Clinical Spectrum Of Mitochondrial Disorders Research Articles

The relevance of migraine in the clinical spectrum of mitochondrial disorders

Recent scientific evidence suggests a link between migraine and brain energy metabolism. In fact, migraine is frequently observed in mitochondrial disorders. We studied 46 patients affected by mitochondrial disorders, through a headache-focused semi-structured interview, to evaluate the prevalence of migraine among patients affected by mitochondrial disorders, the possible correlations between migraine and neuromuscular genotype or phenotype, comorbidities, lactate acid levels and brain magnetic resonance spectroscopy. We explored migraine-related disability, analgesic and prophylactic treatments. Diagnoses were achieved according to International Classification of Headache Disorders, 3rd edition. Lifetime prevalence of migraine was 61% (28/46), with high values in both sexes (68% in females, 52% in males) and higher than the values found in both the general population and previous literature. A maternal inheritance pattern was reported in 57% of cases. MIDAS and HIT6 scores revealed a mild migraine-related disability. The high prevalence of migraine across different neuromuscular phenotypes and genotypes suggests that migraine itself may be a common clinical manifestation of brain energy dysfunction. Our results provide new relevant indications in favour of migraine as the result of brain energy unbalance.

Genetics of Mitochondrial Myopathies

Pearson syndrome. Clinical spectrum of mitochondrial disorders is broad, so consensus diagnostic criteria for mitochondrial disorders have been proposed for children and adults. Sequence map of human mitochondrial genome with its normal and patho­ genic variants is publicly available. In this review, we will discuss genetic features of mitochondrial myopathies as well as their key findings. Representative syndromes will be described in detail and the less common entities will be summarized in Table 1.

Mitochondrial DNA polymerase γ mutations: an ever expanding molecular and clinical spectrum

Mutations in the POLG gene have emerged as one of the most common causes of inherited mitochondrial diseases in children and adults. This study sequenced the exons and flanking intronic...

Biochemical diagnosis of mitochondrial disorders

Establishing a diagnosis in patients with a suspected mitochondrial disorder is often a challenge. Both knowledge of the clinical spectrum of mitochondrial disorders and the number of identified disease-causing molecular genetic defects are continuously expanding. The diagnostic examination of patients requires a multi-disciplinary clinical and laboratory evaluation in which the biochemical examination of the mitochondrial functional state often plays a central role. In most cases, a muscle biopsy provides the best opportunity to examine mitochondrial function. In addition to activity measurements of individual oxidative phosphorylation enzymes, analysis of mitochondrial respiration, substrate oxidation, and ATP production rates is performed to obtain a detailed picture of the mitochondrial energy-generating system. On the basis of the compilation of clinical, biochemical, and other laboratory test results, candidate genes are selected for molecular genetic testing. In patients in whom an unknown genetic variant is identified, a compatible biochemical phenotype is often required to firmly establish the diagnosis. In addition to the current role of the biochemical analysis in the diagnostic examination of patients with a suspected mitochondria disorder, this report gives a future perspective on the biochemical diagnosis in view of both the expanding genotypes of mitochondrial disorders and the possibilities for high throughput molecular genetic diagnosis.

Assaying ATP synthesis in cultured cells: A valuable tool for the diagnosis of patients with mitochondrial disorders

Mitochondrial ATP synthase plays a central role in cell function by synthesising most of the ATP in human tissues. In different cells, active regulation of mitochondrial ATP synthase in response to cellular energy demand has been demonstrated, as well as its alteration under several pathological conditions affecting oxidative phosphorylation (OXPHOS). Traditionally, detection of OXPHOS defects is based on the spectrophotometric measurement of respiratory chain complex activities in muscle biopsies. Considering the broad clinical spectrum of mitochondrial disorders, and the difficulty in arriving at a single diagnostic method, in this study we propose measurement of ATP synthesis in mitochondria from skin fibroblasts as an effective screening tool. In the light of our results this assessment emerges as a useful marker of impaired energy production in primary OXPHOS disorders of childhood and as a tool with the potential to drive further molecular genetic studies.

Mitochondrial DNA Deletion in a Child With Mitochondrial Encephalomyopathy, Growth Hormone Deficiency, and Hypoparathyroidism

We report an 11-year-old boy with short stature, bilateral ptosis, sensorineural hearing loss, muscle weakness, and endocrine abnormalities. Brain magnetic resonance imaging (MRI) showed a bilateral abnormal signal in the globus pallidus and in the midbrain tegment. Muscle biopsy specimens showed ragged red and cytochrome c oxidase negative fibers, and biochemical analysis of muscle homogenate showed a partial defect of complex I and IV activities of the respiratory chain enzymes. Analysis of mitochondrial DNA by a polymerase chain reaction screening procedure and Southern blot revealed a novel heteroplasmic single mitochondrial DNA deletion of 7.8 kb in different tissues. This deletion was absent in the blood DNA of his mother and brother. This case further expands and confirms the wide clinical spectrum of mitochondrial disorders associated with single large-scale mitochondrial DNA deletions.

Hair anomalies as a sign of mitochondrial disease.

In 8 out of 25 children with a mitochondrial disorder, slow growing, sparse and fragile hair was observed as an early sign of their disease. Microscopic examination of the hair showed the presence of trichorrhexis nodosa and pili torti. Hair abnormalities can be added to the wide clinical spectrum of mitochondrial disorders. Microscopic hair examination is an easy, first level diagnostic tool that can lead to a suspected mitochondrial defect in the early stages of the disease, before symptoms of progressive multi-organ involvement develop.

Mitochondrial disorders: clinical presentation and diagnostic dilemmas.

The number of genes known to be involved in mitochondrial energy production and the elucidation of the function of their individual transcripts is still increasing. Although at this stage it is impossible to predict the number of human genes necessary for mitochondrial biogenesis and maintenance, the total number in humans will most probably exceed the number of mitochondrial genes found in, for example, the budding yeast, which is about 800. Without doubt we have only seen the tip of the iceberg of the clinical spectrum of mitochondrial disorders. Recent findings such as mutations in structural complex II genes in certain tumours emphasize the need to think outside the classical clinical presentation. We propose the consideration of a mitochondrial disorder in every chronic, intermittent or progressive disorder with single system or multisystem involvement, even if lactic acid is normal, and discuss such dilemmas as whether we should 'scrape the barrel' in every patient that are raised by this statement. The characterization of mitochondrial and nuclear DNA mutations in patients with enzymatically established mitochondrial defects has taught us that several of the current clinical and diagnostic assumptions have to be altered or even eliminated. The most challenging future task will be the development of new diagnostic criteria covering the expanding clinical spectrum of mitochondrial disorders.

Mitochondrial myopathies

Major new advances in the genetic and biochemical characterization of mitochondrial myopathies are discussed, within a general presentation of this important new area of human pathology. Mitochondrial disorders can be due to mutations in either nuclear or mitochondrial genes involved in the synthesis of individual respiratory chain subunits or in their posttranslational control. Although no mutations of nuclear-encoded oxidative phosphorylation subunits have been reported so far in humans, numerous biochemically defined disorders are attributed to nuclear gene defects. In contrast, molecular lesions of mitochondrial DNA are recognized as an increasingly frequent cause of defective oxidative phosphorylation. Numerous new mutations recently have been identified, including both maternally inherited point mutations and sporadic large-scale rearrangements. In addition, the identification of new or overlap syndromes has substantially broadened the clinical spectrum of mitochondrial disorders. To gain insight into the pathogenesis of these disorders, the relationship between specific clinical presentations and the mitochondrial genotype has been intensively investigated. In most cases, the phenotypic expression of the mitochondrial DNA mutations depends on the interplay among the relative amount of mutated vs wild-type genomes, ie, the degree of mitochondrial heteroplasmy and its tissue and cell distribution, the reliance of the affected tissues on aerobic energy supply, the age and gender of the individual, and other still poorly understood factors including individual "nuclear genetic background" and environmental factors.

Dopa and Parkinsonism

In a nonalcoholic woman with multiple symmetric lipomatosis (MSL), muscle histochemistry showed ragged-red fibers and cytochrome c oxidase negative fibers. Southern blot analysis revealed a single deletion of mitochondrial DNA (mtDNA). We suggest that MSL is an uncommon manifestation of the wide clinical spectrum of mitochondrial disorders, in particular of those associated with single mtDNA deletions. <b>NEUROLOGY 1996;47: </b> 1012-1014