RESUMO
Metachromatic leukodystrophy (MLD) is a rare, inherited, demyelinating lysosomal storage disorder caused by mutations in the arylsulfatase-A gene (ARSA). In patients, levels of functional ARSA enzyme are diminished and lead to deleterious accumulation of sulfatides. Herein, we demonstrate that intravenous administration of HSC15/ARSA restored the endogenous murine biodistribution of the corresponding enzyme, and overexpression of ARSA corrected disease biomarkers and ameliorated motor deficits in Arsa KO mice of either sex. In treated Arsa KO mice, when compared with intravenously administered AAV9/ARSA, significant increases in brain ARSA activity, transcript levels, and vector genomes were observed with HSC15/ARSA Durability of transgene expression was established in neonate and adult mice out to 12 and 52 weeks, respectively. Levels and correlation between changes in biomarkers and ARSA activity required to achieve functional motor benefit was also defined. Finally, we demonstrated blood-nerve, blood-spinal and blood-brain barrier crossing as well as the presence of circulating ARSA enzyme activity in the serum of healthy nonhuman primates of either sex. Together, these findings support the use of intravenous delivery of HSC15/ARSA-mediated gene therapy for the treatment of MLD.SIGNIFICANCE STATEMENT Herein, we describe the method of gene therapy adeno-associated virus (AAV) capsid and route of administration selection leading to an efficacious gene therapy in a mouse model of metachromatic leukodystrophy. We demonstrate the therapeutic outcome of a new naturally derived clade F AAV capsid (AAVHSC15) in a disease model and the importance of triangulating multiple end points to increase the translation into higher species via ARSA enzyme activity and biodistribution profile (with a focus on the CNS) with that of a key clinically relevant biomarker.
Assuntos
Arilsulfatases , Terapia Genética , Leucodistrofia Metacromática , Animais , Camundongos , Macaca fascicularis , Arilsulfatases/genética , Camundongos Knockout , Leucodistrofia Metacromática/genética , Leucodistrofia Metacromática/fisiopatologia , Leucodistrofia Metacromática/terapia , Modelos Animais de Doenças , Dependovirus/genética , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Encéfalo/enzimologia , Transtornos Motores/genética , Transtornos Motores/terapia , Administração Intravenosa , Biomarcadores/análise , Barreira Hematoencefálica , Masculino , Feminino , HumanosRESUMO
INTRODUCTION: Metachromatic leukodystrophy (MLD) refers to leukodystrophy caused by the accumulation of sulfatide from arylsulfatase A (ARSA) gene mutations. Sulfatide also accumulates in various organs, including the peripheral nerves, kidney, and gallbladder. Proliferative changes in the gallbladder have been reported in several patients, while gallbladder cancer is reported in only two adult MLD cases. We report what is likely the first pediatric case of MLD with gallbladder cancer. CASE REPORT: The patient was a 5-year-old girl diagnosed with MLD using head magnetic resonance imaging and detecting a homozygous mutation of c.302G>A (p.Gly101Asp) in ARSA. Abdominal bloating was observed at the age of 4 years; CT revealed a giant tumor in the gallbladder and massive ascites. Cholecystectomy was performed and pathological examination revealed adenocarcinoma. Measurement of serum sulfatide revealed increased levels compared to the average healthy range. DISCUSSION: Rapidly increased ascites and large polyps which are reported as risk factors for cancer were characteristic in our MLD case. When such lesions are detected, they should be removed immediately because of the possibility of cancer, even in a pediatric patient.
Assuntos
Neoplasias da Vesícula Biliar/etiologia , Neoplasias da Vesícula Biliar/fisiopatologia , Leucodistrofia Metacromática/complicações , Ascite/complicações , Cerebrosídeo Sulfatase/genética , Pré-Escolar , Feminino , Humanos , Japão , Leucodistrofia Metacromática/fisiopatologia , Imageamento por Ressonância Magnética , Mutação , PóliposRESUMO
Plasmalogens are the most abundant form of ether phospholipids in myelin and their deficiency causes Rhizomelic Chondrodysplasia Punctata (RCDP), a severe developmental disorder. Using the Gnpat-knockout (KO) mouse as a model of RCDP, we determined the consequences of a plasmalogen deficiency during myelination and myelin homeostasis in the central nervous system (CNS). We unraveled that the lack of plasmalogens causes a generalized hypomyelination in several CNS regions including the optic nerve, corpus callosum and spinal cord. The defect in myelin content evolved to a progressive demyelination concomitant with generalized astrocytosis and white matter-selective microgliosis. Oligodendrocyte precursor cells (OPC) and mature oligodendrocytes were abundant in the CNS of Gnpat KO mice during the active period of demyelination. Axonal loss was minimal in plasmalogen-deficient mice, although axonal damage was observed in spinal cords from aged Gnpat KO mice. Characterization of the plasmalogen-deficient myelin identified myelin basic protein and septin 7 as early markers of dysmyelination, whereas myelin-associated glycoprotein was associated with the active demyelination phase. Using in vitro myelination assays, we unraveled that the intrinsic capacity of oligodendrocytes to ensheath and initiate membrane wrapping requires plasmalogens. The defect in plasmalogens was rescued with glyceryl 1-myristyl ether [1-O-tetradecyl glycerol (1-O-TDG)], a novel alternative precursor in the plasmalogen biosynthesis pathway. 1-O-TDG treatment rescued myelination in plasmalogen-deficient oligodendrocytes and in mutant mice. Our results demonstrate the importance of plasmalogens for oligodendrocyte function and myelin assembly, and identified a novel strategy to promote myelination in nervous tissue.
Assuntos
Éteres de Glicerila/farmacologia , Oligodendroglia/metabolismo , Plasmalogênios/metabolismo , Animais , Axônios/metabolismo , Sistema Nervoso Central/metabolismo , Condrodisplasia Punctata Rizomélica/metabolismo , Doenças Desmielinizantes , Modelos Animais de Doenças , Leucodistrofia Metacromática/fisiopatologia , Camundongos , Camundongos Knockout , Bainha de Mielina/metabolismo , Bainha de Mielina/fisiologia , Oligodendroglia/fisiologia , Peroxissomos , Medula Espinal/metabolismoRESUMO
Allogeneic fetal-derived human neural stem cells (hfNSCs) that are under clinical evaluation for several neurodegenerative diseases display a favorable safety profile, but require immunosuppression upon transplantation in patients. Neural progenitors derived from patient-specific induced pluripotent stem cells (iPSCs) may be relevant for autologous ex vivo gene-therapy applications to treat genetic diseases with unmet medical need. In this scenario, obtaining iPSC-derived neural stem cells (NSCs) showing a reliable "NSC signature" is mandatory. Here, we generated human iPSC (hiPSC) clones via reprogramming of skin fibroblasts derived from normal donors and patients affected by metachromatic leukodystrophy (MLD), a fatal neurodegenerative lysosomal storage disease caused by genetic defects of the arylsulfatase A (ARSA) enzyme. We differentiated hiPSCs into NSCs (hiPS-NSCs) sharing molecular, phenotypic, and functional identity with hfNSCs, which we used as a "gold standard" in a side-by-side comparison when validating the phenotype of hiPS-NSCs and predicting their performance after intracerebral transplantation. Using lentiviral vectors, we efficiently transduced MLD hiPSCs, achieving supraphysiological ARSA activity that further increased upon neural differentiation. Intracerebral transplantation of hiPS-NSCs into neonatal and adult immunodeficient MLD mice stably restored ARSA activity in the whole central nervous system. Importantly, we observed a significant decrease of sulfatide storage when ARSA-overexpressing cells were used, with a clear advantage in those mice receiving neonatal as compared with adult intervention. Thus, we generated a renewable source of ARSA-overexpressing iPSC-derived bona fide hNSCs with improved features compared with clinically approved hfNSCs. Patient-specific ARSA-overexpressing hiPS-NSCs may be used in autologous ex vivo gene therapy protocols to provide long-lasting enzymatic supply in MLD-affected brains. Stem Cells Translational Medicine 2017;6:352-368.
Assuntos
Técnicas de Reprogramação Celular , Reprogramação Celular , Cerebrosídeo Sulfatase/biossíntese , Terapia Genética/métodos , Células-Tronco Pluripotentes Induzidas/transplante , Leucodistrofia Metacromática/cirurgia , Células-Tronco Neurais/transplante , Transplante de Células-Tronco/métodos , Animais , Diferenciação Celular , Linhagem Celular , Movimento Celular , Cerebrosídeo Sulfatase/genética , Técnicas de Cocultura , Modelos Animais de Doenças , Indução Enzimática , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Células-Tronco Pluripotentes Induzidas/enzimologia , Leucodistrofia Metacromática/enzimologia , Leucodistrofia Metacromática/genética , Leucodistrofia Metacromática/fisiopatologia , Camundongos Endogâmicos NOD , Camundongos SCID , Regeneração Nervosa , Células-Tronco Neurais/enzimologia , Fenótipo , Sulfoglicoesfingolipídeos/metabolismo , TranscriptomaRESUMO
Inborn errors of metabolism (IEM) comprise an assorted group of inherited diseases, some of which are due to disordered lysosomal or peroxisomal function and some of which might be improved following hematopoietic cell transplantation (HCT). In these disorders the onset in infancy or early childhood is typically accompanied by rapid deterioration, resulting in early death in the more severe phenotypes. Timely diagnosis and immediate referral to an IEM specialist are essential steps in optimal management. Treatment recommendations are based on the diagnosis, its phenotype, rate of progression, prior extent of disease, family values, and expectations, and the risks and benefits associated with available therapies, including HCT. International collaborative efforts are of utmost importance in determining outcomes of therapy for these rare diseases, and have improved those outcomes significantly over the last decades. In this review, we will focus on the neurodevelopmental outcomes after HCT in IEM, providing an international perspective on progress, limitations, and future directions.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Erros Inatos do Metabolismo/terapia , Transtornos do Neurodesenvolvimento/fisiopatologia , Adrenoleucodistrofia/complicações , Adrenoleucodistrofia/fisiopatologia , Adrenoleucodistrofia/psicologia , Adrenoleucodistrofia/terapia , Humanos , Leucodistrofia de Células Globoides/complicações , Leucodistrofia de Células Globoides/fisiopatologia , Leucodistrofia de Células Globoides/psicologia , Leucodistrofia de Células Globoides/terapia , Leucodistrofia Metacromática/complicações , Leucodistrofia Metacromática/fisiopatologia , Leucodistrofia Metacromática/psicologia , Leucodistrofia Metacromática/terapia , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/fisiopatologia , Erros Inatos do Metabolismo/psicologia , Mucopolissacaridose I/complicações , Mucopolissacaridose I/fisiopatologia , Mucopolissacaridose I/psicologia , Mucopolissacaridose I/terapia , Transtornos do Neurodesenvolvimento/etiologia , Transtornos do Neurodesenvolvimento/psicologiaAssuntos
Transplante de Células-Tronco Hematopoéticas , Leucodistrofia Metacromática/terapia , Adolescente , Adulto , Criança , Pré-Escolar , Cognição , Estudos de Coortes , Humanos , Leucodistrofia Metacromática/epidemiologia , Leucodistrofia Metacromática/fisiopatologia , Países Baixos/epidemiologia , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
The purpose of this study was to determine whether transplantation of umbilical cord blood from unrelated donors before the development of symptoms could halt the progression of early juvenile onset cases of MLD in whom the disease was diagnosed based on the family history. Three asymptomatic children (aged 2 years 4 months, 2 years 8 months and 5 years 5 months, two of whom were sisters) underwent unrelated umbilical cord blood transplantation (UCBT) and two untreated symptomatic siblings were included in the study. In 14-year and 6-year follow-ups after transplantation, clinical examination, ARSA enzyme levels, neurophysiological, neuroimaging, and psychological status were assessed. All three transplanted patients remain well, and the parameters evaluated remain stable. Of the treated patients, the two sisters had ongoing evidence of demyelinating sensorimotor neuropathy on nerve conduction tests, and with a early sensorimotor neuropathy in the older sister , and the other patient has mild intellectual impairment. One of the two un-transplanted controls, 15 years after MLD diagnosis, has relentlessly progressed to full dependency with epilepsy, severe mental retardation, dystonic movements, dysphagia and recurrent respiratory problems. Six years after diagnosis, the other control has a slowly progressive course with spastic dystonic quadriplegia, epilepsy, dysphagia, continual drooling and incontinence. Our data show that, in comparison with their untreated siblings, UCBT significantly slowed the progression of the disease in the treated patients. We conclude that UCBT benefits children with pre-symptomatic early juvenile onset MLD by favourably altering the natural history of the disease.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Leucodistrofia Metacromática/terapia , Pré-Escolar , Feminino , Seguimentos , Humanos , Leucodistrofia Metacromática/genética , Leucodistrofia Metacromática/patologia , Leucodistrofia Metacromática/fisiopatologia , Masculino , Irmãos , Transplante Homólogo/métodos , Resultado do TratamentoRESUMO
BACKGROUND: Sulfatides, the most abundant glycosphingolipids, are a major component of myelin. They are degraded by the combined action of sphingolipid activator protein and arylsulfatase A. Deficiency of either of these entities causes metachromatic leukodystrophy (MLD). On the basis of age of onset, this entity is divided into late infantile, juvenile, and adult subtypes. Late infantile form, the commonest subtype, can exhibit peripheral neuropathy as the initial manifestation. The other two forms usually manifest peripheral neuropathy later in the disease course. PATIENT: A 1.5-year-old girl with preexisting isolated motor delay presented with acute-onset ascending flaccid quadriparesis, ptosis, and respiratory failure. Ptosis and respiratory failure responded completely to intravenous immunoglobulin, whereas quadriparesis showed minimal improvement. Nerve biopsy revealed metachromatic granules with demyelination, and serum arylsulfatase A levels were undetectable. CONCLUSION: The severity and nature of the disease coupled with the response to immunotherapy makes this case unusual. This child may represent either an atypical presentation of MLD with coincidental response to immunotherapy or an episode of immune mediated neuropathy in an individual with already diseased nerves due to MLD.
Assuntos
Leucodistrofia Metacromática/diagnóstico , Diagnóstico Diferencial , Feminino , Humanos , Lactente , Leucodistrofia Metacromática/patologia , Leucodistrofia Metacromática/fisiopatologia , Leucodistrofia Metacromática/terapia , Nervos Periféricos/patologia , Nervos Periféricos/fisiopatologia , Polirradiculoneuropatia/diagnósticoRESUMO
Metachromatic leukodystrophy (MLD) is an inherited demyelinating disease that causes progressive neurologic deterioration, leading to severe motor disability, developmental regression, seizures, blindness, deafness, and death. The disease presents as a late-infantile, juvenile, or adult form. Hematopoietic stem cell transplantation has been shown to slow disease progression. The purpose of this longitudinal study was to evaluate long-term treatment outcomes after unrelated donor umbilical cord blood (UCB) transplantation in pediatric patients according to disease burden and age at onset (ie, late-infantile versus juvenile). Engraftment, survival, treatment-related toxicity, graft-versus-host disease, neurophysiologic measures, and neurodevelopmental function were assessed. To evaluate whether signal intensity abnormalities on magnetic resonance imaging (ie, modified Loes scores) predict post-transplant cognitive and gross motor development, a general linear mixed model was fit to the data. Twenty-seven patients underwent transplantation after myeloablative chemotherapy; 24 patients engrafted after the initial transplantation. Seven patients died of infection, regimen-related toxicity, or disease progression. Twenty patients (6 with late-infantile onset and 14 with juvenile onset) were followed for a median of 5.1 years (range, 2.4 to 14.7). We found that patients with motor function symptoms at the time of transplant did not improve after transplantation. Brainstem auditory evoked responses, visual evoked potentials, electroencephalogram, and/or peripheral nerve conduction velocities stabilized or improved in juvenile patients but continued to worsen in most patients with the late-infantile presentation. Pretransplant modified Loes scores were highly correlated with developmental outcomes and predictive of cognitive and motor function. Children who were asymptomatic at the time of transplantation benefited most from the procedure. Children with juvenile onset and minimal symptoms showed stabilization or deterioration of motor skills but maintained cognitive skills. Overall, children with juvenile onset had better outcomes than those with late-infantile onset. As in other leukodystrophies, early intervention correlated with optimal outcomes. We conclude that UCB transplantation benefits children with presymptomatic late-infantile MLD or minimally symptomatic juvenile MLD.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Doença Enxerto-Hospedeiro/terapia , Leucodistrofia Metacromática/terapia , Agonistas Mieloablativos/uso terapêutico , Adolescente , Idade de Início , Criança , Pré-Escolar , Progressão da Doença , Eletroencefalografia , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/fisiopatologia , Humanos , Lactente , Leucodistrofia Metacromática/diagnóstico , Leucodistrofia Metacromática/mortalidade , Leucodistrofia Metacromática/fisiopatologia , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Destreza Motora/efeitos dos fármacos , Condução Nervosa/efeitos dos fármacos , Análise de Sobrevida , Resultado do Tratamento , Doadores não RelacionadosRESUMO
Unrelated umbilical cord blood transplantation (UCBT) was used to treat three siblings with juvenile metachromatic leukodystrophy (jMLD). The efficacy of this therapy was measured over a 5-year period with serial neurological examinations, neuroimaging, nerve conduction studies (NCS), and neuropsychological evaluations (NPE). Outcomes were a function of disease stage at time of UCBT with alteration of disease course occurring in the first 2 years after UCBT and then subsequent halting of progression and stabilization of symptoms and disease.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Leucodistrofia Metacromática/terapia , Adolescente , Encéfalo/diagnóstico por imagem , Encéfalo/enzimologia , Encéfalo/patologia , Cerebrosídeo Sulfatase/genética , Cerebrosídeo Sulfatase/metabolismo , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Leucodistrofia Metacromática/diagnóstico , Leucodistrofia Metacromática/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Cintilografia , Irmãos , Resultado do TratamentoRESUMO
We evaluated the autonomic control of the cardiovascular system and the skin innervation of a patient from a new Italian family with a genetically proven diagnosis of adult-onset autosomal dominant leukodystrophy (ADLD) due to lamin B1 gene duplication. Cardiovascular reflexes and pharmacological assessment indicated a selective sympathetic failure, sparing cardiovagal function. Microneurography revealed absent sympathetic activity. The evaluation of autonomic innervation of skin annexes showed severely depleted and morphologically abnormal noradrenergic dopamine-ß-hydroxylase (DßH) immunoreactive fibres with preserved cholinergic vasoactive intestinal polypeptide (VIP) immunoreactive fibres. This peculiar autonomic dysfunction may represent a hallmark for ADLD.
Assuntos
Doenças do Sistema Nervoso Autônomo/etiologia , Doenças do Sistema Nervoso Autônomo/fisiopatologia , Leucodistrofia Metacromática/complicações , Leucodistrofia Metacromática/fisiopatologia , Norepinefrina/deficiência , Genes Dominantes/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Norepinefrina/biossínteseRESUMO
Haematopoietic stem cell transplantation has an unproven role in the management of late-onset metachromatic leukodystrophy: theoretically justified through the engraftment of enzyme-replete haematopoietic progenitors and restoration of capacity for sulphatide catabolism in neural tissue through enzyme recapture, the long-term outcome is unknown. The rarity of the psycho-cognitive variant and slow progression of late-onset disease impairs evaluation of treatment. We report detailed clinical and neuropsychological assessments after haematopoietic stem-cell transplantation in a patient with a late-onset psycho-cognitive form of metachromatic leukodystrophy. Cognitive decline, indistinguishable from the natural course of the disease, was serially documented over 11 years despite complete donor chimaerism and correction of leukocyte arylsulphatase A to wild type values; subtle motor deterioration was similarly noted and progressive cerebral volume loss was evident upon magnetic resonance imaging. Sensory nerve conduction deteriorated 17 months post-transplantation with apparent stabilisation at 11-year review. Haematopoietic stem-cell transplantation was ineffective for this rare attenuated variant of metachromatic leukodystrophy. In the few patients identified pre-symptomatically or with early-phase disease, clear recommendations are lacking; when transplantation is considered, umbilical cord blood grafts from enzyme-replete donors with adjunctive mesenchymal stem cell infusions from the same source may be preferable. Improved outcomes will depend on enhanced awareness and early diagnosis of the disease, so that promising interventions such as genetically modified, autologous stem cell transplantation have the best opportunity of success.
Assuntos
Transtornos Cognitivos/etiologia , Cognição , Transplante de Células-Tronco Hematopoéticas , Leucodistrofia Metacromática/cirurgia , Adulto , Idade de Início , Cerebrosídeo Sulfatase/sangue , Cerebrosídeo Sulfatase/deficiência , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/enzimologia , Transtornos Cognitivos/fisiopatologia , Transtornos Cognitivos/psicologia , Progressão da Doença , Feminino , Humanos , Leucócitos/enzimologia , Leucodistrofia Metacromática/complicações , Leucodistrofia Metacromática/diagnóstico , Leucodistrofia Metacromática/enzimologia , Leucodistrofia Metacromática/fisiopatologia , Leucodistrofia Metacromática/psicologia , Imageamento por Ressonância Magnética , Condução Nervosa , Exame Neurológico , Testes Neuropsicológicos , Fatores de Tempo , Falha de Tratamento , Adulto JovemRESUMO
Metachromatic leukodystrophy (MLD) is a rare lysosomal sphingolipid storage disorder, caused by a deficiency of arylsulfatase A (ASA). It is inherited in an autosomal recessive way, among Caucasians three causing alleles are frequent. Demyelination is the hallmark of MLD. Interest in the disease has increased as therapeutic options such as stem cell transplantation, enzyme replacement and gene therapy are topics of current research. A late-infantile (onset before 3 years of age), a juvenile form (onset before 16 years) and an adult form are usually distinguished. Rapid motor decline is typical for the first and also the second forms, the second may be preceded by cognitive and behavioural problems, which mainly characterize the adult form. There is evidence for a genotype-phenotype correlation: patients homozygous for alleles which do not allow the expression of any enzyme activity (null-allele) suffer from the late infantile form; heterozygosity for a null allele and a non-null allele are more associated with the juvenile form and homozygosity for non-null alleles is more frequent in the most attenuated adult onset form.
Assuntos
Leucodistrofia Metacromática , Estudos de Associação Genética , Humanos , Leucodistrofia Metacromática/diagnóstico , Leucodistrofia Metacromática/genética , Leucodistrofia Metacromática/fisiopatologia , Leucodistrofia Metacromática/terapia , Diagnóstico Pré-Natal , Transplante de Células-TroncoAssuntos
Doenças Desmielinizantes/fisiopatologia , Doenças Desmielinizantes/terapia , Esclerose Múltipla/fisiopatologia , Esclerose Múltipla/terapia , Animais , Doenças Desmielinizantes/imunologia , Humanos , Fatores Imunológicos/uso terapêutico , Leucodistrofia Metacromática/patologia , Leucodistrofia Metacromática/fisiopatologia , Imageamento por Ressonância Magnética/métodos , Transplante de Células-Tronco Mesenquimais/métodos , Transplante de Células-Tronco Mesenquimais/tendências , Esclerose Múltipla/imunologia , Polirradiculoneuropatia/patologia , Polirradiculoneuropatia/fisiopatologiaRESUMO
Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) and familial pigmentary orthochromatic leukodystrophy (POLD) present as adult-onset dementia with motor impairment and epilepsy. They are regarded as distinct diseases. We review data from the literature that support their being a single entity. Apart from a slightly older age at onset, a more rapid course, and more prominent pyramidal tract involvement, familial POLD is clinically similar to HDLS. Moreover, the pathologic hallmarks of the two diseases, axonal spheroids in HDLS and pigmented macrophages in POLD, can be identified in both conditions. This supports HDLS and POLD being referred collectively as adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).
Assuntos
Axônios/patologia , Demência Vascular/patologia , Demência/patologia , Leucodistrofia Metacromática/patologia , Degeneração Walleriana/patologia , Idade de Início , Demência/fisiopatologia , Demência Vascular/fisiopatologia , Progressão da Doença , Humanos , Leucodistrofia Metacromática/fisiopatologia , Macrófagos/patologia , Neuroglia/patologia , Degeneração Walleriana/fisiopatologiaRESUMO
Three siblings with metachromatic leukodystrophy underwent umbilical cord blood transplantation at different stages of disease. Neuroimaging, nerve conduction studies, neurological examinations, and neuropsychological examinations were used to measure outcome over 2 years. After transplant, the oldest sibling experienced disease progression. His two siblings had near or total resolution of signal abnormalities on neuroimaging. Their neuropsychological testing remained stable, and nerve conduction studies have shown improvement. These results indicate pretransplantation neurological examinations may be the most significant predictor of outcome after transplant. To our knowledge, this report is the first to document neurological outcome of metachromatic leukodystrophy treated by umbilical cord blood transplantation.
Assuntos
Encéfalo/patologia , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Leucodistrofia Metacromática/diagnóstico , Leucodistrofia Metacromática/terapia , Fatores Etários , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Criança , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/prevenção & controle , Progressão da Doença , Diagnóstico Precoce , Feminino , Humanos , Lactente , Leucodistrofia Metacromática/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Condução Nervosa/fisiologia , Exame Neurológico , Testes Neuropsicológicos , Avaliação de Resultados em Cuidados de Saúde/métodos , Valor Preditivo dos Testes , Prognóstico , Resultado do TratamentoRESUMO
A review is presented of the major clinical features of a number of glycolipidoses including Fabry, Gaucher, Tay-Sachs, metachromatic leukodystrophy as well as CeroidLipofucinosis and Sjogren-Larsson syndrome. The possibilities offered by lipidomics for diagnosis and follow-up after enzyme replacement therapy are presented from a practical perspective. The contribution of HPLC coupled with tandem mass spectrometry has considerably simplified the detection and assay of abnormal metabolites. Corresponding internal standards consisting of weighed mixtures of the stable-isotope labeled metabolites required to calibrate and quantitate lipid components of these orphan diseases standards have yet to become commercially available. A lipidomics approach has been found to compare favorably with DNA-sequence analysis for the rapid diagnosis of pre-birth syndromes resulting from these multiple gene defects. The method also seems to be suitable for screening applications in terms of a high throughput combined with a low rate of false diagnoses based on the wide differences in metabolite concentrations found in affected patients as compared with normal subjects. The practical advantages of handling samples for lipidomic diagnoses as compared to enzyme assay are presented for application to diagnosis during pregnancy.
Assuntos
Terapia Enzimática , Genômica/métodos , Lipidoses/diagnóstico , Lipídeos/química , Doença de Fabry/diagnóstico , Doença de Fabry/fisiopatologia , Doença de Fabry/terapia , Doença de Gaucher/diagnóstico , Doença de Gaucher/fisiopatologia , Doença de Gaucher/terapia , Humanos , Leucodistrofia Metacromática/diagnóstico , Leucodistrofia Metacromática/fisiopatologia , Leucodistrofia Metacromática/terapia , Lipidoses/enzimologia , Lipidoses/terapia , Lipofuscinoses Ceroides Neuronais/diagnóstico , Lipofuscinoses Ceroides Neuronais/fisiopatologia , Lipofuscinoses Ceroides Neuronais/terapia , Síndrome de Sjogren-Larsson/diagnóstico , Síndrome de Sjogren-Larsson/fisiopatologia , Síndrome de Sjogren-Larsson/terapia , Doença de Tay-Sachs/diagnóstico , Doença de Tay-Sachs/fisiopatologia , Doença de Tay-Sachs/terapiaRESUMO
Neural stem cells appear to be best suited for regenerative therapy in neurological diseases. However, the effects of high levels of potentially toxic substances such as sulfatides--which accumulate in metachromatic leukodystrophy (MLD)--on this regenerative ability are still largely unclear. To start addressing this question, in vitro and in vivo experiments were used to examine the behavior of multipotential neural precursors exposed to abnormally high levels of sulfatides. Following transplantation of dissociated neurospheres into the brain of presymptomatic MLD pups, the majority of donor-derived cells were distributed in a caudal to rostral direction, with higher numbers in the cortex. Most if not all of the donor cells acquired an astroglial phenotype. We found no evidence of oligodendrocyte or neuronal commitment of transplanted cells in long-term-treated MLD mice (e.g. up to 1.5 years of age). This was in line with our in vitro findings of sulfatides blocking oligodendrocyte formation after induction of differentiation in sulfatide-treated epidermal growth factor/fibroblast growth factor responsive neurospheres. Transplanted MLD mice showed an improved arylsulfatase A (ARSA) activity and a significant amelioration of sulfatide metabolism, neurodegeneration and motor-learning/memory deficits. Furthermore, transplanted cells were shown to act as a source of ARSA enzyme that accumulated in endogenous brain cells, indicating the occurrence of enzyme cross-correction between transplanted and host cells. These results provide a first insight into the effect of sulfatides on the stemness properties of neural stem cells and on the effects of the MLD environment on the in vivo expectations of using neural stem cells in cell therapy.
Assuntos
Encéfalo , Leucodistrofia Metacromática , Neurônios/fisiologia , Oligodendroglia/fisiologia , Transplante de Células-Tronco , Células-Tronco/fisiologia , Animais , Animais Recém-Nascidos , Comportamento Animal/fisiologia , Encéfalo/citologia , Encéfalo/fisiopatologia , Diferenciação Celular , Sobrevivência Celular , Células Cultivadas , Cerebrosídeo Sulfatase/genética , Cerebrosídeo Sulfatase/metabolismo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Leucodistrofia Metacromática/fisiopatologia , Leucodistrofia Metacromática/terapia , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/fisiologia , Neurônios/citologia , Oligodendroglia/citologia , Células-Tronco/citologia , Sulfoglicoesfingolipídeos/metabolismoRESUMO
A 29-year-old female patient with juvenile metachromatic leukodystrophy diagnosed at age 14 years received a bone marrow transplant at age 16 years. A report was published 6 years after bone marrow transplantation concluding that the disease had slowly progressed in the 2 years following bone marrow transplantation. We now report on a further 7-year follow-up, typified by a steady state of spastic paraplegia and mild dementia. Neurophysiological, neuroradiological, and psychological status also remained stable. In the patient's leukocytes, the activity of arylsulfatase A, the enzyme deficient in untreated metachromatic leukodystrophy, was within the normal range whereas urinary sulfatides remained elevated. Data on the natural course of juvenile metachromatic leukodystrophy are rare, so in the present case it is difficult to establish whether the rather favorable course can be attributed with certainty to bone marrow transplantation. The long-term stabilization in this patient, however, suggested that bone marrow transplantation may halt the progression of juvenile metachromatic leukodystrophy.
Assuntos
Transplante de Medula Óssea/estatística & dados numéricos , Leucodistrofia Metacromática/fisiopatologia , Leucodistrofia Metacromática/terapia , Adolescente , Adulto , Transplante de Medula Óssea/tendências , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Cerebrosídeo Sulfatase/metabolismo , Demência/etiologia , Demência/fisiopatologia , Deficiências do Desenvolvimento/etiologia , Deficiências do Desenvolvimento/fisiopatologia , Progressão da Doença , Potenciais Evocados Auditivos/fisiologia , Feminino , Seguimentos , Humanos , Deficiência Intelectual/etiologia , Deficiência Intelectual/fisiopatologia , Leucodistrofia Metacromática/metabolismo , Condução Nervosa/fisiologia , Paraplegia/etiologia , Paraplegia/fisiopatologia , Nervos Periféricos/metabolismo , Nervos Periféricos/fisiopatologia , Tempo , Resultado do TratamentoRESUMO
Metachromatic leukodystrophy (MLD) is a demyelinating storage disease caused by deficiency of the lysosomal enzyme arylsulfatase A (ARSA). Lack of ARSA activity leads to the accumulation of galactosylceramide-3-O-sulfate (sulfatide) in the central and peripheral nervous systems. Based on the age at onset, the disease is usually classified into three forms: the late-infantile form, which manifests in the second year of life; the juvenile variants (onset between 4 and 12 years), which are subdivided into early-juvenile (EJ, onset before 6 years) and late-juvenile (LJ, onset after 6 years); and the adult form (onset after 12 years of age). Currently, there is no efficient therapy for the late-infantile form of MLD (50% of the patients), death occurring within a few years after onset of neurological symptoms. Allogeneic haematopoietic cell transplantation (HCT), when performed at a very early stage of the disease, may improve selected patients with juvenile or adult forms of MLD. As with other lysosomal storage diseases, the physiopathology of MLD is poorly understood. Demyelination is the main pathological finding, but substantial storage of sulfatides in neurons also occurs, and may contribute to the clinical phenotype. The physiopathological process leading to neuronal and glial cell degeneration and apoptosis involves accumulation of undegraded sulfatides but also secondary abnormalities (storage/mislocalization of unrelated lipids, inflammatory processes). This review summarizes the recent advances in the understanding of the physiopathology of MLD and the new therapeutic perspectives currently under preclinical investigation, including enzyme replacement therapy, gene therapy and cell therapy.