Mitochondrial Disorders Overview

Clinical characteristics.

Mitochondrial diseases are a clinically heterogeneous group of disorders that arise as a result of dysfunction of the mitochondrial respiratory chain. They can be caused by mutation of genes encoded by either nuclear DNA or mitochondrial DNA (mtDNA). While some mitochondrial disorders only affect a single organ (e.g., the eye in Leber hereditary optic neuropathy [LHON]), many involve multiple organ systems and often present with prominent neurologic and myopathic features. Mitochondrial disorders may present at any age. Many individuals with a mutation of mtDNA display a cluster of clinical features that fall into a discrete clinical syndrome, such as the Kearns-Sayre syndrome (KSS), chronic progressive external ophthalmoplegia (CPEO), mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), myoclonic epilepsy with ragged-red fibers (MERRF), neurogenic weakness with ataxia and retinitis pigmentosa (NARP), or Leigh syndrome (LS). However, considerable clinical variability exists and many individuals do not fit neatly into one particular category, which is well-illustrated by the overlapping spectrum of disease phenotypes (including mitochondrial recessive ataxia syndrome (MIRAS) resulting from mutation of the nuclear gene POLG, which has emerged as a major cause of mitochondrial disease. Common clinical features of mitochondrial disease – whether involving a mitochondrial or nuclear gene – include ptosis, external ophthalmoplegia, proximal myopathy and exercise intolerance, cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy, and diabetes mellitus. Common central nervous system findings are fluctuating encephalopathy, seizures, dementia, migraine, stroke-like episodes, ataxia, and spasticity. A high incidence of mid- and late pregnancy loss is a common occurrence that often goes unrecognized.

Diagnosis/testing.

In some individuals, the clinical picture is characteristic of a specific mitochondrial disorder (e.g., LHON, NARP, or maternally inherited LS), and the diagnosis can be confirmed by identification of a pathogenic mtDNA variant on molecular genetic testing of DNA extracted from a blood sample. In many individuals, such is not the case, and a more structured approach is needed, including family history, blood and/or CSF lactate concentration, neuroimaging, cardiac evaluation, and molecular genetic testing for a mtDNA or nuclear gene pathogenic variant. Approaches to molecular genetic testing of a proband to consider are serial testing of single genes, multigene panel testing (simultaneous testing of multiple genes), and/or genomic testing (e.g., sequencing of the entire mitochondrial genome, genome sequencing, or exome sequencing to identify a pathogenic variant in a nuclear gene). In many individuals in whom molecular genetic testing does not yield or confirm a diagnosis, further investigation of suspected mitochondrial disease can involve a range of different clinical tests, including muscle biopsy for respiratory chain function.

Genetic counseling.

Mitochondrial disorders may be caused by defects of nuclear DNA or mtDNA. Nuclear gene defects may be inherited in an autosomal recessive or autosomal dominant manner. Mitochondrial DNA defects are transmitted by maternal inheritance. Mitochondrial DNA deletions generally occur de novo and thus cause disease in one family member only, with an approximate recurrence risk of 1 in 24. Mitochondrial DNA single-nucleotide variants and duplications may be transmitted down the maternal line. The father of a proband is not at risk of having the mtDNA pathogenic variant, but the mother of a proband (usually) has the mitochondrial pathogenic variant and may or may not have symptoms. A male does not transmit the mtDNA pathogenic variant to his offspring. A female harboring a heteroplasmic mtDNA single-nucleotide variant may transmit a variable amount of mutated mtDNA to her offspring, resulting in considerable clinical variability among sibs within the same family. Prenatal genetic testing and interpretation of test results for mtDNA disorders are difficult because of mtDNA heteroplasmy. De novo tissue-specific pathogenic nucleotide variants are rare, but associated with low recurrence risks.

Management.

Treatment of manifestations: The management of mitochondrial disease is largely supportive and may include early diagnosis and treatment of diabetes mellitus, cardiac pacing, ptosis correction, intraocular lens replacement for cataracts, and cochlear implantation for sensorineural hearing loss. Individuals with complex I and/or complex II deficiency may benefit from oral administration of riboflavin; those with ubiquinone (coenzyme Q₁₀) deficiency may benefit from oral coenzyme Q₁₀ therapy; and those with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) may benefit from hematopoietic stem cell transplantation.

Treatment of Manifestations

The management of mitochondrial disease is largely supportive [Chinnery & Turnbull 2001]. The clinician must have a thorough knowledge of the potential complications of mitochondrial disorders to prevent unnecessary morbidity and mortality.

Management issues may include early diagnosis and treatment of diabetes mellitus, cardiac pacing, ptosis correction, intraocular lens replacement for cataracts, and cochlear implantation for sensorineural hearing loss.

A variety of vitamins and co-factors have been used in individuals with mitochondrial disorders, although a Cochrane systematic review has shown that evidence supporting their use is lacking [Chinnery et al 2006].

• Food supplements such as ubiquinone (coenzyme Q₁₀, ubidecarenone) are generally well tolerated and some individuals report a subjective benefit on treatment.
• Individuals with complex I and/or complex II deficiency may benefit from oral administration of riboflavin.

The role of exercise therapy in mitochondrial myopathy is currently being evaluated [Taivassalo et al 2001, Taivassalo et al 2006, Murphy et al 2008].

Coenzyme Q₁₀ is specifically indicated in persons with defects of CoQ₁₀ biosynthesis.

Idebenone shows promise for the treatment of Leber hereditary optic neuropathy.

Some secondary causes of mitochondrial dysfunction, such as ethylmalonic aciduria, may have specific treatments [Tiranti et al 2009].

Those with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) may benefit from hematopoietic stem cell transplantation.

Prevention Strategies Under Investigation

The possibility of nuclear transfer as a means of preventing transmission of pathogenic mtDNA variants is currently being explored [Craven et al 2010].