Mitochondrial cytopathies: clinical, morphological and genetic characteristics.

BACKGROUND AND PURPOSE: Mitochondrial cytopathies are heterogeneous disorders affecting multiple systems but most commonly involving the skeletal muscle and central nervous system. The variety of symptoms and signs requires biochemical, morphological and genetic evaluation. The results of genetic studies indicate that there is no direct correlation between genotype and phenotype in mitochondrial cytopathies. This study is the first such analysis of a group of Polish patients with mitochondrial cytopathies. Its aim is to define the clinical features of mitochondrial cytopathies in relation to their genetic defects. MATERIAL AND METHODS: In a retrospective study, 46 patients with final diagnosis of mitochondrial cytopathy were evaluated clinically and electrophysiologically. Each patient underwent electromyography, electroneurography, and some patients were also assessed using electroencephalography. Clinical diagnoses were confirmed through the histopathological evaluation of muscle biopsies. In 36 cases mitochondrial DNA (mtDNA) testing was performed. RESULTS: Eight different clinical syndromes were diagnosed among the evaluated patients. In the skeletal muscle biopsy, ragged-red fibres, which are a significant symptom for these disorders, were present in the majority of cases (93%). The presence of specific gene mutations was confirmed in 9 out of the 36 cases in which mtDNA was examined. CONCLUSIONS: The results of our study confirm the remarkable clinical heterogeneity of mitochondrial cytopathies. Final diagnosis in many cases could only be confirmed by detection of the genetic defects. Molecular diagnosis may in the future have a significant impact on new therapeutic approaches.

[Metabolic myopathies - an overview]. / Metabolische Myopathien - ein Uberblick.

Metabolic disorders of energy production characterise the group of rare, mainly autosomal recessively inherited metabolic muscular diseases which are often associated with multi-systemic symptoms. In this report, an update on the clinics, pathophysiology, pathomorphology and current treatment options of metabolic myopathies will be given. Beyond classic phenotypes of these disorders, one should be aware of oligosymptomatic patients who can be easily missed. The relevant gene mutations and the pathophysiology and pathomorphology they cause are now known for almost all these metabolic diseases. Establishing the correct diagnosis has become even more important since highly specific therapy options are now available for at least some of these inherited disorders, e.g. enzyme replacement therapy in Pompe disease.

Brain magnetic resonance imaging findings in patients with mitochondrial cytopathies.

BACKGROUND: Mitochondrial cytopathies (MCs) are a heterogeneous group of clinical entities, some of which have classic phenotypes. Magnetic resonance imaging (MRI) has been reported to be helpful in the diagnosis of MC. OBJECTIVE: To correlate the most common brain MRI findings reported in patients with MC with the clinical findings in patients in different MC subgroups. DESIGN: Case series. SETTING: Patients with MCs seen at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubiran, Mexico City, Mexico. PATIENTS: Twenty-one patients with MC with the following phenotypes: chronic progressive external ophthalmoplegia (n = 7), Kearns-Sayre syndrome (n = 7), mitochondrial neurogastrointestinal encephalopathy (n = 6), and myoclonic epilepsy with ragged red fiber myopathy (n = 1). RESULTS: Brain MRI abnormalities were found in 20 (95%) of 21 patients. The most frequent abnormalities were widespread white matter hyperintensity in 19 patients (90%), supratentorial cortical atrophy in 18 patients (86%), and cerebellar atrophy in 13 patients (62%). Widespread white matter hyperintensity (P<.001) and supratentorial cortical atrophy (P = .001) were each correlated significantly with MC. Subsequent subgroup analyses showed that the absence of basal ganglia hyperintensity was correlated with Kearns-Sayre syndrome (P < .001) and the presence of supratentorial cortical atrophy was correlated with mitochondrial neurogastrointestinal encephalopathy (P = .005). CONCLUSIONS: The presence of widespread white matter hyperintensity and/or supratentorial cortical atrophy in brain MRI may help to establish the diagnosis of MC. The radiologist has a role to play in the workup of MC by confirming the diagnosis and possibly distinguishing different subgroups of MC.

Neuro-ophthalmology of mitochondrial diseases.

PURPOSE OF REVIEW: To review recent data on mitochondrial diseases with emphasis on their neuro-ophthalmic manifestations. RECENT FINDINGS: Numerous studies have associated mitochondrial diseases with neuro-ophthalmic manifestations. Although there has been an explosion of studies on the genetics of mitochondrial diseases over the past few years, pathogenesis is only partly understood and therapy remains very limited. Over the past year, new mutations in Leber's hereditary optic neuropathy have been reported, and at least three genes associated with autosomal dominant chronic progressive external ophthalmoplegia have been described. These findings allow a better definition of the specific genetic mutations and gene products as well as pathophysiology of Leber's hereditary optic neuropathy and chronic progressive external ophthalmoplegia. The current development of animal models allows a better understanding of the pathophysiology of human mitochondrial diseases. SUMMARY: The afferent and efferent visual pathways within the central nervous system are frequently involved in mitochondrial diseases. Neuro-ophthalmic signs figure prominently and may be the presenting or even sole manifestation of these disorders. The four most common neuro-ophthalmic abnormalities seen in mitochondrial disorders are bilateral optic neuropathy, ophthalmoplegia with ptosis, pigmentary retinopathy, and retrochiasmal visual loss.

Mitochondrial diseases.

Since the first reports of disorders associated with mitochondrial DNA (mtDNA) defects more than a decade ago, the small mtDNA circle has been a Pandora's box of pathogenic mutations associated with human diseases. The "morbidity map" of mtDNA has gone from one point mutation and a few deletions in 1988 to more than 110 point mutations as of September, 2001. Nuclear DNA defects affecting mitochondrial function and mtDNA replication and integrity have also been identified in the past few years and more are expected. As a result, human "mitochondrial" diseases have evolved beyond the novelty diagnoses of a decade ago into an important area of medicine, and thus, the diagnostic principles of these disorders ought to be familiar to the clinician. In this article, the authors, we summarize the principles of mitochondrial genetics and discuss the common phenotypes, general diagnostic approach, and possible therapeutic venues for these fascinating disorders.

Survey of human mitochondrial diseases using new genomic/proteomic tools.

BACKGROUND: We have constructed Bayesian prior-based, amino-acid sequence profiles for the complete yeast mitochondrial proteome and used them to develop methods for identifying and characterizing the context of protein mutations that give rise to human mitochondrial diseases. (Bayesian priors are conditional probabilities that allow the estimation of the likelihood of an event - such as an amino-acid substitution - on the basis of prior occurrences of similar events.) Because these profiles can assemble sets of taxonomically very diverse homologs, they enable identification of the structurally and/or functionally most critical sites in the proteins on the basis of the degree of sequence conservation. These profiles can also find distant homologs with determined three-dimensional structures that aid in the interpretation of effects of missense mutations. RESULTS: This survey reports such an analysis for 15 missense mutations, one insertion and three deletions involved in Leber's hereditary optic neuropathy, Leigh syndrome, mitochondrial neurogastrointestinal encephalomyopathy, Mohr-Tranebjaerg syndrome, iron-storage disorders related to Friedreich's ataxia, and hereditary spastic paraplegia. We present structural correlations for seven of the mutations. CONCLUSIONS: Of the 19 mutations analyzed, 14 involved changes in very highly conserved parts of the affected proteins. Five out of seven structural correlations provided reasonable explanations for the malfunctions. As additional genetic and structural data become available, this methodology can be extended. It has the potential for assisting in identifying new disease-related genes. Furthermore, profiles with structural homologs can generate mechanistic hypotheses concerning the underlying biochemical processes - and why they break down as a result of the mutations.

[Mitochondrial and metabolic myopathies]. / Myopathies mitochondriales et métaboliques.

Mitochondrial and metabolic myopathies constitute a group of disorders characterised by abnormal muscular metabolism of energy. Most of these disorders are genetically transmitted. Recent progress in the field has led to spectacular advances in their classification and the understanding of the mechanisms involved, particularly in mitochondrail myopathies. Diagnosis can be made et any age; the patient can present manifestations that can be misleading for the clinician. Lipid myopathies and glycogenoses usually present as a myopathic syndrome associated with cramps, spasm and myalgia, with fatigue on effort. Acute episodes of rhabdomyolysis on effort can occur, with an attendant risk of renal failure. Mitochondrial myopathies have multi-organ manifestations and muscular involvement is not always at the forefront. Although diagnosis may be suggested by clinical factors, it should be confirmed by teams and laboratories that specialize in muscular disorders.

A comparison of genetic mitochondrial disease and nucleoside analogue toxicity. Does fetal nucleoside toxicity underlie reports of mitochondrial disease in infants born to women treated for HIV infection?

Recent reports of mitochondrial disease in infants whose mothers were treated in pregnancy with nucleoside analogues are of concern. Chronic nucleoside analogue treatment of adults has long been known to cause mitochondrial DNA depletion with the risk of multisystem disease. Combination nucleoside analogue treatment regimens may have the greatest risk of toxicity. This paper briefly presents the underlying biochemical etiologies and phenotypes of some common genetic mitochondrial diseases in order to provide a comparison with reports of infant toxicity. A standardized method for the diagnosis and evaluation of mitochondrial disease is discussed. A hypothesis, with predictions of the effects of antenatal nucleoside analogue treatment on the fetus, is presented and future directions for research on this problem are suggested.

[Aspects of neuropathy in mitochondrial diseases]. / Caracterización de la neuropatía en las enfermedades mitocondriales.

INTRODUCTION: The existence of neuropathy has been described in mitochondrial disorders such as MELAS, MERRF, Leigh's syndrome, the Kearns-Saye syndrome, myoneurogastro-intestinal encephalopathy and progressive external ophthalmoplegia and constitutes a basic component of the NARP (neuropathy, ataxia and retinosis pigmentosa). However, the general prevalence of the neuropathy and its characteristics within the mitochondrial encephalopathies is not well understood. OBJECTIVES: To characterize the neuropathy and try to establish a genotype-phenotype correlation. PATIENTS AND METHODS: Within study guidelines, we made a retrospective study of 27 patients, diagnosed as having mitochondrial disease, who had had neurophysiological studies (EMG-ENG). In those in whom neuropathy had been found we analysed the clinical, neurophysiological and genetic characteristics. RESULTS: Neuropathy was present in 37% of the patients who had an average age of 13 years, ranging from 1 to 25 years. Syndromic diagnoses were: 7 encephalomyopathies, one MELAS, one MERRF and one NARP. Four of the patients were classified genetically. In all but two of the patients the neuropathy was asymptomatic. The biochemical alterations seen were: deficit of Complex 1 in 3 patients, of complex III in 3 patients, of complex IV in 2 and of pyruvate dehydrogenase in one patient. The type of neuropathy found was varied, with predominance of axonal-type motor neuropathy but no correlation with either biochemical defects or genetic diagnosis. CONCLUSIONS: Neuropathy is a common finding in mitochondrial disorders and probably is under-diagnosed. The axonal form predominates. We have not been able to establish correlations between phenotypes and genotypes.

[Diagnostic strategy for mitochondrial diseases]. / Estrategia diagnóstica de las enfermedades mitocondriales.

OBJECTIVE: The variability of both phenotypic and genotypic expression in mitochondrial diseases makes clinical diagnosis difficult, which is essential to establish therapy, aid in genetic counselling or for performing prenatal diagnosis. We have therefore proposed a strategy to help determine correct diagnosis of these alterations, in an attempt to rationalize the number of tests and, whenever possible, avoid tissue biopsy and minimize the size of the biopsy when indicated. DEVELOPMENT: Based on mitochondrial metabolism and molecular bases, as well as their alterations, a preliminary metabolic examination is carried out including at least one study of cytoplasmatic (lactate/pyruvate) and mitochondrial oxide reduction (hydroxibutirate/acetoacetate) in basal conditions or, if required, following glucose overload or an effort test. Metabolic study, in addition to clinical exploration, are the screening tests used to determine the need for tissue biopsy in which biochemical (pyruvate dehydrogenase, free and total carnitine, beta oxidation enzymes and respiratory chain complexes), genetic (mitochondrial DNA or nuclear alterations) and histologic tests are carried out to confirm diagnosis. CONCLUSIONS: a) Metabolic exploration may discard mitochondrial disease and many cases, avoid the use of an invasive procedure such as tissue biopsy. b) Biochemical study of tissue biopsy is the only useful key in the confirming of the diagnosis when no mitochondrial and/or nuclear DNA are observed.

[Classification of mitochondrial diseases]. / Clasificación de las enfermedades mitocondriales.

Clinical and biochemical classifications of mitochondrial disorders have given way to an as yet incomplete genetic classification system based on alterations of the mitochondrial genome, the nuclear genome, or both. The first group includes mitochondrial disorders due to specific mutations of mitochondrial DNA such as the MELAS, MERRF or NARP encephalomyopathies, various conditions involving deafness (non-syndromic or associated with diabetes), Leber's optic neuropathy and a small group of cases of maternally transmitted Leigh's syndrome. All these diseases are transmitted through maternal line. conditions which are usually sporadic are due to deletion or duplication of mitochondrial DNA, and give rise to myopathies, with or without ophthalmoplegia, and to more complex disorders such as Kearns Sayre syndrome are also included. The second group is composed of all the mitochondrial disorders in which the nuclear genes which codify sub-units of mitochondrial DNA contain a genetic defect. This includes most cases of Leigh's syndrome, Alpers polydystrophies, the myoneurogastrointestinal syndrome, Barth's syndrome and Friedreich's disease. Amongst the disorders secondary to defects in communication between the nuclear and mitochondrial genomes is a progressive external ophthalmoplegic form with autosomal dominance which arises secondary to mutations on chromosomes 3 and 10. Further mitochondrial disorders due to faults in the relationship between the two genomes will probably be found in the near future.

Mitochondria in neuromuscular disorders.

This review considers primary mitochondrial diseases affecting the respiratory chain. As diseases due to mitochondrial DNA defects defy traditional anatomical classifications, we have not limited our discussion to neuromuscular disorders, but have extended it to include mitochondrial encephalomyopathies. Primary mitochondrial diseases can be due to mutations in either the nuclear or the mitochondrial genome. Nuclear mutations can affect (i) genes encoding enzymatic or structural mitochondrial proteins; (ii) translocases; (iii) mitochondrial protein importation; and (iv) intergenomic signaling. We review briefly recent molecular data and outstanding questions regarding these mendelian disorders, with special emphasis on cytochrome c oxidase deficiency and coenzyme Q10 deficiency. Mitochondrial DNA mutations fall into three main categories: (i) sporadic rearrangements (deletions/duplications); (ii) maternally inherited rearrangements (duplications); and (iii) maternally inherited point mutations. We summarize the most common clinical presentations and discuss pathogenic mechanisms, which remain largely elusive. Uncertainties about pathogenesis extend to the process of cell death, although excitotoxicity in neurons and apoptosis in muscle seem to have important roles.

Cardiac involvement in patients with myotonic dystrophy, Becker's muscular dystrophy and mitochondrial myopathy.

The aim of this prospective study was to classify cardiac involvement in myopathies by means of a comprehensive cardiac investigation, to determine the rate of cardiac involvement in myopathies according to this classification and to compare the validity of previously reported electro-cardiographic myopathy indices (QT/PQs, P/PQs, R/S) with that of the comprehensive cardiac investigation. We included 14 patients with myotonic dystrophy, 6 patients with Becker's muscular dystrophy and 10 patients with mitochondrial myopathy. Cardiac involvement was classified as either "definite", "equivocal" or "absent" by assessing cardiovascular history, physical examination, electrocardiography, echocardiography and 24-hour ambulatory electrocardiography. "Definite"/"equivocal"/"absent" cardiac involvement was found in 12/2/0 myotonic dystrophy, 3/3/0 Becker's muscular dystrophy and 6/3/1 mitochondrial myopathy patients. Electrocardiographic myopathy indices were pathologic in 3 Becker's muscular dystrophy, 6 mitochondrial myopathy but in none of the myotonic dystrophy patients. The proposed comprehensive cardiac investigation is simple, inexpensive and effective in assessing cardiac involvement in patients with myotonic dystrophy. Becker's muscular dystrophy and mitochondrial myopathy. In case of cardiac involvement, cardiac therapy might be one of the few therapeutic options for these patients.