RESUMO
BACKGROUND AND PURPOSE: Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous monogenic disorders. To date, nearly 70 genes are known to be causative. The aim of this project was to identify the genetic cause of autosomal dominantly inherited pure HSP in two large, unrelated non-consanguineous families. METHODS: The two families were characterized clinically and selected members underwent whole exome sequencing. Potentially disease-causing variants were confirmed by Sanger sequencing and their functional consequences on protein function were predicted by bioinformatic prediction tools. RESULTS: The patients presented with pure spastic paraplegia with age of onset between 9 and 46 years. In both families, a novel heterozygous missense variant in ERLIN2, c.386G>C; p.Ser129Thr, was the only potentially pathogenic variant identified that segregated with the disease. CONCLUSIONS: Biallelic variants in ERLIN2 are known to cause recessive HSP type SPG18. Here, the first two families with an autosomal dominant, pure form of HSP caused by a novel ERLIN2 heterozygous missense variant are described. These findings expand the mutational and inheritance spectrum of SPG18. ERLIN2 variants should also be considered in the diagnostic evaluation of patients with autosomal dominant HSP.
Assuntos
Heterozigoto , Proteínas de Membrana/genética , Mutação , Paraplegia Espástica Hereditária/genética , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , LinhagemRESUMO
Within the last decade, autoantibody-associated encephalitis and encephalomyelitis have stepped into the focus of clinical research and practice. Besides the "classic" autoantibodies against intracellular neuronal antigenes, a growing number of antibodies directed against pre- and postsynaptic surface proteins of neurons have been described since the millennium change. Whereas the "classic" are closely linked to paraneoplastic syndromes, this association is loose for most of the yet known surface antigen-antibodies. The immune-mediated encephalomyelitic syndromes are thus classified not only by their clinical symptoms, but also by their specific antibodies. The definition of the entity of N-methyl-D-aspartate-receptor encephalitis is a prominent example. The presented work gives an overview on the clinical and pathological correlates and the underlying immunologic processes of autoantibody-associated encephalitis from a neuropsychiatric perspective.
Assuntos
Doenças Autoimunes/complicações , Encefalomielite/etiologia , Autoanticorpos/imunologia , Doenças Autoimunes/imunologia , Doenças Autoimunes/terapia , Encefalomielite/imunologia , HumanosRESUMO
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a recently defined inflammatory central nervous system (CNS) disorder, prominently involving the brainstem and in particular the pons. The condition features a combination of clinical symptoms essentially referable to brainstem pathology and a characteristic magnetic resonance imaging (MRI) appearance with punctate and curvilinear gadolinium enhancement 'peppering' the pons. The radiological distribution is focused in the pons and adjacent rhombencephalic structures such as the cerebellar peduncles, cerebellum, medulla and the midbrain. While the lesion burden with a perivascular pattern is typically most dense in these pontine and peripontine regions, enhancing lesions may additionally extend into the spinal cord and supratentorial structures such as the thalamus, basal ganglia, capsula interna, corpus callosum and the cerebral white matter. Another core feature is clinical and radiological responsiveness to glucocorticosteroid (GCS)-based immunosuppression. As withdrawal of GCS treatment results commonly in disease exacerbation, long-term immunosuppressive therapy appears to be mandatory for sustained improvement. Diagnosis of CLIPPERS is challenging, and requires careful exclusion of alternative diagnoses. A specific serum or cerebrospinal fluid (CSF) biomarker for the disorder is currently not known. Pathogenesis of CLIPPERS remains poorly understood, and the nosological position of CLIPPERS has still to be established. Whether CLIPPERS represents an independent, actual new disorder or a syndrome that includes aetiologically heterogeneous diseases and/or their prestages remains a debated and not finally clarified issue. Clinicians and radiologists should be aware of this condition and its differential diagnoses, given that CLIPPERS constitutes a treatable condition and that patients may benefit from an early introduction of GCS ensued by long-term immunosuppression. Based on previous reports in literature - currently encompassing more than 50 reported cases of CLIPPERS - this review addresses clinical features, diagnostic criteria, differential diagnoses and therapeutic management of this peculiar disorder.
Assuntos
Doenças do Sistema Nervoso Central/diagnóstico , Doenças do Sistema Nervoso Central/tratamento farmacológico , Inflamação/diagnóstico , Inflamação/tratamento farmacológico , Ponte/patologia , Esteroides/uso terapêutico , Doenças do Sistema Nervoso Central/etiologia , Humanos , Inflamação/etiologia , Imageamento por Ressonância Magnética , NeuroimagemRESUMO
N,N-Diethyldithiocarbamate and its disulfide are used as pesticides, in industrial processes, and as therapeutic agents, providing numerous opportunities for human exposure. Animal studies and in vitro investigations have demonstrated adverse effects following exposure to dithiocarbamates. The ability of dithiocarbamates to decompose to parent amine and CS2 suggests that these adverse effects may be mediated through release of CS2. The toxicity of CS2 is well established, and covalent cross-linking of proteins has been presented as a potential molecular mechanism of CS2 induced neuropathy. In the present investigation the ability of N,N-diethyldithiocarbamate to effect covalent cross-linking of proteins under physiological conditions is examined. Using 13C NMR, cross-linking was observed to proceed through dithiocarbamate formation on protein amino groups followed by the production of bis(thiocarbamoyl) disulfide, dithiocarbamate ester, and thiourea cross-linking structures. The presence of bis(lysyl) thiourea cross-linking structures was verified by complete protein hydrolysis in conjunction with GC/MS. Generation of inter- and intramolecular cross-linking was established using denaturing polyacrylamide gel electrophoresis under reducing conditions and revealed that cross-linking proceeded more rapidly for N,N-diethyldithiocarbamate than for equimolar CS2 under similar conditions. Covalent cross-linking of solubilized neurofilament triplet proteins, the putative neurotoxic targets, was examined. Both N,N-diethyldithiocarbamate and CS2 were able to covalently cross-link the low molecular weight component of the neurofilament triplet proteins, but neither produced intermolecular cross-linking of the medium or high molecular weight component. These results establish that N,N-diethyldithiocarbamate promoted protein cross-linking occurs under physiological conditions and proceeds through liberation of CS2.(ABSTRACT TRUNCATED AT 250 WORDS)