In the present thesis, a clinical, neuropsychiatric and biochemical evaluation of patients affected by different types of Mucopolysaccharidosis (MPS) was performed, with the aim to analyze the natural history of these pathologies, and therefore their onset and their progression over time, but also to evaluate the effects, on the natural history, of the therapies available today and to identify early markers of severity.
This project is part of a more extensive multi-center project on mucopolysaccharidoses, which also includes a preclinical evaluation performed on mouse models, not reported in this thesis. Furthermore, the project produced an IT platform, accessible remotely from all the Operating Units involved in the project, on which it will be possible to continue patients’ data uploading over time, in order to increase as much as possible, the number of samples to be analyzed.
This thesis reports the results of the analysis performed on the 58 MPS patients so far available, at 3 different stages of progressive evaluation.
The analysis of the sample here evaluated confirmed that MPS patients are diagnosed with some delay, and this is especially true for those suffering from MPS III, diagnosed on average after 5 years of age; this may also be due to the particular clinical manifestations of this specific syndrome. Moreover, this data could be influenced by the heterogeneity of the analyzed sample, which includes both recent diagnoses and dated diagnostic pathways. The clinical suspicion on these diseases has certainly increased in recent years and this will undoubtedly help an early diagnosis.
With respect to the signs and symptoms at the onset, 41% of the patients in the sample present at the same time more signs and symptoms, and for almost 30% of the MPS subjects the suspicion that leads to the diagnosis is of musculoskeletal origin. Among the neuronopathic MPS analyzed, 37.5% of MPS II and 38.5% of MPS III patients present at the onset neurological signs and symptoms. This last data is particularly interesting, since we commonly consider the peripheral involvement in MPS III as being limited. From the present analysis, this does not appear to be true at the onset, when in more than 60% of cases, MPS III patients presented with non-neurological signs and symptoms, being this an important aspect to consider during diagnosis.
From a neurological point of view, it was evident how, independently from the different forms of MPS, both neuronopathic and not, on average half of the patients present macrocephaly at diagnosis, with peaks of 85% in the case of MPS I.
In neuronopathic forms, there are different signs and symptoms that occur at diagnosis and/or during disease progression; in this thesis, in particular language disorders and intellectual disability were analyzed. As already known, the analysis carried out in this thesis confirms that the intellectual disability does not receive any benefits from the administration of the enzyme replacement therapy, in particular for patients suffering from the severe form of MPS II, in which a significant increase in the degree of neuro-cognitive severity is progressively registered. As expected, the psychiatric features of the different MPS, such as sleep disturbances and behavioral disorders, also do not receive benefits from ERT administration.
On the other hand, some peripheral variables have shown benefits from replacement therapy, although in most cases only a tendency to an improvement has been shown, while a statistically significant improvement has been registered for hepatosplenomegaly and urinary glycosaminoglycan (GAG) levels.
Interestingly, the analysis carried out highlighted some significant correlations between quantitative urinary GAG analysis and the neuropsychiatric involvement, and between the urinary levels of heparan-sulfate, identified by qualitative test, and the same clinical aspects.
In these diseases, the identification of biomarkers helping to understand, even in the very early stage of the disease, what could be its progression, would be of considerable importance for the management of the patient and his family, and for the evaluation of a correct therapeutic choice.
It is hoped that soon a critical analysis of many clinical and biochemical data obtained from a large cohort of patients will allow to identify other biomarkers, useful for an early diagnosis and possibly a prognosis on the severity of its progression.