NARP syndrome in a patient harbouring an insertion in the MT-ATP6 gene that results in a truncated protein.

BACKGROUND: Neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP) syndrome have been associated to m.8993T>G/C mutations in the subunit 6 of the ATP synthase (p.MT-ATP6). METHODS: We have performed a mutational screening of the mitochondrial DNA gene encoding for this protein in 62 patients with the disease, that do not carry any of the common mutations described to date. RESULTS: We report clinical and molecular data in one patient who harbours a de novo insertion in the MT-ATP6 gene that results in a truncated subunit. The mutation was heteroplasmic (85%) in muscle DNA and the BN-PAGE analysis showed a clear decrease in the amount of ATP synthase. CONCLUSION: Molecular analysis of NARP patients cannot be limited to the search of the m.8993T>G/C and either the ATP6 or the whole mtDNA should be sequenced.

Cognitive dysfunction and hypogonadotrophic hypogonadism in a Brazilian patient with mitochondrial neurogastrointestinal encephalomyopathy and a novel ECGF1 mutation.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is caused by mutations in the thymidine phosphorylase gene (ECGF1). We present the first detailed report of a Brazilian MNGIE patient, harboring a novel ECGF1 homozygous mutation (C4202A, leading to a premature stop codon, S471X). Multiple deletions and the T5814C change were found in mitochondrial DNA. Together with gastrointestinal symptoms, endocrine involvement and memory dysfunction, not reported in MNGIE to date, were the most preeminent features.

Enfermedades del sistema de fosforilación oxidativa mitocondrial humano / Diseases of the human mitochondrial oxidative phosphorylation system

Objetivo. Las enfermedades del sistema de fosforilaciónoxidativa se originan por una deficiente producción de adenosíntrifosfato (ATP) por la mitocondria. Estas enfermedades se diagnosticanfrecuentemente entre pacientes con síntomas multisistémicosaparentemente no relacionados. Las mutaciones del ácidodesoxirribonucleico mitocondrial (ADNmt) pueden ser de herenciamaterna, esporádicas o producirse como consecuencia de mutacionesen genes nucleares que regulan la biosíntesis del ADNmt, y, portanto, con herencia mendeliana, o por causas ambientales. Estarevisión pretende actualizar, desde un punto de vista genético, elconocimiento sobre las enfermedades mitocondriales, a la vez quemostrar las dificultades que comporta el estudio de esta patología.Desarrollo. Para reflejar estas dificultades se utilizan ejemplos seleccionadosde mutaciones en el genoma mitocondrial asociadas adeterminadas enfermedades. También se revisan los avances recientessobre patología mitocondrial debida a mutaciones en genesnucleares, codificantes de proteínas mitocondriales que, directa oindirectamente, participan en el buen funcionamiento del sistemade fosforilación oxidativa. Conclusiones. La secuenciación completadel ADNmt, por su accesibilidad, debería ser parte del perfilbásico en el estudio de las enfermedades mitocondriales, pero dadala cantidad de genes nucleares que pueden afectar el sistema defosforilación oxidativa, su estudio debería estar sustentado en sólidosindicios bioquímicos

Aim. The diseases of the oxidative phosphorylation system consist of a group of disorders originated by a deficientsynthesis of adenosine triphosphate (ATP). These diseases are increasingly being diagnosed among patients with multisystemicdisorders. Mitochondrial deoxyribonucleic acid (mtDNA) mutations are usually maternally inherited, but they alsocan be sporadic or secondary to nuclear mutations, that are inherited in a Mendelian mode, or due to environmental hazards.In this review we will update, from a genetic point of view, the knowledge on human mitochondrial diseases, remarking thedifficulties to study these pathologies. Development. To mirror these difficulties, we will use selected examples of mutations inthe mitochondrial genome, and review recent advances on mitochondrial pathology due to mutations in the nuclear genescodifying for mitochondrial proteins that participate in a good performance of the oxidative phosphorylation system.Conclusions. Sequencing of the complete human mtDNA should be part of the basic profile in the study of mitochondrialdiseases. Due to the increasing number of nuclear genes involved in the oxidative phosphorylation system performance, theiranalysis should be based on solid biochemical clues

[Diseases of the human mitochondrial oxidative phosphorylation system]. / Enfermedades del sistema de fosforilación oxidativa mitocondrial humano.

AIM: The diseases of the oxidative phosphorylation system consist of a group of disorders originated by a deficient synthesis of adenosine triphosphate (ATP). These diseases are increasingly being diagnosed among patients with multisystemic disorders. Mitochondrial deoxyribonucleic acid (mtDNA) mutations are usually maternally inherited, but they also can be sporadic or secondary to nuclear mutations, that are inherited in a Mendelian mode, or due to environmental hazards. In this review we will update, from a genetic point of view, the knowledge on human mitochondrial diseases, remarking the difficulties to study these pathologies. DEVELOPMENT: To mirror these difficulties, we will use selected examples of mutations in the mitochondrial genome, and review recent advances on mitochondrial pathology due to mutations in the nuclear genes codifying for mitochondrial proteins that participate in a good performance of the oxidative phosphorylation system. CONCLUSIONS: Sequencing of the complete human mtDNA should be part of the basic profile in the study of mitochondrial diseases. Due to the increasing number of nuclear genes involved in the oxidative phosphorylation system performance, their analysis should be based on solid biochemical clues.

[Mitochondrial DNA deletions in Kearns-Sayre syndrome]. / Deleciones del ADN mitocondrial asociadas al síndrome de Kearns-Sayre.

INTRODUCTION: Kearns-Sayre syndrome (KSS) is a mitochondrial disorder characterized by progressive external ophthalmoplegia, pigmentary retinopathy, onset before 20 years, and ragged-red fibers on muscle biopsy. KSS has been associated to mitochondrial DNA (mtDNA) mutations. We report neurological manifestations and mtDNA deletions in KSS. METHODS: Six KSS patients underwent neurological examination, biochemical analysis (muscle enzymes, lactate, cerebrospinal fluid analysis), electromicrography, muscle biopsy (Gomori stain, electronic microscopy), electrocardiogram, echocardiography, MRI/CT scan. MtDNA deletions were studied in blood and muscle samples using Southern blotting and long polymerase chain reaction. RESULTS: Four males and two females (mean age: 27.7 years; range: 17-42; mean age at onset: 8.2 years) were studied. Initial symptoms were ptosis and gaze restriction, fatigue, exercise intolerance and proximal limb weakness. Syncope and neurosensory hypoacusia were initial symptoms in two patients. All of them presented a unique deletion in the mitochondrial genome, in heteroplasmy, and their size was in the range of 4,420 and 9,437 basis pairs. Three of these deletions are reported for the first time in this article. Most of the deletions are flanked by small direct repeats elements. CONCLUSIONS: Proximal muscle weakness and fatigue appear frequently in KSS patients during follow up. The syndrome in these patients has been caused by mtDNA deletions.

Mitochondrial DNA delections in Kearns-Sayre síndrome / Deleciones del AND mitochondrial asociadas al síndrome de Kearns-Sayre

Introduction: Kearns-Sayre syndrome (KSS) is a mitochondrial disorder characterized by progressive external ophthalmoplegia, pigmentary retinopathy, onset before 20 years, and ragged-red fibers on muscle biopsy. KSS has been associated to mitochondrial DNA (mtDNA) mutations. We report neurological manifestations and mtDNA deletions in KSS. Methods: Six KSS patients underwent neurological examination, biochemical analysis (muscle enzymes, lactate, cerebrospinal fluid analysis), electromicrography, muscle biopsy (Gomori stain, electronic microscopy), electrocardiogram, echocardiography, MRI/CT scan. MtDNA deletions were studied in blood and muscle samples using Southern blotting and long polymerase chain reaction. Results: Four males and two females (mean age: 27.7 years; range: 17-42; mean age at onset: 8.2 years) were studied. Initial symptoms were ptosis and gaze restriction, fatigue, exercise intolerance and proximal limb weakness. Syncope and neurosensory hypoacusia were initial symptoms in two patients. All of them presented a unique deletion in the mitochondrial genome, in heteroplasmy, and their size was in the range of 4,420 and 9,437 basis pairs. Three of these deletions are reported for the first time in this article. Most of the deletions are flanked by small direct repeats elements. Conclusions: Proximal muscle weakness and fatigue appear frequently in KSS patients during follow up. The syndrome in these patients has been caused by mtDNA deletions (AU)

Introducción. El síndrome de Kearns-Sayre (SKS) es un fenotipo mitocondrial caracterizado por oftalmoplejía externa progresiva, retinitis pigmentaria, inicio antes de los 20 años y fibras rojo rasgadas en la biopsia muscular y que ha sido asociado a mutaciones en el ADN mitocondrial (ADNmt). Métodos. Se realizaron exámenes neurológicos en seis pacientes con SKS, determinación de enzimas musculares y de lactato en sangre, análisis de líquido cefalorraquídeo (LCR), electromiografía, biopsia muscular, electrocardiograma, ecocardiograma y estudios de neuroimagen. Asimismo se llevó a cabo un análisis genético moleculares del ADNmt en muestras de sangre y músculo, por técnicas de hibridación Southern y amplificación por reacción en cadena de la polimerasa larga para estudiar la presencia de posibles deleciones. Encontramos manifestaciones neurológicas y deleciones en el ADNmt en el SKS. Resultados. Se han estudiado cuatro varones y dos mujeres (edad media: 27,7 años; rango: 17-42) con una edad media de inicio de los síntomas a los 8,2 años. La clínica inicial fue ptosis palpebral, seguida de limitación progresiva de la mirada vertical y horizontal, fatiga e intolerancia al ejercicio y debilidad de músculos proximales. En dos pacientes los síntomas iniciales fueron síncopes de repetición y sordera neurosensorial. Todos los pacientes presentaban una deleción única en el ADNmt, en heteroplasmia y con un tamaño que variaba entre 4.420 y 9.437 pares de bases. Tres de estas deleciones se describen por primera vez. La mayoría presenta secuencias de repetición directa en las zonas que flanquean la deleción. Conclusiones. El SKS evoluciona en el tiempo con debilidad muscular proximal y fatiga. Todos están causados por deleciones del ADNmt (AU)

[A single deletion of mitochondrial DNA in a Brazilian patient with chronic progressive external ophthalmoplegia]. / Deleción en el ADN mitocondrial de una paciente brasileña con oftalmoplejía cróncia progresiva externa.

INTRODUCTION: The syndrome of chronic progressive external ophthalmoplegia (CPEO) has been associated to the presence of large deletion, single or multiple, in the mitochondrial DNA of skeletal muscle. CASE REPORT: We report a sporadic case of chronic progressive external ophthalmoplegia that began at age 19 years and was associated with ragged red fibers in skeletal muscle. Genetic analysis of mitochondrial DNA revealed the presence of a single deletion of 4237 bp that encompasses the nucleotide positions 9486 to 13722, a location that has not been described before, and flanked by a direct repeat sequence. The deletion is flanked by a direct repeat. CONCLUSIONS: The amount of deleted mitochondrial DNA (55%) in this patient's muscle suggests that this deletion is the molecular cause of the phenotypic presentation of this patient.

Deleción en el ADN mitocondrial de una paciente brasileña con oftalmoplejía crónica progresiva externa / A single deletion of mitocondrial DNA in a Brazilian patient with chronic progressive external ophthalmoplegia

Introducción. El síndrome de oftalmoplejía crónica progresiva externa (CPEO) se ha asociado a la presencia de grandes deleciones, únicas o múltiples, en el ADN mitocondrial (ADNmt) del tejido muscular esquelético. Caso clínico. Presentamos un caso esporádico de CPEO que comenzó a los 19 años de edad y que se asocia a la presencia de fibras rojas rasgadas en el músculo esquelético. El análisis genético del ADNmt mostró la presencia de una deleción única de 4.237 pb, comprendida entre los nucleótidos 9486 y 13722, y flanqueada por una repetición directa. Conclusiones. La cantidad de moléc ulas de ADNmt delecionadas en el músculo de esta paciente (55%) sugiere que esta deleción es la causa molecular de la presentación fenotípica de esta paciente (AU)

Introduction. The syndrome of chronic progressive external ophthalmoplegia (CPEO) has been associated to the presence of large deletion, single or multiple, in the mitochondrial DNA of skeletal muscle. Case report. We report a sporadic case of chronic progressive external ophthalmoplegia that began at age 19 years and was associated with ragged-red fibers in skeletal muscle. Genetic analysis of mitochondrial DNA revealed the presence of a single deletion of 4237 bp that encompasses the nucleotide positions 9486 to 13722, a location that has not been described before, and flanked by a direct repeat sequence. The deletion is flanked by a direct repeat. Conclusions. The amount of deleted mitochondrial DNA (55%) in this patient’s muscle suggests that this deletion is the molecular cause of the phenotypic presentation of this patient(AU)

[Drug prescription in primary care. Pharmacoepidemiologic study in the Albacete area]. / Prescripción de medicamentos en Atención Primaria. Estudio fármacoepidemiológico en el área de Albacete.

Prescribing medication is a clinical procedure used quite often in Primary Care (PC). The quality of some prescriptions in the province of Albacete is studied, evaluating the characteristics of the PC physicians. The bottles of Cephalosporins, broad-spectrum Penicillins, Rawolfias, Diuretics, Beta-Blockers and Cerebral Blood Vessel Dilating Medications have been analyzed. Respectively, 38.4%, 30.8% and 28.5% of the physicians prescribed antibiotics, antihypertensives and blood vessel dilating medications acceptably. The logistic regression analysis only reveals a slight indication of: a better prescribing of antibiotics (p less than 0.02) at an older age, when employed in an urban environment and having a smaller number of patients to care for; and a better prescribing of cerebral blood vessel dilating medications (p less than 0.05) for specialists by way of MIR. The commercial information on medications could standardize behaviour with regard to writing prescriptions. To improve quality, it would be necessary to improve the scientific attitude of health care professionals.