MYELIN BASIC PROTEIN-LIKE MATERIAL--DELAYED MYELOGENESIS MONITOR

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This proposal rests on the hypothesis that the level of a urinary peptide which is immunoreactive with myelin basic protein (MBP) correlates with myelinogenesis and can provide a monitor of successful or failed myelinogenesis in children. The uncertain course, subclinical involvement and clinical and biological heterogeneity within the population of MR/DD patients render attempts at therapeutic or interventional trials based on clinical evaluation difficult, of long duration, and often inconclusive. To some extent, the problem represents an inability to assess injury or failed neurodevelopment adequately and accurately. This proposal represents a potentially powerful means of addressing this issue in a noninvasive manner and the advancing diagnostic and prognostic capabilities and monitoring the effectiveness of intervention strategies. The specific aims of this study are: (A) to document the normative developmental course of myelinogenesis in terms of the presence of MBPLM in urine from birth through 4 years of age (Study 1); (B) to determine in a very low birthweight (VLBW), less than 1000 gm, sample at high risk for peri-ventricular leukomalacia (PVL) and abnormal myelinogenesis, the presence of MBPLM at birth through 4 years of age (Study 2); (C) to conduct a longitudinal study of VLBW children from birth to 4 years of age to ascertain individual growth curves and to test for gender differences in MBPLM over time (Study 3); (D) to relate levels of MBPLM and their changes over time to clinical manifestations of MR/DD in the cross-sectional and longitudinal samples of VLBW children; (E) to characterize by high performance liquid chromatography (HPLC) the features of MBPLM at birth through 4 years; (F) to search for the presence of MBPLM encoded by exon 2 or MBP, expressed only during myelinogenesis; (G) to search for the presence of material cross-reactive with the citrullinated (C8) isomer of MBP, among the first charged isomers to appear during myelinogenesis; and (H) to acquire an archival clinical database on MBPLM levels in children (Study 4) with specific, relatively rare developmental disabilities associated with disorders of myelinogenesis, e.g. hypothyroidism, leukodystrophies, organic acid disorders, and amino acid disorders (including PKU). We recognize that the proposed studies are exploratory in terms of yielding meaningful information. However, reliable non-invasive markers of myelinogenesis re presently lacking. This recent methodologic breakthrough provides a unique opportunity to correlate neurodevelopmental characteristics in well-established and delineated cohorts with a marker of myelinogenesis. Thus, these studies have substantial potential for advancing knowledge about understanding normal and aberrant development.