Analysis of clinical phenotype and genetic variants in a child with mitochondrial F-S disease due to variants of FDXR gene / 中华医学遗传学杂志

OBJECTIVE@#To analyze the clinical phenotype and genetic variants of a child suspected for mitochondrial F-S disease.@*METHODS@#A child with mitochondrial F-S disease who visited Department of Neurology, Hunan Provincial children's Hospital on November 5, 2020 was selected as research subject of this study. Clinical data of the child was collected. The child was subjected to whole exome sequencing (WES). Bioinformatics tools were used to analyze the pathogenic variants. Candidate variants were verified by Sanger sequencing of the child and her parents.@*RESULTS@#WES revealed that the child has harbored compound heterozygous variants of the FDXR gene, namely c.310C>T (p.R104C) and c.235C>T (p.R79C), which were inherited from her father and mother, respectively. Neither variant has been reported in HGMD, PubMed, 1000 Genomes, and dbSNP databases. Both of the variants have been suggested as deleterious according to the prediction results from different bioinformatics analysis software.@*CONCLUSION@#Mitochondrial diseases should be suspected for patients with multiple system involvement. The compound heterozygous variants of the FDXR gene probably underlay the disease in this child. Above finding has enriched the spectrum of FDXR gene mutations underlying mitochondrial F-S disease. WES can facilitate the diagnosis of mitochondrial F-S disease at the molecular level.

The advances and new technologies for the study of mitochondrial diseases / Avanços e novas tecnologias para o estudo das doenças mitocondriais

ABSTRACT Genetic mitochondrial disorders are responsible for the most common inborn errors of metabolism, caused by mutations in either nuclear genes or in mitochondrial DNA. This article presents the prokaryotic origin of the organelle and the relation between nuclear and mitochondrial genomes, as well as current evolutionary models for such mechanisms. It also addresses the structure of mitochondrial genes, their expression pattern, clinical features of gene defects, risk of transmission and current techniques to avoid these events in assisted human reproduction. Finally, it discusses the ethical implications of these possibilities.

RESUMO As doenças genéticas mitocondriais são responsáveis pelos erros inatos do metabolismo mais comuns, causados por mutações tanto em genes nucleares como no DNA mitocondrial. Este artigo apresenta a origem procariótica dessa organela, e a relação entre os genomas nuclear e mitocondrial, bem como modelos evolutivos correntes para esses mecanismos. Também trata da estrutura dos genes mitocondriais, seu padrão de expressão, características clínicas de defeitos genéticos, riscos de transmissão e técnicas atualmente utilizadas para evitar esses eventos em reprodução humana assistida. Finalmente, discute as implicações éticas dessas possibilidades.

Coenzyme Q10 defects may be associated with a deficiency of Q10-independent mitochondrial respiratory chain complexes

BACKGROUND: Coenzyme Q10 (CoQ10 or ubiquinone) deficiency can be due either to mutations in genes involved in CoQ10 biosynthesis pathway, or to mutations in genes unrelated to CoQ10 biosynthesis. CoQ10 defect is the only oxidative phosphorylation disorder that can be clinically improved after oral CoQ10 supplementation. Thus, early diagnosis, first evoked by mitochondrial respiratory chain (MRC) spectrophotometric analysis, then confirmed by direct measurement of CoQ10 levels, is of critical importance to prevent irreversible damage in organs such as the kidney and the central nervous system. It is widely reported that CoQ10 deficient patients present decreased quinone-dependent activities (segments I + III or G3P + III and II + III) while MRC activities of complexes I, II, III, IV and V are normal. We previously suggested that CoQ10 defect may be associated with a deficiency of CoQ10-independent MRC complexes. The aim of this study was to verify this hypothesis in order to improve the diagnosis of this disease. RESULTS: To determine whether CoQ10 defect could be associated with MRC deficiency, we quantified CoQ10 by LC-MSMS in a cohort of 18 patients presenting CoQ10-dependent deficiency associated with MRC defect. We found decreased levels of CoQ10 in eight patients out of 18 (45 %), thus confirming CoQ10 disease. CONCLUSIONS: Our study shows that CoQ10 defect can be associated with MRC deficiency. This could be of major importance in clinical practice for the diagnosis of a disease that can be improved by CoQ10 supplementation.

La mitocondria en la medicina legal y forense / The Mitochondrion in legal and forensic medicine

Las mitocondrias son las organelas intracelulares encargadas de suministrar la mayor parte de la energía necesaria para la actividad celular. Actúan, por lo tanto, como centrales energéticas de la célula y sintetizan ATP a expensas de los sustratos metabólicos. La intoxicación con ácido cianhídrico inhibe estos mecanismos y las alteraciones en el funcionamiento del metabolismo mitocondrial de origen genético o congénito producen innumerables patologías. El conocimiento de las patologías y disfunción de las mitocondrias es de importancia para realizar correctamente el diagnóstico de las causas de muerte. El ADN mitocondrial es de suma importancia en la medicina legal y forense para la identificación de las personas.

Mitochondria are organelles in the cell cytoplasm which supply most of the energy needed for cellular activity. They behave as cell’s power plants and synthesize ATP using metabolic substrates. Intoxication with Hydrocyanic Acid inhibits the synthesis of ATP, generating alterations in the mitochondrial metabolism, either genetic or congenital. The consequences of those alterations are innumerables pathologies. Understanding the pathologies and malfunctions of mitochondria help us to make the right diagnostic about the cause of death. In forensic medicine, mitochondrial DNA is of paramount relevance to people identification.

Mitochondrial disorders: Challenges in diagnosis & treatment.

Mitochondrial dysfunctions are known to be responsible for a number of heterogenous clinical presentations with multi-systemic involvement. Impaired oxidative phosphorylation leading to a decrease in cellular energy (ATP) production is the most important cause underlying these disorders. Despite significant progress made in the field of mitochondrial medicine during the last two decades, the molecular mechanisms underlying these disorders are not fully understood. Since the identification of first mitochondrial DNA (mtDNA) mutation in 1988, there has been an exponential rise in the identification of mtDNA and nuclear DNA mutations that are responsible for mitochondrial dysfunction and disease. Genetic complexity together with ever widening clinical spectrum associated with mitochondrial dysfunction poses a major challenge in diagnosis and treatment. Effective therapy has remained elusive till date and is mostly efficient in relieving symptoms. In this review, we discuss the important clinical and genetic features of mitochondrials disorders with special emphasis on diagnosis and treatment.

Clinical and molecular findings in eight Egyptian patients with suspected mitochondrial disorders and optic atrophy

Mitochondrial respiratory chain disorders [RCD] are a group of genetically and clinically heterogeneous diseases, caused due to defects of the respiratory chain. This study aimed to investigate the presence of common mtDNA point mutations in tRNALeu [UUR], tRNALys, MT-ATPase 6, MT-ND4, MT-ND1, MT-ND6 genes in eight Egyptian patients suspected to have mtDNA disease and optic atrophy. PCR-RFLP analysis was done for the detection of 3243A > G, 327IT > C, 8344A > G, and 8993T > G/C mtDNA point mutations. DNA direct sequencing was pursued for the detection of 11778G > A, 3460G > A and 14484T > C mtDNA point mutations. No point mutation of 3243A > G, 327IT > C, 8344A > G, and 8993T > G/C was detected in our group of patients. Four mtDNA polymorphisms in MT-ND1 and MT-ND4 genes [11467A > G, 11719G > A, 3348A > G and 3357G > A] were detected in three patients. Mitochondrial disorders are caused by a variety of genetic and racial factors, which differ among populations. The negative results of this study indicate that the chosen mutations might not be specific in Egyptians. Another explanation might be due to the low heteroplasmic levels of the mtDNA mutation. A registry for the different mtDNA mutations in Egyptian patients is highly recommended

Ataxia crónica en pediatría / [Chronic ataxia in childhood].

Chronic ataxias are an heterogeneous group of disorders that affect the child at different ages. Thus, the congenital forms, generally non progressive are observed from first months of life and are expressed by hypotonia and motor delay long before the ataxia became evident. The cerebral magnetic resonance images (MRI) may be diagnostic in some pictures like Joubert syndrome. The group of progressive hereditary ataxias, usually begin after the infant period. The clinical signs are gait instability and ocular apraxia that can be associated with oculocutaneous telangiectasias (ataxia-telangiesctasia) or with sensory neuropathy (Friedreich ataxia). In this review are briefly described congenital ataxias and in more detailed form the progressive hereditary ataxias autosomal recessive, autosomal dominants and mitochondrials. The importance of genetic study is emphasized, because it is the key to obtain the diagnosis in the majority of these diseases. Although now there are no treatments for the majority of progressive hereditary ataxias, some they have like Refsum disease, vitamine E deficiency, Coenzyme Q10 deficiency and others, thus the diagnosis in these cases is even more important. At present the diagnosis of childhood hereditary ataxia not yet treatable is fundamental to obtain suitable handling, determine a precise outcome and to give to the family an opportune genetic counseling.

Enfermedad mitocondrial y ototoxicidad". Enfermedad mitocondrial sindrómica, mutación G7444A / Mitochondrial disease and ototoxicity

Como parte del programa de “screening” genético para la pérdida de la audición; se realizó el estudio de mutaciones en los genes rRNA 12S y tRNAser (UCN), a partir del DNA mitocondrial, que están asociadas con la pérdida de audición inducida por antibióticos aminoglucósidos (ATB-AG) y de presentación no sindrómica. Se estudiaron 40 pacientes con sorderaneurosensorial, la cual podría haber sido causada posterior al tratamiento con ATB-AG. El sujeto afectado y el control, luego del examen físico completo y extracción de DNA a partir de sangre periférica, se amplificó y estudió segmentos en el gen 12S rRNA y en el gen tRNAser (UCN) por PCR-RFLP. En presencia de una mutación, se analizó el genoma mitocondrial completo en el probando y su familia por línea materna. Estos resultadosse han correlacionado con los valores de la relación dela citocromo oxidasa / citrato sintasa, el cual indica unapobre actividad de la citocromo oxidasa. La clínica en el“pedigree” por línea materna y los estudios moleculares,bioquímicos y morfológicos, podría indicar que se tratade una presentación sindrómica de la mutación 7444G>Aen Córdoba - Argentina.

As part of the "screening" for genetic hearing loss,was performed to study mutations in 12S rRNA and tRNAser(UCN) genes from mitochondrial DNA, which are associatedwith hearing loss induced by antibiotics aminoglycosides(ATB-AG) and non-syndromic presentation. We studied40 patients with sensorineural hearing loss, which could have been caused subsequent to treatment with ATB - AG. The affected individual and control, after a completephysical examination and extraction of DNA fromperipheral blood, was amplified and studied segments inthe 12S rRNA and tRNAser (UCN) genes by PCR-RFLP. In the presence of a mutation, we analyzed the complete mitochondrial genome in the proband and his family from maternal line. These results werecorrelated with the values of the ratio of the cytochromeoxidase / citrate synthase, which indicates a poor activity of cytochrome oxidase. The clinic in the "pedigree" frommaternal line and molecular, biochemical and morphological might indicate that it is a syndromic presentation of the mutation 7444G> A in Córdoba - Argentina.

Síndrome de Pearson: Reporte de un caso / Pearson syndrome: Case report

Entre las etiologías de anemias en la infancia, las citopatías mitocondriales son poco frecuentes. El síndrome de Pearson se diagnostica principalmente durante etapas iniciales de la vida y es caracterizado por anemia sideroblástica refractaria con vacuolización de células progenitoras en la médula ósea, disfunción del páncreas exocrino y variables alteraciones neurológicas, hepáticas, renales y endocrinas. En el siguiente informe reportamos un nuevo caso de lactante mayor femenino de 14 meses de edad, evaluada de forma multicéntrica con diagnostico clínico y molecular de síndrome de Pearson, con la deleción común de 4.977 pares de bases del ADN mitocondrial. Esta entidad ha sido asociada a diversos fenotipos dentro del amplio espectro clínico de las enfermedades mitocondriales.

Among the etiologies of anemia in the infancy, the mitochondrial cytopathies are infrequent. Pearson syndrome is diagnosed principally during the initial stages of life and it is characterized by refractory sideroblastic anemia with vacuolization of marrow progenitor cells, exocrine pancreatic dysfunction and variable neurologic, hepatic, renal and endocrine failures. We report the case of a 14 month-old girl evaluated by a multicentric study, with clinic and molecular diagnosis of Pearson syndrome, with the 4,977-base pair common deletion of mitochondrial DNA. This entity has been associated to diverse phenotypes within the broad clinical spectrum of mitochondrial disease.

Neuroftalmología de las Enfermedades Mitocondriales / Neurophthalmology of Mitochondrial Diseases

Se realiza una revisión del tema: Neuroftalmología de las enfermedades mitocondriales con el objetivo de analizar las alteraciones neuroftalmológicas que con mayor frecuencia aparecen en estas entidades que no son más que la expresión de una mutación en el ADN mitocondrial, así como abordar el comportamiento genético de las mismas. Para ello nos auxiliamos de diversos trabajos publicados por doctores cubanos y extranjeros que ayudan a arribar a la conclusión que la neuropatía óptica debe ser considerada un marcador de la enfermedad mitocondrial, que debemos pensar en ella cuando estamos ante un paciente con retinopatía pigmentaria asociada a una enfermedad sistémica o neurológica indefinida y que una mutación puntual en el ADN mitocondrial será heredada de forma materna y defectos en el ADN nuclear, aún afectando éstos a la mitocondria, serán trasmitidos por la clásica herencia Mendeliana.

There has been done a revision of the topic: Neurophthalmology of mitochondrial disease with the purpose to analize the neurophthalmological alterations that appear with more frequency in these entities that are the expression a mutation in mitochondrial DNA, as well as to tackle the genetic behaviour of it. To do this we consulted different published papers of Cuban and foreign doctors that help us to arrive to the conclusion that optic neuropathy should be consider as a of mitochondrial disease, that we have to think about it when having a patient with pigmentary retinopathy associated to a indefinite sistemic or neurological disease and that because of a punctual mutation in the mitochondrial DNA will be inherited maternally and defects in the nuclear DNA, even affecting it to the mitochondrion, will be transmitted by classic Mendelian heredity.

Diabetes mellitus associado à mutação mitocondrial A3243G: freqüência e caracterização clínica / Diabetes mellitus associated with the mitochondrial mutation A3243G: frequency and clinical presentation

Diabetes mitocondrial é freqüentemente associado à mutação mitocondrial A3243G. A prevalência desse subtipo de diabetes na população diabética varia de 0,5 a 3 por cento, dependendo do grupo populacional estudado. OBJETIVO: Examinar a freqüência e o quadro clínico do diabetes associado com a mutação mitocondrial A3243G em pacientes brasileiros com tolerância a glicose alterada. MÉTODOS: A população estudada foi composta por 78 indivíduos portadores de diabetes mellitus tipo 1 (grupo I), 148 diabéticos tipo 2 (grupo II), 15 diabéticos tipo 1 ou tipo 2 portadores de disacusia (grupo III) e 492 indivíduos da comunidade nipo-brasileira com vários graus de intolerância a glicose. O DNA foi extraído de leucócitos do sangue periférico e a mutação A3243G foi determinada através da amplificação por PCR e digestão por Apa 1. Em alguns pacientes, o DNA também foi extraído da mucosa oral e folículo capilar. A mutação A3243G foi identificada em três indivíduos, todos do grupo III, resultando em uma prevalência de 0,4 por cento. Os carreadores da mutação apresentavam diagnóstico do diabetes em idade jovem, índice de massa corpórea normal ou baixo e requerimento de insulina. CONCLUSÃO: Diabetes mitocondrial é um subtipo raro de diabetes em nossa população e deve ser investigado naqueles indivíduos portadores de diabetes e surdez.

Maternal inherited diabetes and deafness (MIDD) has been related to an A to G transition in the mitochondrial RNA Leu (UUR) at base pair 3243. The prevalence of MIDD in the diabetes population ranges between 0.5-3.0 percent depending on the ethnic background. AIM: To examine the frequency and clinical features of diabetes associated with this mutation in Brazilian patients with glucose intolerance. METHODS: The study population comprised: 78 type 1 diabetic subjects (group I), 148 patients with type 2 diabetes (group II), 15 patients with either type 1 or type 2 diabetes and hearing loss (group III) and 492 Japanese Brazilians with varying degrees of glucose intolerance. DNA was extracted from peripheral blood leucocytes and the A3243G mutation was determined by PCR amplification and Apa 1 digestion. In some individuals DNA was also extracted from buccal mucosa and hair follicles. The 3243 bp mutation was found in three individuals, all from group III, resulting in a prevalence of 0.4 percent. These subjects had an early age of diagnosis of diabetes, low or normal body mass index and requirement of insulin therapy. In conclusion MIDD is rare in our population and should be investigate in patients with diabetes and deafness.

Síndrome psicótica evoluindo com demência como manifestação clinica de deleção do DNA mitocondrial / Psycothic syndrome developing into dementia as a clinical manifestation of mitochondrial DNA deletion

As manifestações das doenças mitocondriais são variadas, acometendo, mais freqüentemente, órgãos com alto metabolismo aeróbico em que são mais abundantes, como, por exemplo, o sistema nervoso. O início dos sintomas em geral é observado na infância havendo relatos de início na idade adulta. Apresentamos caso atípico de doença mitocondrial associada à deleção do DNA mitocondrial em um homem de 39 anos com sintomas psiquiátricos configuraram quadro clínico inicial e somente 12 anos após o início dos sintomas surgiram alterações neurológicas. O diagnóstico da doença mitocondrial foi confirmado por biópsia de músculo sendo documentada deleção do DNA mitocondrial.

The manifestations of mitochondrial disease are variable, affecting more frequently the organs with high aerobic metabolism in which they are more abundant, for example the nervous system. The beginning of symptoms in general is observed at chilhood, but some patients presented on adult age. We present an atypical case associated with mitochondrial DNA deletion. A 39-years-old man with psychiatric symptoms that configured initial clinical picture and only after 12 years of the beginning of symptoms neurological alterations became noticeable. The diagnosis of mitochondrial illness was confirmed by muscle biopsy being documented mitochondrial DNA deletion.

Skeletal muscle mitochondrial dysfunction & diabetes.

Skeletal muscle insulin resistance is a key contributor to the pathophysiology of type 2 diabetes. Recent studies have shown that insulin resistance in a variety of conditions including type 2 diabetes, ageing and in offspring of type 2 diabetes is associated with muscle mitochondrial dysfunction. The important question is whether insulin resistance results from muscle mitochondrial dysfunction or vise versa. Gene array studies from muscle biopsy samples showed that transcript levels of several genes, especially OXPHOS genes are altered in type 2 diabetic patients during poor glycaemic control but many of these alterations are normalized by insulin treatment suggesting that reduced insulin action is a factor involved in muscle mitochondrial dysfunction. Moreover, insulin infusion while maintaining glucose and amino acid levels results in increase in muscle mitochondrial gene transcript levels and ATP production indicating that insulin is a key regulator of muscle mitochondrial biogenesis. At a similar post-absorptive insulin levels both type 2 diabetic patients and non diabetic controls have similar muscle mitochondrial ATP production but increasing insulin from low to high levels stimulate ATP production only in non diabetic people but not in the diabetic people. The lack of muscle mitochondrial response to insulin in type 2 diabetic patients is likely to be related to insulin resistance and reduced substrate utilization.

Mitochondrial hepatopathies.

Hepatocyte mitochondrion functions as a cause and as a target of liver injury. Since the mitochondria are under dual control of nuclear DNA and mitochondrial DNA (mtDNA), mutations in genes of both classes have been associated with inherited mitochondrial hepatopathies. Point mutations, deletions, insertions, rearrangements, DNA depletion--all have been identified. Many factors influence the prevalence of mitochondrial disorders, including the mutations rate, inheritance pattern, population structure, and the genetic background. In primary disorders, mitochondrial defect is the primary cause of liver disease often producing fatal hepatic failure in infancy or childhood. In secondary disorders, insult to mitochondria is caused by either a gene defect that affects non-mitochondrial proteins or by an exogenous injury to mitochondria. Diagnosis should be suspected in cases of liver disease with neuromuscular symptoms, multisystem involvement that cannot be explained by a single pathology or rapidly progressive liver failure in early childhood. Laboratory findings in the blood and urine show an altered redox status. Various antioxidants, vitamins, cofactors, and electron acceptors have been for proposed but none is effective. Presence of neuromuscular or extraintestinal involvement in primary disorder precludes the use of liver transplantation.