Mitochondrial dysfunction and autism

Beautiful pic of mitochondria

Mitochondria are the powerhouses of the cell, the biology teachers will tell you. These organelles also happen to be likely former bacteria that once were independently living cells, capable of dividing on their own to make new mitochondria. Indeed, they continue to divide by a kind of binary fission as our cells divide, ensuring that a double dose is available for partitioning into the two new cells that result from cell division.

To achieve these feats, mitochondria have their own DNA, their own proteins, and their own protein-making machinery. That means that they also have the potential to undergo genetic mutations that affect the sequence of the proteins their genes encode. Because most of the proteins in mitochondria are mission critical and must function exactly right, the persistence of such mutations is relatively rare. But they do happen, causing disease. One question that has arisen in the study of the causes of autism is whether or not such changes might underlie at least a portion of the cases of this developmental difference.

The high-profile Hannah Poling case

Certainly lending a high profile to this question was the case of Hannah Poling, whose mitochondrial disorder appeared to be linked to her autism symptoms and may have interacted with a bolus of vaccine doses she received, followed by a high fever. Fevers can tax our cellular powerhouses, and if mitochondrial function is already compromised, the high temperatures and extra burden may result in chronic negative outcomes.

Poling’s case brought to the forefront the question of whether or not people with autism might have mitochondrial dysfunction at greater rates. A recent study in the Journal of the American Medical Association (which steadfastly keeps its articles unavailable behind a paywall) has sought to address that question by measuring markers of mitochondrial dysfunction in children with autism and comparing these endpoints with outcomes in children without autism.

Study specifics: “Full-syndrome autism”

The autistic group in the study had what the researchers called “full syndrome autism,” which I take to mean intense symptoms of autism. They used the Autism Diagnostic Inventory-Revised

(ADI-R) and the Autism Diagnostic Observation Schedule (ADOS) to confirm this diagnosis and to ensure as uniform a population among their autistic group as possible. Ultimately, the study included 10 children in this group, recruited consecutively in the clinic based on their fulfillment of the selection criteria. This study was essentially case control, meaning that the control group consisted of 10 non-autistic children, selected to match as closely as possible the demographic characteristics of the autistic group.

The authors report that while only one child among the 10 who were autistic fulfilled the definitive criteria for a mitochondrial respiratory chain disorder, the children with autism were more likely to have indicators of mitochondrial dysfunction.

A problem with pyruvate dehydrogenase (break out your Krebs notes, folks)

Specifically, six out of ten showed lowered levels of activity for one parameter, while eight out of ten showed higher levels than controls for another metabolic endpoint, and two of ten showed higher levels than controls of a third metabolic endpoint. Overall, the results indicated low activity of a mitochondria-specific enzyme, pyruvate dehydrogenase, which is involved in one of the first steps of carbohydrate metabolism that takes place in the mitochondria. Reduced activity of an enzyme anywhere in this process will result in changes in the enzyme’s own products and products further down the pathway and throw off mitochondrial function. Further, half of the autistic group exhibited higher levels of DNA replication, an indicator of cellular stress, more frequently than controls and also had more deletions in their DNA than controls. Statistical analysis suggested that all of these differences were significant.

What does it mean for autism?

Do these findings mean that all or most people with autism have mitochondrial dysfunction? No. The study results do not support that conclusion. Further, the authors themselves list six limitations of the study. These include the possibility that some findings of statistical significance could be in error because of sample size or confounders within the sample and that there were changes in some of the endpoints in the autistic group in both directions. In other words, some autistic children had much higher values than controls, while some had lower values, muddying the meaning of the statistics. The authors note that a study like this one does not allow anyone to draw conclusions about a cause-and-effect association between autism and mitochondria, and they urge caution with regard to generalizing the findings to a larger population.

If there is an association, questions arise from that conclusion. Does mitochondrial dysfunction underlie autism, producing autistic-like symptoms, as some argued in the Hannah Poling case? Or, do autistic manifestations such as anxiety or high stress or some other autism-related factor influence the mitochondria?

Chickens, eggs, MRI, mitochondria, autism

As interesting as both of these recent autism-related studies are, we still have the “Which came first” question to deal with. Did autism cause the brain or mitochondrial differences, or did the brain or mitochondrial differences trigger the autism? Right now, these chicken-and-egg questions may not matter as much as the findings do for helping to identify autism more specifically and addressing some of its negative aspects. Regardless of your stance on neurodiversity or vaccine or acceptance or cure or the in-betweens where most of us fall, it would be difficult to argue that a mitochondrial dysfunction shouldn’t be identified and ameliorated or that an awareness of brain structure differences won’t lead to useful information about what drives autism behaviors.


Note: More lay-accessible versions of this post and the previous post are available at BlogHer.

Genetic analysis: my results and my reality

A few months ago, it was National DNA Day or something like that, and one of the genetics analysis companies had a sale on their analysis kits, offering a full panel of testing for only $100. Giddy with the excitement of saving almost $1000 on something I’d long been interested in doing, I signed on, ordering one kit each for my husband (a.k.a. “The Viking”) and me. Soon, we found ourselves spending a romantic evening spitting into vials and arguing about whether or not we’d shaken them long enough before packaging them.

The company promised results in six weeks, but they came much faster than that, in about three weeks. Much to my relief, I learned that neither of us carries markers for cystic fibrosis and that I lack either of the two main mutations related to breast cancer. Those basic findings out of the way, things then got more complex and more interesting.

How it works

First, a bit of background. These tests involve sequencing of specific regions to look for very small changes, a single nucleotide, in the DNA. If there is a study that has linked a specific mutation to a change in the average risk for a specific disorder or trait, then the company notes that. The more data there are supporting that link, the stronger the company indicates the finding is. Thus, four gold stars in their nomenclature means, “This is pretty well supported,” while three or fewer slate stars means, “There are some data for this but not a lot,” or “The findings so far are inconsistent.”

Vikings and Ireland

The Viking is a private person, so I can’t elaborate on his findings here except to say that (a) he is extraordinarily healthy in general and (b) what we thought was a German Y chromosome seems instead to be strictly Irish and associated with some Irish king known as Niall of the Nine Hostages. Why hostages and why nine, I do not know. But it did sort of rearrange our entire perception of his Y chromosome and those of our three sons to find this out. For the record, it matches exactly what we learned from participating in the National Geographic Genographic project. I’d ask the Viking if he were feeling a wee bit o’ the leprachaun, but given his somewhat daunting height and still Viking-ish overall demeanor (that would be thanks to his Scandinavian mother), I’m thinking he doesn’t. Lord of the Dance, he is not.

Markers that indicate an increased risk for me

I have an increased risk of…duh

Looking at the chart to the left (it’s clickable), you can see where I earned myself quite a few four gold stars, but the ones that seem most relevant are those with a 2x or greater increased risk: lupus, celiac disease, and glaucoma. The first two do not surprise me, given my family’s history of autoimmune disorders.

If you focus on a list like this too long, you can start to get a serious case of hypochondria, worrying that you’re gonna get all of these things thanks to those glaring golden stars. But to put it into context, for the lupus–for which my risk is 2.68 times higher than a regular gal’s–that still leaves me in the population in which 0.66 persons out of every 100 will develop this disorder. Compare that to the 0.25 out of every 100 in the regular-gal population, and it doesn’t strike me as that daunting.

Some of those other things on there? Well, let’s just say they’re close. My risk of thyroid cancer might be raised…but I no longer have a thyroid. Hypertension risk is increased–and I have stage 2 hypertension. Gallstones, gout, alcholism, asthma…based on family history, it’s no surprise to me to see some mixed or clear risk involved with these, although I have none of them. Does that mean that someone else with these increased risks will have related real-life findings? No. It only means that you’re at a bit more risk. It’s like riding a motorcycle vs. driving a car. The former carries more risk of a fatal wreck, but that doesn’t mean you’re absolutely gonna die on it if you ride it.

Disorders for which my risk is allegedly decreased

I have a decreased risk of...

None of my decreased risk findings are very eye catching in terms of actual drop in risk except for Type II diabetes (now where is my bag of sugar?). As I have been under evaluation for multiple sclerosis and have a family member with it, it’s interesting to see that my risk for it, based on existing studies and known polymorphisms, is decreased. And even though I know that much of this is largely speculative and based on little firm data, it’s still sort of comforting to see “decreased risk” and things like “melanoma” in the same group.

Don’t make my brown eyes blue!

And they didn’t. They nailed the eye color and other trait-related analysis, such as level of curl to the hair, earwax type, alcohol flush reaction, lactose intolerance (unlikely), and muscle performance (I am not nor have I ever been a sprinter). And even though I do not have red hair, they reported that I had a good chance of it, also true given family history. I am not resistant to malaria but allegedly resistant to norovirus. I wish someone had informed my genes of that in 2003 when I was stricken with a horrible case of it.

Ancestral homeland

Yep. They nailed this one. One hundred percent European mutt. Mitochondria similar to…Jesse James…part of a haplogroup that originated in the Near East about 45,000 years ago then traveled to Ethiopia and Egypt and from there, presumably, into Europe. It’s a pretty well traveled haplotype and happens to match exactly with the one identified by the National Geographic Genographic project. When it comes to haplotypes, we’re batting 1000.

In summary

Some of these findings are reliable, such as the absence of the standard breast cancer mutations or the presence of certain mutations related to autoimmune disorders, while other findings are iffy. The company duly notes their iffiness  in the reports, along with the associated citations, polymorphisms, and level of risk identified in each study. They don’t promise to tell you that your ancestors lived in a castle 400 years ago or hailed from Ghana. From this company, at any rate, the results are precise and precisely documented, and as I noted, pretty damned accurate. And they’re careful to be a clear as possible about what “increased risk” or “decreased risk” really means.

It’s fascinating to me that a little bit of my spit can be so informative, even down to my eye color, hair curl, and tendency to hypertension, and I’ve noted that just in the days since we received our results, they’ve continually updated as new data have come in. Would I be so excited had I paid $1100 for this instead of $200? As with any consideration of the changes in risk these analyses identified, that answer would require context. Am I a millionaire? Or just a poor science writer? Perhaps my genes will tell.

Turkey taming happened twice

The taming of the turkey

It’s not unusual for our domesticated familiars to have gone through several cycles of domestication. In the Old World, pigs and sheep and cows submitted to the process several times. But the New World has only a few examples of its own homegrown domesticates, and now, thanks to some fossilized poop, we can trace the taming of the turkey.

Mitochondria and coprolites

Using coprolites–that’s the poop–and mitochondrial DNA, researchers describe in a study published in PNAS having nailed down the domestication of the turkey in the American Southwest. The previous idea was that the turkey was like beans, maize, and squash–it made its domesticated way to the Southwest by way of trade routes from southern Mexico. Indeed, in southern Mexico, indigenous peoples had domesticated their own version of the bird.

But the southwesterners had their own version, too, and mitochondrial DNA–which passes from mother to offspring and accumulates mutations at a slow, predictable rate–shows that their turkeys came from a different species.

Modern turkeys are imports

You might think that the turkeys around today came from one or the other of these turkey lines, so carefully bred 2000 years ago. Nope. Europeans showed up, took some turkeys back to Europe. There, other Europeans produced some deeply inbred turkeys that then made their way via import back to the Americas. The turkeys we eat today, the ones that make the centerpiece around a Thanksgiving table or in a Sarah Palin interview, may trace back to southern Mexico, but they’re now really inbred European imports. Good thing Ben Franklin didn’t get his way when he allegedly proposed the turkey as the national bird for his fledgling nation.

Ideas for questions

Why do you think mitochondrial DNA accumulates mutations more slowly than, say, nuclear DNA?

Explain why mitochondrial DNA passes only from mother to offspring.

How do you think the researchers could tell whether or not turkeys were inbred?

Coprolites are trace fossils, while fossilized bones are body fossils. What are other examples of trace fossils? What can these trace fossils tell us in the absence of body fossil information?

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