Diagnosis and therapies for mucopolysaccharidoses

Date
2017
Journal Title
Journal ISSN
Volume Title
Publisher
University of Delaware
Abstract
Mucopolysaccharidoses (MPS) are lysosomal storage disorders characterized by progressive accumulation of glycosaminoglycans (GAGs) due to deficiency of specific lysosomal enzymes. MPS are classified according to the enzyme deficiency and accumulated GAGs. GAGs are negatively charged polysaccharides composed of repeating disaccharides and are important components of extracellular matrix, having a range of functions in multiple tissues. In MPS, GAGs accumulate in lysosomes, disrupting cellular homeostasis and leading to irreversible and progressive cell and tissue damage. All types of MPS are chronic and progressive with an extensive range of clinical manifestations such as skeletal dysplasia, corneal clouding, coarse facial features, joint rigidity or laxity, hepatosplenomegaly, neurodegeneration, and cardiac and respiratory dysfunction. The combined incidence of all MPSs is estimated as 1:25,000 live births. Most patients are asymptomatic at birth, so are not usually diagnosed until signs and symptoms arise in the first few years of life. Although no cure exists for MPS, some treatment approaches are available, including hematopoietic stem cell transplantation (HSCT), enzyme replacement therapy (ERT), substrate reduction therapy and chaperone therapy. Methods to evaluate treatment success are limited, and there is an overall consensus that treatments should begin before signs and symptoms appear. Current techniques for assessment of disease progression are invasive, and effort-dependent so cannot be used to evaluate young, wheelchair-bound and neurologically impaired patients. Thus, new diagnostic approaches (prenatal to newborn) and better techniques to evaluate disease progression are needed to improve outcomes for patients. ☐ In this study, I have established the efficacy of two non-invasive assessments for measuring disease progression in all MPS IV patients (Chapter 3) and developed a diagnostic approach using GAG analysis by liquid chromatography tandem mass spectrometry to understand natural history of MPSs (Chapter 4), and measure efficacy of different treatments (Chapter 5). ☐Skeletal abnormalities in some MPS IV patients precluded examination of bone mineral density (BMD) from conventional body sites, but it was discovered that BMD analysis could be performed on the lateral distal femur (LDF) of all MPS IV patients, regardless of physical or mental ability. Using BMD of LDF it was possible to determine the positive impact of ambulation in preserving BMD. Data from this study provides guidance to patients and their families on the importance of physical exercise in reducing the onset of disability. The subset of non-invasive pulmonary function tests demonstrated that restrictive and obstructive lung diseases are not always present in MPS IV, in which patients have small but functioning lungs. These tests will be able to inform clinicians of disease progression and should be valuable in evaluating the efficacy of treatment, allowing for a much wider range of patients to take part in clinical trials. ☐ The majority of established GAG detection protocols are based on colorimetric assays that are limited by false negative results and also cannot be applied to blood samples. The GAG detection protocol using tandem mass spectrometry is very specific and sensitive, discriminating most MPS patients from unaffected controls at all ages in a variety of samples (amniotic fluid, blood, cerebrospinal fluid, dried blood spots and urine). In my study, the focus was on samples from newborn patients, and results indicate that GAG measurements can be used for newborn screening. This will enable early diagnosis of MPS and thereby allow early treatment to significantly improve outcomes for MPS patients. ☐ I used this tandem mass spectrometry method in a study that showed that HSCT results in better outcomes for MPS II patients than ERT. GAG levels were lower in HSCT treated patients, who also had higher scores in an activity of daily living survey and fewer brain anomalies revealed by MRI than ERT treated patients. These new findings indicate that MPS II patients should be treated with HSCT at an early age and that, contrary to earlier reports, HSCT for these patients can have a positive impact on reducing neurological defects. ☐ The methodologies established here for GAG measurements and non-invasive techniques to assess disease progression have the potential to drastically improve the quality of life for MPS patients. The laboratory test enables both early diagnosis and evaluation of treatment efficacy and the non-invasive assessment protocols can be used to follow clinical efficacy. This highly innovative and state of the art study can be applied to the next generation of patient care in MPSs. The BMD and lung function assessments are also likely to be useful in the management of other diseases unrelated to MPS (skeletal dysplasias or neurological conditions), broadening the impact of this work. Early detection will also impact the choice of the most adequate treatment as well as reduce mortality, morbidity, and public health costs.
Description
Keywords
Pure sciences, Biological sciences, Enzyme replacement therapy, Glycosaminoglycans, Hematopoietic stem cell transplantation, Mucopolysaccharidoses, Newborn screening, Tandem mass spectrometry
Citation