Farewell, UCD label

Question: Do all urea cycle disorders result in excess plasma ammonia?

Answer: yes.  Which kind of makes sense, but I had to confirm it.

So, where to from here?  We discard the "UCD" label, and start looking at the broader category of protein metabolism disorders.  That can probably be referred to just as "amino acid disorders", since they describe problems that happen after proteins have been broken down.  Best known is PKU, but I was screened for that at birth.  There is also Maple Syrup Urine Disease (BCKD deficiency), which is an inability to process the valine family (valine, leucine, isoleucine) which is common in animal products.

Those are two of them.  There's a whole host of others; understandable, given how many amino acids we deal with.  These include:

Branched chain amino acid disorders

• Isovaleric acidemia (leucine): creates a sweaty smell
• Propionic acidemia 
• Maple Syrup Urine Disease

Methionine metabolism disorders (homocysteineuria and related sulfur metabolism problems)

Tyrosine metabolism disorders

• Tyrosinemia type I
• Tyrosinemia type II
• Alkaptonuria

D-glyceric aciduria 

Iminoglycinuria (proline, hydroxyproline, glycine)

Guanidinoacetate methyltransferase deficiency

Hyperprolinemia, type I and II; usually benign

Δ1-Pyrroline-5-carboxylate synthetase deficiency (associated with high ammonia levels)

Prolidase deficiency (proline, hydroxyproline)

Hyperlysinemia (lysine)

Glutaric acidemia type I (carnitine, lysine, tryptophan)

Nonketotic hyperglycinemia (Glycine)

γ-Glutamylcysteine synthetase deficiency (glutathione deficiency); tied in with G6PD

Pyroglutamic aciduria (glutathione); tied in with G6PD

Hyper-β-alaninemia (alanine, taurine, GABA, β-aminoisobutyrate)

Methylmalonate/malonate semialdehyde dehydrogenase issues

Pyridoxine dependency

GABA-transaminase deficiency (GABA, β-alanine, carnosine)

4-Hydroxybutyric aciduria (glycine)

Most of these are non-starters, and I don't see any which are explicitly tied to arginine, but it's worth sifting through them to see what might fit.

Every question spawns a hundred more questions.  This is the boring footwork of diagnosis, but it's essential.  Somewhere out there is the answer, all I have to do is sniff it out.

There goes that hypothesis

What a lot of non-scientists don't understand is the role of the hypothesis, and the role of the theory.

I just got my blood tests back from the challenge diet.  My plasma ammonia levels went from a baseline of 42 (normal) to.... 30.  Statistically the same.

What does this mean?  It means that this hypothesis, that my chronic pain was caused by hyperammonemia, has been disproven.  Assuming the lab didn't screw up, that's not what's going on.  When I eat protein, I don't end up with a buildup of ammonia in my blood.

So I'll toss that hypothesis, look at the data again, and form a new one.  But these hypotheses that I'm testing are meant to answer the specific question, "what is the mechanism that connects my diet with my chronic pain?"  They don't address the larger question, "Does my diet affect my chronic pain?", nor the slightly smaller question, "Is protein intake directly related to my pain level?"  Both of those have been answered to my satisfaction.  The evidence I've collected, such as the fact that arginine helps tremendously all on its own, and that my feet are better when I eat less protein *and* elevate them for a period, all fits together.  I can put the pieces together to make a big picture that makes sense.

That big picture is my theory: I have some form of protein-metabolism disorder.  Did the ammonia test disprove my theory?  No.  It just showed me that the picture is more complex than I had first assumed.  All of the other evidence still supports my theory.

I have learned that I was asking the wrong question.  Now I need to find the right one to ask next. 

The broadest swath of protein-metabolism disorders are UCDs, so that's the label I've been using to find information.  The next logical question to ask would be, "Do all UCDs result in elevated plasma ammonia levels?"  If the answer is "No", I may have just narrowed the possibilities dramatically.  If the answer is "Yes", I need to broaden my search terms to other metabolic disorders.

This is what scientists mean when we say that failure is just a different kind of information.  My results weren't what I expected, so now I use that to figure out what to do next.  It's all part of the process.

(But I don't mind telling you, my first reaction was "Damn, we're getting into really deep Zebra territory here.")

Technical resources

These resources are not the friendly sort that take you by the hand and say gently "We'll teach you how to cope".  These are the technical, professional, hard-science resources that provide the facts necessary to build those friendly guidelines.

If long words and blocks of medical jargon don't make your eyes glaze, you might want to check some of these out; this is the best list I have so far of information available to laypeople.  Most aren't provided by people trying to sell you something.

Rare Diseases Clinical Research Network (from the US National Institutes of Health) has a UCD Consortium.
National Urea Cycle Disorders Foundation (and some links to their partners).
National Organization for Rare Disorders has a Urea Cycle Disorders page.
The NIH Genetics Home Reference.
Hyperammonemia (discovery and treatment of a serious case of late-onset UCD)
Suggested Guidelines for the Diagnosis and Treatment of Urea Cycle Disorders
NAGS deficiency (CarbaGlu sells a pharma treatment, but they have some very useful info on UCDs nonetheless)


NORD's Rare Disease Database has been exceptionally helpful, while RDCRN has a nifty diagram of the urea cycle with accompanying descriptions of how each of the disorders result from a break in the system.  I need to spend some more quality time with both.