RESUMEN
A 60-year-old Nigerian man, who had lived in Europe for 30 years but had returned home frequently, presented with right frontalis muscle weakness and right ulnar nerve palsy, without skin lesions. Neurophysiology showed a generalised neuropathy with demyelinating features. Blood tests were positive for HIV, with a normal CD4 count. There was nerve thickening both clinically and on MRI. Nerve biopsy showed chronic endoneuritis and perineuritis (indicating leprosy) without visible mycobacteria. His neuropathy continued to deteriorate (lepra reaction) before starting treatment with WHO multidrug therapy, highly active antiretroviral therapy and corticosteroids. There are 10 new cases of leprosy diagnosed annually in the UK. Coinfection with HIV is rare but paradoxically does not usually adversely affect the outcome of leprosy or change treatment. However, permanent nerve damage in leprosy is common despite optimal therapy. Leprosy should be considered in patients from endemic areas who present with mononeuritis multiplex.
Asunto(s)
Infecciones por VIH/complicaciones , Lepra/etiología , Biopsia , Complejo CD3/metabolismo , Infecciones por VIH/diagnóstico , Humanos , Lepra/diagnóstico por imagen , Lepra/virología , Linfocitos/metabolismo , Linfocitos/patología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Enfermedades del Sistema Nervioso Periférico/etiología , Enfermedades del Sistema Nervioso Periférico/virologíaRESUMEN
Hereditary spastic paraplegias (HSPs) are genetically and clinically heterogeneous axonopathies primarily affecting upper motor neurons and, in complex forms, additional neurons. Here, we report two families with distinct recessive mutations in TFG, previously suggested to cause HSP based on findings in a single small family with complex HSP. The first carried a homozygous c.317G>A (p.R106H) variant and presented with pure HSP. The second carried the same homozygous c.316C>T (p.R106C) variant previously reported and displayed a similarly complex phenotype including optic atrophy. Haplotyping and bisulfate sequencing revealed evidence for a c.316C>T founder allele, as well as for a c.316_317 mutation hotspot. Expression of mutant TFG proteins in cultured neurons revealed mitochondrial fragmentation, the extent of which correlated with clinical severity. Our findings confirm the causal nature of bi-allelic TFG mutations for HSP, broaden the clinical and mutational spectra, and suggest mitochondrial impairment to represent a pathomechanistic link to other neurodegenerative conditions.
Asunto(s)
Mutación Missense , Proteínas/genética , Proteínas/metabolismo , Paraplejía Espástica Hereditaria/patología , Animales , Células Cultivadas , Femenino , Predisposición Genética a la Enfermedad , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Ratones , Mitocondrias/patología , Neuronas/citología , Neuronas/metabolismo , Neuronas/patología , Linaje , Análisis de Secuencia de ADN , Paraplejía Espástica Hereditaria/genética , Paraplejía Espástica Hereditaria/metabolismoRESUMEN
The neuromuscular junction (NMJ) is a specialized synapse with a complex molecular architecture that provides for reliable transmission between the nerve terminal and muscle fiber. Using linkage analysis and whole-exome sequencing of DNA samples from subjects with distal hereditary motor neuropathy type VII, we identified a mutation in SLC5A7, which encodes the presynaptic choline transporter (CHT), a critical determinant of synaptic acetylcholine synthesis and release at the NMJ. This dominantly segregating SLC5A7 mutation truncates the encoded product just beyond the final transmembrane domain, eliminating cytosolic-C-terminus sequences known to regulate surface transporter trafficking. Choline-transport assays in both transfected cells and monocytes from affected individuals revealed significant reductions in hemicholinium-3-sensitive choline uptake, a finding consistent with a dominant-negative mode of action. The discovery of CHT dysfunction underlying motor neuropathy identifies a biological basis for this group of conditions and widens the spectrum of disorders that derive from impaired NMJ transmission. Our findings compel consideration of mutations in SLC5A7 or its functional partners in relation to unexplained motor neuronopathies.
Asunto(s)
Enfermedad de la Neurona Motora/genética , Enfermedad de la Neurona Motora/metabolismo , Terminales Presinápticos/metabolismo , Simportadores/genética , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Simportadores/metabolismoAsunto(s)
Autoanticuerpos/sangre , Moléculas de Adhesión Celular/sangre , Leucemia Linfocítica Crónica de Células B/sangre , Enfermedad de la Neurona Motora/sangre , Factores de Crecimiento Nervioso/sangre , Conducción Nerviosa/fisiología , Anciano , Humanos , Leucemia Linfocítica Crónica de Células B/complicaciones , Leucemia Linfocítica Crónica de Células B/diagnóstico por imagen , Masculino , Enfermedad de la Neurona Motora/complicaciones , Enfermedad de la Neurona Motora/diagnóstico por imagenRESUMEN
Notch signaling is a highly conserved intercellular pathway with tightly regulated and pleiotropic roles in normal tissue development and homeostasis. Dysregulated Notch signaling has also been implicated in human disease, including multiple forms of cancer, and represents an emerging therapeutic target. Successful development of such therapeutics requires a detailed understanding of potential on-target toxicities. Here, we identify autosomal dominant mutations of the canonical Notch ligand Jagged1 (or JAG1) as a cause of peripheral nerve disease in 2 unrelated families with the hereditary axonal neuropathy Charcot-Marie-Tooth disease type 2 (CMT2). Affected individuals in both families exhibited severe vocal fold paresis, a rare feature of peripheral nerve disease that can be life-threatening. Our studies of mutant protein posttranslational modification and localization indicated that the mutations (p.Ser577Arg, p.Ser650Pro) impair protein glycosylation and reduce JAG1 cell surface expression. Mice harboring heterozygous CMT2-associated mutations exhibited mild peripheral neuropathy, and homozygous expression resulted in embryonic lethality by midgestation. Together, our findings highlight a critical role for JAG1 in maintaining peripheral nerve integrity, particularly in the recurrent laryngeal nerve, and provide a basis for the evaluation of peripheral neuropathy as part of the clinical development of Notch pathway-modulating therapeutics.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth , Genes Dominantes , Proteína Jagged-1 , Mutación Missense , Transducción de Señal/genética , Sustitución de Aminoácidos , Animales , Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/metabolismo , Femenino , Glicosilación , Humanos , Proteína Jagged-1/genética , Proteína Jagged-1/metabolismo , Masculino , Ratones , Receptores Notch/genética , Receptores Notch/metabolismoRESUMEN
The importance of solute adsorption in the biofouling membrane has been clearly verified for the performance of membrane bioreactor (MBR). In order to quantify the mechanism of static adsorption in biofouling during of MBR process, we characterize membrane biofouling caused by model solutions containing a protein (bovine serum albumin, BSA), a humic substance (humic acid, HA) and a polysaccharide (alginic acid, Alg) on commercial hydrophilic polyethersulfone (PES) membrane. For static adsorption experiments, membranes were immersed in well-defined model solutions in three temperatures (298, 308 and 318 K) to obtain equilibrium data. To determine the characteristic parameters for this process, 7 isotherm models were applied to the experimental data. Three error analysis methods; the coefficient of nonlinear regression (R(2)), the sum of the squared errors (SSE) and standard deviation of residuals (S(yx)), were used to evaluate the data and determine the best fit isotherm for each model solutions. The error values demonstrated that the Sips isotherm model provided the best fit to the experimental data. AFM images were used for determination of changes in membrane surface after adsorption. These images confirmed the results obtained from adsorption isotherm study. Thermodynamic parameters such as standard free energy (Δ(r)G(θ)), enthalpy (Δ(r)H(θ)) and entropy (Δ(r)S(θ)) changes were determined; these adsorption processes were found to be feasible and endothermic but not spontaneous. The distribution of the substances adsorbed on PES surface were more chaotic than that in the aqueous solutions. Parameters obtained in this study can be used to determine the "fouling potential" of a given feed stream and a membrane.