What is the biological relevance of the present finding? MPA has been shown to cause a reduction of the cellular GTP pools through the inhibition of IMPDH which is required for the de novo biosynthesis of GTP [41, 42] . A decrease in GTP concentrations could potentially have a negative effect on the capping of mRNAs. Evidence for this mechanism comes from studies performed with both the Sindbis virus and the Borna disease virus that showed that the viruses cannot replicate in cultured cells treated with ribavirin because the level of GTP falls too low to permit the capping of viral RNAs [48, 64, 65] . However, mounting evidence indicates that the antiproliferative/antimicrobial effect of MPA is not mediated entirely through the reduction of the intracellular GTP pool. For instance, MPA is not always a potent viral inhibitor [66] . The second mechanism by which MPA could inhibit the capping of mRNAs is by directly inhibiting the activity of GTases, as we demonstrated in the current study. Moreover, we do not exclude the possibility that MPA may have an increased frequency of utilization in vivo when the levels of GTP are lowered through the inhibition of IMPDH. In the present study, we demonstrated that MPA can inhibit RNA guanylyltransferases and ligases. MPA therefore appears as a pleiotropic agent that may function through multiple targets (IMPDH, RNA guanylyltransferase, ligases), as recently suggested through proteomic analysis [67] . As such, MPA shares many properties with ribavirin. Both compounds lead to a reduction of the de novo synthesis of GTP through IMPDH inhibition, and both molecules can inhibit RNA capping, albeit through different mechanisms of inhibition. Long-term follow-up and treatment of congenital alveolar proteinosis BACKGROUND: Clinical presentation, diagnosis, management and outcome of molecularly defined congenital pulmonary alveolar proteinosis (PAP) due to mutations in the GM-CSF receptor are not well known. CASE PRESENTATION: A 2 1/2 years old girl was diagnosed as having alveolar proteinosis. Whole lung lavages were performed with a new catheter balloon technique, feasible in small sized airways. Because of some interstitial inflammation in the lung biopsy and to further improve the condition, empirical therapy with systemic steroids and azathioprin, and inhaled and subcutaneous GMCSF, were used. Based on clinical measures, total protein and lipid recovered by whole lung lavages, all these treatments were without benefit. Conversely, severe respiratory viral infections and an invasive aspergillosis with aspergilloma formation occurred. Recently the novel homozygous stop mutation p.Ser25X of the GMCSF receptor alpha chain was identified in the patient. This mutation leads to a lack of functional GMCSF receptor and a reduced response to GMCSF stimulation of CD11b expression of mononuclear cells of the patient. Subsequently a very intense treatment with monthly lavages was initiated, resulting for the first time in complete resolution of partial respiratory insufficiency and a significant improvement of the overall somato-psychosocial condition of the child. CONCLUSIONS: The long term management from early childhood into young adolescence of severe alveolar proteinosis due to GMCSF receptor deficiency requires a dedicated specialized team to perform technically demanding whole lung lavages and cope with complications. Pulmonary alveolar proteinosis (PAP) is characterized by a substantial and persistent increase in surfactant pool size [1, 2] . There are several causes of this rare condition; mouse models with deletion of granulocyte-macrophagecolony stimulating factor (GM-CSF) or the GM-CSF receptor (GM-CSFR) beta-chain showed the first evidence for involved molecularly mechanisms [3, 4] . Autoantibodies against GM-CSF, blocking GM-CSF signaling, are the cause for the most frequent form of PAP, mainly found in adults and also called autoimmune PAP [5] . In 2008 the first two families with congenital PAP and mutations in the alpha-chain of the receptor for GM-CSF were described [6, 7] and very recently another six families were reported [8] . The patients presented with progressive dyspnea of insidious onset between the ages of 1.5 and 9 years; some were asymptomatic. Short term responsiveness to whole lung lavage (WLL) treatment has been described, however not much information on the long term outcome of molecularly defined patients is yet available.