Mitochondrial Disease in the news again

13 Aug

Before I start I want to thank Prometheus who explained this in as plain language as he could. If I’ve made any errors then they’re mine, not Prom’s.

OK, so, as Kristina has already blogged, Mitochondrial Disease has raised its head into the autism world again. A new study has reported that prior to previous thoughts of a prevalence of 1 in 5000, it may actually be as high as 1 in 200.

Of course, that has also prompted a HuffPo post from David who wants to bring our attention to the fact that there are no studies that say that vaccines don’t cause mitochondrial disorder and hence (with the right sort point mutation) autism. David states that prevalence estimates range between 7 and 20% for mito causing autism. That’s not actually correct. In terms of published science its between 4 and 7%. There are suspicions amongst some researchers that it may go as high as 20% but nothing is published yet.

But back to this new study. David _seems_ to be implying that 1 in 200 people with mito disorders means that between 7 and 20% of 0.5% (1 in 200) of people have mito induced autism (0.001% if we go with David’s unpublished 20%).

But that is not the case. This study is not claiming that 1 in 200 people have a mitochondrial induced _illness_ . It is saying that:

In conclusion, at least one in 200 healthy humans harbors a pathogenic mtDNA mutation that potentially causes disease in the offspring of female carriers.

Key phrase – ‘in the offspring’.

According to the UMDF (United Mitochondrial Disease Foundation) there is only a 1 in 4 chance that even two parents who share the same gene mutation (autism in our case) will produce a child affected with the disorder.

So are the study authors claiming that 1 in 200 could have a mito disease? No, they’ve shown that one in 200 people has _a_ mutation in a mitochondrial gene that (_if_ it were homozygous – could lead to a disease).

So, to establish prevalence for a single gene (which theoretically induces autism in our example) we are looking at:

0.005 * 0.005 * 0.25 = 0.00000625 (1 in 160,000)

(0.005 is 1 in 200. 0.25 is 1 in 4).

Thats quite a lot different than 1 in 200.

Reading the study, you’ll find that what the authors found was that 15 of 3168 (0.47%, 1 in 211) newborns they studied had one of ten types of mutation seen in mitochondrial diseases. Of these 15, the authors were able to find 8 maternal blood samples to determine if these were new (de novo) or inherited mutations. Of the eight, three of the mutations (37.5%) were not seen in the mother’s mitochondrial DNA, suggesting that they were new mutations.

Taken altogether, this suggests that – had maternal blood samples been available for all fifteen children with mitochondrial DNA mutations, that 5.6 of them (0.17%; 1 in 568) would have been new mutations.

Note that none of the newborns – even those with mutations in their mitochondrial DNA – and *none of the five mothers who were found to have mitochondrial mutations were reported to have mitochondrial disease*. What the authors mention as their concern is that couples considering having children be made aware of the risks of mitochondrial disease and that testing for the more common mutations leading to mitochondrial disease be available.

Bottom line: having the mutation does not equal having the disease.

This is an unbelievably complicated area. We’re talking as lay people about an area even the experts talk about as barely mapped out. I am not suggesting David intended to mislead people with the 1 in 200 figure I merely want to highlight the fact that it is not as cut and dried as that.

If you liked this post, thank Prometheus. I could not have written it without his generous help.

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10 Responses to “Mitochondrial Disease in the news again”

  1. Orac August 13, 2008 at 13:21 #

    I am not suggesting David intended to mislead people with the 1 in 200 figure I merely want to highlight the fact that it is not as cut and dried as that.

    I am. I think Kirby knows damned well that, even if the study is correct, it does not mean that 1/200 people have mitochondrial disease (has Kirby ever heard of “silent” mutations?) or that their offspring are somehow susceptible to “vaccine-induced autism.” He’s just being David Kirby and laying down an intense screen of B.S. to obfuscate the fact that his claim that vaccines somehow cause or “trigger” autism is the incredible shrinking hypothesis.

    Indeed, your estimate of 1/160,000 that two parents would produce a homozygous mutation is really too high, mainly because that’s for just one gene assuming that the rate of that one mutation is 1/200. The odds are really much lower than 1/160,000.

  2. Genevieve August 13, 2008 at 14:25 #

    I agree. You are being way too nice to Kirby, who knows exactly what kind of distortions he is generating. Perhaps one could give Kirby the benefit of the doubt if the post were taken in isolation, but Kirby has a well established pattern of distortion and manipulation in his “reporting” of scientific studies.

  3. kristina August 13, 2008 at 14:38 #

    “Intent to mislead” is, one sadly suspects, too often a “covert agenda” in all postings Kirbyesque.

  4. alyric August 13, 2008 at 14:59 #

    One point here. Isn’t the conclusion that the potential ‘disease’ wil show up in female carriers? But autism is 4:1 male.

  5. Schwartz August 13, 2008 at 16:05 #

    Alyric,

    It sound like it is children of female carriers which means male or female.

  6. Prometheus August 13, 2008 at 22:26 #

    Not to further muddy the waters, but the study that started all of this “excitement” (Elliot et al, 2008) was looking at mutations in the mitochondrial DNA (mtDNA). Since the mtDNA is not organized into chromosome pairs like human nuclear DNA, there are no heterozygous/homozygous or dominant/recessive genes.

    The mtDNA codes for 37 genes, 22 tRNA’s, 2 rRNA’s and 13 proteins. That’s all. The rest of the genes needed for the mitochondria to function and reproduce are on the chromosomes – they’ve moved there over evolutionary time.

    Because each mitochondrion has between 5 and 12 copies of its DNA and each human cell has somewhere between a few dozen to hundreds of mitochondria, there are a lot of mtDNA copies. And since there are a lot of mitochondria, it is possible to have a mutation – even a serious mutation – in some of them and still have the cell keep running along normally.

    Finally, all of the mitochondria in mammalian (including human) cells come from the mother, so there is no transmission of mtDNA mutations from father to children.

    What was interesting about the study is that they found so many mutations in the mtDNA – more than would have been predicted from the number of people with clinically apparent mitochondrial diseases.

    And what makes this even more interesting is that a lot of mitochondrial diseases are caused by mutations of genes located on the chromosomes, so mtDNA mutations would be expected to cause only a fraction of mitochondrial diseases.

    Of the 15 subjects with mtDNA mutations, 3 had a mutation in the NADH subunit 6 gene (T14484C) – which is associated with Leber Hereditary Optic Neuropathy (LHON). Two had 100% of their mtDNA with this mutation and the other had 89%. Another child had a G11778A mutation in 100% of the mtDNA – this mutation is also associated with LHON.

    The other 11 children with detected mtDNA mutations all had less than 75% of their mtDNA involved; most had less than 10% (median = 10.2%).

    The authors were able to go back and get blood samples from eight of the mothers of the children with mtDNA mutations. Of the three children with 100% of their mtDNA showing mutations, the two mothers (one set of twins) also had 100% of their mtDNA with the same mutation.

    Since the disease associated with these mtDNA mutations (LHON) is manifested in early adult life, it is curious that none of the mothers was reported to have a mitochondrial disorder, especially since one of the authors – Patrick Chinnery – is an expert on LHON. Of course, LHON is only clinically apparent in 50% of the males and 15% of the females with the mutation. Still, with 100% of their mtDNA showing the mutation, it is curious that none of them manifested the disease.

    I have to agree with the authors in their conclusion:

    “Detecting heteroplasmic mtDNA mutations in [greater than] 1 in 200 individuals of the background population has implications for studies reporting mtDNA mutations in specific disease groups. Our data show that putative disease associations, such as the reported high frequency of m.3243A/G in diabetes mellitus could be a chance finding irrelevant to pathogenesis.”

    Perhaps Mr. Kirby should read the entire article before screaming, “The sky is falling!”

    Prometheus

  7. Schwartz August 14, 2008 at 04:33 #

    This is interesting:
    “Since the disease associated with these mtDNA mutations (LHON) is manifested in early adult life, it is curious that none of the mothers was reported to have a mitochondrial disorder, especially since one of the authors – Patrick Chinnery – is an expert on LHON. Of course, LHON is only clinically apparent in 50% of the males and 15% of the females with the mutation. Still, with 100% of their mtDNA showing the mutation, it is curious that none of them manifested the disease.”

    and this:

    “Our data show that putative disease associations, such as the reported high frequency of m.3243AG in diabetes mellitus could be a chance finding irrelevant to pathogenesis.”

    Let’s go back and review some quotes from “experts” oft quoted here talking about mtDNA mutations.

    Dr. Novella:
    “This makes option 4 very plausible – it would be an incredible coincidence if this child just happened to have a mutation in a gene that was known to cause their exact constellation of neurological signs and symptoms and yet the mutation was not the sole or primary cause of those symptoms.”

    Orac:
    “Ultimately, a metabolic disorder, specifically a mitochondrial disorder was suspected, and ultimately confirmed through genetic testing, which showed “a mitochondrial DNA (“mtDNA”) point mutation analysis revealed a single nucleotide change in the 16S ribosomal RNA gene (T2387C).” As part of her course, the child also developed a seizure disorder.”

    Dr. DiMauri:
    “Salvatore DiMauro, who has studied links between autism and mitochondrial mutations at Columbia University in New York, agrees. “My guess is that if she had a mitochondrial mutation, sooner or later she would have shown something abnormal,” he says.”

    This statement is quite correct.
    “Perhaps Mr. Kirby should read the entire article before screaming, “The sky is falling!””

    And I think this applies to a lot of other people too.

  8. Kev August 14, 2008 at 10:11 #

    Call me dumb Schwartz but I don’t get your point.

  9. Schwartz August 14, 2008 at 12:58 #

    The quotes all speak with such certainty that an mtDNA mutation in Hannah Poling would result in mito disorder.

    The quotes from this study and Prometheus show that it is far from a certain thing.

  10. Kev August 14, 2008 at 19:54 #

    Oh, I get you. Thanks.

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