Cerebral Spinal Fluid levels of Cytokines are elevated in Patients with Metachromatic Leukodystrophy.
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ABSTRACT:
SUBMITTER: Thibert KA
PROVIDER: S-EPMC4832325 | biostudies-other | 2016 Apr
REPOSITORIES: biostudies-other
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Project description:The genome-wide analysis of T lympocytes from 24 MLD patients and a corresponding number of matched controls reveals a list of differentially expressed genes that can be used to build classifiers that correctly classify not only patients and controls with high sensitivity and specificity, but also MLD patients into early- and late-onset clinical classes. Among the most differentially expressed genes, the class of metallothioneins shows a consistent and significant over-expression, confirmed also in affected tissues of patients and mouse models of MLD and other Lysosomal Storage Disorders, indicating metallothioneins a novel dynamic biomarker of disease progression and treatment response in this class of diseases. Moreover, gene onthology analysis performed on the microarray data suggest an involvement of stress response- and autophagy-related pathways as pathological mechanisms in MLD.
2013-11-21 | GSE23350 | GEO
Project description:ObjectiveMetachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disorder due to deficient activity of arylsulfatase A (ASA) that causes accumulation of sulfatide and lysosulfatide. The disorder is associated with demyelination and axonal loss in the central and peripheral nervous systems. The late infantile form has an early-onset, rapidly progressive course with severe sensorimotor dysfunction. The relationship between the degree of nerve damage and (lyso)sulfatide accumulation is, however, not established.MethodsIn 13 children aged 2-5 years with severe motor impairment, markedly elevated cerebrospinal fluid (CSF) and sural nerve sulfatide and lysosulfatide levels, genotype, ASA mRNA levels, residual ASA, and protein cross-reactive immunological material (CRIM) confirmed the diagnosis. We studied the relationship between (lyso)sulfatide levels and (1) the clinical deficit in gross motor function (GMFM-88), (2) median and peroneal nerve motor and median and sural nerve sensory conduction studies (NCS), (3) median and tibial nerve somatosensory evoked potentials (SSEPs), (4) sural nerve histopathology, and (5) brain MR spectroscopy.ResultsEleven patients had a sensory-motor demyelinating neuropathy on electrophysiological testing, whereas two patients had normal studies. Sural nerve and CSF (lyso)sulfatide levels strongly correlated with abnormalities in electrophysiological parameters and large myelinated fiber loss in the sural nerve, but there were no associations between (lyso)sulfatide levels and measures of central nervous system (CNS) involvement (GMFM-88 score, SSEP, and MR spectroscopy).InterpretationNerve and CSF sulfatide and lysosulfatide accumulation provides a marker of disease severity in the PNS only; it does not reflect the extent of CNS involvement by the disease process. The magnitude of the biochemical disturbance produces a continuously graded spectrum of impairments in neurophysiological function and sural nerve histopathology.
| S-EPMC4435706 | biostudies-literature
Project description:Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder characterized by accumulation of sulfatides in both glial cells and neurons. MLD results from an inherited deficiency of arylsulfatase A (ARSA) and myelin degeneration in the central and peripheral nervous systems. Currently, no effective treatment is available for the most frequent late infantile (LI) form of MLD after symptom onset. The LI form results in rapid neurological degradation and early death. ARSA enzyme must be rapidly and efficiently delivered to brain and spinal cord oligodendrocytes of patients with LI MLD in order to potentially stop the progression of the disease. We previously showed that brain gene therapy with adeno-associated virus serotype rh10 (AAVrh10) driving the expression of human ARSA cDNA alleviated most long-term disease manifestations in MLD mice but was not sufficient in MLD patient to improve disease progression. Herein, we evaluated the short-term effects of intravenous AAVPHP.eB delivery driving the expression of human ARSA cDNA under the control of the cytomegalovirus/b-actin hybrid (CAG) promoter in 6-month-old MLD mice that already show marked sulfatide accumulation and brain pathology. Within 3 months, a single intravenous injection of AAVPHP.eB-hARSA-HA resulted in correction of brain and spinal cord sulfatide storage, and improvement of astrogliosis and microgliosis in brain and spinal cord of treated animals. These results strongly support to consider the use of AAVPHP.eB-hARSA vector for intravenous gene therapy in symptomatic rapidly progressing forms of MLD.
| S-EPMC8175802 | biostudies-literature
Project description:Metachromatic leukodystrophy (MLD) is a rare metabolic disorder leading to demyelination and rapid neurologic deterioration. As therapeutic options evolve, it seems essential to understand and quantify progression of the natural disease. The aim of this study was to assess cerebral volumetric changes in children with MLD in comparison to normal controls and in relation to disease course.Eighteen patients with late-infantile MLD and 42 typically developing children in the same age range (20-59 months) were analyzed in a cross-sectional study. Patients underwent detailed genetic, biochemical, electrophysiologic, and clinical characterization. Cerebral gray matter (GM) and white matter (WM) volumes were assessed by multispectral segmentation of T1- and T2-weighted MRI. In addition, the demyelinated WM (demyelination load) was automatically quantified in T2-weighted images of the patients, and analyzed in relation to the clinical course.WM volumes of patients did not differ from controls, although their growth curves were slightly different. GM volumes of patients, however, were on average 10.7% (confidence interval 6.0%-14.9%, p < 0.001) below those of normally developing children. The demyelination load (corrected for total WM volume) increased with disease duration (p < 0.003) and motor deterioration (p < 0.001).GM volume in patients with MLD is reduced when compared with healthy controls, already at young age. This supports the notion that, beside demyelination, neuronal dysfunction caused by neuronal storage plays an additional role in the disease process. The demyelination load may be a useful noninvasive imaging marker for disease progression and may serve as reference for therapeutic intervention.
| S-EPMC4098858 | biostudies-literature
Project description:The genome-wide analysis of T lympocytes from 24 MLD patients and a corresponding number of matched controls reveals a list of differentially expressed genes that can be used to build classifiers that correctly classify not only patients and controls with high sensitivity and specificity, but also MLD patients into early- and late-onset clinical classes. Among the most differentially expressed genes, the class of metallothioneins shows a consistent and significant over-expression, confirmed also in affected tissues of patients and mouse models of MLD and other Lysosomal Storage Disorders, indicating metallothioneins a novel dynamic biomarker of disease progression and treatment response in this class of diseases. Moreover, gene onthology analysis performed on the microarray data suggest an involvement of stress response- and autophagy-related pathways as pathological mechanisms in MLD. Total RNA extracted from T-lymphocytes of 24 MLD patients and 24 age-and sex-matched controls
2013-11-21 | E-GEOD-23350 | biostudies-arrayexpress
Project description:Leukodystrophies (LDs) are rare, often devastating genetic disorders with neurologic symptoms. There are currently no disease-specific therapeutic approaches for these diseases. In this review we use metachromatic leukodystrophy as an example to outline in the brief the therapeutic approaches to MLD that have been tested in animal models and in clinical trials, such as enzyme-replacement therapy, bone marrow/umbilical cord blood transplants, ex vivo transplantation of genetically modified hematopoietic stem cells, and gene therapy. These studies suggest that to be successful the ideal therapy for MLD must provide persistent and high level expression of the deficient gene, arylsulfatase A in the CNS. Gene therapy using adeno-associated viruses is therefore the ideal choice for clinical development as it provides the best balance of potential for efficacy with reduced safety risk. Here we have summarized the published preclinical data from our group and from others that support the use of a gene therapy with AAVrh.10 serotype for clinical development as a treatment for MLD, and as an example of the potential of gene therapy for LDs especially for Krabbe disease, which is the focus of this special issue. © 2016 Wiley Periodicals, Inc.
| S-EPMC5027970 | biostudies-literature
Project description:Metachromatic leukodystrophy (MLD) is a rare progressive neurological disorder, often accompanied by motor impairments that are challenging to treat. In this case series, we report the course of treatment with intrathecal baclofen (ITB), aimed at improving daily care and comfort in children and young adults with MLD. All patients with MLD in our centre on ITB treatment for a minimum of 6 months were included (n=10; 4 males, 6 females; mean age 10y 8mo [range 6-24y]). Eight patients had MLD with a predominant spastic movement disorder (sMLD) and two were mainly dyskinetic. Patients with sMLD were compared with matched patients with spastic cerebral palsy (CP). Complication rates related to ITB treatment were similar in both groups. ITB treatment course in the first 6 months after pump implantation appears to show more dose increase in most patients MLD, compared to patients with spastic CP. This may be due to the progressive disease in MLD. ITB is a feasible therapy to improve daily care and comfort in patients with MLD and should therefore be considered early. WHAT THIS PAPER ADDS: Intrathecal baclofen (ITB) is a feasible therapy to improve comfort and daily care in children and young people with metachromatic leukodystrophy (MLD). In the first 6 months of ITB treatment, MLD seems to show more dose increase compared to spastic cerebral palsy.
| S-EPMC7379712 | biostudies-literature
Project description:Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal disorder caused by the deficiency of arylsulfatase A (ASA), resulting in impaired degradation of sulfatide, an essential sphingolipid of myelin. The clinical manifestations of MLD are characterized by progressive demyelination and subsequent neurological symptoms resulting in severe debilitation. The availability of therapeutic options for treating MLD is limited but expanding with a number of early stage clinical trials already in progress. In the development of therapeutic approaches for MLD, scientists have been facing a number of challenges including blood-brain barrier (BBB) penetration, safety issues concerning therapies targeting the central nervous system, uncertainty regarding the ideal timing for intervention in the disease course, and the lack of more in-depth understanding of the molecular pathogenesis of MLD. Here, we discuss the current status of the different approaches to developing therapies for MLD. Hematopoietic stem cell transplantation has been used to treat MLD patients, utilizing both umbilical cord blood and bone marrow sources. Intrathecal enzyme replacement therapy and gene therapies, administered locally into the brain or by generating genetically modified hematopoietic stem cells, are emerging as novel strategies. In pre-clinical studies, different cell delivery systems including microencapsulated cells or selectively neural cells have shown encouraging results. Small molecules that are more likely to cross the BBB can be used as enzyme enhancers of diverse ASA mutants, either as pharmacological chaperones, or proteostasis regulators. Specific small molecules may also be used to reduce the biosynthesis of sulfatides, or target different affected downstream pathways secondary to the primary ASA deficiency. Given the progressive neurodegenerative aspects of MLD, also seen in other lysosomal diseases, current and future therapeutic strategies will be complementary, whether used in combination or separately at specific stages of the disease course, to produce better outcomes for patients afflicted with this devastating inherited disorder.
| S-EPMC3743609 | biostudies-other
Project description:ObjectiveWe aimed to gain more insight into the pathomechanisms of metachromatic leukodystrophy (MLD), by comparing magnitude and direction of diffusion between patients and controls at diagnosis and during follow-up.MethodsFour late-infantile, 16 juvenile and 8 adult onset MLD patients [of which 13 considered eligible for hematopoietic cell transplantation (HCT)] and 47 controls were examined using diffusion tensor imaging. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) were quantified and compared between groups using tract-based spatial statistics (TBSS). Diffusion measures were determined for normal-appearing white matter (NAWM), corpus callosum, thalamus (all based on subject-wise segmentation), and pyramidal tracts, determined with probabilistic tractography. Measures were compared between HCT-eligible patients, non-eligible patients and controls using general linear model and nonparametric permutation analyses (randomise) for TBSS data, considering family-wise error corrected p < 0.05 significant.ResultsThroughout white matter (WM), FA was decreased and MD and RD increased in both patient groups compared to controls, while AD was decreased in NAWM and corpus callosum. In the thalamus, no differences in FA were observed, but all diffusivities were increased in both patient groups. Differences were most pronounced between controls and patients non-eligible for HCT. Longitudinally (median follow-up 3.9 years), diffusion measures remained relatively stable for HCT-treated patients, but were progressively abnormal for non-eligible patients.InterpretationThe observed diffusion measures confirm that brain microstructure is changed in MLD, reflecting different pathological processes including loss of myelin and sulfatide accumulation. The observation of both increased and decreased AD probably reflects a balance between myelin and axonal loss vs. intracellular sulfatide storage in macrophages, depending on region and disease stage.
| S-EPMC5834549 | biostudies-literature
Project description:Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive, multiple congenital anomaly syndrome with cognitive impairment and a distinct behavioral phenotype that includes autistic features. SLOS is caused by a defect in 3β-hydroxysterol Δ(7)-reductase which leads to decreased cholesterol levels and elevated cholesterol precursors, specifically 7- and 8-dehydrocholesterol. However, the pathological processes contributing to the neurological abnormalities in SLOS have not been defined. In view of prior data suggesting defects in SLOS in vesicular release and given the association of altered serotonin metabolism with autism, we were interested in measuring neurotransmitter metabolite levels in SLOS to assess their potential to be used as biomarkers in therapeutic trials. We measured cerebral spinal fluid levels of serotonin and dopamine metabolites, 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) respectively, in 21 SLOS subjects. Results were correlated with the SLOS anatomical severity score, Aberrant Behavior Checklist scores and concurrent sterol biochemistry. Cerebral spinal fluid (CSF) levels of both 5HIAA and HVA were significantly reduced in SLOS subjects. In individual patients, the levels of both 5HIAA and HVA were reduced to a similar degree. CSF neurotransmitter metabolite levels did not correlate with either CSF sterols or behavioral measures. This is the first study demonstrating decreased levels of CSF neurotransmitter metabolites in SLOS. We propose that decreased levels of neurotransmitters in SLOS are caused by a sterol-related defect in synaptic vesicle formation and that CSF 5HIAA and HVA will be useful biomarkers in development of future therapeutic trials.
| S-EPMC4166510 | biostudies-literature