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
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.
