Muscles

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.