The genetics of mitochondrial disease

The discovery that defects in mitochondria and mitochondrial DNA could cause human disease has led to the development of a rapidly expanding group of disorders known as mitochondrial disease. Mitochondrial disease is so named because of the common feature of impaired mitochondrial function. The main function of the mitochondrion is to produce energy for the cell in the form of ATP. ATP is generated by the respiratory chain, a series of complex proteins that are located in the mitochondrial membrane, and are encoded for by both the mitochondrial and nuclear genomes. Consequently, mitochondrial disease can be caused by mutations in either mitochondrial or nuclear DNA. Given the distribution of mitochondria throughout the body, the specific properties of mitochondrial DNA, and the mitochondrion's dependence on nuclear genes for its normal function, the clinical presentation of mitochondrial disease can be highly variable. Thus, familiarity with typical clinical presentations and knowledge of the genes that contribute to mitochondrial function will aid the clinician in the recognition, diagnosis, and management of patients with this group of diverse disorders.     

MERRF: a clinicopathological study. Relationships between myoclonus epilepsies and mitochondrial myopathies

Myoclonus epilepsy associated with ragged-red fibers (MERRF) is a degenerative disease involving dentate nuclei of the cerebellum, globus pallidus, the posterior columns and spinocerebellar tracts of the spinal cord, and skeletal muscles. Abnormal mitochondria were observed in the cells of the cerebellar cortex and of the dentate nuclei. The main symptoms of this disease include cerebellar ataxia and myoclonus in addition to muscular wasting. Patients with MELAS occasionally have myoclonus, but they never have myoclonus as their initial symptoms. Most of the patients with both clinical features of MERRF and MELAS were regarded as belonging to the category of MELAS.     

Multiple defects of the mitochondrial respiratory chain in a mitochondrial encephalopathy (MERRF): a clinical, biochemical and molecular study.

We describe a young man with a progressive neurological disorder including myoclonus, mental retardation, muscle weakness and a mitochondrial myopathy (myoclonus epilepsy and ragged red fibres--MERRF). Multiple abnormalities of the mitochondrial respiratory chain in skeletal muscle are shown by direct measurement of the flux through the individual complexes, low-temperature redox spectroscopy and decreased immunodetectable subunits of complexes I and IV by immunoblotting. No abnormality of mitochondrial DNA was found. This is the first report of combined defects of complexes I, III and IV as a cause of this clinical syndrome. However, we propose that the occurrence of multiple respiratory chain defects may be more common than previously recognised and that this particular combination of defects, involving complexes I, III and IV, may be the predominant biochemical abnormality in MERRF.     

Genetic biochemical and pathophysiological characterization of a familial mitochondrial encephalomyopathy (MERRF).

Myoclonic epilepsy with ragged-red fibers (MERRF) syndrome is a neuromuscular disorder characterized by mitochondrial myopathy and progressive myoclonus epilepsy. A heteroplasmic A to G transition mutation in the mitochondrial encoded tRNA(Lys) gene at nucleotide pair 8344 has been suggested to be linked to the MERRF-syndrome. We have investigated biochemically and histochemically muscle biopsies and studied the mitochondrial genomes of hair, blood and muscle tissue of a family including three cases of MERRF-syndrome as well as unaffected relatives within the maternal lineage. Sequence analysis of the mtDNAs, performed after amplification by the polymerase chain reaction (PCR), confirmed the A to G transition mutation in the tRNA(Lys) gene at position 8344. The additional point mutation at nucleotide pair 750 in the 12 S rRNA gene, which was also found by Shoffner et al. (1990), however, was absent in all investigated tissues. Quantitative analysis of the percentage of mutated mtDNA by mispairing PCR (Seibel et al., 1990) revealed variable contents in different tissues and individuals, including unaffected family members. Mitochondrial protein synthesis in cultured fibroblasts from MERRF patients revealed diminished incorporation of 35S-methionine into lysine-containing peptides.     

Uneven distribution of mitochondrial DNA mutation in MERRF dizygotic twins

A new family of myoclonic epilepsy with ragged-red fibers (MERRF) was studied at clinical, histological, biochemical and molecular genetic levels. There was a remarkable variation in the age of onset, the clinical presentation and the severity of symptoms. Multiple defects affecting respiratory chain complexes I, III and IV were detected in 2 patients. The point mutation at 8344 of the mitochondrial genome was found in all the maternal lineage with a relatively narrow range of variation in the percentage of mutant mitochondrial genomes. The one exception was represented by a set of dizygotic twins, one clinically affected and showing high proportions of mutant mitochondrial DNAs (mtDNAs) in blood cells, while the other was asymptomatic and showed very small amounts of mutant mt-DNAs in blood and skin. This could suggest an early segregation of the mitochondrial genome during ovogenesis.     

Unusual presentations of patients with the mitochondrial MERRF mutation A8344G

MERRF is typically characterized by myoclonus, generalized seizures and ragged-red fibers in muscular biopsy. We report a family (harbouring the A8344G mutation) with a late onset of the disease and an uncommon clinical manifestation, including episodes of reversible respiratory failure, the presence of ophthalmoplegia, and the absence of seizures and myoclonus in most subjects. We conducted histochemical, biochemical and molecular genetic studies. Mutation analysis revealed that the level of mutated mitochondrial DNA (mtDNA) was above 80% in the skeletal muscle of all siblings. Nevertheless, one severely affected individual did neither present cytochrome c oxidase-negative fibers nor ragged-red fibers in the skeletal muscle biopsy. These data extend the phenotypic range associated with the MERRF syndrome. We suggest that the analysis of mtDNA could be of importance in many cases of unclear multisystem disorders in later life.     

How genetics research in Parkinson's disease is enhancing understanding of the common idiopathic forms of the disease

PURPOSE OF REVIEW: Rapid progress in genetics has meant that there are now five genes identified for 'Parkinson's disease'. The detailed phenotypes vary, but generally the dominant genes cause a Lewy body disease spectrum whereas recessive genes cause a milder parkinsonism with variable inclusion body pathology. The subject of this review is to highlight these discoveries and to discuss their relationships to idiopathic Parkinson's disease. RECENT FINDINGS: In January 2004, mutations in PINK1, coding for a mitochondrial kinase, were found to be causal for recessive parkinsonism. Subsequently, several studies have found additional mutations associated with early onset parkinsonism. Some cases have been described with a phenotype much closer to idiopathic Parkinson's disease, but it does not appear that PINK1 is a major risk factor for the sporadic disease. Later in the same year, the LRRK2 gene was shown to cause a dominant disease with a broader phenotype. The protein product was named dardarin and contains GTPase and kinase domains. Lewy bodies have been reported in LRRK2 cases, potentially linking this gene with sporadic Parkinson's disease. One mutation, G2019S, is found in a significant percentage of cases, including sporadic Parkinson's disease. SUMMARY: Mutations in these two genes, along with previously described Mendelian variants, are beginning to yield important information about loss of specific neuronal groups or to protein inclusion pathology. How this relates to sporadic Parkinson's disease, however, is not yet fully defined. There are clear phenotypic overlaps with genetic and sporadic Parkinson's disease, especially for the dominant genes, suggesting that common facets of pathogenesis may exist.     

Identification of the RAG-1 as a suitable mouse model for mitochondrial DNA disease

Previous studies have shown that transfer of human myoblasts carrying a mitochondrial DNA mutation into muscles of the severe combined immunodeficient mouse may provide an important animal model for mitochondrial myopathy. However, a major drawback of this mouse is its extreme sensitivity to ionising radiation, a pre-treatment which enhances the efficiency of myoblast transfer success. We implanted human myoblasts into the tibialis anterior muscles of another immunodeficient mouse, mutated in the recombinase activating gene-1 (RAG-1), to determine if this mouse could be an alternative to the severe combined immunodeficient for our mitochondrial myoblast transfer model. We also examined several different methods of muscle degeneration prior to myoblast transfer to determine which method resulted in the greatest amount of human tissue in implanted muscles. Our results show that the RAG-1 mouse displayed no sensitivity to the irradiation process compared to the high sensitivity in the severe combined immunodeficient mouse which resulted in early termination of the study. We also show that degeneration of host muscles by the myotoxin barium chloride (BaCl(2)) resulted in the greatest amount of regenerating human muscle fibres in both the severe combined immunodeficient and RAG-1 mice. In addition, the maximum amount of human fibres observed in transplanted muscles was similar in each mouse strain. The average number of fibres throughout muscles was significantly greater in severe combined immunodeficient mice injured by BaCl(2), but was similar between all other muscle groups. This study suggests that the RAG-1 mouse is a suitable host for the mitochondrial myoblast transfer model and may also prove valuable for other myoblast transfer models such as muscular dystrophy.     

Novel mitochondrial DNA ND5 mutation in a patient with clinical features of MELAS and MERRF

BACKGROUND: The mitochondrial DNA gene encoding subunit 5 of complex I (ND5) has turned out to be a hot spot for mutations associated with mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes (MELAS) and various overlap syndromes. OBJECTIVE: To describe a novel mutation in the ND5 gene in a young man man with an overlap syndrome of MELAS and myoclonus epilepsy with ragged-red fibers. DESIGN: Case report. PATIENT: A 25-year-old man had recurrent strokes, seizures, and myoclonus. His mother also had multiple strokes. A muscle biopsy specimen showed no ragged-red fibers but several strongly succinate dehydrogenase-reactive blood vessels. RESULTS: Biochemical analysis showed isolated complex I deficiency and molecular analysis revealed a novel heteroplasmic mutation (G13042A) in the ND5 gene. CONCLUSIONS: These data confirm that ND5 is a genetic hot spot for overlap syndromes, including MELAS and strokelike and myoclonus epilepsy with ragged-red fibers.     

Leber's disease and dystonia: a mitochondrial disease

We studied a kindred in which 8 members had the neuroretinopathy of Leber's disease; 14 had a progressive, generalized dystonia attributed to striatal degeneration; and 1 had both disorders. The mode of inheritance was compatible with maternal transmission. This neurologic disorder may be a mitochondrial disease.     

Progress towards understanding the genetics of posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) is a complex syndrome that occurs following exposure to a potentially life threatening traumatic event. This review summarises the literature on the genetics of PTSD including gene–environment interactions (GxE), epigenetics and genetics of treatment response. Numerous genes have been shown to be associated with PTSD using candidate gene approaches. Genome-wide association studies have been limited due to the large sample size required to reach statistical power. Studies have shown that GxE interactions are important for PTSD susceptibility. Epigenetics plays an important role in PTSD susceptibility and some of the most promising studies show stress and child abuse trigger epigenetic changes. Much of the molecular genetics of PTSD remains to be elucidated. However, it is clear that identifying genetic markers and environmental triggers has the potential to advance early PTSD diagnosis and therapeutic interventions and ultimately ease the personal and financial burden of this debilitating disorder.     

The expanding mutational spectrum of MERRF substitution G8361A in the mitochondrial tRNALys gene

In a case of childhood-onset myoclonus epilepsy with "ragged-red fibers" (MERRF), a hitherto unreported mutation within the mitochondrial tRNA(Lys) gene was identified as the cause of the disease. Substitution G8361A was maternally inherited, heteroplasmic in all tissues tested, and correlated with mitochondrial dysfunction in individual muscle fibers. The growing number of MERRF-associated mutations within the tRNA(Lys) gene affirms the specific role of this mitochondrial tRNA in the pathogenesis of the disease.     

The molecular genetics of holoprosencephaly: a model of brain development for the next century

The recent identification of some of the human holoprosencephaly genes is beginning to elucidate the intricate developmental programs that pattern normal and abnormal brain development. Here we present some of these advances in the context of our present understanding and conclude with some speculations regarding the direction for future investigations. We are living in a tremendously exciting time in medicine with the rapid application of molecular genetic approaches to the understanding of human disease. It is the purpose of this review to stress the underlying principals of our approach at a level that can be readily appreciated by colleagues who themselves are experts in brain anatomy but not necessarily the molecular genetics of brain development.     

In vivo magnetic resonance spectroscopy of brain and muscle in a type of mitochondrial encephalomyopathy (MERRF)

Phosphorus magnetic resonance spectroscopy allows noninvasive measurement of the intracellular phosphate-containing metabolites and intracellular pH in localized volumes of human muscle and brain in vivo. This technique was used to study 8 patients with a mitochondrial cytopathy (myoclonus epilepsy with ragged red fibers). Phosphorus magnetic resonance spectroscopy of resting gastrocnemius muscle demonstrated significantly increased relative intracellular inorganic phosphate concentrations (p less than 0.0005) and decreased phosphocreatine to inorganic phosphate concentration ratios (p less than 0.01) in the patients, although only 3 had myopathic signs or symptoms. We propose, therefore, that phosphorus magnetic resonance spectroscopy of resting skeletal muscle is a useful clinical test in evaluation of progressive myoclonus epilepsy. In contrast to results from muscle, however, the relative phosphate metabolite concentrations and intracellular pH in central volumes of the brains of these patients were normal, despite evidence from our previous positron emission tomography studies suggesting that there is diffuse impairment of cerebral oxidative metabolism.