2007-04-17 - Is there a congenital disorder of glycosylation-like process in PWS?

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.

CDGs are the result of defects in what's known as glycosylation in which carbohydrate chains consisting of combinations of mannose, glucose, galactose, and other sugars are attached to proteins. Among other things, the carb chains help the protein fold properly so it can act as an enzyme, signaling molecule or receptor. There are two broad types of CDGs. Type I CDGs are the result of defects in the assembly and transfer of the carb chains to the protein; as a result the carb chains are completely missing from the protein. Type II CDGs are the result of processing errors after the carb chain has been attached to the protein, so its carb chains are structurally abnormal. From what I've been able to determine, elevated asialotransferrin is only found in type I CDGs. (The a-sialo means the transferrin protein has no sialic acid carb chains.)

The high asialotransferrin and initial CDG diagnosis are very interesting for several reasons:

1. Aside from CDGs, asialotransferrin is typically elevated in alcoholism, which is why it's used as a diagnostic marker for chronic alcohol abuse.
2. Aside from elevated asialotransferrin (in type I), some of the symptoms and signs of CDG include -
   • clotting problems (including diagnosis of Von Willebrands)
   • other blood abnormalities (neutropenia, thrombocytopenia - evident in PWS NICU lab tests)
   • recurrent infections
   • obesity
   • lipomas and abnormal fat distribution (evident in PWS around the wrists)
   • transiently elevated liver transaminases (AST, ALT - evident in PWS lab tests)
   • hypoproteinemia (evident in PWS lab tests)
   • hypoalbuminemia (low serum albumin - evident in PWS lab tests)
   • hypotonia
   • lethargy
   • ataxia
   • eye anomalies (strabismus, myopia)
   • feeding problems including swallowing difficulties and reflux
   • failure to thrive
   • digestive problems (protein-losing enteropathy, malaborption, steatorrhea)
   • seizure disorders (common in PWS)
   • stroke-like episodes
   • cognitive impairment
   • developmental delays
   • speech delays and other speech-related problems
   • skeletal abnormalities, including scoliosis and kyphosis
   • clinodactyly
   • osteopenia (common in PWS)
   • hypoglycemia (probably more common in PWS than is recognized)
   • hypothyroidism (one study found 19% incidence in PWS)
   • hepatic steatosis (reported in PWS)
   • slow growth
   • hypogonadism
   • almond-shaped eyes
   • reduced fetal movement
   • mild intrauterine growth retardation
   • cryptorchidism
   • inverted nipples
   • bowel movements described as being like battery acid, burning holes in the skin and smelling like baked bread (which may help explain the reports of severe diaper rash in some infants on CF).
   • reduced alpha-mannosidase (in type IA). A recent whole genome assay of gene expression in PWS found a 1.6-fold reduction in expression of the MAN1B1 gene that codes for alpha-mannosidase class 1B member 1. A deficiency of any of the cytostolic or lysomal forms of alpha-mannosidase typically results in the intracellular accumulation of mannose-containing oligosaccharides used in protein glycosylation, thereby causing alpha-mannosidosis, a disorder that also has some interesting overlaps with PWS symptomology, including -
     • gingival hyperplasia (found in some with PWS)
     • emotional, behavioral and psychiatric problems, including an increased incidence (25%) of psychotic episodes (common in PWS)
     • ataxia
     • skeletal dysmorphisms (dysostosis multiplex), including scoliosis, kyphosis and hip dysplasia
     • immune deficiency and frequent infections
     • neurocognitive impairment and learning problems
     • developmental delays, including delayed speech
     • hearing impairment and speech problems
     • facial dysmorphias
     • short stature
3. A PubMed search on mannosi* + asialotransferrin turns up empty, suggesting that elevated asialotransferrin is not a feature of alpha-mannosidosis and so although there may be a relatively mild alpha-mannosidosis-like condition in PWS due to down-regulated MAN1B1, elevated asialotransferrin in PWS would probably be due to a more general, CDG-like impairment of the pathways that synthesize and catabolize glycoproteins (or increased endogenous alcohol synthesis). That's significant because glycosylated proteins play a huge role in the body, including G-proteins (important part of the body's signaling system), immune system, skeletal development (e.g., cartilage formation, chondroitin sulfate (a glycoprotein), bone mineralization), and hormones (follicle stimulating hormone, luteinizing hormone, thyroid stimulating hormone, human chorionic gonadotropin, alpha-fetoprotein and erythropoietin (EPO) are all glycoproteins). CDGs as diagnostic entities are relatively new, so new types are still being identified and the underlying genetic defects still have not been determined for some types. As a result, CDGs are probably significantly underdiagnosed.
4. Interestingly, the following article came up while researching alpha-mannosidosis at PubMed, which hints that a possible link between it and PWS may have been noticed 40 years ago -
   Acta Paediatr Scand. 1968.
   The Prader-Labhart-Willi syndrome: review of the literature and report of nine cases.
   Dunn HG.
   No abstract available.

I've collected abstracts about CDGs here and have also collected abstracts about alpha-mannosidosis

At least one type of CDG (Ib) can be successfully treated with mannose supplementation. Also, several older articles mention that zinc and cobalt increase alpha-mannosidase activity in vitro; a later article found that off-and-on use of zinc in two patients for 10 years did not seem to result in "substantial" benefit but the same may not be true in PWS (besides, I think any type of possible benefit, substantial or not, is worth investigating). The reference to cobalt also makes me wonder if the reported benefit of methylcobalamin (methyl B-12) shots for at least one boy with PWS is the result not of the B-12 but the cobalt contained therein increasing alpha-mannosidase activity. (Alternatively, the in vitro cobalt-induced increase in alpha-mannosidase activity might have been the result of increased B-12 activity.) In addition, enzyme replacement studies are being conducted in guinea pig models of alpha-mannosidosis.

Capillary zone electrophoresis for carbohydrate-deficient transferrin is typically used for the initial diagnosis of CDGs, however it is not performed by most labs.