RESUMO
Glycogen storage disease type IV (GSD IV) is an ultra-rare autosomal recessive disorder caused by pathogenic variants in GBE1 which results in reduced or deficient glycogen branching enzyme activity. Consequently, glycogen synthesis is impaired and leads to accumulation of poorly branched glycogen known as polyglucosan. GSD IV is characterized by a remarkable degree of phenotypic heterogeneity with presentations in utero, during infancy, early childhood, adolescence, or middle to late adulthood. The clinical continuum encompasses hepatic, cardiac, muscular, and neurologic manifestations that range in severity. The adult-onset form of GSD IV, referred to as adult polyglucosan body disease (APBD), is a neurodegenerative disease characterized by neurogenic bladder, spastic paraparesis, and peripheral neuropathy. There are currently no consensus guidelines for the diagnosis and management of these patients, resulting in high rates of misdiagnosis, delayed diagnosis, and lack of standardized clinical care. To address this, a group of experts from the United States developed a set of recommendations for the diagnosis and management of all clinical phenotypes of GSD IV, including APBD, to support clinicians and caregivers who provide long-term care for individuals with GSD IV. The educational resource includes practical steps to confirm a GSD IV diagnosis and best practices for medical management, including (a) imaging of the liver, heart, skeletal muscle, brain, and spine, (b) functional and neuromusculoskeletal assessments, (c) laboratory investigations, (d) liver and heart transplantation, and (e) long-term follow-up care. Remaining knowledge gaps are detailed to emphasize areas for improvement and future research.
Assuntos
Doença de Depósito de Glicogênio Tipo IV , Doença de Depósito de Glicogênio , Doenças Neurodegenerativas , Pré-Escolar , Humanos , Doença de Depósito de Glicogênio Tipo IV/diagnóstico , Doença de Depósito de Glicogênio Tipo IV/genética , Doença de Depósito de Glicogênio Tipo IV/terapia , Doença de Depósito de Glicogênio/diagnóstico , Doença de Depósito de Glicogênio/genética , Doença de Depósito de Glicogênio/terapia , GlicogênioRESUMO
There is increasing evidence that whole exome sequencing (WES) has a high diagnostic yield and is cost-efficient for individuals with neurological phenotypes. However, there is limited data on the use of WES in non-Western populations, including populations with a high rate of consanguinity. Retrospective chart review was performed on 24 adults with undiagnosed neurological symptoms evaluated in genetics and neurology clinics in a tertiary care facility on the Arabian Peninsula, and had WES between 2014 and 2016. Definitive diagnoses were made in 13/24 (54%) of cases. Of these, 5/13 (38%) revealed novel pathogenic variants. Of the known 19/24 (79%) consanguineous cases, diagnostic rate was slightly higher, 11/19 (58%) as compared to 2/5 (40%) among non-consanguineous cases. Autosomal recessive disorders comprised 10/13 (77%) of molecular diagnoses, all found to be due to homozygous pathogenic variants among consanguineous cases. WES in this cohort of adults with neurological symptoms had a high diagnostic rate likely due to high consanguinity rates in this population, as evidenced by the high diagnostic rate of homozygous pathogenic variants.
Assuntos
Consanguinidade , Sequenciamento do Exoma/métodos , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/genética , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
The regeneration of oligodendrocytes is a crucial step in recovery from demyelination, as surviving oligodendrocytes exhibit limited structural plasticity and rarely form additional myelin sheaths. New oligodendrocytes arise through the differentiation of platelet-derived growth factor receptor α (PDGFRα) expressing oligodendrocyte progenitor cells (OPCs) that are widely distributed throughout the CNS. Although there has been detailed investigation of the behavior of these progenitors in white matter, recent studies suggest that disease burden in multiple sclerosis (MS) is more strongly correlated with gray matter atrophy. The timing and efficiency of remyelination in gray matter is distinct from white matter, but the dynamics of OPCs that contribute to these differences have not been defined. Here, we used in vivo genetic fate tracing to determine the behavior of OPCs in gray and white matter regions in response to cuprizone-induced demyelination. Our studies indicate that the temporal dynamics of OPC differentiation varies significantly between white and gray matter. While OPCs rapidly repopulate the corpus callosum and mature into CC1 expressing mature oligodendrocytes, OPC differentiation in the cingulate cortex and hippocampus occurs much more slowly, resulting in a delay in remyelination relative to the corpus callosum. The protracted maturation of OPCs in gray matter may contribute to greater axonal pathology and disease burden in MS.
Assuntos
Cuprizona/toxicidade , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/patologia , Inibidores da Monoaminoxidase/toxicidade , Células Precursoras de Oligodendrócitos/efeitos dos fármacos , Fatores Etários , Animais , Proteínas Relacionadas à Autofagia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Diferenciação Celular/genética , Linhagem da Célula/efeitos dos fármacos , Linhagem da Célula/genética , Corpo Caloso/efeitos dos fármacos , Corpo Caloso/patologia , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , RNA não Traduzido/genética , RNA não Traduzido/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Remielinização/efeitos dos fármacos , Remielinização/fisiologiaRESUMO
Recessive mutations in GJA12/GJC2, the gene that encodes the gap junction protein connexin47 (Cx47), cause Pelizaeus-Merzbacher-like disease (PMLD), an early onset dysmyelinating disorder of the CNS, characterized by nystagmus, psychomotor delay, progressive spasticity and cerebellar signs. Here we describe three patients from one family with a novel recessively inherited mutation, 99C>G (predicted to cause an Ile>Met amino acid substitution; I33M) that causes a milder phenotype. All three had a late-onset, slowly progressive, complicated spastic paraplegia, with normal or near-normal psychomotor development, preserved walking capability through adulthood, and no nystagmus. MRI and MR spectroscopy imaging were consistent with a hypomyelinating leukoencephalopathy. The mutant protein forms gap junction plaques at cell borders similar to wild-type (WT) Cx47 in transfected cells, but fails to form functional homotypic channels in scrape-loading and dual whole-cell patch clamp assays. I33M forms overlapping gap junction plaques and functional channels with Cx43, however, I33M/Cx43 channels open only when a large voltage difference is applied to paired cells. These channels probably do not function under physiological conditions, suggesting that Cx47/Cx43 channels between astrocytes and oligodendrocytes are disrupted, similar to the loss-of-function endoplasmic reticulum-retained Cx47 mutants that cause PMLD. Thus, GJA12/GJC2 mutations can result in a milder phenotype than previously appreciated, but whether I33M retains a function of Cx47 not directly related to forming functional gap junction channels is not known.
Assuntos
Conexinas/genética , Mutação , Paraplegia Espástica Hereditária/genética , Adulto , Encéfalo/patologia , Conexina 43/genética , Conexina 43/metabolismo , Conexinas/metabolismo , Potenciais Evocados , Feminino , Células HeLa , Humanos , Imageamento por Ressonância Magnética , Masculino , Microscopia de Fluorescência , Pessoa de Meia-Idade , Técnicas de Patch-Clamp , Linhagem , Fenótipo , Paraplegia Espástica Hereditária/metabolismo , Paraplegia Espástica Hereditária/patologiaRESUMO
Genetic diseases demonstrate that the normal function of CNS myelin depends on connexin32 (Cx32) and Cx47, gap junction (GJ) proteins expressed by oligodendrocytes. GJs couple oligodendrocytes and astrocytes (O/A channels) as well as astrocytes themselves (A/A channels). Because astrocytes express different connexins (Cx30 and Cx43), O/A channels must be heterotypic, whereas A/A channels may be homotypic or heterotypic. Using electrophysiological and immunocytochemical approaches, we found that Cx47/Cx43 and Cx32/Cx30 efficiently formed functional channels, but other potential heterotypic O/A and A/A pairs did not. These results suggest that Cx30/Cx30 and Cx43/Cx43 channels mediate A/A coupling, and Cx47/Cx43 and Cx32/Cx30 channels mediate O/A coupling. Furthermore, Cx47/Cx43 and Cx32/Cx30 channels have distinct macroscopic and single-channel properties and different dye permeabilities. Finally, Cx47 mutants that cause Pelizaeus-Merzbacher-like disease do not efficiently form functional channels with Cx43, indicating that disrupted Cx47/Cx43 channels cause this disease.
Assuntos
Astrócitos/fisiologia , Conexinas/fisiologia , Junções Comunicantes/metabolismo , Canais Iônicos/fisiologia , Oligodendroglia/fisiologia , Astrócitos/metabolismo , Conexinas/química , Junções Comunicantes/química , Junções Comunicantes/fisiologia , Células HeLa , Humanos , Ativação do Canal Iônico/fisiologia , Canais Iônicos/química , Oligodendroglia/metabolismoRESUMO
In vertebrates, a family of related proteins called connexins form gap junctions (GJs), which are intercellular channels. In the central nervous system (CNS), GJs couple oligodendrocytes and astrocytes (O/A junctions) and adjacent astrocytes (A/A junctions), but not adjacent oligodendrocytes, forming a "glial syncytium." Oligodendrocytes and astrocytes each express different connexins. Mutations of these connexin genes demonstrate that the proper functioning of myelin and oligodendrocytes requires the expression of these connexins. The physiological function of O/A and A/A junctions, however, remains to be illuminated.
Assuntos
Astrócitos/metabolismo , Conexinas , Junções Comunicantes/metabolismo , Oligodendroglia/metabolismo , Animais , Astrócitos/citologia , Axônios/metabolismo , Axônios/ultraestrutura , Soluções Tampão , Conexinas/química , Conexinas/genética , Conexinas/metabolismo , Junções Comunicantes/ultraestrutura , Humanos , Modelos Moleculares , Bainha de Mielina/metabolismo , Oligodendroglia/citologia , Potássio/metabolismo , Conformação Proteica , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismoRESUMO
Oligodendrocyte generation in the adult CNS provides a means to adapt the properties of circuits to changes in life experience. However, little is known about the dynamics of oligodendrocytes and the extent of myelin remodeling in the mature brain. Using longitudinal in vivo two-photon imaging of oligodendrocytes and their progenitors in the mouse cerebral cortex, we show that myelination is an inefficient and extended process, with half of the final complement of oligodendrocytes generated after 4 months of age. Oligodendrocytes that successfully integrated formed new sheaths on unmyelinated and sparsely myelinated axons, and they were extremely stable, gradually changing the pattern of myelination. Sensory enrichment robustly increased oligodendrocyte integration, but did not change the length of existing sheaths. This experience-dependent enhancement of myelination in the mature cortex may accelerate information transfer in these circuits and strengthen the ability of axons to sustain activity by providing additional metabolic support.
Assuntos
Bainha de Mielina/fisiologia , Neurogênese/fisiologia , Oligodendroglia/fisiologia , Sensação/fisiologia , Córtex Somatossensorial/fisiologia , Envelhecimento/fisiologia , Animais , Animais Recém-Nascidos , Axônios/fisiologia , Encéfalo/crescimento & desenvolvimento , Encéfalo/fisiologia , Meio Ambiente , Feminino , Masculino , Camundongos , Plasticidade Neuronal/fisiologia , Estimulação Luminosa , Privação Sensorial , Células-TroncoRESUMO
A 6-year-old girl presented with a history of leg pain and cramping that progressively worsened over a 2- to 3-week period of time. Her examination was notable for normal vital signs, limited range of motion of her left hip, and a limp. Inflammatory markers were slightly elevated, but the serum electrolytes, calcium, and magnesium, complete blood cell count and differential, and creatine kinase level were normal. She was hospitalized for further diagnostic evaluation and was noted to have abnormal muscle movements classified as myokymia (continuous involuntary quivering, rippling, or undulating movement of muscles). Electromyography confirmed the myokymia but did not reveal evidence of a myopathy or neuropathy, prompting additional evaluation for a systemic etiology.
Assuntos
Neuroblastoma/diagnóstico , Síndromes Paraneoplásicas do Sistema Nervoso/diagnóstico , Criança , Feminino , Humanos , Perna (Membro) , Cãibra Muscular/etiologia , Mioquimia/etiologia , Neuroblastoma/complicações , Síndromes Paraneoplásicas do Sistema Nervoso/complicaçõesRESUMO
Recessive mutations in GJA12/Cx47, the gene encoding the gap junction protein connexin47 (Cx47), cause Pelizaeus-Merzbacher-like disease (PMLD), which is characterized by severe CNS dysmyelination. Three missense PMLD mutations, P87S, Y269D and M283T, were expressed in communication-incompetent HeLa cells, and in each case the mutant proteins appeared to at least partially accumulate in the ER. Cells expressing each mutant did not pass Lucifer Yellow or neurobiotin in scrape loading assays, in contrast to robust transfer in cells expressing wild type Cx47. Dual whole-cell patch clamping of transfected Neuro2A cells demonstrated that none of the mutants formed functional channels, in contrast to wild type Cx47. Immunostaining sections of primate brains demonstrated that oligodendrocytes express Cx47, which is primarily localized to their cell bodies. Thus, the Cx47 mutants associated with PMLD likely disrupt the gap junction coupling between astrocytes and oligodendrocytes.