AIMTo identify the disease-causing gene mutation in a Chinese pedigree with autosomal dominant cone-rod dystrophy (adCORD).METHODSA southern Chinese adCORD pedigree including 9 affected individuals was studied. Whole-...AIMTo identify the disease-causing gene mutation in a Chinese pedigree with autosomal dominant cone-rod dystrophy (adCORD).METHODSA southern Chinese adCORD pedigree including 9 affected individuals was studied. Whole-exome sequencing (WES), coupling the Agilent whole-exome capture system to the Illumina HiSeq 2000 DNA sequencing platform was used to search the specific gene mutation in 3 affected family members and 1 unaffected member. After a suggested variant was found through the data analysis, the putative mutation was validated by Sanger DNA sequencing of samples from all available family members.RESULTSThe results of both WES and Sanger sequencing revealed a novel nonsense mutation c.C766T (p.Q256X) within exon 5 of CRX gene which was pathogenic for adCORD in this family. The mutation could affect photoreceptor-specific gene expression with a dominant-negative effect and resulted in loss of the OTX tail, thus the mutant protein occupies the CRX-binding site in target promoters without establishing an interaction and, consequently, may block transactivation.CONCLUSIONAll modes of Mendelian inheritance in CORD have been observed, and genetic heterogeneity is a hallmark of CORD. Therefore, conventional genetic diagnosis of CORD would be time-consuming and labor-intensive. Our study indicated the robustness and cost-effectiveness of WES in the genetic diagnosis of CORD.展开更多
AIM:To present the clinical manifestations of 5 autosomal dominant cone-rod dystrophy(ad CORD)patients from two Chinese families with cone-rod homeobox(CRX)mutation(p.R41W),and to explore the clinical heterogeneity of...AIM:To present the clinical manifestations of 5 autosomal dominant cone-rod dystrophy(ad CORD)patients from two Chinese families with cone-rod homeobox(CRX)mutation(p.R41W),and to explore the clinical heterogeneity of ad CORD with CRX mutation(p.R41W).METHODS:Interrogation and ophthalmological examinations were undertaken in all patients and unaffected members.Analysis of clinical features was performed by visual acuity,slit lamp examination,visual field examination,fundoscopy,autofluorescence and spectral domain optical coherence tomography.Targeted next-generation sequencing was applied as a useful tool to identify the causative mutation of CORD genes.RESULTS:A CRX missense mutation c.121C>T was identified in all patients,resulting in an amino acid change from arginine acid to tryptophan(p.R41W).The patients presented with early onset,progressive and different severities with CORD.CONCLUSION:This is the first report of the clinical phenotype of CRX mutation(p.R41W)in Chinese families,and the mutation can lead to a wide range of various retinal phenotypes.展开更多
Background: Mutations in the RPGR gene are associated with rod-cone or cone-rod dystrophy, the latter associated with mutations at the distal end. Cone-rod dystrophy (CRD) is a subgroup of hereditary retinal disorders...Background: Mutations in the RPGR gene are associated with rod-cone or cone-rod dystrophy, the latter associated with mutations at the distal end. Cone-rod dystrophy (CRD) is a subgroup of hereditary retinal disorders characterized by the primary degeneration of cone photoreceptors often followed by progressive loss of rod photoreceptors in the peripheral visual field. Purpose: The aim of this study was to describe the milder CRD phenotype associated with a novel pathogenic variant c.1905 + 223C > T (p.Q710X) found in RPGR which results in shortening of the photoreceptor specific isoform RPGR <sup>ORF15</sup>. Method: An 11-year-old boy with symptoms of CRD and two female relatives were referred for detailed ophthalmic examinations. Genetic testing was performed by next-generation sequencing of clinical exome followed by Sanger sequencing for segregation analysis. Results: Genetic analysis identified a novel variant in ORF15 of the RPGR gene (c.1905 + 223C > T, p.Q710X) in the proband considered as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) standards. Segregation study identified the mutation in a heterozygous state in the mother and her sister. Detailed ophthalmological examination revealed slightly reduced color vision and scattered grayish point-like deposits in the posterior pole of the fundus in the male patient. All mutation carriers were myopic. Conclusion: We report a novel pathogenic RPGR variant in a Bulgarian patient with clinical features compatible with the CRD diagnosis. This condition is inherited as an X-linked dominant trait in its familial form presenting with a mild CRD phenotype in the male hemizygous proband and a moderate to high myopia in the female heterozygous carriers.展开更多
Duchenne muscular dystrophy (DMD) is a lethal X-linked recessive neuromuscular disorder caused by mutations in the dystrophin encoding gene, with the characteristics of a severe and progressive destruction of muscle s...Duchenne muscular dystrophy (DMD) is a lethal X-linked recessive neuromuscular disorder caused by mutations in the dystrophin encoding gene, with the characteristics of a severe and progressive destruction of muscle structure and function. Skeletal muscle fibrosis is one of the pathological features of DMD. Tetramethylpyrazine (2,3,5,6-tetramethylpyrazine, TMP) has been demonstrated to reduce heart and liver fibrosis. Meanwhile, previous studies showed that Tetramethylpyrazine nitrone (TBN), a nitrone derivative of TMP, has promising therapeutic effects in several neurodegenerative models and is more potent than TMP. In this study, we investigated the potential effect of TBN on the <em>mdx</em> mouse model of DMD. Eight-week-old <em>mdx</em> mice were administered with TBN (30 mg/kg) intragastrically twice daily, with deflazacort (1 mg/kg) once a day as a positive control, for a total of 24 weeks. Behavioral tests including pole-climbing open-field test were monitored every 4 weeks. Histopathological assessment was conducted in the gastrocnemius and diaphragm muscles. The effects of TBN on protein levels of dysferlin were measured by immunohistochemistry. TBN significantly reduced the climbing time in pole test and increased the total distance moved in an open-field test of <em>mdx</em> mice. TBN attenuated fibrosis in the gastrocnemius and diaphragmatic muscles. In addition, TBN protected gastrocnemius muscle fibers via increasing expression of the dysferlin in <em>mdx </em>mice. In conclusion, this study demonstrated that TBN could improve the motor deficits and muscle pathology of <em>mdx</em> mouse, and it is worth further exploring the mechanism of action of TBN for DMD treatment.展开更多
BACKGROUND Life expectancy in patients with Duchenne muscular dystrophy(DMD)has improved due to advances in medical care.DMD patients develop progressive spinal deformity after loss of ambulatory function and onset of...BACKGROUND Life expectancy in patients with Duchenne muscular dystrophy(DMD)has improved due to advances in medical care.DMD patients develop progressive spinal deformity after loss of ambulatory function and onset of wheelchair dependence for mobility.There is limited published data on the effect of spinal deformity correction on long-term functional outcomes,quality of life(QoL),and satisfaction in DMD patients.AIM To investigate the long-term functional outcomes following spinal deformity correction in DMD patients.METHODS This was a retrospective cohort study from 2000-2022.Data was collected from hospital records and radiographs.At follow-up,patients completed the muscular dystrophy spine questionnaire(MDSQ).Statistical analysis was performed by linear regression analysis and ANOVA to analyse clinical and radiographic factors significantly associated with MDSQ scores.RESULTS Forty-three patients were included with mean age 14.4 years at surgery.Spinopelvic fusion was performed in 41.9%of patients.Mean surgical time was 352.1 min and mean blood loss was 36%of estimated total blood volume.Mean hospital stay was 14.1 d.Postoperative complications occurred in 25.6%of patients.Mean preoperative scoliosis was 58°,pelvic obliquity 16.4°,thoracic kyphosis 55.8°,lumbar lordosis 11.1°,coronal balance 3.8 cm,and sagittal balance+6.1 cm.Mean surgical correction of scoliosis was 79.2%and of pelvic obliquity was 80.8%.Mean follow-up was 10.9 years(range:2-22.5).Twenty-four patients had died at follow-up.Sixteen patients completed the MDSQ at mean age 25.4 years(range 15.2-37.3).Two patients were bed-ridden and 7 were on ventilatory support.Mean MDSQ total score was 38.1.All 16 patients were satisfied with the results of spinal surgery and would choose surgery again if offered.Most patients(87.5%)reported no severe back pain at follow-up.Factors significantly associated with functional outcomes(MDSQ total score)included greater duration of post-operative follow-up,age,scoliosis postoperatively,correction of scoliosis,increased lumbar lordosis postoperatively,and greater age at loss of independent ambulation.CONCLUSION Spinal deformity correction in DMD patients leads to positive long-term effects on QoL and high patient satisfaction.These results support spinal deformity correction to improve long-term QoL in DMD patients.展开更多
Background:To determine the effectiveness of resistive range of motion exercises in improving muscle strength and functional abilities in Duchenne muscular dystrophy.The study was also aimed to determine if resistive ...Background:To determine the effectiveness of resistive range of motion exercises in improving muscle strength and functional abilities in Duchenne muscular dystrophy.The study was also aimed to determine if resistive range of motion exercises can slow down the progression of the disease.Methods:A seven-year-old male child was diagnosed with Duchenne muscle dystrophy presented to outpatient physiotherapy clinic.The patient was presented with difficulty in stair climbing,sitting up from the floor,fatigue,and muscle weakness specifically weakness in the proximal limb muscles.The progressive resistive range of motion training was implemented for four years to improve muscle strength and functional abilities.The medical research council grading scale,north ambulatory assessment scale,and creatine kinase were used to evaluate muscle strength,functional abilities,and creatine kinase levels.Results:The muscular strength and functional abilities did not improve after four years of exercise training.The creatine kinase levels were decreased over the period of four years.Conclusion:Resistive range of motion exercises are helpful in maintaining the muscular strength and functional abilities in Duchenne muscular dystrophy.展开更多
AIM: To describe long term follow-up in a family with GUCY2D dominant cone dystrophy. METHODS: Optical coherence tomography scans and fundus autofluorescence images were obtained. Flash and pattern electroretinograms(...AIM: To describe long term follow-up in a family with GUCY2D dominant cone dystrophy. METHODS: Optical coherence tomography scans and fundus autofluorescence images were obtained. Flash and pattern electroretinograms(ERGs) and occipital pattern reversal visual evoked potentials were recorded. RESULTS: Two members of the same family(father and son) were identified to have the heterozygous R838 C mutation in the GUCY2D gene. The father presented at the age of 45 with bilateral bull’s eye maculopathy and temporal disc pallor. Over 13 y of serial follow up visits, the bull’s eye maculopathy progressed gradually into macular atrophy. Electrophysiological tests were significantly degraded suggesting poor macular function. Spectraldomain optical coherence tomography(SD-OCT) scans showed progressive loss and disruption of the ellipsoid layer at the foveal level. His son presented at the age of 16 with bilateral granular retinal pigment epithelial changes in both maculae. Electrophysiological testing was initially borderline normal but has gradually deteriorated to show reduced cone ERGs and macula function. SD-OCT demonstrated gradual macular thinning and atrophy bilaterally. Unlike his father, there was no disruption of the ellipsoid layer.CONCLUSION: Both family members exhibited gradual changes in their fundi, electrophysiological testing and multimodal imaging. Changes were milder than those observed in other mutations of the same gene.展开更多
基金Supported by the Zhejiang Provincial Natural Science Foundation of China (No.LY12H12001)the Ningbo Key Foundation of Society Development (No.2014C50091)+2 种基金the Ningbo Natural Science Foundation (No.2012A610192)the Ningbo Yinzhou District S&T Foundation (No.YK2013-90)the Shenzhen Municipal Government of China (No.GJHZ20130417140916986)
文摘AIMTo identify the disease-causing gene mutation in a Chinese pedigree with autosomal dominant cone-rod dystrophy (adCORD).METHODSA southern Chinese adCORD pedigree including 9 affected individuals was studied. Whole-exome sequencing (WES), coupling the Agilent whole-exome capture system to the Illumina HiSeq 2000 DNA sequencing platform was used to search the specific gene mutation in 3 affected family members and 1 unaffected member. After a suggested variant was found through the data analysis, the putative mutation was validated by Sanger DNA sequencing of samples from all available family members.RESULTSThe results of both WES and Sanger sequencing revealed a novel nonsense mutation c.C766T (p.Q256X) within exon 5 of CRX gene which was pathogenic for adCORD in this family. The mutation could affect photoreceptor-specific gene expression with a dominant-negative effect and resulted in loss of the OTX tail, thus the mutant protein occupies the CRX-binding site in target promoters without establishing an interaction and, consequently, may block transactivation.CONCLUSIONAll modes of Mendelian inheritance in CORD have been observed, and genetic heterogeneity is a hallmark of CORD. Therefore, conventional genetic diagnosis of CORD would be time-consuming and labor-intensive. Our study indicated the robustness and cost-effectiveness of WES in the genetic diagnosis of CORD.
文摘AIM:To present the clinical manifestations of 5 autosomal dominant cone-rod dystrophy(ad CORD)patients from two Chinese families with cone-rod homeobox(CRX)mutation(p.R41W),and to explore the clinical heterogeneity of ad CORD with CRX mutation(p.R41W).METHODS:Interrogation and ophthalmological examinations were undertaken in all patients and unaffected members.Analysis of clinical features was performed by visual acuity,slit lamp examination,visual field examination,fundoscopy,autofluorescence and spectral domain optical coherence tomography.Targeted next-generation sequencing was applied as a useful tool to identify the causative mutation of CORD genes.RESULTS:A CRX missense mutation c.121C>T was identified in all patients,resulting in an amino acid change from arginine acid to tryptophan(p.R41W).The patients presented with early onset,progressive and different severities with CORD.CONCLUSION:This is the first report of the clinical phenotype of CRX mutation(p.R41W)in Chinese families,and the mutation can lead to a wide range of various retinal phenotypes.
文摘Background: Mutations in the RPGR gene are associated with rod-cone or cone-rod dystrophy, the latter associated with mutations at the distal end. Cone-rod dystrophy (CRD) is a subgroup of hereditary retinal disorders characterized by the primary degeneration of cone photoreceptors often followed by progressive loss of rod photoreceptors in the peripheral visual field. Purpose: The aim of this study was to describe the milder CRD phenotype associated with a novel pathogenic variant c.1905 + 223C > T (p.Q710X) found in RPGR which results in shortening of the photoreceptor specific isoform RPGR <sup>ORF15</sup>. Method: An 11-year-old boy with symptoms of CRD and two female relatives were referred for detailed ophthalmic examinations. Genetic testing was performed by next-generation sequencing of clinical exome followed by Sanger sequencing for segregation analysis. Results: Genetic analysis identified a novel variant in ORF15 of the RPGR gene (c.1905 + 223C > T, p.Q710X) in the proband considered as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) standards. Segregation study identified the mutation in a heterozygous state in the mother and her sister. Detailed ophthalmological examination revealed slightly reduced color vision and scattered grayish point-like deposits in the posterior pole of the fundus in the male patient. All mutation carriers were myopic. Conclusion: We report a novel pathogenic RPGR variant in a Bulgarian patient with clinical features compatible with the CRD diagnosis. This condition is inherited as an X-linked dominant trait in its familial form presenting with a mild CRD phenotype in the male hemizygous proband and a moderate to high myopia in the female heterozygous carriers.
文摘Duchenne muscular dystrophy (DMD) is a lethal X-linked recessive neuromuscular disorder caused by mutations in the dystrophin encoding gene, with the characteristics of a severe and progressive destruction of muscle structure and function. Skeletal muscle fibrosis is one of the pathological features of DMD. Tetramethylpyrazine (2,3,5,6-tetramethylpyrazine, TMP) has been demonstrated to reduce heart and liver fibrosis. Meanwhile, previous studies showed that Tetramethylpyrazine nitrone (TBN), a nitrone derivative of TMP, has promising therapeutic effects in several neurodegenerative models and is more potent than TMP. In this study, we investigated the potential effect of TBN on the <em>mdx</em> mouse model of DMD. Eight-week-old <em>mdx</em> mice were administered with TBN (30 mg/kg) intragastrically twice daily, with deflazacort (1 mg/kg) once a day as a positive control, for a total of 24 weeks. Behavioral tests including pole-climbing open-field test were monitored every 4 weeks. Histopathological assessment was conducted in the gastrocnemius and diaphragm muscles. The effects of TBN on protein levels of dysferlin were measured by immunohistochemistry. TBN significantly reduced the climbing time in pole test and increased the total distance moved in an open-field test of <em>mdx</em> mice. TBN attenuated fibrosis in the gastrocnemius and diaphragmatic muscles. In addition, TBN protected gastrocnemius muscle fibers via increasing expression of the dysferlin in <em>mdx </em>mice. In conclusion, this study demonstrated that TBN could improve the motor deficits and muscle pathology of <em>mdx</em> mouse, and it is worth further exploring the mechanism of action of TBN for DMD treatment.
文摘BACKGROUND Life expectancy in patients with Duchenne muscular dystrophy(DMD)has improved due to advances in medical care.DMD patients develop progressive spinal deformity after loss of ambulatory function and onset of wheelchair dependence for mobility.There is limited published data on the effect of spinal deformity correction on long-term functional outcomes,quality of life(QoL),and satisfaction in DMD patients.AIM To investigate the long-term functional outcomes following spinal deformity correction in DMD patients.METHODS This was a retrospective cohort study from 2000-2022.Data was collected from hospital records and radiographs.At follow-up,patients completed the muscular dystrophy spine questionnaire(MDSQ).Statistical analysis was performed by linear regression analysis and ANOVA to analyse clinical and radiographic factors significantly associated with MDSQ scores.RESULTS Forty-three patients were included with mean age 14.4 years at surgery.Spinopelvic fusion was performed in 41.9%of patients.Mean surgical time was 352.1 min and mean blood loss was 36%of estimated total blood volume.Mean hospital stay was 14.1 d.Postoperative complications occurred in 25.6%of patients.Mean preoperative scoliosis was 58°,pelvic obliquity 16.4°,thoracic kyphosis 55.8°,lumbar lordosis 11.1°,coronal balance 3.8 cm,and sagittal balance+6.1 cm.Mean surgical correction of scoliosis was 79.2%and of pelvic obliquity was 80.8%.Mean follow-up was 10.9 years(range:2-22.5).Twenty-four patients had died at follow-up.Sixteen patients completed the MDSQ at mean age 25.4 years(range 15.2-37.3).Two patients were bed-ridden and 7 were on ventilatory support.Mean MDSQ total score was 38.1.All 16 patients were satisfied with the results of spinal surgery and would choose surgery again if offered.Most patients(87.5%)reported no severe back pain at follow-up.Factors significantly associated with functional outcomes(MDSQ total score)included greater duration of post-operative follow-up,age,scoliosis postoperatively,correction of scoliosis,increased lumbar lordosis postoperatively,and greater age at loss of independent ambulation.CONCLUSION Spinal deformity correction in DMD patients leads to positive long-term effects on QoL and high patient satisfaction.These results support spinal deformity correction to improve long-term QoL in DMD patients.
文摘Background:To determine the effectiveness of resistive range of motion exercises in improving muscle strength and functional abilities in Duchenne muscular dystrophy.The study was also aimed to determine if resistive range of motion exercises can slow down the progression of the disease.Methods:A seven-year-old male child was diagnosed with Duchenne muscle dystrophy presented to outpatient physiotherapy clinic.The patient was presented with difficulty in stair climbing,sitting up from the floor,fatigue,and muscle weakness specifically weakness in the proximal limb muscles.The progressive resistive range of motion training was implemented for four years to improve muscle strength and functional abilities.The medical research council grading scale,north ambulatory assessment scale,and creatine kinase were used to evaluate muscle strength,functional abilities,and creatine kinase levels.Results:The muscular strength and functional abilities did not improve after four years of exercise training.The creatine kinase levels were decreased over the period of four years.Conclusion:Resistive range of motion exercises are helpful in maintaining the muscular strength and functional abilities in Duchenne muscular dystrophy.
基金Supported by Fight Against Blindness Charity Organization
文摘AIM: To describe long term follow-up in a family with GUCY2D dominant cone dystrophy. METHODS: Optical coherence tomography scans and fundus autofluorescence images were obtained. Flash and pattern electroretinograms(ERGs) and occipital pattern reversal visual evoked potentials were recorded. RESULTS: Two members of the same family(father and son) were identified to have the heterozygous R838 C mutation in the GUCY2D gene. The father presented at the age of 45 with bilateral bull’s eye maculopathy and temporal disc pallor. Over 13 y of serial follow up visits, the bull’s eye maculopathy progressed gradually into macular atrophy. Electrophysiological tests were significantly degraded suggesting poor macular function. Spectraldomain optical coherence tomography(SD-OCT) scans showed progressive loss and disruption of the ellipsoid layer at the foveal level. His son presented at the age of 16 with bilateral granular retinal pigment epithelial changes in both maculae. Electrophysiological testing was initially borderline normal but has gradually deteriorated to show reduced cone ERGs and macula function. SD-OCT demonstrated gradual macular thinning and atrophy bilaterally. Unlike his father, there was no disruption of the ellipsoid layer.CONCLUSION: Both family members exhibited gradual changes in their fundi, electrophysiological testing and multimodal imaging. Changes were milder than those observed in other mutations of the same gene.
