RESUMEN
A Prussian blue analogue was synthesized using biomass leather waste as a precursor by doping with Co2+ ions. This material, demonstrates good performance in both the oxygen reduction reaction and oxygen evolution reaction, and exhibits excellent charge-discharge performance and stability in zinc-air batteries.
RESUMEN
Hereditary spastic paraplegia (HSP) is a group of genetic neurodegenerative disorders, which is characterized by the presence of progressive spasticity and weakness in bilateral lower limbs. Spastic paraplegia 62 (SPG62) caused by the endoplasmic reticulum lipid raft associated 1 (ERLIN1) gene mutation is a rare subtype of HSP. Herein, we report the case of the first Chinese SPG62 patient, explore the potential pathogenic mechanism and review ERLIN1-related HSP patients. A 23-year-old man had progressive difficulty in walking and gait abnormalities for more than 11 years. Physical examination showed slightly reduced muscle strength (5-/5) and elevated muscle tone in the lower limbs and hyperreflexia in four limbs. Genetic analysis identified a novel splicing site mutation in ERLIN1 gene (c.504+1G > A), which was predicted to disturb the normal splicing process of mRNA by bioinformatic tools. Minigene experiment further confirmed the mutation c.504+1G > A could cause erroneous deletion of Exon 7 in the mRNA, which may change the conserved prohibitin (PHB) domain of erlin-1 and affect the function of erlin1/2 complex. Thus, we identified a pathogenic mutation of ERLIN1 splicing site causing delayed-onset pure HSP. This study widened the genetic and phenotypic spectrum of SPG62.
Asunto(s)
Paraplejía Espástica Hereditaria , Adulto , Homocigoto , Humanos , Masculino , Mutación , Paraplejía/genética , Linaje , ARN Mensajero , Paraplejía Espástica Hereditaria/diagnóstico , Paraplejía Espástica Hereditaria/genética , Adulto JovenRESUMEN
BACKGROUND: Paroxysmal kinesigenic dyskinesia (PKD) is the most common type of paroxysmal dyskinesias. Only one-third of PKD patients are attributed to proline-rich transmembrane protein 2 (PRRT2) mutations. OBJECTIVE: We aimed to explore the potential causative gene for PKD. METHODS: A cohort of 196 PRRT2-negative PKD probands were enrolled for whole-exome sequencing (WES). Gene Ranking, Identification and Prediction Tool, a method of case-control analysis, was applied to identify the candidate genes. Another 325 PRRT2-negative PKD probands were subsequently screened with Sanger sequencing. RESULTS: Transmembrane Protein 151 (TMEM151A) variants were mainly clustered in PKD patients compared with the control groups. 24 heterozygous variants were detected in 25 of 521 probands (frequency = 4.80%), including 18 missense and 6 nonsense mutations. In 29 patients with TMEM151A variants, the ratio of male to female was 2.63:1 and the mean age of onset was 12.93 ± 3.15 years. Compared with PRRT2 mutation carriers, TMEM151A-related PKD were more common in sporadic PKD patients with pure phenotype. There was no significant difference in types of attack and treatment outcome between TMEM151A-positive and PRRT2-positive groups. CONCLUSIONS: We consolidated mutations in TMEM151A causing PKD with the aid of case-control analysis of a large-scale WES data, which broadens the genotypic spectrum of PKD. TMEM151A-related PKD were more common in sporadic cases and tended to present as pure phenotype with a late onset. Extensive functional studies are needed to enhance our understanding of the pathogenesis of TMEM151A-related PKD. © 2021 International Parkinson and Movement Disorder Society.
Asunto(s)
Corea , Distonía , Proteínas de la Membrana , Adolescente , Niño , Femenino , Humanos , Masculino , Corea/genética , Distonía/genética , Proteínas de la Membrana/metabolismo , Mutación/genética , FenotipoRESUMEN
CSF1R-related leukoencephalopathy is a rare white-matter encephalopathy characterized by motor and neuropsychiatric symptoms due to colony-stimulating factor 1 receptor (CSF1R) gene mutation. Few studies have investigated the intrinsic brain alternations of patients with CSF1R-related leukoencephalopathy. We aim to evaluate the structural and functional changes in those patients. Seven patients with CSF1R-related leukoencephalopathy and 15 age-matched healthy controls (HCs) underwent multimodal magnetic resonance imaging (MRI), including high-resolution T1-weighted imaging, T2-weighted fluid attenuated inversion recovery imaging, diffusion-weighted imaging, diffusion kurtosis imaging (DKI) and resting-state functional MRI. First, to detect structural alterations, the gray matter volumes were compared using voxel-based morphometry analyses. Second, DKI parametric maps were used to evaluate the white matter (WM) connectivity changes. Finally, we constructed a seed-based resting-state functional connectivity matrix based on 90 regions of interest and examined the functional network changes of CSF1R-related leukoencephalopathy. Unlike the HCs, patients with CSF1R-related leukoencephalopathy predominantly had morphological atrophy in the bilateral thalamus and left hippocampus. In addition, the abnormal diffusivity was mainly distributed in the splenium of the corpus callosum, periventricular regions, centrum semiovale, subcortical U-fibers and midline cortex structures. Moreover, the patients had significantly reduced functional connectivity between the bilateral caudate nucleus and their contralateral hippocampus. Therefore, in addition to hyperintensity on the T2-weighted images, CSF1R-related leukoencephalopathy also showed abnormal structural and functional alterations, including subcortical atrophy and reduced functional connectivity, as well as altered diffuse parameters in the WM and subcortical regions. These findings expand our understanding of the potential pathophysiologic mechanism behind this hereditary disease.
Asunto(s)
Leucoencefalopatías , Sustancia Blanca , Encéfalo/diagnóstico por imagen , Sustancia Gris/diagnóstico por imagen , Humanos , Leucoencefalopatías/diagnóstico por imagen , Leucoencefalopatías/genética , Imagen por Resonancia Magnética , Sustancia Blanca/diagnóstico por imagenRESUMEN
BACKGROUND: Mutations in the IRF2BPL gene can cause neurodevelopmental disorders. We describe the clinical and genetic characteristics of a Chinese patient with a novel abnormality in this gene, explore the potential pathogenic mechanism and summarize the clinical characteristics of 25 patients with IRF2BPL mutations. METHODS: We identified the gene mutation sites by whole-exome and Sanger sequencing. The protein-protein interaction network of the IRF2BPL gene was constructed using bioinformatic techniques, and its function was enriched. We conducted a functional experiment to explore the potential pathogenicity of the identified IRF2BPL gene mutation. RESULTS: An 8-year-old girl presented with progressive cerebellar ataxia, including involuntary tremor and slurred speech. Electroencephalography and electromyography revealed no abnormalities. Structural cranial MRI was also normal, but genetic analysis identified a truncating de novo variant in IRF2BPL. Bioinformatics predicted that IRF2BPL would be associated with IRF2 and 10 other genes and involved in ubiquitin binding and other pathways. The cellular location of IRF2BPL was altered, and compared to control cells, the level of ubiquitinated proteins was significantly decreased in cells harbouring the mutation. CONCLUSION: In this study, we identified a truncating de novo variant of IRF2BPL as a causative gene in the neurodevelopmental disorder of a Chinese girl. Impairment of the ubiquitin-proteasome pathway caused by this IRF2BPL mutation may play an important role in this neurodevelopmental disorder.
Asunto(s)
Trastornos del Neurodesarrollo , Proteínas Portadoras/genética , Niño , Electroencefalografía , Femenino , Humanos , Mutación/genética , Trastornos del Neurodesarrollo/genética , Proteínas Nucleares/genética , Secuenciación del ExomaRESUMEN
BACKGROUND: Paroxysmal kinesigenic dyskinesia is a spectrum of involuntary dyskinetic disorders with high clinical and genetic heterogeneity. Mutations in proline-rich transmembrane protein 2 have been identified as the major pathogenic factor. OBJECTIVES: We analyzed 600 paroxysmal kinesigenic dyskinesia patients nationwide who were identified by the China Paroxysmal Dyskinesia Collaborative Group to summarize the clinical phenotypes and genetic features of paroxysmal kinesigenic dyskinesia in China and to provide new thoughts on diagnosis and therapy. METHODS: The China Paroxysmal Dyskinesia Collaborative Group was composed of departments of neurology from 22 hospitals. Clinical manifestations and proline-rich transmembrane protein 2 screening results were recorded using unified paroxysmal kinesigenic dyskinesia registration forms. Genotype-phenotype correlation analyses were conducted in patients with and without proline-rich transmembrane protein 2 mutations. High-knee exercises were applied in partial patients as a new diagnostic test to induce attacks. RESULTS: Kinesigenic triggers, male predilection, dystonic attacks, aura, complicated forms of paroxysmal kinesigenic dyskinesia, clustering in patients with family history, and dramatic responses to antiepileptic treatment were the prominent features in this multicenter study. Clinical analysis showed that proline-rich transmembrane protein 2 mutation carriers were prone to present at a younger age and have longer attack duration, bilateral limb involvement, choreic attacks, a complicated form of paroxysmal kinesigenic dyskinesia, family history, and more forms of dyskinesia. The new high-knee-exercise test efficiently induced attacks and could assist in diagnosis. CONCLUSIONS: We propose recommendations regarding diagnostic criteria for paroxysmal kinesigenic dyskinesia based on this large clinical study of paroxysmal kinesigenic dyskinesia. The findings offered some new insights into the diagnosis and treatment of paroxysmal kinesigenic dyskinesia and might help in building standardized paroxysmal kinesigenic dyskinesia clinical evaluations and therapies. © 2020 International Parkinson and Movement Disorder Society.
Asunto(s)
Distonía , China , Distonía/genética , Humanos , Masculino , Mutación/genética , Proteínas del Tejido Nervioso/genética , FenotipoRESUMEN
OBJECTIVE: To describe the clinical and genetic features of two patients with different phenotypes due to various Dynactin 1 (DCTN1) gene mutations and further explore the phenotype-genotype relationship. METHODS: Patient 1 is a 23-year-old man with congenital foot deformity and life-long distal muscle weakness and atrophy. Patient 2 is a 48-year-old woman with adult-onset progressive weakness, lower limbs atrophy, and pyramid bundle signs. Electrophysiology test showed normal nerve conduction velocity of both patients and neurogenic changes in needle electromyography. Open sural nerve biopsy for Patient 1 showed slight loss of myelinated nerve fibers. Both patients were performed with whole-exome sequencing followed by functional study of identified variants. RESULTS: Two mutations in DCTN1 gene were identified in Patient 1 (c.626dupC) and Patient 2 (c.3823C>T), respectively. In vitro, the wild type mostly located in cytoplasm and colocalized with α-tubulin. However, c.626dupC tended to be trapped into nuclear and the c.3823C>T formed cytoplasmic aggregates, both losing colocalization with α-tubulin. Western blotting showed a truncated mutant with less molecular weight of c.626dupC was expressed. INTERPRETATION: We identify two novel DCTN1 mutations causing different phenotypes: (1) early-onset distal hereditary motor neuropathy plus congenital foot malformation and (2) amyotrophic lateral sclerosis, respectively. We provide the initial evidence that foot developmental deficiency probably arises from subcellular localizing abnormality of Dynactin 1, revealing DCTN1-related spectrum is still expanding.
Asunto(s)
Complejo Dinactina/genética , Deformidades Congénitas del Pie/genética , Atrofia Muscular Espinal/genética , Adulto , Edad de Inicio , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Adulto JovenRESUMEN
BACKGROUND: Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder characterized by calcium deposition in bilateral and symmetric brain. Evidence suggested that PFBC might be associated with paroxysmal kinesigenic dyskinesia (PKD). We aim to investigate the genetic causes in PFBC patients manifested as PKD, and further to explore the pathogenic impact of the identified mutations. METHODS: 4 PKD-mimic PFBC patients were investigated in the study. Clinical assessment including laboratory tests, head computed tomography (CT) were conducted and followed by exome sequencing. Variants of PFBC genes were screened, and Sanger sequencing, segregation analysis were applied to confirm the findings. Functional assessment of the identified mutations was further analyzed. RESULTS: Among the 4 PKD-mimic PFBC patients, 3 presented with brain calcification, and 1 was identified carrying a PFBC mutation but without brain calcification. The clinical characteristics were summarized. Three heterozygous variants (2 novel, 1 documented) in PFBC genes were found. Further functional study showed abnormal accumulation and reduced uptake of Pi of the mutant protein, and the aggregated PDGFB failing to induce membrane ruffles compared with wild-type. CONCLUSIONS: PKD can be a manifestation of PFBC, and brain calcification may be a cause of secondary PKD. So thoroughly evaluation including head CT or genetic screening for paroxysmal dyskinesia and PFBC should be applied before the diagnosis of PKD or PFBC. Moreover, negative brain calcification may not exclude the possibility of PFBC. The possible pathogenesis of primary calcification lie in the dysfunction of the protein or defective signal transduction caused by the mutations.
Asunto(s)
Encefalopatías/diagnóstico , Encefalopatías/genética , Calcinosis/diagnóstico , Calcinosis/genética , Distonía/diagnóstico , Distonía/genética , Adolescente , Adulto , Encefalopatías/complicaciones , Encefalopatías/diagnóstico por imagen , Calcinosis/complicaciones , Calcinosis/diagnóstico por imagen , Células Cultivadas , Distonía/complicaciones , Distonía/diagnóstico por imagen , Femenino , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas , Heterocigoto , Humanos , Masculino , Mutación , Organofosfatos/metabolismo , Proteínas Proto-Oncogénicas c-sis/metabolismo , Tomografía Computarizada por Rayos X , Adulto JovenRESUMEN
BACKGROUND: CSF1R-related leukoencephalopathy, also known as hereditary diffuse leukoencephalopathy with spheroids (HDLS), is a rare white-matter encephalopathy characterized by motor and neuropsychiatric symptoms due to colony-stimulating factor 1 receptor (CSF1R) gene mutation. Few of CSF1R mutations have been functionally testified and the pathogenesis remains unknown. METHODS: In order to investigate clinical and pathological characteristics of patients with CSF1R-related leukoencephalopathy and explore the potential impact of CSF1R mutations, we analyzed clinical manifestations of 15 patients from 10 unrelated families and performed brain biopsy in 2 cases. Next generation sequencing was conducted for 10 probands to confirm the diagnosis. Sanger sequencing, segregation analysis and phenotypic reevaluation were utilized to substantiate findings. Functional examination of identified mutations was further explored. RESULTS: Clinical and neuroimaging characteristics were summarized. The average age at onset was 35.9 ± 6.4 years (range 24-46 years old). Younger age of onset was observed in female than male (34.2 vs. 39.2 years). The most common initial symptoms were speech dysfunction, cognitive decline and parkinsonian symptoms. One patient also had marked peripheral neuropathy. Brain biopsy of two cases showed typical pathological changes, including myelin loss, axonal spheroids, phosphorylated neurofilament and activated macrophages. Electron microscopy disclosed increased mitochondrial vacuolation and disorganized neurofilaments in ballooned axons. A total of 7 pathogenic variants (4 novel, 3 documented) were identified with autophosphorylation deficiency, among which c.2342C > T remained partial function of autophosphorylation. Western blotting disclosed the significantly lower level of c.2026C > T (p.R676*) than wild type. The level of microtubule associated protein 1 light chain 3-II (LC3-II), a classical marker of autophagy, was significantly lower in mutants expressed cells than wild type group by western blotting and immunofluorescence staining. CONCLUSIONS: Our findings support the loss-of-function and haploinsufficiency hypothesis in pathogenesis. Autophagy abnormality may play a role in the disease. Repairing or promoting the phosphorylation level of mutant CSF1R may shed light on therapeutic targets in the future. However, whether peripheral polyneuropathy potentially belongs to CSF1R-related spectrum deserves further study with longer follow-up and more patients enrolled. TRIAL REGISTRATION: ChiCTR, ChiCTR1800015295. Registered 21 March 2018.
RESUMEN
OBJECTIVE: GDP-mannose pyrophosphorylase B (GMPPB) related phenotype spectrum ranges widely from congenital myasthenic syndrome (CMS), limb-girdle muscular dystrophy type 2T (LGMD 2T) to severe congenital muscle-eye-brain syndrome. Our study investigates the clinicopathologic features of a patient with novel GMPPB mutations and explores the pathogenetic mechanism. METHODS: The patient was a 22-year-old woman with chronic proximal limb weakness for 9 years without cognitive deterioration. Weakness became worse after fatigue. Elevated serum creatine kinase and decrements on repetitive nerve stimulation test were recorded. MRI showed fatty infiltration in muscles of lower limbs and shoulder girdle on T1 sequence. Open muscle biopsy and genetic analysis were performed. RESULTS: Muscle biopsy showed myogenic changes. Two missense mutations in GMPPB gene (c.803T>C and c.1060G>A) were identified in the patient. Western blotting and immunostaining showed GMPPB and α-dystroglycan deficiency in the patient's muscle. In vitro, mutant GMPPB forming cytoplasmic aggregates completely colocalized with microtubule-associated protein 1 light chain 3-II (LC3-II), a classical marker of autophagosome. Degradation of GMPPB was accompanied by an upregulation of LC3-II, which could be restored by lysosomal inhibitor leupeptin. INTERPRETATION: We identified two novel GMPPB mutations causing overlap phenotype between LGMD 2T and CMS. We provided the initial evidence that mutant GMPPB colocalizes with autophagosome at subcellular level. GMPPB mutants degraded by autophagy-lysosome pathway is associated with LGMD 2T. This study shed the light into the enzyme replacement which could become one of the therapeutic targets in the future study.
Asunto(s)
Distrofia Muscular de Cinturas/genética , Distrofia Muscular de Cinturas/patología , Nucleotidiltransferasas/genética , Autofagia , Distroglicanos/deficiencia , Distroglicanos/metabolismo , Extremidades , Femenino , Células HEK293 , Humanos , Lisosomas/metabolismo , Imagen por Resonancia Magnética , Proteínas Asociadas a Microtúbulos/metabolismo , Músculos/patología , Mutación Missense , Síndromes Miasténicos Congénitos/genética , Bromuro de Piridostigmina/uso terapéutico , Adulto JovenRESUMEN
OBJECTIVES: To describe the clinical and genetic features of a Chinese peroxisome biogenesis disorder 6B patient with PEX10 mutations and review PEX10-related peroxisomal disorders. PATIENTS AND METHODS: The proband is a 7-year-old boy with mild mental retardation and gait instability, intention tremor and nystagmus. An extensive clinical and laboratory evaluation including molecular genetic studies was performed. Genomic DNA was extracted from peripheral blood using the standardized phenol/chloroform extraction method, and the coding region of the PEX10 gene was sequenced in three family members. RESULTS: Cerebral MRI showed cerebellar atrophy. Magnetic resonance spectroscopy revealed a decreased N-acetyl aspartate peak in the cerebellum. Nerve conduction velocity examination found prolonged motor and sensory nerve potential latencies (proximal obvious), decreased potential amplitude, and slow nerve conduction velocity. Routine blood tests and biochemistries were abnormal. The PEX10 gene test showed compound heterozygous mutations (c.209 G > A, p. G70E and c.830 T > C, p. L277 P). The mutation c.830 T > C, p. L277 P has been previously reported, whereas c.209 G > A, p. G70E is novel. CONCLUSION: We identified an ataxia case of peroxisome biogenesis disorder 6B caused by novel compound heterozygous mutations of the PEX10 gene. Peroxisome biogenesis disorders should be considered in the differential diagnosis of autosomal recessive ataxia, especially cases with early onset.
Asunto(s)
Mutación/genética , Peroxinas/genética , Trastorno Peroxisomal/genética , Receptores Citoplasmáticos y Nucleares/genética , Ataxia Cerebelosa/diagnóstico , Ataxia Cerebelosa/genética , Niño , Pruebas Genéticas/métodos , Humanos , Masculino , Trastorno Peroxisomal/diagnósticoRESUMEN
OBJECTIVE: To unravel if there was muscular ion channel dysfunction in paroxysmal kinesigenic dyskinesia (PKD) patients using the exercises tests (ET). METHODS: Sixty PKD patients including 28 PRRT2 mutations carriers were enrolled in this study, as well as 19 hypokalaemic periodic paralysis (HypoPP) patients as the positive controls and 45 healthy subjects as the negative controls. ET including long exercise test (LET) and short exercise test (SET) was performed in the corresponding subjects. RESULTS: In the LET, both the overall PKD patients and HypoPP patients had greater CMAP amplitude and area increments during exercise than healthy controls. At most 25% of PKD patients were identified from the normality with greater amplitude increment than the area. On the contrary, 50% of HypoPP patients were differentiated with greater area increment than the amplitude. More percentage of PRRT2- patients than PRRT2+ patients had abnormal average amplitude increment. Unexpectedly, five PKD patients had abnormal maximum CMAP amplitude decrements after exercise in the LET, and one had abnormal maximum immediate amplitude decrement in the SET. CONCLUSIONS: Distinct ET manifestations were found in PKD patients compared to normal controls and HypoPP patients. SIGNIFICANCE: Abnormal muscle membrane excitability might be involved in the mechanisms responsible for PKD.