Sensitive quantification of m.3243A>G mutational proportion in non-retinal tissues and its relationship with visual symptoms

Abstract The m.3243A>G mutation in the mitochondrial genome commonly causes retinal degeneration in patients with maternally inherited diabetes and deafness (MIDD) and mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Like other mitochondrial mutations, m.3243A>G is inherited from the mother with a variable proportion of wild type and mutant mitochondrial genomes in different cells. The mechanism by which the m.3243A>G variant in each tissue relates to the manifestation of disease phenotype is not fully understood. Using a digital PCR assay we found that the % m.3243G in skin derived dermal fibroblasts was positively correlated with that of blood from the same individual. The % m.3243G detected in fibroblast cultures remained constant over multiple passages and was negatively correlated with mtDNA copy number. Although the % m.3243G present in blood was not correlated with severity of vision loss, as quantified by Goldmann visual field, a significant negative correlation between % m.3243G and the age of onset of visual symptoms was detected. Together, these results indicate that precise measurement of % m.3243G in clinically accessible tissues such as skin and blood may yield information relevant to the management of retinal m.3243A>G associated disease.

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Maternally Inherited Diabetes Mellitus Associated with a Novel m.15897G>A Mutation in Mitochondrial tRNAThr Gene

Journal of Diabetes Research ◽

10.1155/2020/2057187 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11 ◽

Cited By ~ 1

Author(s):

Ke Li ◽

Lijun Wu ◽

Jianjiang Liu ◽

Wei Lin ◽

Qiang Qi ◽

...

Keyword(s):

Age Of Onset ◽

Complete Mitochondrial Genome ◽

Mutant Cell ◽

Atp Synthesis ◽

Chinese Family ◽

Molecular Characteristics ◽

Clinical Genetic ◽

Mitochondrial Dysfunctions ◽

Inherited Diabetes

We report here the clinical, genetic, and molecular characteristics of type 2 diabetes in a Chinese family. There are differences in the severity and age of onset in diabetes among these families. By molecular analysis of the complete mitochondrial genome in this family, we identified the homoplasmic m.15897G>A mutation underwent sequence analysis of whole mitochondrial DNA genome, which localized at conventional position ten of tRNAThr, and distinct sets of mtDNA polymorphisms belonging to haplogroup D4b1. This mutation has been implicated to be important for tRNA identity and stability. Using cybrid cell models, the decreased efficiency of mitochondrial tRNAThr levels caused by the m.15897G>A mutation results in respiratory deficiency, protein synthesis and assembly, mitochondrial ATP synthesis, and mitochondrial membrane potential. These mitochondrial dysfunctions caused an increase in the production of reactive oxygen species in the mutant cell lines. These data provide a direct evidence that a novel tRNA mutation was associated with T2DM. Thus, our findings provide a new insight into the understanding of pathophysiology of maternally inherited diabetes.

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Determination of Exosome Mitochondrial DNA as a Biomarker of Renal Cancer Aggressiveness

10.21203/rs.3.rs-715664/v1 ◽

2021 ◽

Author(s):

Elena Arance ◽

Viviana Ramírez ◽

Alejandro Rubio-Roldan ◽

Francisco M. Ocaña-Peinado ◽

Catalina Romero-Cachinero ◽

...

Keyword(s):

Mitochondrial Dna ◽

Hypervariable Region ◽

Digital Pcr ◽

Complex Iii ◽

Mtdna Copy Number ◽

Non Invasive ◽

Apocytochrome B ◽

Cancer Aggressiveness ◽

Next Generation Sequencing Ngs ◽

First Time

Abstract Background: Components of liquid biopsy are promising non-invasive biomarkers for monitoring the renal cell carcinoma (RCC) status. Present study tries to evaluate the role of exosomes and mitochondrial DNA (mtDNA) as promise, novel and stable biomarkers that could improve current ones in RCC. Methods: A total of 140 fractions obtained by ultracentrifugations of whole blood samples stored in EDTA anticoagulant from 28 (13 patients and 15 controls) were included in present study. An exosome collection protocol and exhaustive analysis of all phases obtained by ultracentrifugations (named from B to F) was performed. Subsequently, an analysis of dPCR (digital PCR) using the QuantStudio™ 3D Digital PCR platform and the quantification of mtDNA copy number using by QuantStudioTM 12K Flex Real-Time PCR System (qPCR) was developed. Moreover, Next Generation Sequencing (NGS) analyses were included using MiSeq system (Illumina, CA, USA). Results: F fraction, which contains all exosomes´ data and all mitochondrial markers (hypervariable region 1 (HV1) and apocytochrome b of complex III (MT-CYB)) were statistically identified in dPCR and qPCR (p values < 0.05) when a comparison between cases and controls was performed. Moreover, the studied mitochondrial genes shown a relevant significance in RCC aggressiveness analyses (metastasis and stages 4).Conclusions: To sum up, this is the first time a relation between mtDNA genetic markers in exosome and clinical management of RCC is suggested.

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Gut microbiota in Parkinson’s disease patients: hospital-based study

The Egyptian Journal of Neurology Psychiatry and Neurosurgery ◽

10.1186/s41983-021-00407-z ◽

2021 ◽

Vol 57 (1) ◽

Author(s):

Eman M. Khedr ◽

Anwar M. Ali ◽

Enas Deaf ◽

Hebatallah M. Hassan ◽

Ahmed Alaa ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Lactic Acid ◽

Gut Microbiota ◽

Rating Scale ◽

Pesticide Exposure ◽

Age Of Onset ◽

Significant Negative Correlation ◽

Control Group ◽

Dominant Type

Abstract Background Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. There is accumulating evidence that link gut microbiota to symptomatology and pathophysiology of PD. The aim of this study was to describe the pattern of gut microbiota and its association with PD and identify the effect of environmental factors on gut microbiota. This case–control study included 46 patients diagnosed as Parkinson’s disease (PD) and 31 healthy volunteers age and sex matched. Detailed history including age of onset, duration of disease, environmental risk factors, diet data, treatment, Unified Parkinson’s Disease Rating Scale (UPDRS), and gastrointestinal tract (GIT) domain of Non‐Motor Symptoms Scale (NMSS) were assessed. After extraction of bacterial DNA from the fecal samples, bacterial abundance was quantified by qPCR using 16S rRNA group-specific primers. Results Significant high abundance of Clostridium cluster IV, Akkermansia, Bifidobacterium, and lactic acid bacteria were found in the PD group compared with the control group (P < 0.001, 0.04, 0.02 and < 0.001, respectively), while Firmicutes were significantly less abundant in the PD group (P < 0.001) compared with the control group. The naive PD patients had significant abundance of Bifidobacterium, and lactic acid compared with control group. Interestingly, Akkermansia was more abundant in treated than untreated patients. There were significant associations between pesticide exposure and Bifidobacterium (P = 0.002), while no significant correlations between different gut microbiota and demographic, environment data, different rating scores or dominant type of PD. There was a significant negative correlation between the Bifidobacterium with the duration of illness (P = 0.012). Conclusion The present study highlighted a significant connection between PD and levels of certain types of gut microbiota, in support of a possible link between gut microbiota and a neurodegenerative cascade of PD.

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Patterns of Uveitis in Children According to Age: Comparison of Visual Outcomes and Complications in a Tertiary Center

10.21203/rs.2.80/v2 ◽

2019 ◽

Author(s):

Christiane Al-Haddad ◽

Alaa BouGhannam ◽

Maamoun Abdul Fattah ◽

Hani Tamim ◽

Zeinab Ali El Moussawi ◽

...

Keyword(s):

Anterior Uveitis ◽

Visual Loss ◽

Vision Loss ◽

Age Of Onset ◽

Age Groups ◽

Age Group ◽

Visual Outcomes ◽

Common Diagnosis ◽

Tertiary Center ◽

Two Age Groups

Abstract Background: Uveitis in the pediatric population is uncommon, accounting for 2 to 14% of all uveitis cases, yet resulting in significant ocular morbidity. A number of studies have focused on patterns and complications of uveitis in the pediatric age group (≤ 16 years). In this report, we studied children with uveitis syndromes focusing on demographics, anatomic distribution, etiologies, treatment, and complications. We additionally divided subjects into two age groups to look into any differential characteristics pertaining to the younger age group and the role of amblyopia as a cause of visual loss. Methods: Retrospective chart review of 80 eyes of 49 uveitis patients aged ≤16years. Subjects were categorized by age of onset into visually immature (≤8 years) and visually mature group (>8 years). Data compared between the two age groups included demographics, disease characteristics, visual outcomes and complications. Results: Idiopathic uveitis was the most common diagnosis (51%). Anterior uveitis complications (posterior synechiae and band keratopathy) were more common in the younger group (p=0.002 and p=0.03 respectively) while posterior uveitis manifestations (vitreous haze and vasculitis) were more common in the older age group (p=0.04 and p<0.001 respectively). Amblyopia was the most common cause of vision loss in the visually immature versus cataract in the visually mature. Conclusion: Anterior uveitis and its complications were more common in visually immature group in our cohort. Amblyopia was identified as the main cause of visual loss in the younger population.

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Global and regional cortical thinning in first-episode psychosis patients: relationships with clinical and cognitive features

Psychological Medicine ◽

10.1017/s003329171000200x ◽

2010 ◽

Vol 41 (7) ◽

pp. 1449-1460 ◽

Cited By ~ 47

Author(s):

B. Crespo-Facorro ◽

R. Roiz-Santiáñez ◽

R. Pérez-Iglesias ◽

J. M. Rodriguez-Sanchez ◽

I. Mata ◽

...

Keyword(s):

Cortical Thickness ◽

Age Of Onset ◽

Significant Negative Correlation ◽

First Episode ◽

Significant Group ◽

Brain Scans ◽

Cortical Thinning ◽

Schizophrenia Spectrum ◽

First Episode Schizophrenia ◽

Parietal Cortices

BackgroundThe thickness of the cortical mantle is a sensitive measure for identifying alterations in cortical structure. We aimed to explore whether first episode schizophrenia patients already show a significant cortical thinning and whether cortical thickness anomalies may significantly influence clinical and cognitive features.MethodWe investigated regional changes in cortical thickness in a large and heterogeneous sample of schizophrenia spectrum patients (n=142) at their first break of the illness and healthy controls (n=83). Magnetic resonance imaging brain scans (1.5 T) were obtained and images were analyzed by using brains2. The contribution of sociodemographic, cognitive and clinical characterictics was investigated.ResultsPatients showed a significant total cortical thinning (F=17.55, d=−0.62, p<0.001) and there was a diffuse pattern of reduced thickness (encompassing frontal, temporal and parietal cortices) (all p's<0.001, d's>0.53). No significant group×gender interactions were observed (all p's>0.15). There were no significant associations between the clinical and pre-morbid variables and cortical thickness measurements (all r's<0.12). A weak significant negative correlation between attention and total (r=−0.24, p=0.021) and parietal cortical thickness (r=−0.27, p=0.009) was found in patients (thicker cortex was associated with lower attention). Our data revealed a similar pattern of cortical thickness changes related to age in patients and controls.ConclusionsCortical thinning is independent of gender, age, age of onset and duration of the illness and does not seem to significantly influence clinical and functional symptomatology. These findings support a primary neurodevelopment disorder affecting the normal cerebral cortex development in schizophrenia.

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Early onset retinal dystrophies: clinical clues to diagnosis for pediatricians

Italian Journal of Pediatrics ◽

10.1186/s13052-019-0760-5 ◽

2019 ◽

Vol 45 (1) ◽

Author(s):

Agnese Suppiej ◽

Silvia Marino ◽

Maria Eleonora Reffo ◽

Veronica Maritan ◽

Giovanna Vitaliti ◽

...

Keyword(s):

Vision Loss ◽

Clinical Symptoms ◽

Disease Onset ◽

Retinal Dystrophy ◽

Primary Care Providers ◽

Visual Development ◽

Cone Dystrophy ◽

Care Providers ◽

Visual Symptoms ◽

Retinal Dystrophies

Abstract Introduction Inherited retinal dystrophies are major cause of severe progressive vision loss in children. Early recognition and diagnosis are essential for timely visual rehabilitation during the appropriate stages of the visual development, as well as for genetic diagnosis and possible gene therapy. The aim of this study is to characterize a pattern of the initial visual symptoms, which could help the pediatricians and the primary care providers to suspect an inherited retinal disorder in its early stage. Methods We analyzed the initial clinical symptoms, based on parental report during the first visit to specialist, in 50 children diagnosed with retinal dystrophy confirmed by full-field electroretinography. The analysis included the age of symptoms onset and the type of visual symptoms, both in the total population and in the following diagnostic subgroups: rod-cone dystrophy (n.17), cone-rod dystrophy (n.12), achromatopsia (n.13), congenital stationary night blindness (n.6) and Leber’s congenital amaurosis (n.2). Results The majority of children (80%) had the onset of clinical symptoms before one year of age. The most frequent visual complaints reported by parents were nystagmus (76%), visual loss (28%) and photophobia (8%). Nystagmus was the first symptom reported by parents if the disease onset was before the age of six months, while the onset after the six months of age was more likely associated with the complain of vision loss. Conclusions Low vision and nystagmus observed by parents, particularly in the first year of life, may represent a red flag, prompting an appropriate ophthalmological workup for inherited retinal dystrophy.

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Detailed clinical characterisation, unique features and natural history of autosomal recessive RDH12-associated retinal degeneration

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2018-313580 ◽

2019 ◽

pp. bjophthalmol-2018-313580 ◽

Cited By ~ 5

Author(s):

Abigail T Fahim ◽

Zaina Bouzia ◽

Kari H Branham ◽

Neruban Kumaran ◽

Mauricio E Vargas ◽

...

Keyword(s):

Natural History ◽

Retinal Degeneration ◽

Early Onset ◽

Vision Loss ◽

Age Of Onset ◽

Retinal Dystrophy ◽

Loss Of Function ◽

Phenotypic Data ◽

History Of ◽

Clinical Records

BackgroundDefects in retinol dehydrogenase 12 (RDH12) account for 3.4%–10.5 % of Leber congenital amaurosis and early-onset severe retinal dystrophy (EOSRD) and are a potential target for gene therapy. Clinical trials in inherited retinal diseases have unique challenges, and natural history studies are critical to successful trial design. The purpose of this study was to characterise the natural history of RDH12-associated retinal degeneration.MethodsA retrospective chart review was performed in individuals with retinal degeneration and two likely disease-causing variants in RDH12.Results57 subjects were enrolled from nine countries. 33 subjects had clinical records available from childhood. The data revealed an EOSRD, with average age of onset of 4.1 years. Macular atrophy was a universal clinical finding in all subjects, as young as 2 years of age. Scotopic and photopic electroretinography (ERG) responses were markedly reduced in all subjects, and a non-recordable ERG was documented as young as 1 year of age. Assessment of visual acuity, visual field and optical coherence tomography revealed severe loss of function and structure in the majority of subjects after the age of 10 years. Widefield imaging in 23 subjects revealed a unique, variegated watercolour-like pattern of atrophy in 13 subjects and sparing of the peripapillary area in 18 subjects.ConclusionsThis study includes the largest collection of phenotypic data from children with RDH12-associated EOSRD and provides a comprehensive description of the timeline of vision loss in this severe, early-onset condition. These findings will help identify patients with RDH12-associated retinal degeneration and will inform future design of therapeutic trials.

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The Clinical Variability of Maternally Inherited Diabetes and Deafness Is Associated with the Degree of Heteroplasmy in Blood Leukocytes

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2008-2680 ◽

2009 ◽

Vol 94 (8) ◽

pp. 3025-3030 ◽

Cited By ~ 55

Author(s):

M. Laloi-Michelin ◽

T. Meas ◽

C. Ambonville ◽

C. Bellanné-Chantelot ◽

S. Beaufils ◽

...

Keyword(s):

Significant Positive Correlation ◽

Significant Negative Correlation ◽

Molecular Study ◽

Rare Form ◽

Blood Leukocytes ◽

Pattern Dystrophy ◽

Mitochondrial Diabetes ◽

And Gender ◽

Different Levels ◽

Inherited Diabetes

Context: Maternally inherited diabetes and deafness (MIDD) is a rare form of diabetes with a matrilineal transmission, sensorineural hearing loss, and macular pattern dystrophy due to an A to G transition at position 3243 of mitochondrial DNA (mtDNA) (m.3243A>G). The phenotypic heterogeneity of MIDD may be the consequence of different levels of mutated mtDNA among mitochondria in a given tissue. Objective: The aim of the present study was thus to ascertain the correlation between the severity of the phenotype in patients with MIDD and the level of heteroplasmy in the blood leukocytes. Participants: The GEDIAM prospective multicenter register was initiated in 1995. Eighty-nine Europid patients from this register, with MIDD and the mtDNA 3243A>G mutation, were included. Patients with MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) or with mitochondrial diabetes related to other mutations or to deletions of mtDNA were excluded. Results: A significant negative correlation was found between levels of heteroplasmy and age of the patients at the time of sampling for molecular analysis, age at the diagnosis of diabetes, and body mass index. After adjustment for age at sampling for molecular study and gender, the correlation between heteroplasmy levels and age at the diagnosis of diabetes was no more significant. The two other correlations remained significant. A significant positive correlation between levels of heteroplasmy and HbA1c was also found and remained significant after adjustment for age at molecular sampling and gender. Conclusions: These results support the hypothesis that heteroplasmy levels are at least one of the determinants of the severity of the phenotype in MIDD.

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Traumatic Optic Nerve Sheath Hematoma

Case Reports in Ophthalmology ◽

10.1159/000514188 ◽

2021 ◽

pp. 569-573

Author(s):

Aria Ghahramani ◽

Mona L. Camacci ◽

Rucha Borkhetaria ◽

Anne Poulsen ◽

Samuel Beckstead ◽

...

Keyword(s):

Optic Nerve ◽

Visual Field ◽

Corticosteroid Therapy ◽

Visual Field Defect ◽

Vision Loss ◽

Optic Nerve Sheath ◽

Visual Symptoms ◽

Nerve Sheath ◽

Patient Reported ◽

Field Defect

The aim of this report is to present a patient with traumatic optic nerve sheath hematoma (ONSH), a rare diagnosis with high potential for visual sequelae. This case involves a 41-year-old male who presented promptly following blunt trauma to the right eye and orbit that resulted in acute vision loss. Following computed tomography and ophthalmic examination, a diagnosis of ONSH was made and medical therapy with methylprednisolone was initiated. He reported significant improvements in visual symptoms following intravenous corticosteroid therapy. Although the patient reported significant improvements and had normal Snellen visual acuities in follow-up, he continued to have an inferior visual field defect at 1 week in the affected eye. ONSH causing subsequent localized compression of the optic nerve is a rare mechanism of traumatic optic neuropathy in patients following head trauma. The localized compartment syndrome of the optic nerve and subjective visual symptoms were relieved following corticosteroid therapy with no initial need for surgical decompression. Although central visual acuity returned to baseline, the patient had a persistent visual field defect and relative afferent pupillary defect.

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