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2.
Hum Mutat ; 40(7): 842-864, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30882951

RESUMO

Mutations in the GNPTAB and GNPTG genes cause mucolipidosis (ML) type II, type III alpha/beta, and type III gamma, which are autosomal recessively inherited lysosomal storage disorders. GNPTAB and GNPTG encode the α/ß-precursor and the γ-subunit of N-acetylglucosamine (GlcNAc)-1-phosphotransferase, respectively, the key enzyme for the generation of mannose 6-phosphate targeting signals on lysosomal enzymes. Defective GlcNAc-1-phosphotransferase results in missorting of lysosomal enzymes and accumulation of non-degradable macromolecules in lysosomes, strongly impairing cellular function. MLII-affected patients have coarse facial features, cessation of statural growth and neuromotor development, severe skeletal abnormalities, organomegaly, and cardiorespiratory insufficiency leading to death in early childhood. MLIII alpha/beta and MLIII gamma are attenuated forms of the disease. Since the identification of the GNPTAB and GNPTG genes, 564 individuals affected by MLII or MLIII have been described in the literature. In this report, we provide an overview on 258 and 50 mutations in GNPTAB and GNPTG, respectively, including 58 novel GNPTAB and seven novel GNPTG variants. Comprehensive functional studies of GNPTAB missense mutations did not only gain insights into the composition and function of the GlcNAc-1-phosphotransferase, but also helped to define genotype-phenotype correlations to predict the clinical outcome in patients.


Assuntos
Mucolipidoses/genética , Mutação , Transferases (Outros Grupos de Fosfato Substituídos)/genética , Éxons , Humanos , Íntrons , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/classificação , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/genética , Mucolipidoses/classificação , Fenótipo , Prognóstico , Domínios Proteicos , Transferases (Outros Grupos de Fosfato Substituídos)/química
3.
Biochem Biophys Res Commun ; 504(3): 623-628, 2018 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-29524416

RESUMO

Cholesterol, sphingolipids and glycerophospholipids are critical constituents of the brain, subserving neuronal membrane architecture and providing a platform for biochemical processes essential for proper neurodevelopment and function. When lysosomal defects arise in a lipid metabolic pathway, it is therefore easy to imagine that neurological decline will transpire, however for deficits in non-lipid pathways, this becomes harder to envisage. Here we suggest the working hypothesis that neurodegenerative lysosomal storage disorders might manifest as primary and/or secondary disorders of lipid metabolism. Evidence suggests that the mere process of lysosomal substrate accumulation, ubiquitous in all lysosomal storage disorders, impairs lysosome integrity resulting in secondary lipid accumulation. Impaired lysosomal degradation of a specific lipid defines a primary disorder of lipid metabolism and as these lysosomal storage disorders additionally show secondary lipid alterations, all primary disorders can also be considered secondary disorders of lipid metabolism. The outcome is a generalized cellular lipid dyshomeostasis and consequently, the physiological architecture of the lipid-enriched plasma membrane is perturbed, including the lipid composition of specialized membrane microdomains, often termed lipid rafts. Neurotoxicity results from the complex interplay of malfunctioning signaling and vesicular trafficking important for neuronal communication and synaptic plasticity-induced by the imbalance in physiological membrane lipid composition - together with compensatory mechanisms aimed at restoring lipid homeostasis.


Assuntos
Encéfalo/metabolismo , Metabolismo dos Lipídeos , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/metabolismo , Doenças Neurodegenerativas/metabolismo , Animais , Encéfalo/patologia , Homeostase , Humanos , Lipídeos de Membrana/metabolismo , Modelos Biológicos , Neurônios/metabolismo
4.
Hum Mol Genet ; 27(10): 1711-1722, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29514215

RESUMO

Defects in the MFSD8 gene encoding the lysosomal membrane protein CLN7 lead to CLN7 disease, a neurodegenerative lysosomal storage disorder belonging to the group of neuronal ceroid lipofuscinoses. Here, we have performed a SILAC-based quantitative analysis of the lysosomal proteome using Cln7-deficient mouse embryonic fibroblasts (MEFs) from a Cln7 knockout (ko) mouse model. From 3335 different proteins identified, we detected 56 soluble lysosomal proteins and 29 highly abundant lysosomal membrane proteins. Quantification revealed that the amounts of 12 different soluble lysosomal proteins were significantly reduced in Cln7 ko MEFs compared with wild-type controls. One of the most significantly depleted lysosomal proteins was Cln5 protein that underlies another distinct neuronal ceroid lipofuscinosis disorder. Expression analyses showed that the mRNA expression, biosynthesis, intracellular sorting and proteolytic processing of Cln5 were not affected, whereas the depletion of mature Cln5 protein was due to increased proteolytic degradation by cysteine proteases in Cln7 ko lysosomes. Considering the similar phenotypes of CLN5 and CLN7 patients, our data suggest that depletion of CLN5 may play an important part in the pathogenesis of CLN7 disease. In addition, we found a defect in the ability of Cln7 ko MEFs to adapt to starvation conditions as shown by impaired mammalian target of rapamycin complex 1 reactivation, reduced autolysosome tubulation and increased perinuclear accumulation of autolysosomes compared with controls. In summary, depletion of multiple soluble lysosomal proteins suggest a critical role of CLN7 for lysosomal function, which may contribute to the pathogenesis and progression of CLN7 disease.


Assuntos
Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/genética , Glicoproteínas de Membrana/genética , Proteínas de Membrana Transportadoras/genética , Lipofuscinoses Ceroides Neuronais/genética , Animais , Modelos Animais de Doenças , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/fisiopatologia , Lisossomos/genética , Lisossomos/metabolismo , Camundongos , Camundongos Knockout , Lipofuscinoses Ceroides Neuronais/fisiopatologia , Processamento de Proteína Pós-Traducional , Transporte Proteico/genética , Proteínas/genética , Serina-Treonina Quinases TOR/genética
5.
J Clin Lab Anal ; 32(5): e22375, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29314318

RESUMO

BACKGROUND: Carbamoyl phosphate synthetase 1 deficiency (CPS1D) is a rare autosomal recessive disorder of the urea cycle, mostly characterized by hyperammonemia and the concomitant leukodystrophy. The onset of CPS1D can be at any age, and the clinical manifestations are variable and atypical. Genetic tests are indispensable for accurate diagnosis of CPS1D on the basis of biochemical tests. METHODS: Blood tandem mass spectrometric analysis and urea organic acidemia screening were performed on a Chinese neonatal patient with low activity, recurrent seizures, and hyperammonemia. Next-generation sequencing and Sanger sequencing were followed up for making a definite diagnosis. Bioinformatics tools were used for the conservation analysis and pathogenicity predictions of the identified mutations. RESULTS: Increased lactate in urea and decreased citrulline in blood were detected in the patient. Two novel mutations (c.173G>T, p.G58V in exon 2 and c.796G>A, p.G266R in exon 8) in CPS1 identified in the neonatal patient were found through coseparation verification. Both of the two mutations were predicted to be deleterious, and the two relevant amino acids exerted highly evolutionarily conserved. The final diagnosis of the patient was compound heterozygous CPS1D. CONCLUSION: This study described the specific clinical characteristics and the variations of physiological and biochemical indices in a Chinese neonatal patient with CPS1D, which facilitated the diagnosis and mechanism research of the disease. Two novel causative missense mutations were identified, which enriched the mutation spectrum of CPS1D in China and worldwide. Advice of prenatal diagnosis was given to the family for a new pregnancy.


Assuntos
Carbamoil-Fosfato Sintase (Amônia)/genética , Doença da Deficiência da Carbamoil-Fosfato Sintase I/complicações , Doença da Deficiência da Carbamoil-Fosfato Sintase I/genética , Hiperamonemia/etiologia , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/etiologia , Mutação/genética , Carbamoil-Fosfato Sintase (Amônia)/metabolismo , Análise Mutacional de DNA , Saúde da Família , Feminino , Genótipo , Humanos , Masculino , Modelos Moleculares , Espectrometria de Massas em Tandem
6.
Rev Neurol ; 64(s03): S25-S28, 2017 May 17.
Artigo em Espanhol | MEDLINE | ID: mdl-28524215

RESUMO

INTRODUCTION: Individually, neurometabolic diseases are ultra rare, but for some of them there is an effective treatment. DEVELOPMENT: Several recent therapeutic advances are reviewed. Today, the possibilities of treatment for lysosomal diseases have improved. In recent years the use of enzyme replacement therapy has become more widely extended to treat mucopolysaccharidosis type IVA (Morquio A), mucopolysaccharidosis type VII (Sly syndrome), lysosomal acid lipase deficiency and alpha-mannosidosis. It has been proven that very early treatment of mucopolysaccharidoses can change their natural course. Intrathecal enzyme replacement therapy is being tried in some mucopolysaccharidoses with cognitive involvement, in an attempt to halt neurodegeneration. Very positive results have been obtained with genetically modified autotransplants in late-onset infantile metachromatic leukodystrophy and research is being conducted on other pathologies (mucopolysaccharidosis type III, X-linked adrenoleukodystrophy). Novel outcomes are also being achieved in the treatment of some encephalopathies that are sensitive to vitamins or cofactors: triple therapy in pyridoxine dependency, treatment with thiamine for some subacute encephalopathies with involvement of the basal ganglia, treatment with folinic acid for children with cerebral folate deficiency, or treatment with cyclic pyranopterin monophosphate in molybdenum cofactor deficiency type A. CONCLUSIONS: As neuropaediatricians we must update our knowledge, especially in the case of treatable neurometabolic pathologies, since early treatment can change their prognosis significantly.


Assuntos
Encefalopatias Metabólicas Congênitas/terapia , Intervenção Médica Precoce , Doenças do Sistema Nervoso/terapia , Terapias em Estudo , Deficiência de Vitaminas/terapia , Encefalopatias Metabólicas Congênitas/diagnóstico , Encefalopatias Metabólicas Congênitas/genética , Proteínas de Transporte/metabolismo , Criança , Ensaios Clínicos como Assunto , Coenzimas/deficiência , Coenzimas/uso terapêutico , Diagnóstico Precoce , Terapia de Reposição de Enzimas , Epilepsia/genética , Epilepsia/metabolismo , Epilepsia/terapia , Terapia Genética , Humanos , Recém-Nascido , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/tratamento farmacológico , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/genética , Doenças do Sistema Nervoso/diagnóstico
7.
J Neurochem ; 140(5): 703-717, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28027395

RESUMO

Alzheimer's disease (AD) is the most common cause of dementia, and its prevalence will increase significantly in the coming decades. Although important progress has been made, fundamental pathogenic mechanisms as well as most hereditary contributions to the sporadic form of the disease remain unknown. In this review, we examine the now substantial links between AD pathogenesis and lysosomal biology. The lysosome hydrolyses and processes cargo delivered by multiple pathways, including endocytosis and autophagy. The endo-lysosomal and autophagic networks are central to clearance of cellular macromolecules, which is important given there is a deficit in clearance of amyloid-ß in AD. Numerous studies show prominent lysosomal dysfunction in AD, including perturbed trafficking of lysosomal enzymes and accumulation of the same substrates that accumulate in lysosomal storage disorders. Examination of the brain in lysosomal storage disorders shows the accumulation of amyloid precursor protein metabolites, which further links lysosomal dysfunction with AD. This and other evidence leads us to hypothesise that genetic variation in lysosomal genes modifies the disease course of sporadic AD.


Assuntos
Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Autofagia , Lisossomos/patologia , Doença de Alzheimer/metabolismo , Animais , Humanos , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/patologia , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/fisiopatologia , Lisossomos/metabolismo
8.
Neurobiol Dis ; 98: 77-87, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27913291

RESUMO

Saposin deficiency is a childhood neurodegenerative lysosomal storage disorder (LSD) that can cause premature death within three months of life. Saposins are activator proteins that promote the function of lysosomal hydrolases that mediate the degradation of sphingolipids. There are four saposin proteins in humans, which are encoded by the prosaposin gene. Mutations causing an absence or impaired function of individual saposins or the whole prosaposin gene lead to distinct LSDs due to the storage of different classes of sphingolipids. The pathological events leading to neuronal dysfunction induced by lysosomal storage of sphingolipids are as yet poorly defined. We have generated and characterised a Drosophila model of saposin deficiency that shows striking similarities to the human diseases. Drosophila saposin-related (dSap-r) mutants show a reduced longevity, progressive neurodegeneration, lysosomal storage, dramatic swelling of neuronal soma, perturbations in sphingolipid catabolism, and sensory physiological deterioration. Our data suggests a genetic interaction with a calcium exchanger (Calx) pointing to a possible calcium homeostasis deficit in dSap-r mutants. Together these findings support the use of dSap-r mutants in advancing our understanding of the cellular pathology implicated in saposin deficiency and related LSDs.


Assuntos
Modelos Animais de Doenças , Proteínas de Drosophila/deficiência , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/metabolismo , Doenças Neurodegenerativas/metabolismo , Saposinas/deficiência , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Animais Geneticamente Modificados , Antiporters/genética , Antiporters/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Cálcio/metabolismo , Ceramidas/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster , Homeostase/fisiologia , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/patologia , Doenças Neurodegenerativas/patologia , Neuroglia/metabolismo , Neuroglia/patologia , Neurônios/metabolismo , Neurônios/patologia , Fenótipo , Saposinas/genética , Esfingosina/metabolismo , Análise de Sobrevida
10.
Brain ; 139(Pt 2): 317-37, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26715604

RESUMO

Single gene disorders of the autophagy pathway are an emerging, novel and diverse group of multisystem diseases in children. Clinically, these disorders prominently affect the central nervous system at various stages of development, leading to brain malformations, developmental delay, intellectual disability, epilepsy, movement disorders, and neurodegeneration, among others. Frequent early and severe involvement of the central nervous system puts the paediatric neurologist, neurogeneticist, and neurometabolic specialist at the forefront of recognizing and treating these rare conditions. On a molecular level, mutations in key autophagy genes map to different stages of this highly conserved pathway and thus lead to impairment in isolation membrane (or phagophore) and autophagosome formation, maturation, or autophagosome-lysosome fusion. Here we discuss 'congenital disorders of autophagy' as an emerging subclass of inborn errors of metabolism by using the examples of six recently identified monogenic diseases: EPG5-related Vici syndrome, beta-propeller protein-associated neurodegeneration due to mutations in WDR45, SNX14-associated autosomal-recessive cerebellar ataxia and intellectual disability syndrome, and three forms of hereditary spastic paraplegia, SPG11, SPG15 and SPG49 caused by SPG11, ZFYVE26 and TECPR2 mutations, respectively. We also highlight associations between defective autophagy and other inborn errors of metabolism such as lysosomal storage diseases and neurodevelopmental diseases associated with the mTOR pathway, which may be included in the wider spectrum of autophagy-related diseases from a pathobiological point of view. By exploring these emerging themes in disease pathogenesis and underlying pathophysiological mechanisms, we discuss how congenital disorders of autophagy inform our understanding of the importance of this fascinating cellular pathway for central nervous system biology and disease. Finally, we review the concept of modulating autophagy as a therapeutic target and argue that congenital disorders of autophagy provide a unique genetic perspective on the possibilities and challenges of pathway-specific drug development.


Assuntos
Autofagia/fisiologia , Encefalopatias Metabólicas Congênitas/genética , Encefalopatias Metabólicas Congênitas/metabolismo , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/genética , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/metabolismo , Agenesia do Corpo Caloso/diagnóstico , Agenesia do Corpo Caloso/genética , Agenesia do Corpo Caloso/metabolismo , Encefalopatias Metabólicas Congênitas/diagnóstico , Catarata/diagnóstico , Catarata/genética , Catarata/metabolismo , Humanos , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/diagnóstico , Lisossomos/genética , Lisossomos/metabolismo , Paraplegia Espástica Hereditária/diagnóstico , Paraplegia Espástica Hereditária/genética , Paraplegia Espástica Hereditária/metabolismo
11.
Cell Rep ; 12(12): 2009-20, 2015 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-26387958

RESUMO

Here, we evaluate the mechanisms underlying the neurodevelopmental deficits in Drosophila and mouse models of lysosomal storage diseases (LSDs). We find that lysosomes promote the growth of neuromuscular junctions (NMJs) via Rag GTPases and mechanistic target of rapamycin complex 1 (MTORC1). However, rather than employing S6K/4E-BP1, MTORC1 stimulates NMJ growth via JNK, a determinant of axonal growth in Drosophila and mammals. This role of lysosomal function in regulating JNK phosphorylation is conserved in mammals. Despite requiring the amino-acid-responsive kinase MTORC1, NMJ development is insensitive to dietary protein. We attribute this paradox to anaplastic lymphoma kinase (ALK), which restricts neuronal amino acid uptake, and the administration of an ALK inhibitor couples NMJ development to dietary protein. Our findings provide an explanation for the neurodevelopmental deficits in LSDs and suggest an actionable target for treatment.


Assuntos
Drosophila melanogaster/genética , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/genética , Lisossomos/metabolismo , MAP Quinase Quinase 4/genética , Complexos Multiproteicos/genética , Junção Neuromuscular/genética , Serina-Treonina Quinases TOR/genética , Quinase do Linfoma Anaplásico , Animais , Proteínas de Ligação ao Cálcio , Proteínas na Dieta/administração & dosagem , Modelos Animais de Doenças , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/metabolismo , Regulação da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/metabolismo , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/patologia , Lisossomos/efeitos dos fármacos , Lisossomos/patologia , MAP Quinase Quinase 4/metabolismo , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Complexos Multiproteicos/metabolismo , Junção Neuromuscular/efeitos dos fármacos , Junção Neuromuscular/metabolismo , Junção Neuromuscular/patologia , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de Sinais , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Sinapses/patologia , Serina-Treonina Quinases TOR/metabolismo
12.
Best Pract Res Clin Endocrinol Metab ; 29(2): 159-71, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25987170

RESUMO

Pharmacological research has always focused on developing new therapeutic strategies capable of modifying a disease's natural history and improving patients' quality of life. Despite recent advances within the fields of medicine and biology, some diseases still represent a major challenge for successful therapy. Neuronopathic lysosomal storage disorders, in particular, have high rates of morbidity and mortality and a devastating socio-economic effect. Many of the available therapies, such as enzyme replacement therapy, can reverse the natural history of the disease in peripheral organs but, unfortunately, are still unable to reach the central nervous system effectively because they cannot cross the blood-brain barrier that surrounds and protects the brain. Moreover, many lysosomal storage disorders are characterized by a number of blood-brain barrier dysfunctions, which may further contribute to disease neuropathology and accelerate neuronal cell death. These issues, and their context in the development of new therapeutic strategies, will be discussed in detail in this chapter.


Assuntos
Barreira Hematoencefálica/metabolismo , Terapia de Reposição de Enzimas/métodos , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Humanos , Infusões Intraventriculares , Infusão Espinal , Injeções Intraventriculares , Injeções Espinhais , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/metabolismo , Chaperonas Moleculares/uso terapêutico , Nanopartículas/uso terapêutico , Proteínas Recombinantes
13.
Eur Rev Med Pharmacol Sci ; 19(7): 1219-26, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25912581

RESUMO

Gaucher disease is a multisystemic disorder that affects men and woman in equal numbers and occurs in all ethnic groups at any age with racial variations and an estimated worldwide incidence of 1/75,000. It is caused by a genetic deficient activity of the lysosomal enzyme glucocerebrosidase due to mutations in the ß-glucocerebrosidase gene, and resulting in lack of glucocerebroside degradation. The subsequent accumulation of glucocerebroside in lysosomes of tissue macrophages primarily in the liver, bone marrow and spleen, causes damage in haematological, skeletal and nervous systems. The clinical manifestations show a high degree of variability with symptoms that varies according to organs involved. In many cases, these disorders do not correlate with mutations in the ß-glucocerebrosidase gene. Although several mutations have been identified as responsible for the deficient activity of glucocerebrosidase, mechanisms by which this enzymatic defect leads to Gaucher disease remain poorly understood. Recent reports indicate the implication of complex mechanisms, including enzyme deficiency, substrate accumulation, unfolded protein response, and macrophage activation. Further elucidating these mechanisms will advance understanding of Gaucher disease and related disorders.


Assuntos
Doença de Gaucher/enzimologia , Doença de Gaucher/genética , Glucosilceramidase/genética , Animais , Doença de Gaucher/diagnóstico , Glucosilceramidase/deficiência , Humanos , Fígado/enzimologia , Fígado/patologia , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/diagnóstico , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/enzimologia , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/genética , Mutação/genética , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/enzimologia , Doenças Neurodegenerativas/genética
14.
Neuromolecular Med ; 16(4): 821-44, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25280894

RESUMO

An ongoing challenge in children presenting with motor delay/impairment early in life is to identify neurogenetic disorders with a clinical phenotype, which can be misdiagnosed as cerebral palsy (CP). To help distinguish patients in these two groups, conventional magnetic resonance imaging of the brain has been of great benefit in "unmasking" many of these genetic etiologies and has provided important clues to differential diagnosis in others. Recent advances in molecular genetics such as chromosomal microarray and next-generation sequencing have further revolutionized the understanding of etiology by more precisely classifying these disorders with a molecular cause. In this paper, we present a review of neurogenetic disorders masquerading as cerebral palsy evaluated at one institution. We have included representative case examples children presenting with dyskinetic, spastic, and ataxic phenotypes, with the intent to highlight the time-honored approach of using clinical tools of history and examination to focus the subsequent etiologic search with advanced neuroimaging modalities and molecular genetic tools. A precise diagnosis of these masqueraders and their differentiation from CP is important in terms of therapy, prognosis, and family counseling. In summary, this review serves as a continued call to remain vigilant for current and other to-be-discovered neurogenetic masqueraders of cerebral palsy, thereby optimizing care for patients and their families.


Assuntos
Paralisia Cerebral/diagnóstico , Deficiências do Desenvolvimento/diagnóstico , Erros de Diagnóstico , Doenças Genéticas Inatas/diagnóstico , Técnicas de Diagnóstico Molecular , Doenças do Sistema Nervoso/diagnóstico , Adulto , Asfixia Neonatal/diagnóstico , Asfixia Neonatal/genética , Traumatismos do Nascimento/diagnóstico , Traumatismos do Nascimento/genética , Encéfalo/embriologia , Encefalopatias Metabólicas/diagnóstico , Encefalopatias Metabólicas/genética , Movimento Celular , Paralisia Cerebral/genética , Criança , Pré-Escolar , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Deficiências do Desenvolvimento/genética , Diagnóstico Diferencial , Exoma , Feminino , Doenças Genéticas Inatas/genética , Estudo de Associação Genômica Ampla , Genômica , Globo Pálido/patologia , Humanos , Hipóxia Encefálica/diagnóstico , Hipóxia Encefálica/genética , Recém-Nascido , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/genética , Leucoencefalopatias/metabolismo , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/diagnóstico , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/genética , Masculino , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Transtornos dos Movimentos/diagnóstico , Transtornos dos Movimentos/genética , Espasticidade Muscular/diagnóstico , Espasticidade Muscular/genética , Doenças do Sistema Nervoso/genética , Neurotransmissores/metabolismo , Acidente Vascular Cerebral/congênito , Acidente Vascular Cerebral/diagnóstico , Análise Serial de Tecidos
15.
Swiss Med Wkly ; 144: w14001, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25144910

RESUMO

The endoplasmic reticulum (ER) is an intracellular compartment dedicated to the synthesis and maturation of secretory and membrane proteins, totalling about 30% of the total eukaryotic cells proteome. The capacity to produce correctly folded polypeptides and to transport them to their correct intra- or extracellular destinations relies on proteostasis networks that regulate and balance the activity of protein folding, quality control, transport and degradation machineries. Nutrient and environmental changes, pathogen infection aging and, more relevant for the topics discussed in this review, mutations that impair attainment of the correct 3D structure of nascent polypeptide chains may compromise the activity of the proteostasis networks with devastating consequences on cells, organs and organisms' homeostasis. Here we present a review of mechanisms regulating folding and quality control of proteins expressed in the ER, and we describe the protein degradation and the ER stress pathways activated by the expression of misfolded proteins in the ER lumen. Finally, we highlight select examples of proteopathies (also known as conformational disorders or protein misfolding diseases) caused by protein misfolding in the ER and/or affecting cellular proteostasis and therapeutic interventions that might alleviate or cure the disease symptoms.


Assuntos
Estresse do Retículo Endoplasmático , Retículo Endoplasmático/metabolismo , Doenças Neurodegenerativas/metabolismo , Dobramento de Proteína , Deficiências na Proteostase/metabolismo , Deficiências na Proteostase/terapia , Fator 6 Ativador da Transcrição/metabolismo , Fibrose Cística/genética , Fibrose Cística/metabolismo , Endorribonucleases/metabolismo , Terapia de Reposição de Enzimas , Fator de Iniciação 2 em Eucariotos/metabolismo , Hemofilia A/genética , Hemofilia A/metabolismo , Humanos , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/genética , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/metabolismo , Chaperonas Moleculares/uso terapêutico , Doenças Neurodegenerativas/genética , Proteínas Serina-Treonina Quinases/metabolismo , Deficiências na Proteostase/genética , Transdução de Sinais , Resposta a Proteínas não Dobradas/efeitos dos fármacos , eIF-2 Quinase/metabolismo
16.
Metab Brain Dis ; 29(1): 1-8, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24307179

RESUMO

Lysosomal storage diseases are inherited metabolic disorders caused by genetic defects causing deficiency of various lysosomal proteins, and resultant accumulation of non-degraded compounds. They are multisystemic diseases, and in most of them (>70%) severe brain dysfunctions are evident. However, expression of various phenotypes in particular diseases is extremely variable, from non-neuronopathic to severely neurodegenerative in the deficiency of the same enzyme. Although all lysosomal storage diseases are monogenic, clear genotype-phenotype correlations occur only in some cases. In this article, we present an overview on various factors and processes, both general and specific for certain disorders, that can significantly modulate expression of phenotypes in these diseases. On the basis of recent reports describing studies on both animal models and clinical data, we propose a hypothesis that efficiency of production of compounds that cannot be degraded due to enzyme deficiency might be especially important in modulation of phenotypes of patients suffering from lysosomal storage diseases.


Assuntos
Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/patologia , Animais , Comportamento/fisiologia , Modelos Animais de Doenças , Progressão da Doença , Enzimas/genética , Enzimas/fisiologia , Interação Gene-Ambiente , Genótipo , Humanos , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/genética , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/metabolismo , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/psicologia , Lisossomos/enzimologia , Redes e Vias Metabólicas/genética , Redes e Vias Metabólicas/fisiologia , Camundongos , Camundongos Knockout , Modelos Biológicos , Neurônios/metabolismo , Penetrância , Fenótipo
17.
Dev Disabil Res Rev ; 17(3): 226-46, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23798011

RESUMO

BACKGROUND: The lysosomal-autophagocytic system diseases (LASDs) affect multiple body systems including the central nervous system (CNS). The progressive CNS pathology has its onset at different ages, leading to neurodegeneration and early death. METHODS: Literature review provided insight into the current clinical neurological findings, phenotypic spectrum, and pathogenic mechanisms of LASDs with primary neurological involvement. CONCLUSIONS: CNS signs and symptoms are variable and related to the disease-specific underlying pathogenesis. LAS dysfunction leads to diverse global cellular consequences in the CNS ranging from specific axonal and dendritic abnormalities to neuronal death. Pathogenic mechanisms for disease progression vary from impaired autophagy, massive storage, regional involvement, to end-stage inflammation. Some of these features are also found in adult neurodegenerative disorders, for example, Parkinson's and Alzheimer's diseases. Lack of effective therapies is a significant unmet medical need.


Assuntos
Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Transtornos Heredodegenerativos do Sistema Nervoso , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso , Animais , Progressão da Doença , Transtornos Heredodegenerativos do Sistema Nervoso/diagnóstico , Transtornos Heredodegenerativos do Sistema Nervoso/metabolismo , Transtornos Heredodegenerativos do Sistema Nervoso/patologia , Humanos , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/diagnóstico , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/metabolismo , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/patologia
18.
Dev Disabil Res Rev ; 17(3): 247-53, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23798012

RESUMO

Newborn screening (NBS) is a public health program aimed at identifying treatable conditions in presymptomatic newborns to avoid premature mortality, morbidity, and disabilities. Currently, every newborn in the Unites States is screened for at least 29 conditions where evidence suggests that early detection is possible and beneficial. With new or improved treatment options and development of high-throughput screening tests, additional conditions have been proposed for inclusion into NBS programs. Among those are several conditions with a strong neuronopathic component. Some of these conditions have already been added to a few national and international screening programs, whereas others are undergoing pilot studies to determine the test performance metrics. Here, we review the current state of NBS for 13 lysosomal storage disorders, X-adrenoleukodystrophy, Wilson disease, and Friedreich ataxia.


Assuntos
Ataxia de Friedreich/diagnóstico , Degeneração Hepatolenticular/diagnóstico , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/diagnóstico , Triagem Neonatal , Transtornos Peroxissômicos/diagnóstico , Diagnóstico Precoce , Humanos , Recém-Nascido , Estados Unidos
19.
Dev Disabil Res Rev ; 17(3): 269-82, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23798015

RESUMO

Lipid storage diseases, also known as the lipidoses, are a group of inherited metabolic disorders in which there is lipid accumulation in various cell types, including the central nervous system, because of the deficiency of a variety of enzymes. Over time, excessive storage can cause permanent cellular and tissue damage. The brain is particularly sensitive to lipid storage as the contents of the central nervous system must occupy uniform volume, and any increases in fluids or deposits will lead to pressure changes and interference with normal neurological function. In addition to primary lipid storage diseases, lysosomal storage diseases include the mucolipidoses (in which excessive amounts of lipids and carbohydrates are stored in the cells and tissues) and the mucopolysaccharidoses (in which abnormal glycosylated proteins cannot be broken down because of enzyme deficiency). Neurological dysfunction can be a manifestation of these conditions due to substrate deposition as well. This review will explore the modalities of neuroimaging that may have particular relevance to the study of the lipid storage disorder and their impact on elucidating aspects of brain function. First, the techniques will be reviewed. Next, the neuropathology of a few selected lipid storage disorders will be reviewed and the use of neuroimaging to define disease characteristics discussed in further detail. Examples of studies using these techniques will be discussed in the text.


Assuntos
Encéfalo/metabolismo , Encéfalo/patologia , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso , Imagem por Ressonância Magnética , Neuroimagem , Encéfalo/fisiopatologia , Imagem de Tensor de Difusão , Humanos , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/diagnóstico , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/metabolismo , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/patologia , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/fisiopatologia , Espectroscopia de Ressonância Magnética/métodos , Lipofuscinoses Ceroides Neuronais/diagnóstico , Transtornos Peroxissômicos/diagnóstico , Prótons
20.
J Inherit Metab Dis ; 36(3): 437-49, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23609350

RESUMO

The neurons of the central nervous system (CNS) require precise control of their bathing microenvironment for optimal function, and an important element in this control is the blood-brain barrier (BBB). The BBB is formed by the endothelial cells lining the brain microvessels, under the inductive influence of neighbouring cell types within the 'neurovascular unit' (NVU) including astrocytes and pericytes. The endothelium forms the major interface between the blood and the CNS, and by a combination of low passive permeability and presence of specific transport systems, enzymes and receptors regulates molecular and cellular traffic across the barrier layer. A number of methods and models are available for examining BBB permeation in vivo and in vitro, and can give valuable information on the mechanisms by which therapeutic agents and constructs permeate, ways to optimize permeation, and implications for drug discovery, delivery and toxicity. For treating lysosomal storage diseases (LSDs), models can be included that mimic aspects of the disease, including genetically-modified animals, and in vitro models can be used to examine the effects of cells of the NVU on the BBB under pathological conditions. For testing CNS drug delivery, several in vitro models now provide reliable prediction of penetration of drugs including large molecules and artificial constructs with promising potential in treating LSDs. For many of these diseases it is still not clear how best to deliver appropriate drugs to the CNS, and a concerted approach using a variety of models and methods can give critical insights and indicate practical solutions.


Assuntos
Barreira Hematoencefálica/anatomia & histologia , Barreira Hematoencefálica/fisiologia , Fármacos do Sistema Nervoso Central/administração & dosagem , Sistema Nervoso Central/metabolismo , Animais , Transporte Biológico/fisiologia , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Permeabilidade da Membrana Celular/fisiologia , Sistema Nervoso Central/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Descoberta de Drogas/métodos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/fisiologia , Homeostase/fisiologia , Humanos , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/tratamento farmacológico , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/metabolismo , Modelos Biológicos
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