CLINICAL DIAGNOSTICS OF NEURONAL LYSOSOMAL STORAGE DISEASES AND QUANTIFICATION OF LYSOSOMAL ENZYMES BY MASS SPECTROMETRY
Prof. Dr. rer. nat. Michael Przybylski
To date, at least 13 genetically different neuronal ceroid lipofuscinoses (NCLs) forms have been identified. None of the NCL forms can be cured yet, but an intraventricular enzyme replacement therapy (ERT) has recently been approved for CLN2 disease for the first time (1). For the effective onset of ERT or any other future treatment, early diagnosis is required, which render specific and sensitive diagnostics for NCLs of key importance. So far four NCLs which are caused by mutations in lysosomal enzymes are mainly diagnosed by measurement of their catalytic activity in specialized laboratories using standardized dried blood spot (DBS) analysis with fluorimetric methods. A major drawback of fluorimetric assays is their limitation to single determinations and inability for multiplex assays (2). Enzyme-specific substrates for tandem-mass spectrometric (MS/MS) determinations have been developed for some lysosomal storage diseases (LSDs), feasible for multiplex diagnostics. However, at present there is a lack of standardization of LSD diagnostics using both conventional and new methods, to clearly differentiate between healthy individuals, disease carriers not developing disease, and patients affected by disease.
Therefore, this project aims to develop new tools for the clinical diagnosis of NCLs at low costs using multiplex mass spectrometry in order to improve sensitivity, rapidity, and reliability of NCL diagnosis. Another main objective is the development of new affinity-mass spectrometry technologies for quantitative determination of NCL-related lysosomal proteins lacking enzymatic activity, such as CLN5.
- Schulz A, Ajayi T, Specchio N, et al. (2018) Study of Intraventricular Cerliponase alfa for treatment of CLN2 disease. New Engl J Med DOI:10.1056/NEJMoa1712649
- Gelb MH, Scott CR, Turecek F. (2015) Newborn Screening for Lysosomal Storage Diseases. Clin Chem 61:335–46.