Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rapid progress has been made in the identification of mitochondrial DNA mutations which are typically associated with diseases of the nervous system and muscle. The well established mitochondrial disorders are maternally inherited and males and females are equally affected. An exception is Leber's hereditary optic atrophy (LHON) which is observed much more frequently in males than in females. There are three common point mutations in LHON which can be homoplasmic or heteroplasmic. In mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) most mutations are single base changes and lie within the tRNA-Leu gene. Point mutations in myoclonic epilepsy with ragged red fibres (MERRF) usually occur within the tRNA-Lys gene but mutations of the tRNA-Leu gene are also observed. MELAS and MERRF mutations are heteroplasmic and there is considerable clinical overlap between these diseases. Point mutations within the ATPase6 gene result in either neuropathy, ataxia and retinitis pigmentosa (NARP) or in Leigh's syndrome. The latter occurs if the mutation is present in the majority of mitochondria (extreme heteroplasmy). Finally, mitochondrial DNA deletions are the cause underlying Kearns-Sayre syndrome (KSS). Apart from the well-established mitochondrial diseases, there is increasing evidence that mitochondrial mutations may also play a role in the neurodegenerative disorders Parkinson, Alzheimer and Huntington disease. The complex I defect found in Parkinson disease is especially interesting in this respect. However, no causative mitochondrial mutation has as yet been established in any of these three common disorders.
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PMID:Recent developments in the molecular genetics of mitochondrial disorders. 951 82

Complex I deficiency, either specific or associated with other respiratory chain defects, has been identified in myopathies, encephalomyopathies and in three 'neurodegenerative' disorders: Parkinson's disease, dystonia and Leber's hereditary optic neuropathy. The complex I defect is expressed in blood in all these three but, to date, only in LHON have specific mitochondrial DNA mutations been identified. Recent work with rho degrees cybrids indicates that, in a subgroup of patients at least, the complex I deficiency is determined by mtDNA, in contrast to dystonia where a nuclear gene defect or toxic influence appears a more likely cause. The actions of specific toxins, e.g., MPTP continue to play an important role in our understanding of pathogenesis of neurodegeneration, particularly in PD.
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PMID:Human complex I defects in neurodegenerative diseases. 959 27

Complete sequence analysis of all mitochondrial complex I genes was performed in 22 cases of neuropathologically confirmed idiopathic Parkinson disease (PD). DNA from the substantia nigra was used as a template for polymerase chain reaction-based genomic sequencing. Seven novel mutations causing the exchange of amino acids were detected in subunit genes ND1 (3992 C/ T, 4024 A/G), ND4 (11253 T/C, 12084 C/T), ND5 (13711 G/A, 13768 T/C), and ND6 (14582 T/C). In addition, five known missense mutations affecting the ND1 (3335 T/C, 3338 T/C), ND2 (5460 G/A), ND3 (10398 A/G), and ND5 (13966 A/G) genes as well as three secondary LHON mutations (4216 T/C, 4917 A/ G, 13708 G/A) were found in the PD group. Among the novel mutations, the 11253 T/C transition which changes a conserved isoleucine residue into threonine is most likely to be of functional relevance. Furthermore, 43 synonymous polymorphisms were detected in PD brains, including 20 novel sequence variants. Haplogroup analysis revealed that most unique missense mutations were found in PD cases belonging to the D(c) haplogroup. Our data are in line with the view that PD is not a single disease entity but comprises a genetically heterogeneous group of disorders. The results of our study further suggest that 90% or more of all idiopathic PD cases are not due to sequence variation of mitochondrial complex I, but that mitochondrial mutations may play a pathogenic role in a subset of PD patients.
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PMID:Novel mutations of mitochondrial complex I in pathologically proven Parkinson disease. 1073 23

Though mitochondria have been a major source of energy production in eukaryotae since 15-20 billion years previously, existence of disorders due to primary abnormalities of their DNA has not been known until very recent years. In 1962, Luft et al reported the first case of such myopathy, and another case reported in 1967 by Shy et al was also the first case of generalized disorder with mitochondrial abnormalities. Since then, many case reports have followed including MELAS and other encephalomyopathies. Finally, in 1989, deletion of mitochondria DNA was found by Folt et al. Today, these disorders were able to be classified as follows: 1) LHON and A1555G type deafness as strictly limited non-syndromic type, 2) encephalomyopathies and their incomplete forms due to common and other deletions of mitochondria DNA, 3) encephalomyopathies and their incomplete forms including MIDD, diabetes mellituis, cardiomyopathy, deafness due to point mutations of mitochondria DNA related MELAS and others, 4) Neurodegenerative types including Parkinson's disease, Alzheimer's disease, cerebellar degeneration, and amyotrophic lateral sclerosis, or neurologic disorders mimic to such diseases, 5) Mitochondrial involvement not due to primary abnormalities of mitochondria DNA. Possible mechanisms were discussed, but sufficient knowledge is lacking so far to clarify pathophysiology of these disorders and the role of deleterious DNA in aging. Possible effective therapeutic strategies were also discussed, but further development of research works on these disorders in the 21st century are needed to answer these questions.
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PMID:[Current and future aspects of mitochondrial diseases]. 1079 Oct 75

The pathogenesis of Parkinson's disease (PD) is largely unknown. Indirect evidence suggests that mutations in mitochondrial DNA (mtDNA) might play a role, but previous studies have not consistently associated any specific mutations with PD. However, these studies have generally been confined to limited areas of the mitochondrial genome. We therefore sequenced the entire mitochondrial genome from substantia nigra of 8 PD and 9 control subjects. Several sequence variants were distributed differently between PD and control subjects, but all were previously reported polymorphisms. Several secondary LHON mutations were found, as well as a number of novel missense mutations, but all were rare and did not differ between PD and control subjects. Finally, PD and control subjects did not differ in the total number of all mutations, nor the total number of missense mutations. Thus, mtDNA involvement in PD, if any, is likely to be complex and should be reconsidered carefully.
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PMID:Sequence analysis of the entire mitochondrial genome in Parkinson's disease. 1182 Aug 5

As with chromosomal DNA, the mitochondrial DNA (mtDNA) can contain mutations that are highly pathogenic . In fact, many diseases of the central nervous system are known to be caused by mutations in mtDNA. Dysfunction of the mitochondrial Respiratory Chain (RC) has been shown in patients with neurological disease including Alzheimer's disease (AD), Parkinson's disease (PD) and Multiple sclerosis (MS). MS is a demyelinating disease of central nervous system characterized by morphological hallmarks of inflammation, demyelination and axonal loss. Considering this importance, we decided to investigate several highly mutative parts of mtDNA for point mutations as MT-LTI (tRNA(Leucine1(UUA/G))), MT-NDI (NADH Dehydrogenase subunit 1), MT-COII (Cytochrome c oxidase subunit II), MT-TK (tRNA(Lysine)), MT-ATP8 (ATP synthase subunit F0 8) and MT-ATP6 (ATP synthase subunit F0 6) in 20 Iranian MS patients and 80 age-matched control subjects by PCR and automated DNA sequencing to evaluate any probable point mutations. Our results revealed that 15 (75%) out of 20 MS patients had point mutations. Some of point mutations were newly found in this study. This study suggested that point mutation occurred in mtDNA might be involved in pathogenesis of MS.
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PMID:Investigation on mitochondrial tRNA(Leu/Lys), NDI and ATPase 6/8 in Iranian multiple sclerosis patients. 1761 38

While many treatments for mitochondrial electron transport (respiratory) chain disorders have been suggested, relatively few have undergone controlled clinical trials. This review focuses on the recent history of clinical trials of dichloroacetate (DCA), arginine, coenzyme Q(10), idebenone, and exercise in both primary (congenital) disorders and secondary (degenerative) disorders. Despite prior clinical impressions that DCA had a positive effect on mitochondrial disorders, two trials of diverse subjects failed to demonstrate a clinically significant benefit, and a trial of DCA in MELAS found a major negative effect of neuropathy. Arginine also has been used to treat MELAS with promising effects, although a controlled trial is still needed for this potentially toxic agent. The anti-oxidant coenzyme Q(10) is very widely used for primary mitochondrial disorders but has not yet undergone a controlled clinical trial; such a trial is now underway, as well as trials of the co-Q analogue idebenone for MELAS and LHON. Greater experience has accumulated with multi-center trials of coenzyme Q(10) treatment to prevent the progression of Parkinson disease. Although initial smaller trials indicated a benefit, this has not yet been confirmed in subsequent trials with higher doses; a larger Phase III trial is now underway. Similarly, a series of trials of idebenone for Friedreich ataxia have shown some benefit in slowing the progression of cardiomyopathy, and controlled clinical trials are now underway to determine if there is significant neurological protection. Uncontrolled trials of exercise showed an increase of exercise tolerance in patients with disorders of mitochondrial DNA, but did not selectively increase the percentage of normal mtDNA; a larger partially controlled trial is now underway to evaluate this possible benefit. In summary, none of the controlled trials so far has conclusively shown a benefit of treatment with the agents tested, but some promising therapies are currently being evaluated in a controlled manner. These experiences underscore the importance of controlled clinical trials for evaluation of benefits and risks of recommended therapies. Application of such clinical trials to future more effective therapies for mitochondrial disorders will require multi-center collaboration, organization, leadership, and financial and advocacy support.
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PMID:Treatment of mitochondrial electron transport chain disorders: a review of clinical trials over the past decade. 2006 Mar 49