Kuramochi et al (2007) report on "a 16-year old girl with Prader-Willi syndrome who developed cardiac tamponade as an initial finding of systemic lupus erythematosus." Lupus is extremely rare in children, so this is really a notable report that makes me wonder if there is a lupus-like condition in some with PWS, given the unexplained fever spikes, cataplexy-like episodes, photosensitive rashes and blood abnormalities I'm seeing in many of the lab tests. I'll be following this possibility on the new lupus page.

Someone on the HolisticPWS list asked about calcium intake for those PWS and because osteoporosis is a serious issue for many with PWS, I spent some time addressing the question in some detail. [ Read the rest of this entry ]

Several weeks ago I received an e-mail from a mother with a 4-year-old son who was initially diagnosed with a congenital disorder of glycosylation (CDG) based on a finding of elevated asialotransferrin. Shortly thereafter the genetic diagnosis of PWS/UPD was made and the CDG diagnosis was dropped with the parents being told the elevated asialotransferrin was a "red herring" that probably didn't mean much although it could be something that hadn't been noticed before in PWS. That of course was a clear indication that CDGs needed to be looked into. [ Read the rest of this entry ]

A new study found that 24% of females with PWS due to UPD have what's called X-chromosome inactivation skewness, which means they are at increased risk for X-chromosome-linked disorders. For an explanation of X-chromosome skewness, see here.

Another muscle biopsy report, this one for a two-week-old boy subsequently diagnosed with PWS due to UPD has been added to the muscle biopsy page. The new biopsy report, like the other one (also from an infant with PWS/UPD), lends further weight to the suggestion that mitochondrial dysfunction is probably common in those with PWS.

The Hypoventilation and Apnea in PWS article has been updated to recommend that a polysomnography should be performed promptly following the diagnosis of PWS. In addition, the following was added to the article:

Tips for infant sleep studies

• Have the sleep technician hook up all of the sensors before the child goes to sleep (I know of at least one infant's PSG that was botched because the tech said to let her go to sleep first, but then the baby woke up while the sensors were being attached and never went back to sleep again).
• If a CPAP test is going to be performed during the PSG, make sure beforehand that they have an infant-sized mask (for example, one of the highest regarded pediatric sleep study programs in Los Angeles didn't have a mask small enough for a 9-month-old).
• If a CPAP test is going to be done during the PSG, try to get a mask several weeks ahead of time so that you can desensitize the child to it beforehand because many infants and small children will react with terror to the sense of breath claustrophobia caused by a mask, which is exacerbated when the CPAP machine is turned on because of the strong air flow. Start out with brief periods of playing with the mask, such as putting on yourself, a teddy bear or doll and then the child, and try to work up to where the child will tolerate wearing the mask for at least several minutes. If you can't get a CPAP mask, you might instead try using a filter mask like those available at Home Depot, etc. Also, try to get the child used to the sensation of a pretty strong air stream against their face by blowing on them, starting with gentle puffs and working up to strong blowing, especially around their nose. You might also try something like directing the air from a small aquarium air pump around their face. Do NOT point the airflow directly at the eyes, though!

The following is the first paragraph of a new page on functional protein starvation and PWS that has been added to the Research Notes section:

My interest in the relationship between Prader-Willi syndrome (PWS) and functional protein starvation arose when I reviewed the NICU lab test results for a neonate subsequently diagnosed with PWS due to UPD and found very low levels of albumin and total protein, hypoaminoacidemia, and other results suggestive of a severe functional protein deficiency. The protein deficiency is functional because the neonate was receiving adequate nutrition, but due to a probable severe impairment in glucose and fatty acid metabolism was forced to shift to massive protein catabolism in order to obtain amino acids for oxidation (energy production) in order to survive. The table below correlates the symptomology and laboratory findings between protein starvation and PWS. Below the table is a collection of relevant research abstracts. [ Visit this page ]

An acylcarnitine profile for an 11-month-old boy and a table with lab test results shared by a number of parents have been added over the past week, as have many research abstracts. Also, various pages in the research notes section have been added or supplemented with new material.

My friend inadvertently bought some L-carnitine fumarate for use with her baby with PWS and it looks like it might provide significant benefits beyond those provided by other forms of carnitine. She reports that her baby is noticeably stronger, more energetic yet calmer, smiling and talking/babbling more, showing more curiosity, and reacting to things quicker than she was on the previous combination of acetyl and L-carnitine [tartrate]. The difference may lie in the fumarate, which is a substrate in the Kreb's cycle for the mitochondrial production of energy. The following is an adaption of a post to the HolisticPWS list about L-carnitine fumarate. [ Read the full entry ]

Scattered throughout the medical literature about Prader-Willi Syndrome (PWS) are a number of reports of the occurrence of rapid deterioration during seemingly minor illnesses, as well as during or following surgery, including the development of sepsis-like conditions and sudden unexpected death (SED). Although the literature is mostly silent on the point, it appears that mitochondrial disorders, including respiratory chain transport deficiency, are common (if not universal) in PWS. Interestingly, rapid deterioration during minor illness and the development of sepsis-like conditions, including SED, are also relatively common in other genetic syndromes where mitochondrial respiratory chain transport is impaired, such as Leigh syndrome, Kearns-Sayre syndrome, etc.

Today I came across some recent research that helps to explain why those with PWS and other genetic syndromes characterized by impaired mitochondrial function are so vulnerable to minor illnesses, as it turns out that the body's inflammatory responses to infection can set off a whole cascade of events that results in a major reduction in mitochondrial respiratory chain activity. That's obviously not good in someone who already has significant mitochondrial impairment and helps to explain why those with PWS can have such potentially catastrophic reactions to even a mild respiratory infection. The good news is that research has found that acetyl-l-carnitine, vitamin C and other substances have remarkable protective effects against the collapse of respiratory chain activity in sepsis. So I have another article in the works about a supplement protocol for use when those with PWS come down with a cold, flu or other infectious illness. [Update: see Sepsis-like Conditions and Mitochondrial Function in PWS.]

One of the mothers on the HolisticPWS list finally received the results from a muscle biopsy performed when her son was 16-days-old. Enzyme activities in all four mitochondrial respiratory chain complexes are impaired. Complex II (succinate dehydrogenase) is the worst at 31% of mean reference values, while Complex I (NADH-ferricyanide dehydrogenase) is at 63%, Complex II + III (succinate-cytochrome c reductase) is at 68%, and Complex IV (cytochrome c oxidase) is 63%. Also, citrate synthase (first step in the Krebs enerygy production cycle) is only 60%. There are also abnormalities in muscle glycogen and lipid storage, indicating problems in glucose and lipid metabolism, as well as some muscle structure abnormalities such as poor muscle fiber differentiation and an increased number of mitochondria. There were no mtDNA point mutations or deletions detected, which means the cause lies in nuclear DNA defects, that is, the PWS region on chromosome 15. A copy of the biopsy results is posted here.

Normally it would be strange to say this, but in some ways this actually good news because impairments in mitochondrial function and energy metabolism are generally more treatable than a "central hypothalamic dysfunction." I will be writing much more about this, but in the meantime I feel pretty confident in recommending that any parent of a child with PWS ask their pediatrician for referral to a metabolic specialist. Parents may also want to print out a copy of the biopsy results and the Stefan 2005 study about impaired energy metabolism in PWS as background material for their pediatrician and other health care providers.

The mother of a young man with PWS reports that when he was 19, growth hormone treatment was ended, apparently without tapering down the dose. Over the next three weeks he became psychotic, delusional and aggressive with clammy sweats, rapid heartbeat, insomnia and vomiting, all of which are symptoms of low blood sugar (hypoglycemia), a diagnosis confirmed by emergency room testing. All of his symptoms resolved within a day after growth hormone treatment was reinstituted. GH stimulation tests when he was younger had shown severe GH deficiency. The following is an adaption of a post I wrote for the HolisticPWS list about a possible explanation for why the young man developed such severe hypoglycemia when GH treatment was ended. [ Read the full entry ]

In the Stefan 2005 PWS mouse model, essentially nil glucagon levels lead to severe hypotonia and poor suck due to profound energy starvation caused by the failure of gluconeogenesis. Since glucagon also signals for the mobilization of triglycerides from peripheral tissues, the pups are unable to access fat stores for energy production. As a result, the neonate mice are entirely reliant on fatty acid oxidation of lipids directly obtained from nursing. All of this makes me wonder if expression of genes involved in the muscles' use of glucose becomes somewhat permanently down-regulated in PWS and, as a result, muscle uptake and utilization of glucose for energy is impaired. That in turn makes me interested in the use of creatine as a way to increase muscle glucose uptake, as it has been used with some benefit for certain mitochondrial myopathies (e.g., Beneficial effects of creatine, CoQ(10), and lipoic acid in mitochondrial disorders (2006) and Nutritional cofactor treatment in mitochondrial disorders (2003)).

Today I added a very interesting study, Creatine supplementation increases glucose oxidation and AMPK phosphorylation and reduces lactate production in L6 rat skeletal muscle cells (2004), that found that "creatine supplementation does not alter insulin-stimulated glucose uptake and glucose metabolism; however, it activates AMPK, shifts basal glucose metabolism towards oxidation and reduces lactate production in L6 rat skeletal muscle cells." Something more to investigate and ponder.

There is likely to be an impairment of fat metabolism in PWS, but I think there also might be a significant impairment in glucose metabolism, especially gluconeogenesis (the making of new glucose by the liver from fats and amino acids). That suspicion initially arose because of the neonatal presentation of profound hypotonia and mental and physical lethargy which, in the absence of any of the known inborn errors of metabolism, suggests either severe hypoglycemia or hyperammonemia. I haven't been able to find any suggestion of neonatal hyperammonemia in the PWS literature, but have found a few scattered hints at hypoglycemia. What really strengthened my suspicion about impaired glucose metabolism in PWS, though, was an Oct. 2005 article in the journal Endocrinology by Stefan et al, Hormonal and metabolic defects in a Prader-Willi syndrome mouse model with neonatal failure to thrive. If folks haven't read it yet, I really recommend doing so, as my sense is that it may represent the most important research into PWS to date. Basically what they did was develop transgenic mice in which the PWS region was deleted and then monitored the energy metabolism of fetal and newborn pups. This is what they found: [ Read the full entry ]