DIAGNOSTICS AND BIOMARKER DISCOVERY-ABSTRACT/PROJECT SUMMARY Congenital disorders of glycosylation (CDG) have rapidly developed into one of the largest group of metabolic disorders, yet they are poorly described without natural histories, affective treatment, validated biomarkers correlating with disease severity and without comprehensive diagnostic tools. PMM2-CDG and congenital disorders of galactosylation (e.g. SLC35A2-CDG, PGM1-CDG) are the most common N-glycosylation disorders with emerging potential therapies. Congenital disorders of de-glycosylation is a recently discovered group of abnormal glycosylation with a potential noninvasive diagnostic biomarker in NGLY1 deficiency. Some long-known CDG types, like ALG13-CDG however still have no reliable, validated diagnostic methods. Our overall objective and overreaching aim is to develop and validate new biochemical diagnostic techniques and therapeutic biomarkers for future CDG clinical trials. We will overcome the shortcomings of current biochemical techniques and biomarkers in measuring therapeutic efficacy and diagnostics of specific CDG. To address the unmet need and accomplish our overall objective, we will 1) develop and validate biomarkers to monitor therapeutic efficacy in clinical trials for PMM2-CDG; 2) develop quantitative biomarkers to diagnose PGM1-CDG and monitor galactose therapy efficacy; 3) develop quantitative biomarkers to diagnose SLC35A2-CDG and monitor galactose therapy efficacy; 4) validate biomarker to diagnose and follow NGLY1 deficiency and monitor N-acetylglucosamine (GlcNAc) therapy response; 5) validate novel diagnostic biomarkers for ALG13-CDG; 6) qualify and admit new patients to the general CDG population. The impact of this aim on the CDG community is twofold. We will significantly improve diagnostics of patients with CDG, and through improved diagnostics and identification of biomarkers we will increase clinical trial readiness. Achieving these aims should enable us to correlate disease progression and disease severity (Project 1) and their response to therapy (Project 3) with quantifiable biochemical assays. Parallel measurements of the same biomaterial at the different laboratories will not only increase reliability, but will be integral to the validation process and facilitate the process of developing standard biochemical test for diagnosis of the disorders. Such improved diagnostics will be important to assess disease severity and through validation of biochemical outcome measures or biomarkers our efforts will support upcoming clinical trials in CDG. The multiple approaches using state-of-the- art technologies will provide data to assess the overall success of the project. Moreover, the biochemical validations may provide a framework for assessing other emerging or yet-to-be identified glycosylation disorders.
