Abnormal polyamine metabolism is unique to the neuropathic forms of MPS: potential for biomarker development and insight into pathogenesis.

The mucopolysaccharidoses (MPS) are rare genetic disorders marked by severe somatic and neurological symptoms. Development of treatments for the neurological manifestations of MPS has been hindered by the lack of objective measures of central nervous system disease burden. Identification of biomarkers for central nervous system disease in MPS patients would facilitate the evaluation of new agents in clinical trials. High throughput metabolite screening of cerebrospinal fluid (CSF) samples from a canine model of MPS I revealed a marked elevation of the polyamine, spermine, in affected animals, and gene therapy studies demonstrated that reduction of CSF spermine reflects correction of brain lesions in these animals. In humans, CSF spermine was elevated in neuropathic subtypes of MPS (MPS I, II, IIIA, IIIB), but not in subtypes in which cognitive function is preserved (MPS IVA, VI). In MPS I patients, elevated CSF spermine was restricted to patients with genotypes associated with CNS disease and was reduced following hematopoietic stem cell transplantation, which is the only therapy currently capable of improving cognitive outcomes. Additional studies in cultured neurons from MPS I mice showed that elevated spermine was essential for the abnormal neurite overgrowth exhibited by MPS neurons. These findings offer new insights into the pathogenesis of CNS disease in MPS patients, and support the use of spermine as a new biomarker to facilitate the development of next generation therapeutics for MPS.

Correlation of CSF flow using phase-contrast MRI with ventriculomegaly and CSF opening pressure in mucopolysaccharidoses.

BACKGROUND: Very little is known about the incidence and prevalence of hydrocephalus in patients with mucopolysaccharidoses (MPS). The biggest challenge is to distinguish communicating hydrocephalus from ventricular dilatation secondary to brain atrophy, because both conditions share common clinical and neuroradiological features. The main purpose of this study is to assess the relationship between ventriculomegaly, brain and cerebrospinal fluid (CSF) volumes, aqueductal and cervical CSF flows, and CSF opening pressure in MPS patients, and to provide potential biomarkers for abnormal CSF circulation. METHODS: Forty-three MPS patients (12 MPS I, 15 MPS II, 5 MPS III, 9 MPS IV A and 2 MPS VI) performed clinical and developmental tests, and T1, T2, FLAIR and phase-contrast magnetic resonance imaging (MRI) followed by a lumbar puncture with the CSF opening pressure assessment. For the analysis of MRI variables, we measured the brain and CSF volumes, white matter (WM) lesion load, Evans' index, third ventricle width, callosal angle, dilated perivascular spaces (PVS), craniocervical junction stenosis, aqueductal and cervical CSF stroke volumes, and CSF glycosaminoglycans concentration. RESULTS: All the scores used to assess the supratentorial ventricles enlargement and the ventricular CSF volume presented a moderate correlation with the aqueductal CSF stroke volume (ACSV). The CSF opening pressure did not correlate either with the three measures of ventriculomegaly, or the ventricular CSF volume, or with the ACSV. Dilated PVS showed a significant association with the ventriculomegaly, ventricular CSF volume and elevated ACSV. CONCLUSIONS: In MPS patients ventriculomegaly is associated with a severe phenotype, increased cognitive decline, WM lesion severity and enlarged PVS. The authors have shown that there are associations between CSF flow measurements and measurements related to CSF volumetrics. There was also an association of volumetric measurements with the degree of dilated PVS.

Hydrocephalus and mucopolysaccharidoses: what do we know and what do we not know?

INTRODUCTION: The precise incidence of hydrocephalus in patients with mucopolysaccharidoses (MPS) is hard to determine, because the condition lacks a formal, consensus-based definition. The diagnosis of hydrocephalus depends on symptom profile, presence of neuroimaging features, and the outcome of diagnostic tests. Although numerous techniques are used to identify MPS patients who are most likely to have hydrocephalus and respond to treatment, no definitive method exists to prove diagnosis. PURPOSE: The authors propose an algorithm to aid in the diagnosis and management of hydrocephalus in MPS patients. CONCLUSIONS: The theory of venous hypertension associated with the morphological changes in the skull base and craniocervical junction indicate the need for future neuroimaging studies including cerebrospinal fluid (CSF) and venous flow measurements to monitor hydrocephalus progression and select therapeutic interventions in MPS patients. Preoperative planning should also be based on the increased risk of intraoperative and postoperative hemorrhagic complications.

Glycan-based biomarkers for mucopolysaccharidoses.

The mucopolysaccharidoses (MPS) result from attenuation or loss of enzyme activities required for lysosomal degradation of the glycosaminoglycans, hyaluronan, heparan sulfate, chondroitin/dermatan sulfate, and keratan sulfate. This review provides a summary of glycan biomarkers that have been used to characterize animal models of MPS, for diagnosis of patients, and for monitoring therapy based on hematopoietic stem cell transplantation and enzyme replacement therapy. Recent advances have focused on the non-reducing terminus of the glycosaminoglycans that accumulate as biomarkers, using a combination of enzymatic digestion with bacterial enzymes followed by quantitative liquid chromatography/mass spectrometry. These new methods provide a simple, rapid diagnostic strategy that can be applied to samples of urine, blood, cerebrospinal fluid, cultured cells and dried blood spots from newborn infants. Analysis of the non-reducing end glycans provides a method for monitoring enzyme replacement and substrate reduction therapies and serves as a discovery tool for uncovering novel biomarkers and new forms of mucopolysaccharidoses.