Mitochondrial Medicine: Mitochondrial Metabolism, Diseases, Diagnosis and Therapy

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Advances in Mitochondrial Medicine

Article first published online: January 10, ; Issue published: January 1, Received: October 24, ; Accepted: This article is distributed under the terms of the Creative Commons Attribution 4. Mitochondrial Disease Clinical Trials. Tips on citation download. Treatment of mitochondrial disorders: Review of clinical trials for mitochondrial disorders: Google Scholar , Crossref , Medline. New treatments for mitochondrial disease-no time to drop our standards. Why are there no proven therapies for genetic mitochondrial diseases?

Design and implementation of the first randomized controlled trial of coenzyme CoQ 1 0 in children with primary mitochondrial diseases. Toward a therapy for mitochondrial disease. Nutritional interventions in primary mitochondrial disorders: Accessed 24 October Practice patterns of mitochondrial disease physicians in North America. Diagnosis and management of mitochondrial disease: Patient care standards for primary mitochondrial disease: Urine is increasingly recognized as a useful specimen for mtDNA genome analysis, given the high content of mtDNA in renal epithelial cells.

The mtDNA deletion and duplication syndromes manifest along a spectrum of three phenotypic presentations: KSS, chronic progressive external ophthalmoplegia, and Pearson syndrome. The most commonly used methods for detection of mtDNA deletions previously included Southern blot and long-range deletion-specific polymerase chain reaction analysis.

However, Southern blot analysis lacks sufficient sensitivity to detect low levels of heteroplasmic deletions. In contrast, array comparative genome hybridization detects deletions and also estimates the deletion breakpoints and deletion heteroplasmy. The mtDNA depletion syndromes are a genetically and clinically heterogeneous group of disorders characterized by a significant reduction in mtDNA copy number in affected tissues. Abnormalities in mtDNA biogenesis or maintenance underlie the pathophysiology of this class of mitochondrial disorders. They typically result from nDNA mutations in genes that function in mitochondrial deoxynucleotide synthesis or in mtDNA replication.

More than 1, nuclear genes are either directly or indirectly involved in mitochondrial function. In addition to single-gene testing, there are many diagnostic laboratories that offer next-generation sequencing-based panels of multiple genes. Some companies offer panels with a small number of targeted genes, varying from a few to a dozen or so per mitochondrial disease phenotype e.

Larger panels of more than , , or 1, nuclear genes are also available. Whole-exome sequencing became clinically available in , and it is an increasingly common diagnostic tool utilized in patients with suspected mitochondrial disease. Numerous research reports describe the detection of novel pathogenic mutations in nuclear mitochondrial genes by whole-exome sequencing, but no clear evidence-based practice recommendation has been established related to the use of single-gene sequencing, nuclear gene panels, or whole-exome sequencing for diagnostic purposes in mitochondrial disease patients in clinical practice.

A tissue biopsy, typically muscle, has often been thought of as the gold standard for mitochondrial diagnosis, although the test is affected by concerns of limited sensitivity and specificity. Tissue is typically sent for a variety of histological, biochemical, and genetic studies.

With newer molecular testing, there is less of a need to rely primarily on biochemical testing of tissue for diagnosis, although selectively testing tissue remains a very informative procedure, especially for a clinically heterogeneous condition such as mitochondrial disease. Tissue testing allows for detection of mtDNA mutations with tissue specificity or low-level heteroplasmy and quantification of mtDNA content copy number , directs appropriate molecular studies ensuring that genes of highest interest are covered, and helps validate the pathogenicity of variants of unknown significance found in molecular tests.

In patients with a myopathy, certain other neuromuscular diseases can be excluded by a muscle biopsy. There is debate about whether patients need an open biopsy to preserve histology and perform all the necessary testing. A few centers are experienced in performing needle biopsies for mitochondrial testing.

Because of potential injury to the mitochondria and the risk of artifactual abnormalities, open mitochondrial tissue biopsies require a different technique than routine biopsies that a surgeon may perform; these considerations are reviewed in Table 1. Pediatric patients are less likely to have histopathological abnormalities, and irregularities may only be noted on muscle EM, although normal results can also be seen. Hepatic dysfunction due to mitochondrial disease is mostly seen in pediatric patients. A liver biopsy can show selective histologic and ultrastructural features of mitochondrial hepatopathy, such as steatosis, cholestasis, disrupted architecture, and cytoplasmic crowding by atypical mitochondria with swollen cristae.

Ultrastructural evaluation should be performed routinely in unexplained cholestasis, especially when accompanied by steatosis and hepatocyte hypereosinophilia. Functional in vitro assays in tissue typically muscle have been the mainstay of diagnosis of mitochondrial disorders, especially prior to the recent advances in genomics. Functional assays remain important measures of mitochondrial function.

All of the mitochondrial disease guidelines and diagnostic criteria developed prior to the recent advances in genetic techniques and understanding include results of such biochemical studies to help establish a mitochondrial disease diagnosis. These tests evaluate the various functions of the mitochondrial ETC or respiratory chain. Functional assays include enzyme activities of the individual components of the ETC, measurements of the activity of components, blue-native gel electrophoresis, measurement of the presence of various protein components within complexes and supercomplexes achieved via western blots and gel electrophoresis , and consumption of oxygen using various substrates and inhibitors.

When possible, it is best to perform ETC assays on the tissue s that are most affected i. There are several points worth noting regarding limitations of biochemical studies in tissue Table 2. Defects in the synthesis of coenzyme Q 10 CoQ 10 lead to a variety of potentially treatable mitochondrial diseases.

CoQ 10 levels can be measured directly in muscle, lymphocytes, and fibroblasts, although it is thought that the levels obtained in muscle are most sensitive for diagnosing primary CoQ 10 deficiency. Low CoQ 10 levels can be found as a secondary defect in other disorders. To avoid invasive testing such as an open muscle biopsy, noninvasive mechanisms have been evaluated to diagnosis ETC abnormalities. These results can be normal even when muscle or liver ETC abnormalities are found. Neuroimaging in the form of computed tomography and magnetic resonance imaging of the brain have been used to assist in the diagnosis of mitochondrial disorders.

Some diagnostic criteria protocols include neuroimaging 64 , 65 but some do not. Depending on the type of mitochondrial disorder and type of central nervous system involvement, neuroimaging may or may not show structural alterations. Stroke-like lesions in a nonvascular distribution, diffuse white matter disease, and bilateral involvement of deep gray matter nuclei in the basal ganglia, mid-brain, or brainstem are all known classic findings in syndromic mitochondrial disease.

Thus, they are neither sensitive nor specific enough to allow for a primary mitochondrial disease diagnosis without the presence of other abnormalities. More florid white matter abnormalities are seen in mitochondrial neurogastrointestinal encephalopathy syndrome MNGIE , Leigh syndrome, and mitochondrial disorders due to defects in the aminoacyl-tRNA synthetases.

In addition to qualitative changes, there are quantitative changes that can be seen on specific acquisition sequences, proton magnetic resonance imaging MRS , and diffusion tensor imaging. MRS provides a semiquantitative estimate of brain metabolites, including lactate, creatine, and N -acetyl aspartate in a single- or multi-voxel distribution.

Diffusion tensor imaging detects and quantifies major white matter tracts. MRS and diffusion tensor imaging changes may be found in classic mitochondrial syndromes as well as nonsyndromic patients, but they are not specific to mitochondrial disorders and can be seen in a variety of other metabolic or other brain parenchymal disorders. Stroke-like episodes are a cardinal feature of several mitochondrial syndromes, including MELAS syndrome.

Arginine and citrulline are nitric oxide NO precursors. Endothelial dysfunction due to reduced NO production and disrupted smooth muscle relaxation may cause deficient cerebral blood flow and stroke-like episodes in MELAS syndrome. Numerous studies of animal models , and human patients with varying mitochondrial myopathies both nDNA and mtDNA encoded demonstrate the benefits of endurance exercise in mitochondrial disease.

Studies of endurance training in mitochondrial patients have shown increased mitochondrial content, antioxidant enzyme activity, muscle mitochondrial enzyme activity, maximal oxygen uptake, and increased peripheral muscle strength. Other findings include improved clinical symptoms and a decrease in resting and post-exercise blood lactate levels. Findings are sustained over time. The majority of studies report no deleterious effects to patients with mitochondrial myopathy from slowly accelerated exercise training, either resistance or endurance.

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In particular, there are no reports of elevated creatine kinase levels, negative heteroplasmic shifting, or increased musculoskeletal injuries in mitochondrial patients during supervised progressive exercise aimed at physiological adaptation. Many patients with mitochondrial disease have generally tolerated anesthesia. More recent reports from studies of small populations of mitochondrial patients or limited outcome measures have suggested that anesthetics are generally safe.

Anesthetics generally work on tissues with high-energy requirements and almost every general anesthetic studied has been shown to decrease mitochondrial function. Susceptibility for propofol infusion syndrome has been suggested but not yet proven. Narcotics and muscle relaxants are also frequently used in the operating room. These drugs with the possible exception of morphine are generally tolerated because they do not seem to alter mitochondrial function.

The risk of malignant hyperthermia does not seem to be increased in mitochondrial patients. Finally, mitochondrial patients are often vulnerable to metabolic decompensation during any catabolic state. Catabolism is often initiated in these patients because of anesthesia-related fasting, hypoglycemia, vomiting, hypothermia, acidosis, and hypovolemia. Therefore, limiting preoperative fasting, providing a source of continuous energy via IV dextrose, and closely monitoring basic chemistries are important. Review of the literature found little evidence supporting the management of patients with mitochondrial disease in the acute setting.

It is known that diseased mitochondria create more reactive oxygen species and periodically enter an energy-deficient state. Catabolic stressors require cells to generate higher amounts of energy via increased utilization of protein, carbohydrate, and fat stores. A catabolic state is induced by physiologic stressors such as fasting, fever, illness, trauma, or surgery.

Because of a lower cellular reserve, mitochondrial patients may more quickly enter a catabolic state and create more toxic metabolites and reactive oxygen species during catabolism. These cellular stresses may lead to cell injury and associated worsening of baseline symptoms or the onset of new ones. Recommendations in mitochondrial patients are based on the established management of patients with other inborn errors of metabolism during these vulnerable periods.

Treatments include providing IV dextrose as an anabolic substrate, avoiding prolonged fasting, and preventing exposures to substances that impede mitochondrial function when possible. Multiple vitamins and cofactors are used in the treatment of mitochondrial disease, although such therapies are not standardized and multiple variations of treatments exist.

CoQ 10 in its various forms is the most commonly used nutritional supplement in mitochondrial disease and is an antioxidant that also has many other functions. The evidence base supporting the use of CoQ 10 in mitochondrial diseases other than primary CoQ 10 deficiency is sparse, with few placebocontrolled studies available. ALA is relatively commonly used in mitochondrial disease therapy, but no controlled clinical trial has evaluated its use as monotherapy.

Although B-vitamins alone or as a multivitamin tablet e. Riboflavin use has also been seen to improve clinical and biochemical features in other small, open-label studies. There have been no clinical trials exploring the use of L-carnitine for the treatment of mitochondrial disease, although L-carnitine supplementation is commonly used in this patient population. L-Carnitine supplementation has also been used for the treatment of a number of neurometabolic disorders, including organic acidemias and some fatty-acid oxidation disorders; however, even in these conditions, no randomized, controlled trials have been performed.

L-Carnitine was used as a therapy in case studies, typically combined with other vitamins. Patients with mitochondrial disease, especially those with mtDNA deletion syndromes such as KSS, have potentially low CSF 5-methyltetrahydrofolate, and folinic acid supplementation is relatively common in patients with mitochondrial disease and neurologic signs or symptoms.

Advances in Mitochondrial Medicine - Gregory M. Enns,

Many other compounds were reviewed and the data can be found in the online summaries. The consensus was that further research regarding these compounds is needed. Evidence-based clinical protocols are the preferred method for diagnostic and medical management recommendations. For mitochondrial disease, there are insufficient data on which to base such recommendations. The Delphi process enabled our group to reach consensus-based recommendations with which to guide clinicians who evaluate and treat patients for mitochondrial disease.

This document is not intended to replace clinical judgment and cannot apply to every individual case or condition that may arise. It does not address the potential for inconsistent interpretations between diagnostic laboratories regarding which metabolites and at what levels their changes are considered to reach clinical significance. Each clinician should consult the literature and researchers in mitochondrial disease for updated information when needed. These recommendations should be superseded by clinical trials or high-quality evidence that may develop over time.

In the interim, we hope that these consensus recommendations serve to help standardize the evaluation, diagnosis, and care of patients with suspected or demonstrated mitochondrial disease. Although mitochondrial diseases are collectively common, the incidence of each individual mitochondrial disease etiology or subtype is relatively rare. Large-scale clinical trials in patients with mitochondrial diseases remain difficult.

With the recent advent of the North American Mitochondrial Disease Consortium, a sufficiently large cohort of mitochondrial disease patients is being studied to foster an improved understanding of their natural history and individual differences. Continued research is needed to better understand this important group of patients and develop ideal evidence-based clinical care protocols. The Mitochondrial Medicine Society will continue to evaluate the needs of mitochondrial patients and treating physicians and to advance education, research, and collaboration in the field.

Folate Metabolism, Mitochondrial Disease and ASD - Richard Frye, M.D., Ph.D.

National Center for Biotechnology Information , U. Author manuscript; available in PMC Sep 1. Cohen , MD, 9 Marni J. The publisher's final edited version of this article is available at Genet Med. See other articles in PMC that cite the published article. Abstract Purpose The purpose of this statement is to review the literature regarding mitochondrial disease and to provide recommendations for optimal diagnosis and treatment. Results Consensus-based recommendations are provided for the diagnosis and treatment of mitochondrial disease.

Conclusion The Delphi process enabled the formation of consensus-based recommendations. Caution must be taken to ensure that specimens are collected appropriately, especially for lactate and pyruvate measurements. Postprandial lactate levels are more sensitive than fasting specimens and are preferred when possible. Caution must be taken to not overinterpret small elevations in postprandial lactate. Quantitative 3MG measurements in plasma and urine should be obtained when possible in addition to urine organic acids in patients being evaluated for mitochondrial disease.

Creatine phosphokinase and uric acid should be assessed in patients with muscle symptoms who are suspected of having mitochondrial diseases. When CSF is obtained, it should be sent for lactate, pyruvate, amino acid, and 5-methyltetrahydrofolate measurements. Patients with a strong likelihood of mitochondrial disease because of a mtDNA mutation and negative testing in blood, should have mtDNA assessed in another tissue to avoid the possibility of missing tissue-specific mutations or low levels of heteroplasmy in blood; tissue-based testing also helps assess the risk of other organ involvement and heterogeneity in family members and to guide genetic counseling.

Heteroplasmy analysis in urine can selectively be more informative and accurate than testing in blood alone, especially in cases of MELAS due to the common m. If a single small deletion is identified using polymerase chain reaction—based analysis, then one should be cautious in associating these findings with a primary mitochondrial disorder. When a tissue specimen is obtained for mitochondrial studies, mtDNA content copy number testing via real-time quantitative polymerase chain reaction should strongly be considered for mtDNA depletion analysis because mtDNA depletion may not be detected in blood.

When considering nuclear gene testing in patients with likely primary mitochondrial disease, NGS methodologies providing complete coverage of known mitochondrial disease genes is preferred. Single-gene testing should usually be avoided because mutations in different genes can produce the same phenotype. If no known mutation is identified via known NGS gene panels, then wholeexome sequencing should be considered.

Pathology and biochemical testing of tissue Patholog A tissue biopsy, typically muscle, has often been thought of as the gold standard for mitochondrial diagnosis, although the test is affected by concerns of limited sensitivity and specificity. Table 1 Tissue collection and processing instructions for mitochondrial tissue biopsies.

Open in a separate window. When performing a muscle biopsy, an open biopsy is preferred in the routine analysis for mitochondrial disease, except when the center performing the biopsy is experienced in obtaining an adequate quality and quantity of tissue via a percutaneous biopsy. The vastus lateralis is the preferred site for a muscle biopsy in the evaluation of mitochondrial disease due to this site having been used by most laboratories to establish reference ranges. When possible, extra tissue should be frozen to allow for additional testing.

See Table 1 for special considerations. Biochemical testing in tissue Functional in vitro assays in tissue typically muscle have been the mainstay of diagnosis of mitochondrial disorders, especially prior to the recent advances in genomics. Table 2 Points to consider regarding mitochondrial biochemical testing in tissue.

ETC, electron transport chain. Consensus recommendations for biochemical testing in tissue Biochemical testing in tissue does not always differentiate between primary mitochondrial disease and secondary mitochondrial dysfunction. When obtaining a biopsy in the evaluation of mitochondrial disease, ETC enzymology spectrophotometry of complex I—IV activities in snap-frozen tissue or freshly isolated mitochondria should be obtained.

The affected tissue should be biopsied when possible. These tests are not available in all centers; therefore, they are not considered essential but should be considered in the diagnosis of mitochondrial disease. In some centers, various techniques of evaluating isolated mitochondria, permeabilized myofibers, immunoblot assays, and radiolabeled assays may enhance detection of ETC abnormalities.

However, as stand-alone tests they need validation.

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When interpreting ETC results, one should use published diagnostic criteria. Caution should also be used in providing a primary mitochondrial disease diagnosis based on biochemical abnormalities from tissue testing alone. The findings of significantly reduced ETC components or reduced enzyme activity from isolated components can give supplementary information in evaluating a patient with possible mitochondrial disease.

Tissue analysis of ETC complex enzyme activities may be falsely normal depending on a variety of factors, including the timing of the assay and use of less affected tissue. Therefore, ETC findings should not be used as the sole criterion for excluding mitochondrial dysfunction. Muscle CoQ 10 levels are necessary to determine primary CoQ 10 synthesis defects, especially when genetic studies are not diagnostic. Leukocyte CoQ 10 levels are inadequate to determine primary CoQ 10 synthesis disorders. Reduced CoQ 10 levels in muscle can be seen in other conditions.

Fibroblast ETC assays can help identify mitochondrial dysfunction in some cases, although testing can lead to false-negative results. Buccal swab analysis should not be a first line for mitochondrial testing; additional comparisons of buccal swab ETC results with muscle ETC activity and genetically confirmed patients are needed.

Neuroimaging Neuroimaging in the form of computed tomography and magnetic resonance imaging of the brain have been used to assist in the diagnosis of mitochondrial disorders. Consensus recommendations for neuroimaging When the central nervous system is involved, brain magnetic resonance imaging should be performed in the evaluation of a patient suspected of having a mitochondrial disease. MRS findings of elevated lactate within brain parenchyma are useful as well.

Neuroimaging cannot by itself be the absolute criterion for disease confirmation. Further research is needed regarding the role of MRS and diffusion tensor imaging in helping follow the course of mitochondrial disease. IV arginine hydrochloride should be administered urgently in the acute setting of a stroke-like episode associated with the MELAS m. Patients should be reassessed after 3 days of continuous IV therapy.

The use of daily oral arginine supplementation to prevent strokes should be considered in MELAS syndrome. The role of following plasma arginine and citrulline levels and oral citrulline supplementation in the treatment of MELAS requires further research. Exercise Numerous studies of animal models , and human patients with varying mitochondrial myopathies both nDNA and mtDNA encoded demonstrate the benefits of endurance exercise in mitochondrial disease.

Endurance exercise can increase mitochondrial enzyme activity in muscle and quality-of-life scores, and can reduce the energy cost of activities of daily living. Resistance exercise can increase muscle strength and recruitment of satellite cells in muscle fibers in mitochondrial patients.

A combination of progressive and resistance exercise is optimal for patients with mitochondrial disease and is thought to be safe when instituted in a supervised, progressive fashion with training beginning at a low intensity and duration. Mitochondrial patients should undergo cardiac screening prior to beginning an exercise program. Exercise intolerance is a real phenomenon in patients with mitochondrial disease, but a deconditioned mitochondrial patient should be encouraged to exercise.

Physicians should encourage compliance with exercise programs for mitochondrial patients. High-intensity interval training has been shown to induce similar mitochondrial adaptations as compared with endurance exercise in healthy and diabetic adults, but the effectiveness and safety have not been adequately studied in patients with mitochondrial disease.

Anesthesia Many patients with mitochondrial disease have generally tolerated anesthesia. Consensus recommendations for anesthesia Patients with mitochondrial diseases are at an increased risk of anesthesia-related complications. Preoperative preparation of patients with mitochondrial disease is crucial to their perioperative outcome. Patients should minimize preoperative fasting and have glucose added to their perioperative IV fluids, unless they are on a ketogenic diet or have been demonstrated to have adverse reaction to higher glucose intake. Caution must be used with volatile anesthetics because mitochondrial patients may potentially be hypersensitive.

Caution must be used with muscle relaxants in those mitochondrial patients with a preexisting myopathy or decreased respiratory drive. Mitochondrial patients may be at a higher risk for propofol infusion syndrome and propofol use should be avoided or limited to short procedures. One should consider slow titration and adjustment of volatile and parenteral anesthetics to minimize hemodynamic changes in mitochondrial patients. Treatment during illness Review of the literature found little evidence supporting the management of patients with mitochondrial disease in the acute setting.

Consensus recommendations for treatment during an acute illness Specific decisions about patient management including hospitalization require clinical judgment and should be case-specific. Patients with a mitochondrial disease should carry an emergency care plan that details their underlying disorder and provides management recommendations. Mitochondrial patients should take precautions to prevent entering catabolism, especially when exposed to medical stressors, including avoiding prolonged fasting and receiving dextrose-containing IV fluids before, during, and after procedures and surgeries.

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Dextrose should not be provided or should be provided in limited in quantity as indicated by clinical status in suspected or confirmed disorders of pyruvate metabolism, if the patient is on a ketogenic diet, or the patient has had an adverse response to high glucose delivery. Evaluation of a mitochondrial patient in the acute setting should include evaluation of routine chemistries, glucose, transaminases, and lactate; all other testing is as clinically indicated, although one must keep in mind the potential for cardiac and neurologic decompensations in these patients.

Treatment during acute decompensation should include dextrose-containing IV fluids, stopping exposures to potentially toxic medications, and correction of any metabolic derangements. The IV fluid rate should be based on the clinical situation. Outpatient mitochondrial therapies should be continued when possible.

Lipids can be used when needed in mitochondrial patients, even in the presence of secondary fatty-acid oxidation dysfunction. The following medications should be avoided in patients with mitochondrial disease when possible and, if given, they should be used with caution: Repeat neuroimaging should be considered in any mitochondrial patient with an acute change in neurologic status. Treatment with vitamins and xenobiotics Multiple vitamins and cofactors are used in the treatment of mitochondrial disease, although such therapies are not standardized and multiple variations of treatments exist.

Consensus recommendations for vitamin and xenobiotic use CoQ 10 should be offered to most patients with a diagnosis of mitochondrial disease and not exclusively used for primary CoQ 10 deficiency. Reduced CoQ 10 ubiquinol is the most bioavailable form and, when used, dosing should be appropriately modified. Plasma levels are more variable and less reflective of tissue levels.

Folinic acid should be considered in mitochondrial disease patients with central nervous system manifestations and routinely administered to those with documented CSF deficiency or with disease states known to be associated with deficiency. L-Carnitine should be administered to mitochondrial disease patients when there is a documented deficiency and levels should be monitored during therapy. Goal levels for most vitamin therapy used are not yet known; it is prudent to replace deficiency states.

University of Washington; Seattle, WA: Practice patterns of mitochondrial disease physicians in North America. The in-depth evaluation of suspected mitochondrial disease. Mitochondrial disorders as windows into an ancient organelle. New treatments for mitochondrial disease-no time to drop our standards. Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing.

Linstone HA, Turoff M. A Delphi-based consensus clinical practice protocol for the diagnosis and management of 3-methylcrotonyl CoA carboxylase deficiency. A Delphi clinical practice protocol for the management of very long chain acyl-CoA dehydrogenase deficiency. Diagnostic utility of a modified forearm ischemic exercise test and technical issues relevant to exercise testing. FGF as a biomarker for muscle-manifesting mitochondrial respiratory chain deficiencies: