Muscles

Muscles and PWS

Yes, I suppose whether or not a pathologist considers a biopsy 'negative' depends very much on what he/she is trying to diagnose. I was thinking it would be nice to have someone look at these PWS biopsies from a research perspective (rather than to diagnose a myopathy), and checked the literature and found a study that did show abnormalities in muscle: Muscle histochemistry in the Prader-Willi syndrome. Sone S., Brain Dev, 1994. "In a follow-up study of 259 floppy infants of undetermined cause in my laboratory, 11 patients were later diagnosed as having the Prader- Willi syndrome (PWS). To clarify the pathogenesis of muscle hypotonia in PWS, I examined muscle biopsies by histochemical and morphometric methods and the results were compared with those obtained from floppy infants with only mental retardation but with no other features. The histochemical abnormalities of PWS included (i) fiber size variation of both type 1 and 2 fibers, (ii) type 2 fiber atrophy, (iii) increased numbers of type 2C fibers, and (iv) decreased numbers of type 2B fiber. Although muscle hypotonia in PWS has been thought to be due to central nervous system abnormality, my findings suggest that primary muscle pathology, including muscle fiber immaturity and abnormal muscle fiber type distribution, at least in part, plays a role in muscle hypotonia and weakness."

The PWS pattern is apparently different than some cases of hypotonia due to other disorders; in those cases the type I fiber seemed to be small, in PWS, the type 2 fibers seem small/immature.

Muscle Biopsy

One mother reports that the result of her newborn's muscle biopsy revealed that the mitochondria DNA was fine. The mitochondria respiratory chain > was not. It was explained that their are four different enzymes > that make up this chain. The second one, Complex II, is only > functioning at 30% in the case of her child.

Although it is theoretically possible that he has both PWS _and_ a defect in the enzyme (succinate dehydrogenase aka succinate-coenzyme Q reductase) involved in Complex II, I think that's very unlikely for several reasons:

(1) Complex II defects are very rare.

(2) There are four subunits of succinate dehydrogenase and mutations in one of them (A) often presents as Leigh syndrome (which is caused by a variety of respiratory chain defects due to mutations on chromosomes 2, 5, 7, 9, 10, 11, and 19 and, like PWS, is sometimes responsive to CoQ10). Leigh syndrome is something I've looked at closely in the past few months because of its intriguing overlap with PWS in terms of its symptomology - facial dysmorphism, hypotonia, feeding problems, failure to thrive in infancy, developmental delay, "central" respiratory abnormalities including apnea, nystagmus, encephalopathy and cognitive impairment.[1] That overlap was one of the reasons I kept thinking there has to be a serious problem with energy metabolism in PWS.

(3) Signs of metabolic myopathy have been found in the muscle biopsies of others with PWS.

Given the above, I think it is probable that some level of significant impairment in Complex II activity (most likely in subunit A) is an inherent factor in PWS.

> The puzzling thing is, usually this isn't seen in PWS, per the > neurologist. I brought up the fact that most PWS individuals are not > tested in this manner, right?? He then agreed.

Exactly. Based on what people here have said, muscle biopsies are rare in PWS because they're so invasive. In those few instances when a biopsy is done, if the histological markers (such as ragged red fibers) for one of the already identified myopathies don't show up, everything is typically considered to be "okay" and it's assumed the hypotonia is central (especially after the PWS dx is made). The problem, though, is that impaired respiratory chain function often doesn't show clear pathological changes in muscle tissue or only causes non-specific changes. As a result, it's probably extremely rare for respiratory chain function to be analyzed in PWS.

Anyway, the next step is to find out why Complex II activity is so low. Did the neurologist show any inclination to try to determine that? If not, maybe you could tempt him with visions of glory for being the first to (finally) publish something about impaired mitochondrial function in PWS. :-)

Meanwhile, I'm going to immerse myself in all things Complex II and its upstream processes to see if there is someplace to intervene in terms of improving its activity (aside from CoQ10), because impaired mitochondrial function is a _very_ big deal. (For those not familiar with cellular biology, mitochondria are sort of like little cells (called organelles) inside of muscle cells, brain cells, etc., and are where essentially all of the energy needed for the body to properly function - including muscle contraction, thinking, breathing, neurotransmitter and hormone production, etc. - is produced.)

1. OMIM - http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=256000

Mitochondrial Dysfunction

If I can jump in on the 'mitochondrial dysfunction' bandwagon - I think there is evidence of mitochondrial dysfunction in the mouse model of PWS - which (unfortunately) is not published yet. It is mentioned in the (publicly available) 'lay abstract' from Rob Nicholls project on the metabolic basis of PWS: "....using a mouse model of PWS we have now identified a fetal defect in the pancreas, the organ that produces insulin and other hormones that regulate key energy sources in the body. Similarly, using our PWS mouse model, we have now identified a specific abnormality in the mitochondria, the powerhouse of cells, and that could underlie most or all of the clinical features of PWS. For example, deficient mitochondrial function could explain the hypotonia (poor muscle tone), endocrine dysfunction, and energy metabolism defects that lead to the opposite neonatal failure to thrive and childhood/adult obesity clinical consequences...." http://www.fpwr.org/research/grant/2005/2 This the same mouse model that showed the insulin and glucagon defects.

I agree that even when muscle biopsies are done, they are rarely evaluated for mitochondrial function, so this could easily be missed.

More on Mitochondrial Dysfunction

The results from teh muscle biopsy have finally come in. Contrary to the doctor's initial report of only an impairment in what is called mitochondrial respiratory chain complex II, it turns out that the enzyme activity of all four respiratory chain complexes is impaired. Here is a summary of the findings:

• Complex II (succinate dehydrogenase) activity is the worst at 31% of

mean reference values.

• Complex I (NADH-ferricyanide dehydrogenase) activity is 63% of mean

reference values.

• Complex II III (succinate-cytochrome c reductase) is 68%.
• Complex IV (cytochrome c oxidase) is 63%.
• Citrate synthase (first step in the Krebs energy production cycle)

activity is only 60%.

• There are abnormalities in muscle glycogen and lipid storage,

indicating problems in glucose and lipid metabolism.

• There are some some muscle structure abnormalities such as poor muscle

fiber differentiation and an increased number of mitochondria (some of which are enlarged but otherwise structurally normal).

• There were no mitochondrial DNA mutations or deletions detected, which

means the cause of the abnormal findings lies in nuclear DNA defects, that is, almost certainly the PWS region on chromosome 15.

Overall, the picture is akin to a V-8 engine that is only running on 4 or 5 cylinders. Given that mitochondria are the "power plants" for just about every cell in the body, including in the brain, that's not good news. However, there is also a good news aspect, because mitochondrial impairment is generally more likely to be treatable than central hypothalamic dysfunction and that opens up some potentially exciting possibilities.

One thing that has really struck me while researching other genetic syndromes in which hypotonia is a major feature is how muscle morphology (structure) can sometimes be essentially normal even in the presence of severe respiratory chain deficiencies and other disturbances in mitochondrial function and energy metabolism. Also remarkable is how variable muscle morphology can be even when the exact same genetic mutation or deletion is involved, ranging from essentially normal to severe abnormalities. In other words, the fact that some of the few muscle biopsies on those with PWS came back as supposedly normal does not mean that therefore there is no mitochondrial impairment. Given that, plus the fact that the effects of significant impairment in energy metabolism and mitochondrial function correlate so well with PWS symptomology, I am not inclined to agree with PWS experts who say that impaired mitochondrial function is only present in a small subset (10%) of those with PWS. As the old law school saying puts it, absence of evidence doesn't mean evidence of absence. That is, just because no one has formally studied the question of mitochondrial dysfunction in PWS and announced its presence to the world in a journal article or medical text doesn't mean it's not there. As a result, my working hypothesis is that some level of mitochondrial impairment is probably universal in PWS.

Back in October, Caitlin posted about a "mitochondrial cocktail" of nutritional supplements (including CoQ10 and carnitine) that I believe was suggested by her neuro-geneticist. I am taking a close look at that in an effort to come up with some guidelines for it, including lab tests that can be used to help determine appropriate doses, monitor its effectiveness, etc. It's a pretty complex field of study, so it will take some time to pull all that together. In the meantime, I think CoQ10 and carnitine together are an excellent starting point for those who want to start addressing mitochondrial and energy metabolism issues.

Mitochondrial Links

Given that mitochondrial and metabolic impairment is something that most people probably aren't very familiar with, I thought I'd post some links to some introductory resources to help folks get a handle on the subject.

The Muscular Dystrophy Association has some good articles:

Mitochondrial myopathy: An energy crisis in the cells http://www.mda.org/publications/Quest/q64mito.html

Running on empty - "Keeping Up' With Metabolic Myopathies" http://www.mda.org/publications/Quest/q66metabolic.html

Mitochondrial disease in perspective - symptoms, diagnosis and hope for the future http://www.mda.org/publications/Quest/q65mito.html

Facts About Mitochondrial Myopathies http://www.mda.org/publications/mitochondrial_myopathies.html

From the United Mitochondrial Disease Foundation - http://www.umdf.org/ -

Mitochondrial Cytopathies: A Primer http://www.umdf.org/MITOCYTO.PDF

Mitochondria: An Overview http://www.umdf.org/pdf/Mitochondria-An_Overview.pdf

Anesthesia and Mitochondrial Cytopathies http://www.umdf.org/mitoane.pdf

Emergency room letter for those with mitochondrial dysfunction http://www.umdf.org/pdf/ER_Mito_Letter.pdf

Other resources:

When Mitochondria, the Cell's Energy Producers, Get Sick (thanks to Rachel T for this one :) http://www.myhealthsense.com/F030617_mitochonsdria.html

Mitochondrial Disorders Overview at GeneReviews (a bit more technical) http://www.genetests.org/profiles/mt-overview/index.html