DR. COYLE: Dr. Burlina's paper is open for comment. Yes?
DR. ROSS: So what is your working hypothesis for the elevation in NAAG in Palizaeus-Merzbacher Disease?
DR. BURLINA: I am starting to think that NAAG is really a complex molecule, because we heard from Dr. Wroblewska and also from the other speakers that it has a neuroprotective effect.
It, to me, does seem that is not the only effect. As I have shown, NAAG is high in the CSF of PMD patients, and from our preliminary data it appears that NAAG levels correlate to the severity of disease.
At the moment, I don't have an exact explanation for the elevation of NAAG in the CSF of PMD patients. I know that the functions of PLP are not completely understood. Maybe there is an interaction between PLP and the hydrolytic NAAG enzymes. In some way, NAAG seems to be involved in the dysmyelination process.
A glutamatergic action can be hypothesized in the case of PMD pathogenesis, and, as is well known, developing oligodendrocytes are highly vulnerable to excitotoxicity. Therefore, the presence of elevated levels of NAAG could be relevant for the disease.
I think we need to work more on the animal model of PMD, the jimpy mouse. Interestingly, we detected increased levels of NAAG in the urine of jimpy mice. The results are preliminary, but very encouraging.
DR. COYLE: Regarding the possibility of a second international NAA meeting, I can only speak for myself and not for the entire NAAG and NAA community, but Padua sounds like a fantastic place to have a follow-up second international meeting. Thank you. Danny?
DR. WEINBERGER: I just had a sort of an additional clinical question. Any relationship between NAAG levels in CSF or urine and age of onset, clinical manifestations, anything like that?
DR. BURLINA: As I told you before, it seems that we have some relationship with NAAG in the CSF and the clinical severity of the disease, no clear relationship with the age has appeared yet. Concerning urine data in PMD patients, we detected an increased amount of NAAG, but not in all patients; anyway, analyses are still in progress. I just remind you that few years ago we reported an increased amount of NAAG also in the urine of Canavan patients, in which, of course, NAA is elevated too.
I should mention that when I received the samples I didn't know the genetic result, or the clinical diagnosis, except that it was a leukodystrophy. Therefore, I didn't know if I had a PMD CSF sample, or another kind of leukodystrophy (i.e. Alexander disease, vanishing white matter disease, etc.). In some cases, the NAAG elevation strongly suggested a diagnosis of PMD before the genetic analysis of PLP mutations could be completed.
DR. COYLE: Thank you very much.
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