Lysosomal dysfunction and overload of nucleosides in thymidine phosphorylase deficiency of MNGIE.

Inherited deficiency of thymidine phosphorylase (TP), encoded by TYMP, leads to a rare disease with multiple mitochondrial DNA (mtDNA) abnormalities, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). However, the impact of TP deficiency on lysosomes remains unclear, which are important for mitochondrial quality control and nucleic acid metabolism. Muscle biopsy tissue and skin fibroblasts from MNGIE patients, patients with m.3243 A > G mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) and healthy controls (HC) were collected to perform mitochondrial and lysosomal functional analyses. In addition to mtDNA abnormalities, compared to controls distinctively reduced expression of LAMP1 and increased mitochondrial content were detected in the muscle tissue of MNGIE patients. Skin fibroblasts from MNGIE patients showed decreased expression of LAMP2, lowered lysosomal acidity, reduced enzyme activity and impaired protein degradation ability. TYMP knockout or TP inhibition in cells can also induce the similar lysosomal dysfunction. Using lysosome immunoprecipitation (Lyso- IP), increased mitochondrial proteins, decreased vesicular proteins and V-ATPase enzymes, and accumulation of various nucleosides were detected in lysosomes with TP deficiency. Treatment of cells with high concentrations of dThd and dUrd also triggers lysosomal dysfunction and disruption of mitochondrial homeostasis. Therefore, the results provided evidence that TP deficiency leads to nucleoside accumulation in lysosomes and lysosomal dysfunction, revealing the widespread disruption of organelles underlying MNGIE.

Mitochondrial encephalopathies and myopathies: Our tertiary center's experience.

Mitochondrial diseases have a heterogeneous phenotype and can result from mutations in the mitochondrial or nuclear genomes, constituting a diagnostically and therapeutically challenging group of disorders. We report our center's experience with mitochondrial encephalopathies and myopathies with a cohort of 50 genetically and phenotypically diverse patients followed in the Neurology clinic over the last ten years. Seventeen patients had mitochondrial DNA mutations, presented over a wide range of ages with seizures, feeding difficulties, extraocular movements abnormalities, and had high rates of stroke-like episodes and regression. Twenty-seven patients had nuclear DNA mutations, presented early in life with feeding difficulty, failure-to-thrive, and seizures, and had high proportions of developmental delay, wheelchair dependence, spine abnormalities and dystonia. In six patients, a mutation could not be identified, but they were included for having mitochondrial disease confirmed by histopathology, enzyme analysis and clinical features. These patients had similar characteristics to patients with nuclear DNA mutations, suggesting missed underlying mutations in the nuclear genome. Management was variable among patients, but outcomes were universally poor with severe disability in all cases. Therapeutic entryways through elucidation of disease pathways and remaining unknown genes are acutely needed.

Successful Sequential Liver and Isolated Intestine Transplantation for Mitochondrial Neurogastrointestinal Encephalopathy Syndrome: A Case Report.

BACKGROUND Mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE) is an autosomal recessive disease caused by thymidine phosphorylase deficiency leading to progressive gastrointestinal dysmotility, cachexia, ptosis, ophthalmoparesis, peripheral neuropathy and leukoencephalopathy. Although liver transplantation corrects thymidine phosphorylase deficiency, intestinal deficiency of the enzyme persists. Retrospective chart review was carried out to obtain clinical, biochemical, and pathological details. CASE REPORT We present a case of liver and subsequent intestine transplant in a 28-year-old man with MNGIE syndrome with gastrointestinal dysmotility, inability to walk, leukoencephalopathy, ptosis, cachexia, and elevated serum thymidine. To halt progression of neurologic deficit, he first received a left-lobe partial liver transplantation. Although his motor deficit improved, gastrointestinal dysmotility persisted, requiring total parenteral nutrition. After exhaustive intestinal rehabilitation, he was listed for intestine transplantation. Two-and-half years after liver transplantation, he received an intestine transplant. At 4 years after LT and 20 months after the intestine transplant, he remains off parenteral nutrition and is slowly gaining weight. CONCLUSIONS This is the first reported case of mitochondrial neurogastrointestinal encephalomyopathy to undergo successful sequential liver and intestine transplantation.

FBXL4 mutation-caused mitochondrial DNA depletion syndrome is driven by BNIP3/BNIP3L-dependent excessive mitophagy.

Encephalomyopathic mitochondrial DNA (mtDNA) depletion syndrome 13 (MTDPS13) is an autosomal recessive disorder arising from biallelic F-box and leucine-rich repeat (LRR) protein 4 (FBXL4) gene mutations. Recent advances have shown that excessive BCL2 interacting protein 3 (BNIP3)/ BCL2 interacting protein 3 like (BNIP3L)-dependent mitophagy underlies the molecular pathogenesis of MTDPS13. Here, we provide an overview of these groundbreaking findings and discuss potential therapeutic strategies for this fatal disease.

MT-TN mutations lead to progressive mitochondrial encephalopathy and promotes mitophagy.

Mitochondrial encephalopathy is a neurological disorder caused by impaired mitochondrial function and energy production. One of the genetic causes of this condition is the mutation of MT-TN, a gene that encodes the mitochondrial transfer RNA (tRNA) for asparagine. MT-TN mutations affect the stability and structure of the tRNA, resulting in reduced protein synthesis and complex enzymatic deficiency of the mitochondrial respiratory chain. Our patient cohort manifests with epileptic encephalopathy, ataxia, hypotonia, and bilateral basal ganglia calcification, which differs from previously reported cases. MT-TN mutation deficiency leads to decreased basal and maximal oxygen consumption rates, disrupted spare respiratory capacity, declined mitochondrial membrane potential, and impaired ATP production. Moreover, MT-TN mutations promote mitophagy, a process of selective degradation of damaged mitochondria by autophagy. Excessive mitophagy further leads to mitochondrial biogensis as a compensatory mechanism. In this study, we provided evidence of pathogenicity for two MT-TN mutations, m.5688 T > C and m.G5691A, explored the molecular mechanisms, and summarized the clinical manifestations of MT-TN mutations. Our study expanded the genotype and phenotypic spectrum and provided new insight into mt-tRNA (Asn)-associated mitochondrial encephalopathy.

Late-onset mitochondrial encephalopathy with lactic acidosis and stroke-like episodes and the role of serial imaging.

Mitochondria are essential for human metabolic function. Over 350 genetic mutations are associated with mitochondrial diseases, which are inherited in a matrilineal fashion. In mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), defective mitochondrial function and resultant impaired cellular energy production compromise vascular perfusion in affected tissues. Early diagnostic criteria suggested the diagnosis should be considered in those under 40. However, a broader range of phenotypes are now recognised, including those that present for the first time later in life. The primary presenting feature in MELAS is a stroke-like episode invariably resulting in patients undergoing neuroradiological imaging. We present a case of a woman with a first presentation of a stroke-like episode and seizures in her 40s who was eventually diagnosed with MELAS. We detail her clinical presentation, treatment and diagnosis, emphasising the role of serial imaging in her diagnosis.

The Newcastle Pediatric Mitochondrial Disease Scale: translation and cultural adaptation for use in Brazil / Escala Pediátrica de Doença Mitocondrial de Newcastle: tradução e adaptação cultural para uso no Brasil

ABSTRACT Objective The aim of this study was to translate and adapt the Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) to Portuguese for use in Brazil. Methods The scale was applied in 20 pediatric patients with mitochondrial disease, in three groups: myopathy (n = 4); Leigh syndrome (n = 8); and encephalomyopathy (n = 8). Scores were obtained for the various dimensions of the NPMDS, and comparisons were drawn between the groups. Results There was a statistically significant difference between the myopathy group and the Leigh syndrome group (p = 0.0085), as well as between the myopathy and encephalomyopathy groups (p = 0.01). Conclusions The translation of the NPMDS, and its adaptation to the socioeconomic and cultural conditions in Brazil, make the NPMDS score useful as an additional parameter in the evaluation and monitoring of pediatric patients with MD in Brazil.

RESUMO Objetivo O objetivo do presente estudo foi realizar a tradução e adaptação da escala NPMDS para a população brasileira. Métodos A escala foi aplicada em 20 crianças e adolescentes com doença mitocondrial (DM) divididos em três grupos: miopatia (n=4), síndrome de Leigh (n=8) e encefalomiopatia (n=8). Obteve-se os escores separados das dimensões da escala NPMDS, foram realizadas comparações entre os escores da NPMDS nos diferentes grupos. Conclusão A tradução da escala NPMDS e sua adequação as condições socioeconômicas e culturais de nossa população tornam este instrumento um parâmetro adicional na avaliação e acompanhamento de pacientes pediátricos com DM.

Encefalopatía infantil asociada con la mutación A3243G MELAS / Infantile encephalopathy associated with the MELAS A3243G mutation: case report

Las Encefalopatías mitocondriales son un grupo de enfermedades que tienen base una alteración del ADN mt. (ADN mitocondrial). El fenotipo MELAS (Encefalopatía mitocondrial, con acidosis láctica y accidentes cerebro vasculares) se ha relacionado con la mutación A3243G en aproximadamente el 80 por ciento de los casos reportados. El fenotipo MERRF (epilepsia mioclónica con fibras rojas rasgadas) ha sido relacionado con las mutaciones A8344G y A8566G del tARN Lys. Se describe un lactante femenino de 7 meses de edad, con un cuadro de inicio temprano, que se acompañaba de una encefalopatía asociada a la mutación A3243G. En los exámenes de laboratorio destacaba una acidosis láctica y el estudio EEG mostraba signos compatibles con proceso encefalopático. Se administró ACTH durante un mes con mejoría clínica y encefalográfica. Actualmente recibe tratamiento a base de Vitaminas del complejo B, L-carnitina y alcalinizantes urinarios. Se concluye que en los lactantes que presentan convulsiones, retraso en su desarrollo psicomotor, acidosis láctica y el estudio encefalográfico compatible con una encefalopatía, debería realizarse análisis del ADN mt, para descartar una enfermedad mitocondrial.

Muscle cell outside and inside: the nascent approach of a clinician

Understanding muscle cell in disease and health is an unfinished process. Following the lead of Jaime Alvarez, I have had the opportunity of working on two complementary approaches to this field. One is the study of muscle cell surface molecules. Both synaptic muscle molecules, such as the asymmetric form of acetylcholinesterase, and extrasynaptic molecules, such as the extracellular matrix proteoglycans, are regulated by the motor nerve activity. This illustrates one of Jaime's teachings: cell phenotypes are a dynamic process that reflects the influence of other cells (Alvarez, 2001). Proteoglycans have many functions, including growth factor receptors. Studying them in muscular dystrophy will contribute to the comprehension of the muscle regeneration failure, characteristic of this disease. Muscle cells are highly dependent upon energy production, and the mitochondriae produce most of it. These organelles are unique in having their own genome. Mutations in these genes have recently been recognized as the cause of human disease and originally in muscle pathology. The physiopathology of these diseases is summarized here

Análisis molecular en 29 pacientes con diagnóstico presuntivo de mitocondriopatía: encefalopatía mitocondrial con acidosis láctica y aplopejía (MELAS) / Molecular analysis in mitochondrial encephalophathy with lactic acidosis and stroke (MELAS)

El objetivo de la investigación fue identificar en pacientes con diagnóstico presuntivo de MELAS la mutación A3243G, tradicionalmente asociada con ella. Se secuenciaron los fragmentos 533 pb del genoma mitocondrial correspondiente al tRNA-Leu y parte del gen NDI (posiciones 3162 a 3695) en 29 pacientes con diagnóstico presuntivo de MELAS y en cuatro personas sanas. Todos los pacientes fueron negativos para la mutación A3243G, tampoco se hallaron otras mutaciones descritas en MELAS. Se halló una transición (A3547G) en el gen NDI, hasta ahora no informada en la literatura, en 14 de las muestras secuenciadas. Esta transición, identificada en pacientes y controles, cambia el codón ATC(i) por GTC(V). Al realizar el genotipo del mtDNA de la PCR, se encontró que de las 14 muestras con G en la posición 3547 de NDI, 13 expresaban el haplotipo B. Teniendo en cuenta que la transición detectada se presentó tanto en pacientes como en controles y que I y V son aminoácidos de estructura química semejante, hidrofóbicos, que se localizan en un motivo altamente hidrofóbico de la proteína (LALTIALLL), es posible concluír que este cambio consiste en un polimorfismo. La presencia del Haplotipo B, propia de la población amerindia, indica la alta frecuencia de mitocondria de origen antioqueño. La transición 3547G podría ser un marcador de la población indoamericana con la cual se mezclaron los españoles para constituír la población antioqueña

Encefalomiopatias mitocondriais e epilepsia / Mitochondrial encephalomyophaties and epilepsy

Este artigo visa uma revisäo sumária das encefalomiopatias mitocondriais com ênfase para as manifestaçöes convulsivas, além de induzir o epileptologista a incluí-las na lista dos diagnósticos diferenciais. Comenta desde a estrutura, funçäo e genética mitocondriais, passando pelo quadro clínico, anatomopatológico, anormalidades genéticas e bioquímicas. Focaliza a abordagem diagnóstica, assim como um breve comentário sobre o estágio atual com relaçäo ao tratamento

Lipomatosis múltiples simétricas / Multiple symmetric lipomatosis

Antecedentes: Los lipomas cervicales solitarios no requieren cirugía, salvo que por su volumen produzcan deformidades o dificultades mecánicas. Con las lipomatosis múltiples simétricas existe la controversia entre quienes prefieren la cirugía en aras de una mejor calidad de vida y quienes tratan de evitarla, basados en la incidencia de recurrencias. Objetivo: Analizar los aspectos sobresalientes de la enfermedad y los resultados alcanzados con la conducta adoptada. Lugar de aplicación: Hospital de Agudos y Hospital Oncológico, ambos de atención terciaria. Diseño: Retrospectivo no randomizado. Población: Se analizan 11 enfermos masculinos con una edad media de 51,6 años (44-63). La distribución era generalizada y comprensiva en el 54,5 por ciento. El hábito alcohólico se registró en el 100 por ciento. Métodos: En todos se practicó cirugía radical de los lipomas dominantes o que producían sintomatología comprensiva. En el 72,7 por ciento la resección cervical fue en un tiempo. Resultados: Se produjeron 3 complicaciones menores que se resolvieron sin nuevas cirugía. Sólo 1 (9 por ciento) recidivó. Al cierre de la observación, 8 enfermos se hallan vivos y sin recurrencias. Conclusiones: La cirugía radical es segura y exenta de riesgos. Las recurrencias se relacionan con el grado de meticulosidad de la cirugía

Las encefalomiopatías mitocondriales: a propósito de 3 casos con oftalmoplejia / The mitochondrials encephalomiopaties to purpose of three cases with ophtalmoplejia

Se describe a las encefalomiopatías mitocondriales como un grupo de enfermedades con determinante genético ligado a un defecto en la fosforilación oxidativa. Se describe el cuadro clínico de tres casos con oftalmoplejia. Se discute los casos a la luz de información reciente acerca de las enfermedades descritas y se concluye que no es posible aún demostrar y explicar la razón del fenotipo variable.