scholarly journals Early Infantile Epileptic Encephalopathy in anSTXBP1Patient with Lactic Acidemia and Normal Mitochondrial Respiratory Chain Function

2016 ◽  
Vol 2016 ◽  
pp. 1-5
Author(s):  
Dong Li ◽  
Elizabeth Bhoj ◽  
Elizabeth McCormick ◽  
Fengxiang Wang ◽  
James Snyder ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Dysfunction ◽  
Respiratory Chain ◽  
Mitochondrial Disease ◽  
De Novo ◽  
Intractable Epilepsy ◽  
Epileptic Encephalopathy ◽  
Skeletal Muscle Biopsy ◽  
Wide Range ◽  
Lactic Acidemia

A wide range of clinical findings have been associated with mutations in Syntaxin Binding Protein 1 (STXBP1), including multiple forms of epilepsy, nonsyndromic intellectual disability, and movement disorders.STXBP1mutations have recently been associated with mitochondrial pathology, although it remains unclear if this phenotype is a part of the core feature for this gene disorder. We report a 7-year-old boy who presented for diagnostic evaluation of intractable epilepsy, episodic ataxia, resting tremor, and speech regression following a period of apparently normal early development. Mild lactic acidemia was detected on one occasion at the time of an intercurrent illness. Due to the concern for mitochondrial disease, ophthalmologic evaluation was performed that revealed bilateral midperiphery pigmentary mottling. Optical coherence tomography (OCT) testing demonstrated a bilaterally thickened ganglion cell layer in the perifovea. Skeletal muscle biopsy analysis showed no mitochondrial abnormalities or respiratory chain dysfunction. Exome sequencing identified ade novoc.1651C>T (p.R551C) mutation inSTXBP1.Although mitochondrial dysfunction has been reported in some individuals, our proband had only mild lactic acidemia and no skeletal muscle tissue evidence of mitochondrial disease pathology. Thus, mitochondrial dysfunction is not an obligate feature ofSTXBP1disease.

scholarly journals Anesthesia outside the Operating Room in a Patient with Mitochondrial Disease

2020 ◽  
Vol 2020 ◽  
pp. 1-3
Author(s):  
Alejandra Fadrique-Fuentes ◽  
Beatriz Martínez-Rafael ◽  
Rodrigo Poves-Álvarez ◽  
Estefanía Gómez-Pesquera
Keyword(s):  
Mitochondrial Dysfunction ◽  
Operating Room ◽  
Mitochondrial Disease ◽  
Genetic Disorders ◽  
Metabolic Balance ◽  
Anesthetic Agents ◽  
Wide Range

Mitochondrial dysfunction comprehends a wide range of genetic disorders. These patients’ precarious metabolic balance makes its management difficult. Furthermore, the same systems affected by mitochondrial disease can be altered by many of the frequently used anesthetic agents. Each patient has to be evaluated individually according to their comorbidities and anesthetic requirements.

scholarly journals GNAO1 encephalopathy

2017 ◽  
Vol 3 (2) ◽  
pp. e143 ◽  
Author(s):  
Federica Rachele Danti ◽  
Serena Galosi ◽  
Marta Romani ◽  
Martino Montomoli ◽  
Keren J. Carss ◽  
...  
Keyword(s):  
Hospital Admissions ◽  
De Novo ◽  
Clinical Symptoms ◽  
Molecular Genetic ◽  
Cerebral Atrophy ◽  
Epileptic Encephalopathy ◽  
Causative Role ◽  
Diffuse Astrocytoma ◽  
Who Grade ◽  
Wide Range

Objective:To describe better the motor phenotype, molecular genetic features, and clinical course of GNAO1-related disease.Methods:We reviewed clinical information, video recordings, and neuroimaging of a newly identified cohort of 7 patients with de novo missense and splice site GNAO1 mutations, detected by next-generation sequencing techniques.Results:Patients first presented in early childhood (median age of presentation 10 months, range 0–48 months), with a wide range of clinical symptoms ranging from severe motor and cognitive impairment with marked choreoathetosis, self-injurious behavior, and epileptic encephalopathy to a milder phenotype, featuring moderate developmental delay associated with complex stereotypies, mainly facial dyskinesia and mild epilepsy. Hyperkinetic movements were often exacerbated by specific triggers, such as voluntary movement, intercurrent illnesses, emotion, and high ambient temperature, leading to hospital admissions. Most patients were resistant to drug intervention, although tetrabenazine was effective in partially controlling dyskinesia for 2/7 patients. Emergency deep brain stimulation (DBS) was life saving in 1 patient, resulting in immediate clinical benefit with complete cessation of violent hyperkinetic movements. Five patients had well-controlled epilepsy and 1 had drug-resistant seizures. Structural brain abnormalities, including mild cerebral atrophy and corpus callosum dysgenesis, were evident in 5 patients. One patient had a diffuse astrocytoma (WHO grade II), surgically removed at age 16.Conclusions:Our findings support the causative role of GNAO1 mutations in an expanded spectrum of early-onset epilepsy and movement disorders, frequently exacerbated by specific triggers and at times associated with self-injurious behavior. Tetrabenazine and DBS were the most useful treatments for dyskinesia.

scholarly journals Generation of somatic mitochondrial DNA-replaced cells for mitochondrial dysfunction treatment

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hideki Maeda ◽  
Daisuke Kami ◽  
Ryotaro Maeda ◽  
Akira Shikuma ◽  
Satoshi Gojo
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Disease ◽  
Respiratory Function ◽  
Disease Patient ◽  
Mitochondrial Diseases ◽  
Wild Type ◽  
Mutant Genotype ◽  
Isolated Mitochondria ◽  
Wide Range

AbstractMitochondrial diseases currently have no cure regardless of whether the cause is a nuclear or mitochondrial genome mutation. Mitochondrial dysfunction notably affects a wide range of disorders in aged individuals, including neurodegenerative diseases, cancers, and even senescence. Here, we present a procedure to generate mitochondrial DNA-replaced somatic cells with a combination of a temporal reduction in endogenous mitochondrial DNA and coincubation with exogeneous isolated mitochondria. Heteroplasmy in mitochondrial disease patient-derived fibroblasts in which the mutant genotype was dominant over the wild-type genotype was reversed. Mitochondrial disease patient-derived fibroblasts regained respiratory function and showed lifespan extension. Mitochondrial membranous components were utilized as a vehicle to deliver the genetic materials into endogenous mitochondria-like horizontal genetic transfer in prokaryotes. Mitochondrial DNA-replaced cells could be a resource for transplantation to treat maternal inherited mitochondrial diseases.

scholarly journals Generation of Somatic Mitochondrial DNA-Replaced Cells for Mitochondrial Dysfunction Treatment

2020 ◽  
Author(s):  
Hideki Maeda ◽  
Daisuke Kami ◽  
Ryotaro Maeda ◽  
Akira Shikuma ◽  
Satoshi Gojo
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Disease ◽  
Pluripotent Stem Cells ◽  
Disease Patient ◽  
Mitochondrial Diseases ◽  
Wild Type ◽  
Mutant Genotype ◽  
Wide Range

AbstractMitochondrial diseases currently have no cure regardless of whether the cause is a nuclear or mitochondrial genome mutation. Mitochondrial dysfunction notably affects a wide range of disorders in aged individuals, including neurodegenerative diseases, cancers, and even senescence. Here, we present a procedure to generate mitochondrial DNA-replaced somatic cells with a combination of a temporal reduction in endogenous mitochondrial DNA and coincubation with exogeneous isolated mitochondria. Heteroplasmy in mitochondrial disease patient-derived fibroblasts in which the mutant genotype was dominant over the wild-type genotype was reversed over the long term, even inducing the production of pluripotent stem cells from the mitochondrial DNA-replaced cells to maintain the genotype without a reversion to the original. Both mitochondrial disease patient-derived and aged fibroblasts could regain respiratory function and showed lifespan extension. Mitochondrial membranous components were utilized as a vehicle to deliver the genetic materials into endogenous mitochondria-like horizontal genetic transfer in prokaryotes. The mitochondrial DNA-replaced cells could be a resource for transplantation to treat not only mitochondrial diseases, but also senescence-related diseases.

scholarly journals Thyroid Hormone Protects from Fasting-Induced Skeletal Muscle Atrophy by Promoting Metabolic Adaptation

2019 ◽  
Vol 20 (22) ◽  
pp. 5754 ◽  
Author(s):  
Ucci ◽  
Renzini ◽  
Russi ◽  
Mangialardo ◽  
Cammarata ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Thyroid Hormone ◽  
Muscle Atrophy ◽  
De Novo ◽  
Skeletal Muscle Atrophy ◽  
Metabolic Adaptation ◽  
Cell Proliferation And Differentiation ◽  
Wide Range ◽  
Ubiquitin Proteasome ◽  
Muscle Homeostasis

Thyroid hormones regulate a wide range of cellular responses, via non-genomic and genomic actions, depending on cell-specific thyroid hormone transporters, co-repressors, or co-activators. Skeletal muscle has been identified as a direct target of thyroid hormone T3, where it regulates stem cell proliferation and differentiation, as well as myofiber metabolism. However, the effects of T3 in muscle-wasting conditions have not been yet addressed. Being T3 primarily responsible for the regulation of metabolism, we challenged mice with fasting and found that T3 counteracted starvation-induced muscle atrophy. Interestingly, T3 did not prevent the activation of the main catabolic pathways, i.e., the ubiquitin-proteasome or the autophagy-lysosomal systems, nor did it stimulate de novo muscle synthesis in starved muscles. Transcriptome analyses revealed that T3 mainly affected the metabolic processes in starved muscle. Further analyses of myofiber metabolism revealed that T3 prevented the starvation-mediated metabolic shift, thus preserving skeletal muscle mass. Our study elucidated new T3 functions in regulating skeletal muscle homeostasis and metabolism in pathological conditions, opening to new potential therapeutic approaches for the treatment of skeletal muscle atrophy.

Exome Sequencing Identifying Dual Mutations in Calcium Signaling Genes GNAO1 and ATP2B3 in a Patient with Early Infantile Epileptic Encephalopathy

2016 ◽  
Vol 15 (04) ◽  
pp. 183-186
Author(s):  
Fatema Serajee ◽  
Ahm Huq ◽  
Keisuke Ueda
Keyword(s):  
Calcium Signaling ◽  
Exome Sequencing ◽  
Missense Mutation ◽  
Calcium Homeostasis ◽  
De Novo ◽  
Intractable Epilepsy ◽  
Epileptic Encephalopathy ◽  
Protein Signaling ◽  
Whole Exome ◽  
Spinocerebellar Ataxia 1

Early infantile epileptic encephalopathy (EIEE) is an age-dependent epileptic encephalopathy. It occurs early in life with various types of seizures, especially tonic spasms and its overall prognosis is poor. We report a 5-year-old boy with EIEE, severe developmental delay, intractable epilepsy, and congenital cerebellar ataxia. His infantile spasms were treated successfully with ACTH, but he later developed intractable focal seizures. Whole exome sequencing revealed a maternally inherited missense mutation in the ATP2B3 gene (c.3338C > T/p.T1113M) and a de novo missense mutation in the GNAO1 gene (c.133G > C/p.G45R). Both genes are associated with calcium signaling pathways. The ATP2B3 gene is associated with intracellular calcium clearance, resulting in abnormal calcium homeostasis and X-linked spinocerebellar ataxia-1. The GNAO1 gene is associated with G protein signaling, affecting calcium signaling, and EIEE. Both mutations are related to maintain cellular calcium homeostasis, but the phenotype was not significantly more severe than those which have been reported.

Approaches to Finding the Molecular Basis of Mitochondrial Oxidative Phosphorylation Disorders

2008 ◽  
Vol 11 (4) ◽  
pp. 395-411 ◽  
Author(s):  
Denise M. Kirby ◽  
David R. Thorburn
Keyword(s):  
Mitochondrial Dna ◽  
Oxidative Phosphorylation ◽  
Mitochondrial Disease ◽  
De Novo ◽  
Genetic Diagnosis ◽  
Nuclear Genes ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Inherited Disorders ◽  
Protein Subunits ◽  
Wide Range

AbstractInherited disorders of mitochondrial oxidative phosphorylation are the most common group of inborn errors of metabolism and cause a wide range of clinical presentations. Mitochondrial DNA encodes 13 protein subunits required for oxidative phosphorylation plus 22 transfer RNAs and two ribosomal RNAs, and mutations in most of these genes cause human disease. Nuclear genes encode most of the protein subunits and all other proteins required for mitochondrial biogenesis and mitochondrial DNA replication and expression. Mutations in 64 nuclear genes and 34 mitochondrial genes are now known to cause mitochondrial disease and many novel mitochondrial disease genes await discovery. The genetic complexity of oxidative phosphorylation means that maternal, autosomal recessive, autosomal dominant and X-linked modes of inheritance can occur, along with de novo mutations. This complexity presents a challenge in planning efficient molecular genetic diagnosis of patients with suspected mitochondrial disease. In some situations, clinical phenotype can be strongly predictive of the underlying genotype. However, more often this is not the case and it is usually helpful, particularly with pediatric patients, to determine whether the activity of one or more of the individual oxidative phosphorylation enzymes is deficient before proceeding with mutation analysis. In this review we will summarize the genetic bases of mitochondrial disease and discuss some approaches to integrate information from clinical presentation, laboratory findings, family history, and imaging to guide molecular investigation.

The Spectrum of KCNQ2- and KCNQ3-Related Epilepsy

2021 ◽  
Author(s):  
Anna Portale ◽  
Mattia Comella ◽  
Giulia Salomone ◽  
Alessandra Di Nora ◽  
Lidia Marino ◽  
...  
Keyword(s):  
De Novo ◽  
Epileptic Encephalopathy ◽  
Response To Treatment ◽  
Psychomotor Development ◽  
K Channel ◽  
Loss Of Function ◽  
M Current ◽  
Wide Range ◽  
Cortical Visual Impairment ◽  
Infantile Epilepsy

Abstract KCNQ genes encode for a family of six transmembrane domains, single pore-loop, and K+ channel α-subunits that have a wide range of physiological correlates. In the brain, KCNQ2 and KCNQ3 heteromultimers are thought to underlie the M-current which is essential in raising the threshold for firing an action potential; mutations in these genes may cause several types of infantile epilepsies. KCNQ2-related disorders represent a continuum of overlapping neonatal epileptic phenotypes that range from KCNQ2 benign familial neonatal epilepsy (BFNE), a seizure disorder that occur in children who typically have a normal psychomotor development and are inherited as an autosomal dominant trait, to KCNQ2 early-onset epileptic encephalopathy (EOEE) as the result of a de novo pathogenic variant. KCNQ3-related disorders are rarer and include BFNE, benign familial infantile epilepsy and KCNQ3-related epileptic encephalopathy with intellectual disability with or without seizures and/or cortical visual impairment. For both KCNQ2- and KCNQ3-related disorders, it is possible to use several drugs for different classes of mutations (i.e., gain of function vs. loss of function), and usually their effects vary in relation to the clinical presentation and the phenotype of the patient. However, KCNQ2-EOEE patients have a worse response to treatment than KCNQ2-BFNE patients and usually become drug resistant with multiple daily seizures.

scholarly journals A de novo SCN8A heterozygous mutation in a child with epileptic encephalopathy: a case report

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Kao-Min Lin ◽  
Geng Su ◽  
Fengpeng Wang ◽  
Xiaobin Zhang ◽  
Yuanqing Wang ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Exome Sequencing ◽  
De Novo ◽  
Intractable Epilepsy ◽  
Bioinformatic Analysis ◽  
Epileptic Encephalopathy ◽  
De Novo Mutation ◽  
Heterozygous Mutation ◽  
Targeted Exome Sequencing ◽  
Complex Disorder

Abstract Background Epilepsy is a complex disorder caused by various factors, including genetic aberrance. Recent studies have identified an essential role of the sodium channel Nav1.6, encoded by the gene SCN8A, in epileptic encephalopathy. Case presentation Using parent-offspring trio targeted-exome sequencing, we identified a de novo heterozygous missense mutation c.3953A > G (p.N1318S) in SCN8A in a 3-year-and-9-month Chinese female patient with early infantile epileptic encephalopathy and a normal magnetic resonance imaging of the brain. Conclusions This de novo mutation was only detected in the patient but not in her parents. Bioinformatic analysis indicates the pathogenicity of this mutation. Administration of the sodium channel blocker well controlled seizures in the patient. Therefore, we recommend trio targeted-exome sequencing as a routine method for pathogenic variant screening in patients with intractable epilepsy and a normal MRI.

scholarly journals Decoding mitochondrial heterogeneity in single muscle fibres by imaging mass cytometry

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Charlotte Warren ◽  
David McDonald ◽  
Roderick Capaldi ◽  
David Deehan ◽  
Robert W. Taylor ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Oxidative Phosphorylation ◽  
Single Cell ◽  
Mitochondrial Disease ◽  
Muscle Fibres ◽  
Single Muscle ◽  
Single Cell Level ◽  
Mass Cytometry ◽  
Cell Level ◽  
Wide Range

Abstract The study of skeletal muscle continues to support the accurate diagnosis of mitochondrial disease and remains important in delineating molecular disease mechanisms. The heterogeneous expression of oxidative phosphorylation proteins and resulting respiratory deficiency are both characteristic findings in mitochondrial disease, hence the rigorous assessment of these at a single cell level is incredibly powerful. Currently, the number of proteins that can be assessed in individual fibres from a single section by immunohistochemistry is limited but imaging mass cytometry (IMC) enables the quantification of further, discrete proteins in individual cells. We have developed a novel workflow and bespoke analysis for applying IMC in skeletal muscle biopsies from patients with genetically-characterised mitochondrial disease, investigating the distribution of nine mitochondrial proteins in thousands of single muscle fibres. Using a semi-automated analysis pipeline, we demonstrate the accurate quantification of protein levels using IMC, providing an accurate measure of oxidative phosphorylation deficiency for complexes I–V at the single cell level. We demonstrate signatures of oxidative phosphorylation deficiency for common mtDNA variants and nuclear-encoded complex I variants and a compensatory upregulation of unaffected oxidative phosphorylation components. This technique can now be universally applied to evaluate a wide range of skeletal muscle disorders and protein targets.

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