Novel IBA57 Mutations in Two Chinese Patients and Literature Review of Multiple Mitochondrial Dysfunction Syndrome

2021 ◽  
Author(s):  
Feixia Zhan ◽  
Xiaoli Liu ◽  
Ruilong Ni ◽  
Tiaotiao Liu ◽  
Yuwen Cao ◽  
...  
Keyword(s):  
Literature Review ◽  
Mitochondrial Dysfunction ◽  
Clinical Investigation ◽  
Brain Mri ◽  
Disease Onset ◽  
Nuclear Gene ◽  
Chinese Patients ◽  
Mitochondrial Enzymes ◽  
Clinical Genetic ◽  
Initial Symptoms

Abstract Multiple mitochondrial dysfunction syndrome (MMDS) refers to a class of mitochondrial diseases caused by nuclear gene mutations, which usually begins in early infancy and is classically characterized by markedly impaired neurological development, generalized muscle weakness, lactic acidosis, and hyperglycinemia, cavitating leukoencephalopathy, respiratory failure, as well as early fatality resulted from dysfunction of energy metabolism in multiple systems. So far, six types of MMDS have been identified based on different genotypes, which are caused by mutations in NFU1, BOLA3, IBA57, ISCA2, ISCA1 and PMPCB, respectively. IBA57 encodes a protein involved in the mitochondrial Fe/S cluster assembly process, which plays a vital role in the activity of multiple mitochondrial enzymes. Herein, detailed clinical investigation of 2 Chinese patients from two unrelated families were described, both of them showed mildly delay in developmental milestone before disease onset, and the initial symptoms were all presented with acute motor and mental retrogression, and brain MRI showed diffused leukoencephalopathy with cavities, dysplasia of corpus callosum and cerebral atrophy. Exome sequencing revealed three IBA57 mutations, one shared variant (c.286T > C) has been previously reported, the remaining two (c.189delC and c.580A > G) are novel. To enhance the understanding of this rare disease, we further made a literature review about the current progress in clinical, genetic and treatment of the disorder. Due to the rapid progress of MMDS, early awareness is crucial to prompt and proper administration, as well as genetic counseling.

scholarly journals Epidemiological and Clinical Characteristics of Sporadic Creutzfeldt–Jakob Disease: A Retrospective Study in Eastern China

2021 ◽  
Vol 12 ◽  
Author(s):  
Shuo Feng ◽  
Xinjing Zhao ◽  
Xueying Zhou ◽  
Xiang Ye ◽  
Xiaolin Yu ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Survival Time ◽  
Clinical Characteristics ◽  
Eastern China ◽  
Brain Mri ◽  
Disease Onset ◽  
Brain Magnetic Resonance Imaging ◽  
Chinese Patients ◽  
Mean Survival Time ◽  
Jakob Disease

Objective: We aimed to characterize the epidemiological and clinical characteristics of sporadic Creutzfeldt–Jakob disease (sCJD) in eastern China in this retrospective study.Methods: This study enrolled 67 patients with sCJD hospitalized in a grade-A tertiary hospital in eastern China from January 2010 to January 2020. Demographic data, clinical symptoms, brain magnetic resonance imaging (MRI), electroencephalogram (EEG), cerebrospinal fluid (CSF) 14-3-3 protein test, polymerase chain reaction (PCR), and DNA sequence determination of genes were collected and analyzed.Results: There were 62 patients with probable sCJD and 5 patients with possible sCJD. Male (28 cases) to female (39 cases) ratio was 1:1.39. Mean age at disease onset was 64.42 ± 9.00 years (range: 29–88 years), and mean survival time was 9.39 ± 12.58 months (range: 1–60 months for patients who received the follow-ups). The most common onset symptoms were dementia (49.25%), movement disorder (44.78%), and visual disturbance (22.39%), while the most frequent clinical manifestations were language disorders (74.63%), ataxia (70.15%), and myoclonus (70.15%). The positive rates of brain MRI abnormalities, 14-3-3 protein in CSF, and periodic sharp wave complexes (PSWCs) on EEG were 84.90, 68.00, and 46.03%, respectively. The 14-3-3 protein positive (p = 0.033) and PSWCs on EEG (p = 0.020) acted as the favorable and unfavorable factor for over 1 year of survival time, respectively.Conclusions: There were some differences in epidemiological and clinical characteristics among patients in China and those of other countries. The prognosis and its influencing factors were relatively unexplored in China. The mean survival time of Chinese patients was longer than that of Caucasian patients but shorter than that of Japanese patients. The 14-3-3 protein in CSF and PSWCs on EEG were both closely related to the survival time. It is necessary to promote autopsy or biopsy to better understand sCJD in China.

Riboflavin-responsive multiple Acyl-CoA dehydrogenation deficiency in 13 cases, and a literature review in mainland Chinese patients

2014 ◽  
Vol 59 (5) ◽  
pp. 256-261 ◽  
Author(s):  
Min Zhu ◽  
Xuan Zhu ◽  
Xueliang Qi ◽  
Ding Weijiang ◽  
Yajing Yu ◽  
...  
Keyword(s):  
Literature Review ◽  
Chinese Patients ◽  
Mainland Chinese

scholarly journals The Interplay of Mitophagy and Inflammation in Duchenne Muscular Dystrophy

Life ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 648
Author(s):  
Andrea L. Reid ◽  
Matthew S. Alexander
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Mitochondrial Dysfunction ◽  
Disease Onset ◽  
Exon Skipping ◽  
Dystrophin Gene ◽  
Muscle Disease ◽  
Mitochondrial Morphology ◽  
Gene Therapies ◽  
Dystrophin Protein

Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease caused by a pathogenic disruption of the DYSTROPHIN gene that results in non-functional dystrophin protein. DMD patients experience loss of ambulation, cardiac arrhythmia, metabolic syndrome, and respiratory failure. At the molecular level, the lack of dystrophin in the muscle results in myofiber death, fibrotic infiltration, and mitochondrial dysfunction. There is no cure for DMD, although dystrophin-replacement gene therapies and exon-skipping approaches are being pursued in clinical trials. Mitochondrial dysfunction is one of the first cellular changes seen in DMD myofibers, occurring prior to muscle disease onset and progresses with disease severity. This is seen by reduced mitochondrial function, abnormal mitochondrial morphology and impaired mitophagy (degradation of damaged mitochondria). Dysfunctional mitochondria release high levels of reactive oxygen species (ROS), which can activate pro-inflammatory pathways such as IL-1β and IL-6. Impaired mitophagy in DMD results in increased inflammation and further aggravates disease pathology, evidenced by increased muscle damage and increased fibrosis. This review will focus on the critical interplay between mitophagy and inflammation in Duchenne muscular dystrophy as a pathological mechanism, as well as describe both candidate and established therapeutic targets that regulate these pathways.

scholarly journals Insights into Clinical, Genetic, and Pathological Aspects of Hereditary Spastic Paraplegias: A Comprehensive Overview

2021 ◽  
Vol 8 ◽  
Author(s):  
Liena E. O. Elsayed ◽  
Isra Zuhair Eltazi ◽  
Ammar E. Ahmed ◽  
Giovanni Stevanin
Keyword(s):  
Clinical Symptoms ◽  
Disease Onset ◽  
Lower Limbs ◽  
Special Focus ◽  
Clinical Genetic ◽  
Comprehensive Overview ◽  
Functional Studies ◽  
Hereditary Spastic Paraplegias ◽  
Wide Range ◽  
Complex Forms

Hereditary spastic paraplegias (HSP) are a heterogeneous group of motor neurodegenerative disorders that have the core clinical presentation of pyramidal syndrome which starts typically in the lower limbs. They can present as pure or complex forms with all classical modes of monogenic inheritance reported. To date, there are more than 100 loci/88 spastic paraplegia genes (SPG) involved in the pathogenesis of HSP. New patterns of inheritance are being increasingly identified in this era of huge advances in genetic and functional studies. A wide range of clinical symptoms and signs are now reported to complicate HSP with increasing overall complexity of the clinical presentations considered as HSP. This is especially true with the emergence of multiple HSP phenotypes that are situated in the borderline zone with other neurogenetic disorders. The genetic diagnostic approaches and the utilized techniques leave a diagnostic gap of 25% in the best studies. In this review, we summarize the known types of HSP with special focus on those in which spasticity is the principal clinical phenotype (“SPGn” designation). We discuss their modes of inheritance, clinical phenotypes, underlying genetics, and molecular pathways, providing some observations about therapeutic opportunities gained from animal models and functional studies. This review may pave the way for more analytic approaches that take into consideration the overall picture of HSP. It will shed light on subtle associations that can explain the occurrence of the disease and allow a better understanding of its observed variations. This should help in the identification of future biomarkers, predictors of disease onset and progression, and treatments for both better functional outcomes and quality of life.

scholarly journals Clinical Features and Prognosis in Chinese Patients With Dipeptidyl–Peptidase–Like Protein 6 Antibody–Associated Encephalitis

2022 ◽  
Vol 12 ◽  
Author(s):  
Ailiang Miao ◽  
Yongwei Shi ◽  
Xiaoshan Wang ◽  
Jianqing Ge ◽  
Chuanyong Yu
Keyword(s):  
Neuropsychiatric Symptoms ◽  
Disease Onset ◽  
Brain Magnetic Resonance Imaging ◽  
Dipeptidyl Peptidase ◽  
Chinese Patients ◽  
Normal Brain ◽  
Rare Type ◽  
Epileptiform Discharges ◽  
Psychiatric Disturbances ◽  
Positive Antibody

Objectives:Anti-dipeptidyl–peptidase–like protein 6 (anti-DPPX) encephalitis an extremely rare type of immune-mediated encephalitis. This study aimed to analyze the electroclinical characteristics and prognosis of anti-DPPX encephalitis.Methods:Five patients (all male) with anti-DPPX encephalitis in East China from January 2016 to October 2021 was retrospective analyzed. Electroclinical features and outcomes were reviewed.Results:All five patients were male. The media age at disease onset was 32 years old with a range of 14–56 years. The main symptoms included psychiatric disturbances (2/5), amnesia (4/5), confusion (3/5), and seizures (3/5). Migrating myoclonus were identified in patient 4 with positive DPPX and contactin-associated protein-like 2 antibodies in blood. All of the patients had positive DPPX antibodies in serum. Only one of them had positive antibody in the cerebrospinal fluid. EEG showed diffuse slowing in two patients, but no epileptiform discharges were observed. Eighty percent (4/5) of the patients showed normal brain magnetic resonance imaging. After immunotherapy, improvement of neuropsychiatric symptoms from all of the patients was observed. Over a mean follow-up of 30.8 weeks, all of the patients had marked improvement in the modified Rankin Scale. To date, no tumors were not observed in any patients.Conclusions:Anti-DPPX encephalitis mainly presents as neuropsychiatric symptoms. Cooperation of DPPX antibodies and CASPR2 antibodies might have contributed to the migration of myoclonus in the patient 4. Prompt immunotherapy often results in improvement.

scholarly journals Clinical, Biochemical, and Molecular Analyses of Medium-Chain Acyl-CoA Dehydrogenase Deficiency in Chinese Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhuwen Gong ◽  
Lili Liang ◽  
Wenjuan Qiu ◽  
Huiwen Zhang ◽  
Jun Ye ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Dehydrogenase Deficiency ◽  
Disease Onset ◽  
Chinese Patients ◽  
Gas Chromatography Mass Spectrometry ◽  
Inherited Metabolic Disorder ◽  
Medium Chain ◽  
Chain Acyl ◽  
Generation Sequencing ◽  
Biochemical Abnormalities

ObjectiveMedium-chain acyl-CoA dehydrogenase deficiency (MCADD) is a rare inherited metabolic disorder of fatty acid β-oxidation. The present study aimed to evaluate clinical and biochemical manifestations, and the mutation spectrum of this disorder in a large cohort of Chinese patients.MethodsA total of 24 patients were enrolled, and blood acylcarnitine and urinary organic acid levels were measured by tandem mass spectrometry and gas chromatography–mass spectrometry (GC–MS), respectively. Mutations in the ACADM gene were detected by Sanger or next-generation sequencing. Clinical progression, acylcarnitine spectra, and mutations were analyzed and described in detail.ResultsAmong the 24 patients, six cases were diagnosed because of disease onset with symptoms such as vomiting, diarrhea, convulsion, and hypoglycemia; 18 patients without symptoms were diagnosed by newborn screening (NBS). All patients who accepted treatment after diagnosis developed normal intelligence and physique. The concentrations of octanoylcarnitine, the octanoylcarnitine/decanoylcarnitine ratio, and the octanoylcarnitine/acetylcarnitine ratio in the blood and urinary dicarboxylic acid concentrations were consistently elevated. Blood biomarkers failed to decrease after treatment. DNA sequencing revealed seven known and 17 novel mutations in the ACADM gene of patients. Mutation p.T150Rfs∗4 was most frequent, followed by p.R31C, p.F103Y, p.I223T, p.G362E, and c.387+1delG.ConclusionDespite biochemical abnormalities, medium-chain acyl-CoA dehydrogenase deficiency showed relatively mild clinical phenotypes with low mortality and optimistic prognoses in China. NBS is crucial for early diagnosis, treatment, and prognosis.

A Slc25a46-/- mouse model simulating motor deficit, imbalance of redox system and mitochondria dysfunction during aging

2020 ◽  
Author(s):  
Li Gao ◽  
Min Wang ◽  
Linfeng Liao ◽  
Na Gou ◽  
Piao Xu ◽  
...  
Keyword(s):  
Mouse Model ◽  
Mitochondrial Dysfunction ◽  
Nuclear Gene ◽  
Redox System ◽  
Premature Aging ◽  
Motor Deficit ◽  
Mitochondria Dysfunction ◽  
Respiratory Chain Enzyme ◽  
Knock Out ◽  
Mtdna Mutations

Abstract The mitochondrial theory of aging postulates that accumulation of mtDNA mutations and mitochondrial dysfunction are responsible for producing aging phenotypes. To more comprehensively explore the complex relationship between aging and mitochondria dysfunction, we have developed a mouse model with Slc25a46 knock out, a nuclear gene described as encoding mitochondrial carriers, by CRISPR/Cas9 gene editing to mimic some typical aging phenotypes in human. Slc25a46-/- mice present segmental premature aging phenotypes characterized by shortened lifespan of no more than two months, obviously defective motor ability, gastrocnemius muscle atrophy and imbalance of redox level in brain and liver. The underlying mechanism for multiple organ disorder may attribute to the mitochondrial dysfunction, which is mainly manifested on the damaged mitochondrial structure (e.g., vacuolar structure, irregular swelling and disorganized cristae) and an age-associated decrease in respiratory chain enzyme (mainly complex I and IV) activity. In summary, our study suggests that the Slc25a46-/- mouse is a valid animal model for segmental aging-related pathologies studies based on mitochondrial theory, generating a new platform to both understand mechanisms between aging and mitochondria dysfunction as well as to design mitochondria based therapeutic strategies to improve mitochondrial quality, and thereby the overall healthspan.

scholarly journals COX deficiency and leukoencephalopathy due to a novel homozygous APOPT1/COA8 mutation

2020 ◽  
Vol 6 (4) ◽  
pp. e464 ◽  
Author(s):  
Carola Hedberg-Oldfors ◽  
Niklas Darin ◽  
Christer Thomsen ◽  
Christopher Lindberg ◽  
Anders Oldfors
Keyword(s):  
Genetic Analysis ◽  
Nonsense Mutation ◽  
Clinical Investigation ◽  
Brain Mri ◽  
Homozygous Mutation ◽  
Term Outcome ◽  
Complex Iv ◽  
Long Term Outcome ◽  
Long Term Follow Up

ObjectiveTo describe the long-term follow-up and pathogenesis in a child with leukoencephalopathy and cytochrome c oxidase (COX) deficiency due to a novel homozygous nonsense mutation in APOPT1/COA8.MethodsThe patient was clinically investigated at 3, 5, 9, and 25 years of age. Brain MRI, repeat muscle biopsies with biochemical, morphologic, and protein expression analyses were performed, and whole-genome sequencing was used for genetic analysis.ResultsClinical investigation revealed dysarthria, dysphagia, and muscle weakness following pneumonia at age 3 years. There was clinical regression leading to severe loss of ambulation, speech, swallowing, hearing, and vision. The clinical course stabilized after 2.5 years and improved over time. The MRI pattern in the patient demonstrated cavitating leukoencephalopathy, and muscle mitochondrial investigations showed COX deficiency with loss of complex IV subunits and ultrastructural abnormalities. Genetic analysis revealed a novel homozygous mutation in the APOPT1/COA8 gene, c.310T>C; p.(Gln104*).ConclusionsWe describe a novel nonsense mutation in APOPT1/COA8 and provide additional experimental evidence for a COX assembly defect in human muscle causing the complex IV deficiency. The long-term outcome of the disease seems in general to be favorable, and the characteristic MRI pattern with cavitating leukoencephalopathy in combination with COX deficiency should prompt for testing of the APOPT1/COA8 gene.

Sign in / Sign up

Export Citation Format

Share Document