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.


  1. Interesting write-up, I didn't know that mitochondrial deficiency could have a role in autism. I guess that is why mitochondrial disease testing is becoming more popular. I think it is great we have more science based tests like this now to test for abnormalities.

  2. Hi again! My son who has Asperger's and Tourettes is on Risperdal. Is it plausible that Risperidone can harm a child who may have mitochondrial deficiency? Whenever i tried to even reduce it the tics come back with more severity! Any other options?

  3. Georgia, here below is a very good paper all about tic disorders

    The Management of Tics

    It looks like Clonidine is effective in 50% of cases, This drug is also used to treat autism. You need to find out what dysfunction causes the tics, this may be a case of trial and error. Then you can choose the safest drug that is effective, it probably is not Risperidone. I do not know about its use with mitochondrial dysfunctions, but it doe seem to be a drug with many problems.

    In autism, stimming is usually caused by oxidative stress. The tic could also be made worse by oxidative stress. I would try NAC and see if it helps.

    Read that paper, it gives details on all the drugs used and their dosage.

  4. Hi Peter, iam impressed with this post regressive autism and mitochondria, is all about my son, i remembered his autistic syintoms installed from one day to the other, like a nightmare, i remeberd he sang and danced before that. A News Medical article says that mitochondrial dysfunction was evaluated in lymphocytes form 10 children with autism, findings include mitochondrial dependant oxygen consumption being impaired in lymphocytes and increased cellular oxidative stress. I want to know your opinion of all that, if this is my son¨s case, he was treated with the opposite, valproat ande rispedal are the main toxins! may be is too late.valentina

    1. Valentina, you can do laboratory tests for mitochondrial disease. So if you are worried about it, do the tests. It is an accepted medical condition.

    2. Peter, the hematologist told me that the great loss of lymphocytes is due to an intoxicaton with valproate, and it must be suspendend. Imagine that when i got the lab results, terrible things crossed may mind, in a way, this was expected. Thinking about my son's kind of autism and his electrical activity, what would you use to replace it, what options would be? I think that an antiepileptic drug is too much, but i dont know. I apreciate your help, and sorry for my english. valentina

    3. You could discuss with the neurologist very gradually stopping valproate and start bumetanide. Clearly valproate is not good for your son in the long term.

  5. I have read this post a number of times with great interest and decided to do a trial of L Carnitine. I was fascinated to see that on the days my 8 yo has L Carnitine he is behaviourally excellent. He has shown hugely improved attention, focus and even started using adjectives in his speech.

    This intrigues me because while I have always described my son as having classic autism perhaps I am wrong and I have been using the incorrect description. 4 years ago he was diagnosed as having PDD NOS. Under the old DSM he was given this diagnoses because he didn't exhibit rigid or repetitive behaviours but he did have the social and communication delay. However, after reading the above post I remember very clearly an incident that happened during pregnancy which would have been the first 'hit'. Before the age of 12 months I remember him pointing to the ceiling and saying 'light'. Then around the age of 12 months I remember him becoming sick with a virus, just a run-of-the-mill virus, nothing special, but I remember that afterwards he changed his eating habits and stopped eating a wide variety of foods, eye contact gradually diminished, language grew very slowly. He never obviously regressed (because he was still so young at the time) but his development did plateau. At the time I thought it was just his personality.

    His positive response to L Carnitine has made me rethink a lot. Perhaps he does have some underlying mitochondrial dysfunction and I should try more of the mito antioxidants.

    I tried broccoli sprouts a number of times and each time they had a negative effect and caused further irritability.

    1. Did you try NAC and did it have a negative impact? It seems that some people have reductive stress, which is the opposite of oxidative stress. It is just an imbalance in the opposite direction. Reductive stress is associated with mitochondrial dysfunction and increased reactive oxygen species (ROS) production. It does get complicated and somewhat counter intuitive.

      In theory if you has reductive stress, an oxidant should make you feel better. So if NAC makes you feel worse, paracetamol should make you feel better.

  6. It does get very complicated. I tried fluimucil and pharmaNAC. Initially I thought I saw a slight improvement after a dose of fluimucil in terms of more initiative but that only lasted one day. I continued with fluimucil hoping to see benefits and then I switched to pharmaNAC 900mg and I never made it anywhere near the doses used in the Stanford trial. At the time we were struggling with terrible anxiety and panic attacks. In fact his anxiety was bordering on out of control. I was living in a constant state of nervous tension. I ditched the NAC and changed to propranolol and experienced instant relief.

    It never crossed my mind until now that the NAC could have been making him worse.

    1. Studies show that the great majority of "autism" are associated with oxidative stress. But several people have told me that NAC made things worse and a few of those said the broccoli made things worse. Those cases almost certainly had no oxidative stress, perhaps they were just "right", but likely they were in reductive stress. Reductive stress is a known condition, just not written about much.

      If you had reductive stress you would want to do the opposite of what I am doing with my son. So reduce GSH and do not active the antioxidant genes via Nrf2.

      In the lab tests, they would measure GSH and GSSG.

      In my son there is too little GSH and too much GSSG.

      In reductive stress there would be too much GSH and too little GSSG.

      Or it could be that the Glutathione peroxidases (GPx), whose job is too protect from oxidative damage, are just over activated.

      One reader whose non-verbal child responded negatively to NAC and broccoli, had responded very positively years previously to three doses of MMS, by which I assume she means bleach. Sodium chlorite (NaClO2) is a potent oxidant, but clearly a harmful substance.

      I suggested to her that he son might have the opposite of oxidative stress.

      Autism is actually full of opposites, big heads and small heads, high cholesterol and low cholesterol, high growth factors and low growth factors.

      The safe known OTC oxidant that lowers GSH is paracetamol/acetaminophen. If this improves behavior then it really looks like reductive stress.

  7. I feel like we are starting to make progress now, albeit in a roundabout way, with lots of trial and error, and of course reading your blog. At least I have a better idea of what to avoid.

    It is always a challenge to hear that what your child needs is likely the opposite to what many other people need. But that is the nature of autism, I guess.

    The next test will be to give him a dose of paracetamol and see if he has a good day, but I think I already know what the answer to that will be.

  8. Peter do you know if there is a connection between deficiency in enzyme G6PD and mitochondrial disease? My hypothesis may be irrelevant but I thought I should know.

  9. Petroula, if you read the link below you will see all about G6PD deficiency. It is very common and since it so directly affects oxidative stress it will affect mitochondria to some degree.


    Glucose-6-phosphate dehydrogenase (G6PD) is a key enzyme in the pentose phosphate pathway that generates NADPH and reduced glutathione (GSH). G6PD is essential in maintaining the redox equilibrium to handle oxidative stress, especially in erythrocytes.

    Over 400 million people worldwide have G6PD deficiency resulting from point mutations in G6PD. There are over 160 known point mutations, which give symptoms ranging from chronic non-spherocytic hemolytic anemia (Class I) to almost no clinical manifestation (Class IV). Some mutations reduce catalytic activity, while other mutations reduce the stability of the enzyme without affecting the catalytic activity.G6PD functions as a dimer and a tetramer. In addition to the catalytic NADP+, G6PD also binds a second NADP+ far from the active site. Once the G6P substrate is bound, this structural NADP+ may migrate to the catalytic site. The structural NADP+ is essential for enzyme function, and many Class I mutations are found near the structural NADP+ site.

    Our lab aims to find small molecules that correct G6PD mutations by increasing the catalytic activity and/or stability of the mutant enzyme. This project involves characterizing the stability and activity of mutant G6PD in vitro, in cell culture, and in vivo models. We plan on conducting a high-throughput screen to identify molecules that can correct G6PD mutations.

  10. I came across this interesting titbit from a group looking at a cellular model of Parkinson's & the effect of Alpha Lipoic Acid & Acetyl L Carnitine:

    "when combined, LA and ALC worked at 100-1000-fold lower concentrations than they did individually"

    The cocktail above contains both but maybe sometimes we need more than one to get the best effect..

  11. Oops, think I forgot the link, if not delete this comment:


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