TY - JOUR
T1 - Abnormal polyamine metabolism is unique to the neuropathic forms of MPS
T2 - Potential for biomarker development and insight into pathogenesis
AU - Hinderer, Christian
AU - Katz, Nathan
AU - Louboutin, Jean Pierre
AU - Bell, Peter
AU - Tolar, Jakub
AU - Orchard, Paul J.
AU - Lund, Troy C.
AU - Nayal, Mohamad
AU - Weng, Liwei
AU - Mesaros, Clementina
AU - de Souza, Carolina F.M.
AU - Corte, Amauri Dalla
AU - Giugliani, Roberto
AU - Wilson, James M.
N1 - Publisher Copyright:
© The Author 2017. Published by Oxford University Press. All rights reserved.
PY - 2017/10/1
Y1 - 2017/10/1
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/ddx277
DO - 10.1093/hmg/ddx277
M3 - Article
C2 - 28934395
AN - SCOPUS:85030662517
SN - 0964-6906
VL - 26
SP - 3837
EP - 3849
JO - Human molecular genetics
JF - Human molecular genetics
IS - 19
ER -