Mitochondrial disease (MD) occurs when alteration of mitochondrial respiratory chain complex function caused by genetic mutation produces a detectable disease state. These mutations may be found in either the nuclear or mitochondrial genomes, and may only be present in a subset of cells or body tissues. Thus, the phenotype of MD is extremely variable and the definitive diagnosis of MD is complex. This article provides a brief description of a strategy used in the diagnosis of MD, by integrating data from clinical, imaging, pathologic, molecular, and enzymatic assessments. Additional information on characteristic findings seen in classic MD syndromes is also provided.
Key points
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Mitochondrial diseases (MD) are a heterogeneous group of disorders with symptoms of organ dysfunction across multiple body systems.
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The unifying feature in MD is the dysfunction of mitochondrial respiratory chain complex function caused by genetic mutations.
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Diagnosis of MD is complicated by the lack of gold standard diagnostic testing strategies and the potential for false-negative test results caused by sampling issues.
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By integrating data obtained from clinical, imaging, pathologic, molecular, and enzymatic assessments, it is often possible to identify MD despite these issues.
Features of mitochondrial disease
Mitochondrial disease (MD) occurs when alteration of mitochondrial respiratory chain (RC) complex function caused by genetic mutation produces a detectable disease state. Activities of complexes I to V can be altered ( Fig. 1 ), and physiologic consequences of mitochondrial RC defects include reduced metabolic capacity, reduced ATP synthesis, and increased oxidative and nitrosative stress. Mutations in nuclear DNA (nDNA) or mitochondrial DNA (mtDNA) can lead to defects in the complexes essential for RC function or for the transport and assembly of mitochondrial proteins ( Box 1 ). Additionally, because mtDNA mutations can impair mitochondrial function, mutations that affect the complement of factors that facilitate the recycling, synthesis, and import of nucleotides to the mitochondrial genome can also produce MD.
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The mitochondrial genome encodes 37 genes, encoding two ribosomal RNAs, 22 transfer RNAs, and 13 subunits of RCs.
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There are at least 1000 nuclear genes associated with mitochondrial function.
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Some pathologic patterns (cytochrome oxidase–negative/succinate dehydrogenase–overexpressing fibers) specifically suggest mutations in the mitochondrial genome.
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Gene diagnostic panels are available for disease subsets, along with sequencing of the mitochondrial and nuclear genomes separately.
Because MD can present with an extraordinary range of clinical symptoms and testing abnormalities, it is often in the clinical differential diagnosis of patients with diseases involving the brain, muscle, or liver. Symptoms of MD are manifold and include abnormalities of the motor, sensory, gastrointestinal, endocrine, and cardiovascular systems; intolerance of some general anesthetics and antiepileptic drugs; increased susceptibility to infection; and pregnancy loss. The exceptional variation seen in the MD phenotype can be caused by variations in the amount and distribution of dysfunctional mitochondria throughout the body. Dramatic differences in clinical phenotype are seen in different patients with the same mutation, particularly when that mutation is present in the mitochondrial genome. For MD caused by mtDNA mutation, the clinical phenotype depends on (1) the specific tissues that contain abnormal mitochondria, (2) the proportion of abnormal mitochondria within these tissues, and (3) the number of copies of mutant mtDNA within the tissue. For nuclear-encoded defects, the phenotype is driven by the dependence of that tissue on mitochondrial respiration, and the tissue-specific expression of the protein and of other potentially compensatory proteins. Several distinct MD syndromes have been described ( Box 2 ), but it should be noted that these constitute particularly striking clinical phenotypes rather than the most common presentations of MD. In clinical practice, the most common presentation of MD is nonspecific, and may include the following issues:
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Unexplained combination of neuromuscular and nonneuromuscular symptoms
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Progressive course
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Involvement of an increasing number of seemingly unrelated organs
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Fluctuating symptomatology
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Exercise intolerance caused by premature fatigue after even mild activities (usually disproportionately severe compared with weakness)
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Muscle cramps, stiffness, or the “second wind phenomenon” that is often seen in glycogenoses
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Elevated lactate levels at rest
Mitochondrial encephalomyopathy, lactic acidosis stroke-like episodes
Presentation includes weakness, headaches, followed by episodes of seizures and transient hemiparesis and cortical blindness.
Myoclonic epilepsy with ragged red fibers
Presentation includes myoclonus (often the first symptom) followed by generalized epilepsy, ataxia, weakness, and dementia.
Progressive external ophthalmoplegia plus
Presentation includes ptosis followed by ophthalmoplegia, and this may be associated with weakness of the upper limbs and exercise intolerance.
Alpers syndrome
Presentation includes severe encephalopathy with intractable epilepsy and hepatic failure.
Navajo neurohepatopathy
Presentation includes hepatopathy, peripheral neuropathy, corneal anesthesia and scarring, acral mutilation, cerebral leukoencephalopathy, failure to thrive, and recurrent metabolic acidosis with intercurrent infections
Leigh disease
Presentation includes clinical evidence of brainstem/basal ganglia disease (including stepwise psychomotor retardation or regression), elevated blood or cerebrospinal fluid lactate levels, and imaging abnormalities in the brainstem and basal ganglia.
Diagnostic approaches for MD are currently nonstandard and better diagnostic tools for MD are needed. The clinical heterogeneity of MD complicates diagnosis because it can symptomatically overlap with a broad range of diseases, and testing abnormalities among the MDs are not uniform. MD is often suspected in early childhood, and traditional diagnostic methods for MD include assessment of clinical presentation, family history, pathology, metabolic profiling, enzyme activity levels, electrophysiology, MRI, magnetic resonance spectroscopy, and mtDNA analysis. Despite this arsenal of methods, the diagnostic work-up for the identification of MD is not standard across providers or institutions. Diagnostic algorithms have been used to predict the likelihood of MD. Nevertheless, there is no clear consensus on when MD can be excluded, or where follow-up confirmatory testing should be performed.
MD is likely vastly underdiagnosed at a level of 5 in 100,000 children, whereas its suspected prevalence may be 1 in 5000 adults. Conversely, a subset of patients with other causes of their symptoms may be incorrectly identified as having an MD because of secondary metabolic effects of their disease state. The determination of whether MD is present or can be excluded in a given patient is extremely complex, given the following:
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Mitochondrial function can be secondarily affected because of the disease processes in non-MDs.
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There is no specific or sensitive biomarker that identifies all or even most individuals with MD.
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There is extensive variability in the distribution of abnormal mitochondria within an individual patient, allowing a false-negative testing profile to occur when tissues used for diagnosis do not contain the abnormal mitochondria.
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There are no uniform, clear-cut pathologic abnormalities to distinguish all patients with MD from patients with other disorders, to the extent that some biopsy specimens from MD look structurally normal.
Unfortunately, the lack of standard strategies to identify true MD cases (especially less severe cases that do not have specific pathology) poses a substantial limitation on improving MD diagnosis. In our center, we have adopted a three-strike practice to identify whether genetic testing of the nuclear or mitochondrial genome is likely to be useful ( Box 3 ), which has led to the identification of patients with pathogenic mutations despite underwhelming test abnormalities on some of the other testing modalities. The remainder of this article provides descriptions of the diagnostic testing modalities that are useful in the diagnosis of MD.
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Follow-up genetic testing is performed in cases with significant abnormalities in any three of the following categories
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Clinical history
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Light microscopy
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Electron microscopy
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Electron transport chain activity testing
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mtDNA content
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Recognizing there may be rare false-negatives, we generally do not go forward with genetic testing for mitochondrial disease on cases without abnormalities in at least three of the categories listed previously.
Features of mitochondrial disease
Mitochondrial disease (MD) occurs when alteration of mitochondrial respiratory chain (RC) complex function caused by genetic mutation produces a detectable disease state. Activities of complexes I to V can be altered ( Fig. 1 ), and physiologic consequences of mitochondrial RC defects include reduced metabolic capacity, reduced ATP synthesis, and increased oxidative and nitrosative stress. Mutations in nuclear DNA (nDNA) or mitochondrial DNA (mtDNA) can lead to defects in the complexes essential for RC function or for the transport and assembly of mitochondrial proteins ( Box 1 ). Additionally, because mtDNA mutations can impair mitochondrial function, mutations that affect the complement of factors that facilitate the recycling, synthesis, and import of nucleotides to the mitochondrial genome can also produce MD.
- •
The mitochondrial genome encodes 37 genes, encoding two ribosomal RNAs, 22 transfer RNAs, and 13 subunits of RCs.
- •
There are at least 1000 nuclear genes associated with mitochondrial function.
- •
Some pathologic patterns (cytochrome oxidase–negative/succinate dehydrogenase–overexpressing fibers) specifically suggest mutations in the mitochondrial genome.
- •
Gene diagnostic panels are available for disease subsets, along with sequencing of the mitochondrial and nuclear genomes separately.
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