Leigh Syndrome in a Filipino Child: A case report

Introduction@#Leigh disease and Leigh-like syndrome are a heterogenous group of neurodegenerative disorders involving any level of the neuraxis and may present with a variety of clinical presentations, prominent among them is psychomotor regression. Despite the remarkable number of established disease genes and novel mutations being discovered, many cases of Leigh syndrome remain without a genetic diagnosis, indicating that there are still more disease genes to be identified. @*Case@#Here we present a case of a two and a half-year-old girl who presented with delayed acquisition of developmental milestones with subsequent regression, ataxia, and dyskinesia. Her work-up showed raised blood lactate levels and lactate peak in MR spectroscopy. Mitochondria genome showed absence of mitochondrial DNA mutation, while whole exome sequence analysis revealed a novel dynein gene variant, p.A1577S. Her parents underwent genetic testing as well, and her father also had the same dynein mutation, however, is non-symptomatic. She had an older brother who initially presented with ophthalmoplegia and eventually developed psychomotor regression. He subsequently expired from respiratory failure after almost 2 years from initial presentation. Both siblings were diagnosed with Leigh syndrome. @*Conclusion@#The diagnosis of Leigh syndrome remains based on characteristic clinical and radiologic findings. However, a specific defect must be identified if reliable genetic counseling is to be provided.

Anti-tumor activity of tigecycline: a review / 生物工程学报

Tigecycline is a novel glycylcycline antibacterial drug, which shows both antibiotic function and anti-tumor activity. This review summarizes the single and combined use of tigecycline for tumor treatment and the underpinning mechanisms. As an inhibitor for mitochondrial DNA translation, tigecycline affects the proliferation, migration, and invasion of tumor cells mainly through inhibiting mitochondrial protein synthesis and inducing mitochondrial dysfunction. Although the effect of tigecycline monotherapy is controversial, the efficacy of combined use of tigecycline is satisfactory. Therefore, it is important to explore the molecular mechanisms underpinning the anti-tumor activity of tigecycline, with the aim to use it as a cheap and effective new anti-tumor drug.

Secondary manifestations of mitochondrial disorders / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Mitochondrial disorders (MIDs) are a heterogeneous group of genetic metabolic diseases due to mutations in the mitochondrial DNA (mtDNA) or in the nuclear DNA (nDNA) (Rahman and Rahman, 2018). Some affected genes encode proteins with various functions, or structural RNAs such as transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs). MIDs may also be caused by mutations in non-coding regions (e.g., D-loop of mtDNA) (Rahman and Rahman, 2018). Proteins involved in MIDs include enzymes, assembling factors, transport proteins, signaling proteins, pore proteins, and fusion/fission proteins (Gorman et al., 2016). The pathways most frequently affected by mutations in "mitochondrial genes" are the respiratory chain and the oxidative phosphorylation. Dysfunction of many other pathways (e.g., β-oxidation, pyruvate-dehydrogenase complex, and heme synthesis) may also manifest as MIDs (Hu et al., 2019). The estimated prevalence of MIDs is at least 1:5000 (Ng and Turnbull, 2016).

A Suspected Case of MEHMO – Rare X-linked Mitochondrial Disorder

Introduction: MEHMO (Mental retardation, epilepticseizures, hypogonadism and hypogenitalism, microcephalyand obesity) is a rare and complex X-linked disorder whichcharacterized by profound intellectual disability, epilepticseizures, hypogonadism and hypogenitalism, microcephalyand obesity. By genetic haplotype and linkage analysis,disease locus has been assigned to Xp21.1 - Xp22.13.Case report: The patient was born to non-consanguineousparents near the term of delivery and clinically was verysimilar to the syndromal description of MEHMO. Familyhistory of deaths of 2 maternal uncles below the age of 2 yearssuggests X- linked inheritance.Conclusion: The findings of index case warrant cliniciansto be more vigilant while assessing such cases and calls forthorough clinical examination, family history, detailed labwork up and molecular genetics whenever possible to supportand contribute towards literature in futur

Síndrome de Kearns Sayre: reporte de dos casos / Kearns Sayre Syndrome: Report of two cases

RESUMEN El síndrome de Kearns Sayre (SKS) es una rara mitocondriopatía causada en la mayoría de los casos por deleciones en el ADN mitocondrial, usualmente no heredada y de ocurrencia espontánea. Se caracteriza por disfunción multiorgánica de manifestación antes de los veinte años de edad. Fue descrito por Thomas Kearns y George Sayre, quienes reportaron la tríada de oftalmoplejía externa, retinopatía pigmentaria y bloqueos de la conducción cardíaca, siendo esta última alteración determinante en el pronóstico, así como el número de órganos afectados. Presentamos dos casos de Síndrome de Kearns Sayre con manifestaciones clínicas oftalmológicas en su debut, asociados a debilidad muscular, similar a los casos típicos reportados en la literatura, donde la mayoría de los pacientes presentan compromiso ocular. En la literatura colombiana existen pocos reportes de este síndrome, por lo tanto, esta presentación contribuye al conocimiento de la entidad en nuestro medio, la patología presenta una triada clínica específica, pero a la vez muestra una afección multisistémica que requiere un alto índice de sospecha por parte de las especialidades a las cuales el paciente puede acceder en su cuadro inicial.

SUMMARY The Kearns-Sayre syndrome is a rare mitochondrial disease caused, in most cases by deletions in mitochondrial DNA, usually not inherited and spontaneously occurring. It is characterized by multiorganic dysfunction that typically develops before the age of twenty. Described by Thomas Kearns and George Sayre who reported a case with presence of the triad of external ophthalmoplegia, pigmentary retinopathy and cardiac conduction blocks, the latter being decisive alteration in the forecast, as well as the number of affected organs. We report two cases of Kearns-Sayre syndrome debuting with ophthalmological clinical manifestations, associated with muscle weakness, similar to typical cases reported in the literature where most patients have eye involvement. The Colombian literature there are very few reported cases of this syndrome, so this presentation contributes to the knowledge of this entity in our environment, taking into account that this disease presents a specific clinical triad but both shows multisystem condition, requiring a high index of suspicion on the part of various specialties to which the patient can be accessed.

Subacute necrotizing encephalomyelopathy (Leigh syndrome) in pediatric patients: a retrospective study.

Background: The clinical manifestations of Leigh Syndrome (LS) are heterogeneous and its diagnosis is often based on information acquired from multiple levels of inquiry. To identify LS, Oral Glucose Lactate Stimulation Test (OGLST) and Magnetic Resonance Spectroscopy (MRS) have been used as additional tools for evaluation of this metabolic disorder. The objective of the study was to report the clinical manifestations, neuroimaging assessments, and multidisciplinary approaches of lactate in pediatric patients with LS. Methods: We performed a retrospective charts review of pediatric patients with LS, which underwent the investigations using laboratory tests and Magnetic Resonance Images (MRI)/MRS of the brain. Results: The distributions of the lesions on the MRI of the brain studies were as the following: basal ganglia (7/8), brainstem (7/8), and cortex (3/8). Despite all of the patients showed disorient neurological manifestations and symmetrical lesions over the basal ganglion and brainstem on MRI, elevated levels of serum lactate were detected in 6 of 8 patients by either random serum sample obtained for lactate or OGLST. Subsequently, the remaining 2 cases were demonstrated with lactate peak over the affected areas by MRS. Cranial MRS showed lactate duplex and decreased N-acetylaspartate/creatine ratio over the affected areas in the 5 of 6 patients. Conclusions: The study shows the importance of multidisciplinary approaches in the diagnosis of LS. Approach of LS may not only depend on the elevation of the value of random serum lactate but also can be further aided by OGLST or MRS to evaluate metabolic disorder in such patients.

A peep into mitochondrial disorder: multifaceted from mitochondrial DNA mutations to nuclear gene modulation

Mitochondrial genome is responsible for multiple human diseases in a maternal inherited pattern, yet phenotypes of patients in a same pedigree frequently vary largely. Genes involving in epigenetic modification, RNA processing, and other biological pathways, rather than "threshold effect" and environmental factors, provide more specific explanation to the aberrant phenotype. Thus, the double hit theory, mutations both in mitochondrial DNA and modifying genes aggravating the symptom, throws new light on mitochondrial dysfunction processes. In addition, mitochondrial retrograde signaling pathway that leads to reconfiguration of cell metabolism to adapt defects in mitochondria may as well play an active role. Here we review selected examples of modifier genes and mitochondrial retrograde signaling in mitochondrial disorders, which refine our understanding and will guide the rational design of clinical therapies.

Mitochondrial Disorders

Mitochondria contain respiratory chain enzyme complexes that carry out oxidative phosphorylation and produce a main part of cellular energy in the form of ATP. Mitochondrial disorders occur either due to sporadic or inherited mutations of the genes located in the nuclear or mitochondrial DNA or due to other exogenous factors. Although several proteins related with signalling, assembling, transporting, and enzymatic functions can be impaired in mitochondrial disorders, most frequently the activity of the respiratory chain protein complexes is primarily or secondarily affected, leading to impaired oxygen utilization and reduced energy production. Mitochondrial disorders usually show a chronic and slowly progressive course and present with multiorgan involvement with varying onsets between birth and late adulthood. They represent a diagnostic challenge because of their wide variations in the presentation and the course. The systems frequently affected in mitochondrial disorders are the peripheral nervous system, brain, endocrine system, heart, eyes, ears, guts, kidneys and bone marrow. Although there is actually no specific therapy and cure for mitochondrial disorders, the rapidly increasing understanding of the pathophysiological background of mitochondrial disorders may further facilitate the diagnostic approach and open perspectives to the future and possibly causative therapies.

Long-term Clinical Follow-up of Patients with A3243G Mitochondrial tRNA Mutation : Clinical Phenotype and Natural Course

PURPOSE:Mitochondrial disorder is a progressive disease, but there are no specific treatment modalities to prevent the progression. Also, there has been little understanding on the pattern of disease progression nor natural history. The aim of this study was to elucidate the initial clinical phenotypes, patterns of the disease progression, and its natural history of the patients with mitochondrial A3243G mutation. METHODS:Among the patients with biochemically or genetically confirmed mitochondrial disorders, 7 patients with A3243G mutation were included in a 7 year follow-up observation(range: 3-11 years). We classified the patients into two groups by the initial clinical presentations:systemic and neurologic onset. They were clinically evaluated with serial brain MRI and MRS for the evaluation of the disease evolution patterns. RESULTS:The clinical manifestations of mitochondrial A3243G mutation were extremely variable; seizure, headache, dementia, myopathy, sensorineural hearing loss, external ophthalmoplegia, diabetes mellitus, cardiomyopathy, easy fatigability, and short stature. Among the 7 patients, 4 patients initially presented neurologic symptom such as seizure(3) and headache(1), and 3 patients systemic symptoms such as DM(2) and easy fatigability(1). All the patients with neurologic onset showed relentless progression with recurrent stroke- like episodes and intractable seizures, and finally fell into be functionally dependent states or death. All the patients with systemic onset showed clinically silent periods for 3-10 years, and still they were in functionally independent states despite subsequent neurologic symptoms. CONCLUSION:We could find out the relationship between initial clinical phenotypes and final outcomes in mitochondrial A3243G mutation. However, the population is small in this study so that a larger scaled analysis is needed.

Mitochondrial disorders / 한양의대학술지

Mitochondria contain the respiratory chain enzyme complexes that carry out oxidative phosphorylation and produce the majority of cellular energy in the form of ATP. Mitochondrial disorders are either due to sporadic or inherited mutations of genes located in nuclear or mitochondrial DNA or due to other exogenous factors. Although several proteins related with signalling, assembling, transporting, and enzymatic function can be impaired in mitochondrial disorders, most frequently however, the activity of the respiratory chain protein complexes is primarily or secondarily affected, leading to impaired oxygen utilization and reduced energy production. Mitochondrial disorders usually show a chronic slowly progressive course and present with multiorgan involvement with varying onset between birth and late adulthood. They represent a diagnostic challenge because of their wide variation in presentation and course. Systems frequently affected in mitochondrial disorders are peripheral nervous system, brain, endocrine system, heart, eyes, ears, guts, kidney and bone marrow. Although there is no specific therapy and cure for mitochondrial disorders, the rapidly increasing understanding of the pathophysiological background of the disorders may further facilitate the diagnostic approach and open perspectives to, possibly causative therapies in future.

A Case of Kearns-Sayre Syudrome

Kearns-Sayer syndrome, a rare mitochondrial disorder, is composed of chronic progressive external ophthalmoplegia, atypical retinal pigmentation and complete heart block, and also causes numerous neurologic or endocrinologic symptoms. On muscle biopsy, a "ragged red fiber" was seen with Gomori trichrome stain, On electron microscopy, aggregations of abnormal mitochondria were demonstrated, confirming the diagnosis of mitochondrial myopathy. We report a case of Kearns-Sayer syndrome we have experienced.