A case of mitochondrial DNA depletion syndrome type 11 - expanding the genotype and phenotype.

Mitochondrial DNA depletion syndrome type 11 (MTDPS11) is caused by pathogenic variants in MGME1 gene. We report a woman, 40-year-old, who presented slow progressive drop eyelid at 11-year-old with, learning difficulty and frequent falls. Phisical examination revealed: mild scoliosis, elbow hyperextensibility, flat feet, chronic progressive external ophthalmoplegia with upper eyelid ptosis, diffuse hypotonia, and weakness of arm abduction and neck flexion. Investigation evidenced mild serum creatine kinase increase and glucose intolerance; second-degree atrioventricular block; mild mixed-type respiratory disorder and atrophy and granular appearance of the retinal pigment epithelium. Brain magnetic resonance showed cerebellar atrophy. Muscle biopsy was compatible with mitochondrial myopathy. Genetic panel revealed a homozygous pathogenic variant in the MGME1 gene, consistent with MTDPS11 (c.862C>T; p.Gln288*). This case of MTDPS11 can contribute to the phenotypic characterization of this ultra-rare mitochondrial disorder, presenting milder respiratory and nutritional involvement than the previously reported cases, with possible additional features.

Progressive external ophthalmoplegia (PEO) due to a mutation in the C10orf2 (PEO1) gene mimicking a myasthenic crisis.

We described a case of a patient with autosomal dominant progressive external ophthalmoplegia (PEO) who presented with the acute onset dysphagia, quadriparesis, ptosis and respiratory insufficiency following a cardiac procedure and mimicking a myasthenic crisis. A pathogenic mutation in the C10orf2 (PEO1) gene was confirmed. The unusual presentation of our patient contributes to expand the clinical phenotype of PEO1 mutations and reinforces the need to consider mitochondrial myopathy as differential diagnosis of myasthenia gravis even in the case of acute onset symptoms.

The mutations m.5628T>C and m.8348A>G in single muscle fibers of a patient with chronic progressive external ophthalmoplegia.

We identified a double mutation in a patient with chronic progressive external ophthalmoplegia, located in the tRNA(Ala) (m.5628T>C) and tRNA(Lys) (m.8348A>G) genes. Both mutations were previously described separately and considered pathogenic, however the same mutations were also reported as polymorphisms or phenotype modulator. We analyzed the proportion of each mutation in isolated muscle fibers by single fiber-polymerase chain reaction to investigate the contribution of each mutation to mitochondrial deficiency. Our findings demonstrated that the mutations were heteroplasmic in skeletal muscle and both mutations were present in all single muscle fibers. The proportions of the m.5628T>C mutation were not significantly different between normal and cytochrome-c-oxidase (COX) deficient fibers. However, a significant higher proportion of the m.8348A>G mutation was observed in COX deficient fibers. Homoplasmic m.8348A>G was only observed in COX negative fibers. In conclusion, we provide a piece of evidence toward the pathogenicity of the m.8348A>G mutation and suggest that m.5628T>C is probably a neutral polymorphism.

[Deletions of the mitochondrial DNA associated to chronic progressive external ophthalmoplegia with ragged-red fibers in 2 Brazilian patients]. / Deleciones en el ADN mitocondrial asociadas a oftalmoplejía crónica extrínseca progresiva con fibras rojas rasgadas en 2 pacientes brasileños.

BACKGROUND AND OBJECTIVE: Our purpose was to report the neurological manifestations and molecular-genetic analysis of mitochondrial DNA associated with chronic progressive external ophthalmoplegia (CPEO) and raged red fibers (RRFs). PATIENTS AND METHOD: Two patients, a male and a female (32 and 28 year-old, respectively), were studied due to progressive palpebral ptosis associated with RRFs in muscle biopsy. Both patients were subjected to neurological, histochemical and enzymatic analysis of muscular biopsy, analysis of cerebro-spinal fluid, and molecular analysis of mitochondrial DNA. RESULTS: Symptoms started at ages 24 and 17 years. Initial symptoms were palpebral ptosis, progressive limitation of vertical and horizontal gaze, fatigue and exercise intolerance, and weakness of proximal muscles. Brain MRIs were normal in both patients. Both patients had deletions of muscle mitochondrial DNA with similar size (5,425 and 5,112 base pairs) and location. CONCLUSIONS: CPEO with RRFs is usually associated with huge deletions in mitochondrial DNA. Fatigue and proximal muscle weakness can be found during the follow-up.

[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.

[Genetic diseases of the mitochondrial DNA in humans]. / Enfermedades genéticas del ADN mitocondrial humano.

Mitochondrial diseases are a group of disorders produced by defects in the oxidative phosphorylation system (Oxphos system), the final pathway of the mitochondrial energetic metabolism, resulting in a deficiency of the biosynthesis of ATP. Part of the polypeptide subunits involved in the Oxphos system are codified by the mitochondrial DNA. In the last years, mutations in this genetic system have been described and associated to well defined clinical syndromes. The clinical features of these disorders are very heterogeneous affecting, in most cases, to different organs and tissues and their correct diagnosis require precise clinical, morphological, biochemical and genetic data. The peculiar genetic characteristics of the mitochondrial DNA (maternal inheritance, polyplasmia and mitotic segregation) give to these disorders very distinctive properties. The English version of this paper is available at: http://www.insp.mx/salud/index.html.

[Molecular studies in Cuban patients with progressive external ophthalmoplegia]. / Estudios moleculares en pacientes cubanos con oftalmoplejía externa progresiva.

INTRODUCTION: The mitochondria, subcellular organelles which possess their own DNA (mtDNA), produce most of the energy, in the form of ATP, which is necessary for life. This mtDNA may have diverse molecular defects which have been associated with a great variety of clinical syndromes. Deletions in mtDNA are one of the common mutations in patients with mitochondrial myopathies, which in the great majority present with the common symptom of progressive external ophthalmoplegia. In this study we report our findings in eight Cuban families with suspected mitochondrial disease. OBJECTIVES: To characterize these patients from the molecular point of view, which would allow a preliminary understanding of the behavior of these deletions in Cuban patients. PATIENTS AND METHODS: We studied nine patients from eight Cuban families in whom mitochondrial encephalomyopathy was suspected. We analyzed the presence of ragged red fibres, the enzymatic activity of the mitochondrial respiratory chain and detection of mtDNA mutations. We used the technique of restriction length polymorphism analysis for detection of deletions. RESULTS: Histochemical studies showed the presence of COX negative ragged red fibres in seven of the patients studied. The enzymatic activity of the mitochondrial respiratory chain was normal in all the patients. We detected four patients with single deletions of mtDNA, and one with multiple deletions and of the patients had the A3243G mutation. CONCLUSIONS: With the methods used we were able to determine the presence of a mitochondrial disorder in seven of the eight families studied and deletions of mtDNA were detected as the cause of the illness in five. The disorder was always associated with progressive external ophthalmoplegia and COX negative ragged red fibres.

Mitochondrial DNA defects in Brazilian patients with chronic progressive external ophthalmoplegia.

We report herein on eleven Brazilian patients with mitochondrial DNA (mtDNA) deletions, found among thirteen patients with chronic progressive external ophthalmoplegia (CPEO) and ragged-red fibers (RRF). The molecular data was correlated with the morphological and clinical findings. The muscle biopsies were studied by histochemistry, immunohistochemistry and DNA analysis. Muscle mtDNA deletions were mapped and quantitated by Southern blot analysis, polymerase chain reaction and sequencing. Of the eleven patients, ten had CPEO without multisystemic involvement and one had Kearns-Sayre syndrome. Three patients had multiple deletions, two of them with no apparent family history. Eight patients showed heteroplasmic single deletions, ranging in length from 2309 to 7566 bp; three of them had the same 'common deletion' of 4977 bp. The proportion of deleted mtDNA ranged from 14 to 89%. Immunohistochemical studies revealed decreased reactivity with the mtDNA-encoded subunit II of cytochrome c oxidase (COX) in all patients, but preserved activity with the nuclear-encoded COX subunit IV in COX-deficient fibers. Two cases presented a few COX-negative fibers with reduced COX IV immunostaining. We found a high frequency of mtDNA deletions in Brazilian patients with CPEO. There was no correlation between clinical severity, morphological findings and the size or amount of the mutated mtDNA in muscle, suggesting that there are still unknown factors influencing the disease phenotype.

Identical mitochondrial DNA deletion in mother with progressive external ophthalmoplegia and son with Pearson marrow-pancreas syndrome.

We describe a family in which the mother has progressive external ophthalmoplegia with the common 4977 base pair deletion, and her son has a syndrome similar to the Pearson marrow-pancreas syndrome with the identical deletion. This case extends the clinical phenotype of the Pearson syndrome and raises the possibility that developmentally regulated tissue-specific nuclear factors are responsible for the differential phenotypic expression of these two mitochondrial disorders.