Elsevier

The Lancet Neurology

Volume 9, Issue 8, August 2010, Pages 829-840
The Lancet Neurology

Review
A neurological perspective on mitochondrial disease

https://doi.org/10.1016/S1474-4422(10)70116-2Get rights and content

Summary

Disruption of the most fundamental cellular energy process, the mitochondrial respiratory chain, results in a diverse and variable group of multisystem disorders known collectively as mitochondrial disease. The frequent involvement of the brain, nerves, and muscles, often in the same patient, places neurologists at the forefront of the interesting and challenging process of diagnosing and caring for these patients. Mitochondrial diseases are among the most frequently inherited neurological disorders, and can be caused by mutations in mitochondrial or nuclear DNA. Substantial progress has been made over the past decade in understanding the genetic basis of these disorders, with important implications for the general neurologist in terms of the diagnosis, investigation, and multidisciplinary management of these patients.

Introduction

Over 20 years ago, Holt and colleagues1 reported the first association between a defect in mitochondrial DNA and human disease, and this was quickly followed later the same year by a second report from Wallace and colleagues.2 Since then, the number of disease-associated mitochondrial DNA mutations has expanded rapidly and mutations have been identified that cause classic mitochondrial syndromes such as mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), myoclonic epilepsy and ragged red fibres (MERRF), neuropathy, ataxia, and retinitis pigmentosa (NARP), Kearns-Sayre syndrome, and maternally inherited Leigh syndrome.3 The importance of nuclear genetic mutations in causing mitochondrial dysfunction and human disease has become increasingly clear over the past decade. Indeed, the putative role of mitochondrial respiratory chain deficiency in the pathogenesis of a wide range of neurological disorders has been the subject of intense scientific scrutiny.4, 5, 6, 7 In this Review, we discuss mitochondrial respiratory chain disease in the context of clinical neurology, providing an overview of not only the neurological aspects but also the multisystem effects of mitochondrial disease that neurologists must consider in both children and adults with this disorder. The genetic aetiology of mitochondrial disease has a substantial effect on the investigations requested by treating physicians and the type of counselling that is provided to families. We have therefore discussed the underlying genetics in depth, along with diagnostic and management strategies.

Mitochondria undertake many vital metabolic functions, probably the most important of which is oxidative phosphorylation, the principal method for generating ATP.3 This process is dependent on five intramembrane complexes and two mobile electron carriers (coenzyme Q10 and cytochrome c), which transport electrons between them. Supercomplexes (ie, respirasomes) are combinations of two or more respiratory chain complexes that can further enhance electron transfer. Although their role in the in-vivo action of the human mitochondrial respiratory chain remains contentious, evidence in favour of a multimeric organisation is accumulating.8

An interesting legacy of the primeval origins of mitochondria9 is the persistence of a 16·6 kb, double-stranded circle of DNA (mitochondrial DNA). This semi-autonomous genome encodes 13 structural subunit polypeptides and the machinery (22 transfer RNA molecules and 2 ribosomal RNA molecules) necessary for intramitochondrial protein synthesis.10 Mitochondrial DNA is present in multiple copies, and in any single cell a small number of these genomes might contain mutations; however, the proportion of mutated DNA is usually so small that for practical purposes the tissue can be regarded as homoplasmic (genetically uniform). By contrast, for several mitochondrial DNA mutations, tissue variation in the level of heteroplasmy (the existence of two or more distinct mitochondrial genomes at high concentrations within the same tissue) has a direct effect on the resultant phenotype and even small decreases in the concentrations of wild-type mitochondrial DNA might be sufficient to cause disease.11 However, the variable or single organ phenotypes that occur with homoplasmic mutations12, 13 and the apparent dominant nature of some mitochondrial transfer RNA (mitochondrial tRNA) mutations14 suggest that other, as yet undefined, factors are also important in determining the phenotype. Although nuclear genetic mutations causing mitochondrial dysfunction have been associated with several so-called new clinical phenotypes, some nuclear gene mutations can result in clinical phenotypes that are similar to those in primary mitochondrial DNA disease and the distinction between the two is not always clinically obvious.15

Section snippets

Prevalence of mitochondrial disease

Recent estimates of prevalence suggest that mitochondrial disease is more common than previously thought. Both the mitochondrial tRNA mutations MTTL1, m.3243A>G and MTRNR1, m.1555A>G (aminoglycoside-induced deafness) have frequencies of up to 1 in 400 in the general population,16, 17, 18 but many patients with these mutations remain asymptomatic. Clinical prevalence studies report that mitochondrial disease caused by mutations in mitochondrial DNA affects 9·2 in 100 000 adults aged less than 65

Point mutations of mitochondrial DNA

Novel point mutations in mitochondrial DNA are still being identified by use of high-throughput sequencing technology, some 22 years after the first mutation was identified.2 Most mitochondrial DNA mutations occur in a few families worldwide, but some, such as those that cause Leber's hereditary optic neuropathy (LHON), and the m.3243A>G mutation (in the MTTL1 gene), account for a large proportion of cases of mitochondrial disease. A disproportionately large number of these point mutations

Clinical evidence

The clinical presentation of mitochondrial disease is varied and can occur at almost any stage of life, often with involvement of an unusual combination of organs.3 Multisystem involvement in adult patients commonly occurs in the so-called classic mitochondrial syndromes, but, with the exception of Alpers-Huttenlocher syndrome (AHS) and Leigh syndrome, these classic syndromes are less common in young children with mitochondrial disease.65 A detailed family history can be informative, although

Baseline assessment

In view of the progressive, often multisystem, nature of mitochondrial disease, the health needs of all patients should be assessed in detail at the time of diagnosis and at regular intervals thereafter. We have developed and validated paediatric and adult clinical disease-rating scales specifically for this purpose.66, 67 Basic data relating to weight, height, and body-mass index should be recorded at each clinic visit, and in children this data should be plotted on appropriate growth charts.95

Specific treatment of mitochondrial disease

No specific pharmaceutical drugs have been clearly shown in large-scale clinical trials to treat mitochondrial disease effectively.99 However, there are anecdotal reports of improvement in fatigue and relief of myalgia associated with use of coenzyme Q10 and its analogue idebenone.100 In patients with coenzyme Q10 deficiency, coenzyme Q10 replacement therapy can also be beneficial but requires much higher doses.71 Riboflavin is also effective in some patients with complex I deficiency.101 Some

Conclusions

In a previous review,3 we concluded that nuclear–mitochondrial interaction must be important in the expression of mitochondrial disease and suggested that we were edging towards effective therapy. Although research now supports the first of these conjectures, we remain somewhat short of the mark on the latter. Nevertheless, with the development of national cohorts and registries, the potential for doing systematic large-scale studies of possible treatments is slowly becoming a reality. In

References (130)

  • J Loeffen et al.

    The first nuclear-encoded complex I mutation in a patient with Leigh syndrome

    Am J Hum Genet

    (1998)
  • P Benit et al.

    Large-scale deletion and point mutations of the nuclear NDUFV1 and NDUFS1 genes in mitochondrial complex I deficiency

    Am J Hum Genet

    (2001)
  • L Van den Heuvel et al.

    Demonstration of a new pathogenic mutation in human complex I deficiency: a 5-bp duplication in the nuclear gene encoding the 18kD (AQDQ) subunit

    Am J Hum Genet

    (1998)
  • D Astuti et al.

    Germline SDHD mutation in familial phaeochromocytoma

    Lancet

    (2001)
  • V Massa et al.

    Severe infantile encephalomyopathy caused by a mutation in COX6B1, a nucleus-encoded subunit of cytochrome c oxidase

    Am J Hum Genet

    (2008)
  • C Sugiana et al.

    Mutation of C20orf7 disrupts complex I assembly and causes lethal neonatal mitochondrial disease

    Am J Hum Genet

    (2008)
  • A Saada et al.

    Mutations in NDUFAF3 (C3ORF60), encoding an NDUFAF4 (C6ORF66)-interacting complex I assembly protein, cause fatal neonatal mitochondrial disease

    Am J Hum Genet

    (2009)
  • A Saada et al.

    C6ORF66 is an assembly factor of mitochondrial complex I

    Am J Hum Genet

    (2008)
  • I Visapaa et al.

    GRACILE syndrome, a lethal metabolic disorder with iron overload, is caused by a point mutation in BCS1L

    Am J Hum Genet

    (2002)
  • V Tiranti et al.

    Mutations of SURF-1 in Leigh disease associated with cytochrome c oxidase deficiency

    Am J Hum Genet

    (1998)
  • I Valnot et al.

    Mutations of the SCO 1 gene in mitochondrial cytochrome c oxidase (COX) deficiency with neonatal-onset hepatic failure and encephalopathy

    Am J Hum Genet

    (2000)
  • D Ghezzi et al.

    FASTKD2 nonsense mutation in an infantile mitochondrial encephalomyopathy associated with cytochrome c oxidase deficiency

    Am J Hum Genet

    (2008)
  • Y Zhang et al.

    New insights into mitochondrial fusion

    FEBS Lett

    (2007)
  • C Phoenix et al.

    A scale to monitor progression and treatment of mitochondrial disease in children

    Neuromuscul Disord

    (2006)
  • A Rotig et al.

    Quinone-responsive multiple respiratory chain deficiency due to widespread coenzyme Q10 deficiency

    Lancet

    (2000)
  • SS Chan et al.

    DNA polymerase gamma and mitochondrial disease: understanding the consequence of POLG mutations

    Biochim Biophys Acta

    (2009)
  • R McFarland et al.

    The m.5650G>A mitochondrial tRNAAla mutation is pathogenic and causes a phenotype of pure myopathy

    Neuromuscul Disord

    (2008)
  • O Elpeleg et al.

    Deficiency of the ADP-forming succinyl-CoA synthase activity is associated with encephalomyopathy and mitochondrial DNA depletion

    Am J Hum Genet

    (2005)
  • E Ostergaard et al.

    Deficiency of the alpha subunit of succinate-coenzyme A ligase causes fatal infantile lactic acidosis with mitochondrial DNA depletion

    Am J Hum Genet

    (2007)
  • P Barboni et al.

    Natural history of Leber's hereditary optic neuropathy: longitudinal analysis of the retinal nerve fiber layer by optical coherence tomography

    Ophthalmology

    (2010)
  • Y Ihara et al.

    Mitochondrial encephalomyopathy (MELAS): pathological study and successful therapy with coenzyme Q10 and idebenone

    J Neurol Sci

    (1989)
  • I Holt et al.

    Deletion of muscle mitochondrial DNA in patients with mitochondrial myopathies

    Nature

    (1988)
  • DC Wallace et al.

    Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy

    Science

    (1988)
  • D Mahad et al.

    Review: mitochondria and disease progression in multiple sclerosis

    Neuropathol Appl Neurobiol

    (2008)
  • MT Lin et al.

    Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases

    Nature

    (2006)
  • P Chinnery et al.

    Molecular pathology of MELAS and MERRF: the relationship between mutation load and clinical phenotype

    Brain

    (1997)
  • R McFarland et al.

    Multiple neonatal deaths due to a homoplasmic mitochondrial DNA mutation

    Nat Genet

    (2002)
  • S Sacconi et al.

    A functionally dominant mitochondrial DNA mutation

    Hum Mol Genet

    (2008)
  • WC Copeland

    Inherited mitochondrial diseases of DNA replication

    Annu Rev Med

    (2008)
  • M Bitner-Glindzicz et al.

    Prevalence of mitochondrial 1555A–>G mutation in European children

    N Engl J Med

    (2009)
  • AM Schaefer et al.

    Prevalence of mitochondrial DNA disease in adults

    Ann Neurol

    (2008)
  • PF Chinnery et al.

    The mitochondrial ND6 gene is a hot spot for mutations that cause Leber's hereditary optic neuropathy

    Brain

    (2001)
  • D Liolitsa et al.

    Is the mitochondrial complex I ND5 gene a hot-spot for MELAS causing mutations?

    Ann Neurol

    (2003)
  • R McFarland et al.

    De novo mutations in the mitochondrial ND3 gene as a cause of infantile mitochondrial encephalopathy and complex I deficiency

    Ann Neurol

    (2004)
  • DM Kirby et al.

    Mutations of the mitochondrial ND1 gene as a cause of MELAS

    J Med Genet

    (2004)
  • LM Cree et al.

    A reduction of mitochondrial DNA molecules during embryogenesis explains the rapid segregation of genotypes

    Nat Genet

    (2008)
  • T Wai et al.

    The mitochondrial DNA genetic bottleneck results from replication of a subpopulation of genomes

    Nat Genet

    (2008)
  • JB Stewart et al.

    Strong purifying selection in transmission of mammalian mitochondrial DNA

    PLoS Biol

    (2008)
  • J Loeffen et al.

    Mutations in the complex I NDUFS2 gene of patients with cardiomyopathy and encphalomyopathy

    Ann Neurol

    (2001)
  • P Benit et al.

    Mutant NDUFV2 subunit of mitochondrial complex I causes early onset hypertrophic cardiomyopathy and encephalopathy

    Hum Mutat

    (2003)
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