is the most useful paper related to autism that I have come across, and that is thousands of papers.

Autism secondary to Mitochondrial Disease (AMD)

Most children with autism secondary to mitochondrial disease (“AMD”) experience a single episode of injury, while a few suffer two or more periods of regression during a characteristic window of vulnerability between 12 and 30 months. The subsequent natural history of AMD is typical for regressive autism, with most children showing partial recovery between 3 and 10 years. The principal clinical differences between AMD and non-regressive autism are, variably, a mild myopathy, abnormal fatigue, and, occasionally, minor motor seizures in the years following the first episode of injury. Others with biochemically defined AMD experience a period of only developmental stagnation lasting several months or more between ages 12 and 30 months and show overall better recovery than those who experience a severe autistic regression during this period of neurological fragility. More noteworthy, but uncommonly identified, are sibs of AMD individuals who have all the biochemical features of AMD with no or only minimal developmental or behavioral abnormalities, such as ADHD or obsessive-compulsive disorder.

While permanent developmental losses in AMD can be substantial, especially in the few individuals who suffer more than one episode of regression, recovery can be almost complete in some children when treatment is started early after the first episode of regression, and a partial response to metabolic therapy remains possible indefinitely. Treatment of AMD includes augmentation of residual complex I activity with carnitine, thiamine, nicotinamide, and antothenate, and protection against free radical injury with several antioxidants, including vitamin C, vitamin E, alpha-lipoic acid, and coenzyme Q10 (CoQ10).

Although a deficiency of mitochondrial complex I may be the most common identifiable cause of regressive autism, the relatively mild biochemical abnormalities often are missed by “routine” metabolic testing. In some cases, all test results are in the normal range for the laboratory, but abnormal ratios of metabolites offer clues to the diagnosis.

The identification of patients with AMD has now become routine Kennedy Krieger Institute, in part because of its specialization in both ASD and metabolic diseases and in part because of the availability of onsite biochemical testing.

Natural History of Autism with Mitochondrial Disease. The natural history of AMD and the events surrounding the period of regression are as important as the biochemical abnormalities in establishing the diagnosis. Before regression, all affected children have had normal or even advanced language and cognitive development and no neurological abnormalities apart from mildly delayed gross motor milestones and hypotonia in a few. Regression often can be dated to a specific event, most often a simple childhood illness, such as otitis media, streptococcal pharyngitis, or viral syndrome, or, rarely, an immunization, most often the MMR vaccine or the former DPT. The common feature of all identified precipitants is inflammation. Regression occurs either acutely during the illness or within 14 days of immunization with the MMR attenuated virus vaccine. Regression is otherwise typical for autism and includes acute or subacute loss of language, onset of perseverative behaviors, and loss of eye contact and other social skills. Although neurological regression in many mitochondrial diseases and other metabolic disorders often occurs because of illness-associated fasting, most children with AMD continue to eat normally during the crisis. Moreover, regression during an illness can occur whether or not there is fever. The nature of the regression and its timing suggest that mitochondrial failure is caused by immune-mediated destabilization of mitochondria as part of a TNF-alpha/caspase-mediated apoptosis cascade [5]. Because “steady state” loading of complex I in brain is close to 50% [6,7], if a child had a 50% reduction in complex I activity due to  aplo insufficiency for a complex I null mutation, just a 5 or 10% further reduction in mitochondrial activity could cause neurons to cross the threshold for energy failure and cell death. 

The well-defined role of nutritional factors in modulating the inflammatory response and the shift from animal fats to vegetable-derived fats in western diets are important factors to consider in the cause and treatment of AMD. The increase in the consumption of pro-inflammatory omega-6 fatty acids in infancy and early childhood over the last generation has been particularly striking. The established role of inflammation in causing mitochondrial destabilization [8,9] could explain an increasing incidence of regressive autism in individuals who have otherwise asymptomatic variants of complex I deficiency, which may have specific adaptive function in host defense and cognitive development [10]. In this respect, AMD, which in our experience is the cause of most regressive autism, could be another inflammatory disorder among several that have seen a markedly increased incidence over the last 20 to 30 years: asthma, inflammatory bowel disease, atopic dermatitis, eosinophilic gastroenteritis, and type I diabetes [11]. The recognition of inflammation as an apparently common cause of regression in AMD recommends the use of anti-inflammatory agents, including ibuprofen and leukotriene receptor inhibitors (i.e. montelukast, zafirlukast), to prevent further injury in children with AMD. For example, the recently reported increased risk for post-MMR autistic regression in children given pro-oxidant acetaminophen [12] could also be interpreted as an increased risk for developmental regression in those who were not given ibuprofen. Moreover, the effect of the gradual elimination of aspirin use in children between the 1980s and 1990s following the Reye syndrome epidemic 6 may have contributed to the rise in the incidence of autism, although, epidemiologically, aspirin elimination alone is not likely to be a major factor in the rising incidence of regressive autism.
Although most patients with AMD have a discrete episode of acute or subacute language loss and social regression, some will manifest only relative stagnation of development for a period of several months to a year or more. At least 90% of such events––developmental regression or stagnation––occur in a window of vulnerability between 12 and 30 months.

The goals for treatment of AMD due to complex I deficiency are:

1)    Augment residual complex I activity

2)    Enhance natural systems for protection of mitochondria from reactive oxygen species

3) Avoid conditions known to impair mitochondrial function or increase energy demands, such as prolonged fasting, inflammation, and the use of drugs that inhibit complex I.

Combining the first and second parts of the treatment plan, the following is a typical prescription for treating AMD:

L-Carnitine 50 mg/kg/d                Alpha Lipoic acid 10 mg/kg/d
Coenzyme Q10 10 mg/kg/d       Pantothenate 10 mg/kg/d
Vitamin C 30 mg/kg/d                  Nicotinamide 7.5 mg/kg/d (optional)
Vitamin E 25 IU/kg/d                    Thiamine 15 mg/kg/d (optional)

Immediate behavioral improvement with carnitine treatment in a child with regressive autism makes complex I deficiency the most likely cause

Another important clinical observation is that many children with mitochondrial diseases are more symptomatic (irritability, weakness, abnormal lethargy) in the morning until they have had breakfast, although this phenomenon is not as common in AMD as it is in other mitochondrial diseases.

When early morning signs of disease are observed or suspected, giving uncooked cornstarch (1 g/kg; 1 tbsp = 10g) at bedtime effectively shortens the overnight fasting period. Uncooked cornstarch, usually given in cold water, juice (other than orange juice), yogurt, or pudding, provides a slowly digested source of carbohydrate that, in effect, shortens overnight fasting by 4 to 5 hours. 

the MMR vaccine has been temporally associated, if rarely, with regression in AMD and other mitochondrial diseases when given in the second year. Doubtless some of these regressions are coincidental, since the usual age for giving the MMR falls within the typical window of vulnerability for AMD regression. In some children, however, MMR-suspected regression has coincided with the peak inflammatory response on days 8 to 10 post-immunization, as measured by IL-10 levels [28]. Unfortunately, the falling rates of immunization with MMR in the United States and other countries all but guarantees that major outbreaks of measles, mumps, and rubella will occur in the near future

Nutritional Factors Diet is another variable to consider in the treatment of AMD. Vegetable oils that are “pro-inflammatory” due to low levels of omega-3 (n-3) fatty acids and increased amounts of linoleic acid and other omega-6 (n-6) fatty acids today predominate in infant formulas and most prepared foods, largely because 13 of nutritional recommendations to avoid animal fats containing saturated fatty acids and cholesterol. The serious consequences of this trend are now being felt. A study in 2000 [29] showed that two- to four-month old breast-fed infants had more than twice the level of docosahexaenoic acid (C22:6n-3) and higher levels of most other n-3 fatty acids compared to formula-fed infants, although immunological consequences of the difference could not be demonstrated using limited immunological assays in that particular study. While the average child may suffer no obvious ill effects from diets deficient in n-3 fatty acids, the possible proinflammatory effect of these diets could be a contributing factor to infection-induced regressive autism in a child who has a metastable mitochondrial disorder. Moreover, in view of a recent study that associated decreased synthesis of cholesterol with rare cases of non-regressive autism [30], the early termination of breast-feeding and the major shift in infant diets toward low-cholesterol vegetable fats could be contributing factors to the apparent rise in the incidence of both regressive and non-regressive autism. Indeed, studies over the last two decades have shown that absence or early termination of breast-feeding is associated with higher rates of autism [31]. The simplest way to assure a adequate amount of C22:6n-3 and related fatty acids for children on typical vegetable-oil enriched diets is to provide an oil supplement, such as flaxseed oil, which is enriched in the precursors for C20 and C22 n-3 fatty acids, or salmon oils, which contain substantial amounts of DHA and EPA and a relatively low mercury content compared to many other fish species. C. Medications Certain behavior medications used in the treatment of ASD are inhibitors of complex I and, therefore, warrant consideration in treating children with AMD. Although these medications appear to have little effect on overall energy metabolism in individuals with normal mitochondria, clinically significant compromise of mitochondrial function can occur when complex I is impaired and relatively high doses of the more inhibitory drugs are prescribed. The complex I-inhibiting drugs most likely to be used in the treatment of ASD include both typical and atypical neuroleptics, such as risperidone (Risperdal), haloperidol, and some SSRIs. Although these medications are used most often in older children who are beyond the vulnerable period for autistic regression, this theoretical risk should be considered when prescribing older generation neuroleptics, such as haloperidol and related drugs, with a higher risk for development of tardive dyskinesias.

These older neuroleptics have been shown to inhibit complex I activity in direct proportion to their propensity to cause tardive dyskinesia [32]. However, there is no evidence that the newer “atypical” neuroleptics, such as risperidone and quetiapine, which have a low risk for extrapyramidal damage, are contraindicated in children with AMD and other mitochondrial diseases. Indeed one of the commonly used atypical neuroleptics, risperidone, has been shown to possibly against mitochondrial injury via modulation of damaging stress induced calcium influxes into mitochondria [33].

Novel Mitochondrial Drugs

Edison Pharmaceuticals is developing treatments for mitochondrial disease.

EPI - 743
EPI-743 is a drug candidate in clinical development primarily focused on inherited mitochondrial diseases. EPI-743 is administered orally, passes into the brain, and works by regulating key enzymes involved in the synthesis and regulation of energy metabolism.
Through expanded access protocols and prospective clinical trials, EPI-743 has been dosed for more than a cumulative 130,000 patient dosing days (as of November, 2013), and has recorded a favorable human safety profile. Subjects with over 15 discrete diseases have been treated. 

Genetic Dysfunctions

The prevalence of mitochondrial disorders (excluding autism) is estimated to be about 1:8500

and yet it is estimated that 1 in 200 people have a defective gene linked to a mitochondrial disorder. 

This implies a multiple hit mechanism, like we saw with cancer in an earlier post.  It also shows the potential to be misled by genetic information.  Just because the defect is there does not mean it will actually cause anything to happen, further rare events may also be needed to trigger it.

Alternatively, maybe there are far more people with a mitochondrial disease than the above studies suggest.  They are not including people with regressive autism, for one.  Something like 1 in 200 people have regressive autism.

What happened to Dr Richard Kelley?

If you have read the full paper by Dr Kelley you are probably wondering what else he has to say about autism.  He is an extremely rare mainstream clinician who actually does know about the subject.

You might also be wondering how come such a doctor can write about vaccination triggering mitochondrial disease and then autism, albeit in rare cases.

Perhaps this is why he does not write further about autism?

Dr.Kelley's research has focused on the elucidation of the biochemical basis of genetic disorders. Through the application of various techniques of biochemical analysis but especially mass spectrometry, Dr. Kelley has discovered the biochemical cause, and thereby the genetic etiology, of more than a dozen different diseases.

People do write about autism and mitochondrial disease, but some of these researchers are from the fringe and are not taken very seriously by the mainstream.