The in-depth evaluation of suspected mitochondrial disease
Section snippets
Lactate and pyruvate analysis
Lactic acid elevation in blood (typically considered >2.1 mM) or CSF can be an important, albeit non-specific, marker of mitochondrial disease. Mitochondrial disease patients, may however, have normal lactate and pyruvate levels unless undergoing a metabolic crisis or following exercise [9]. Furthermore, many patients with mitochondrial disease consistently have normal or only minimally elevated lactic acid levels, as occurs in mitochondrial polymerase gamma (POLG1)-associated diseases, Leber
Invasive tissue investigations
The first decision to be made when invasive procedures are deemed necessary is the selection of which tissue to investigate for evidence of mitochondrial dysfunction. The best choice is the tissue most profoundly affected by the disease process in a given patient [51]. Although skin biopsy seems preferable to muscle biopsy due to its relatively lower invasiveness, it is common for many children who have an OXPHOS defect detectable in skeletal muscle to have normal respiratory chain enzyme
Mitochondrial DNA analysis
Performing thorough mitochondrial DNA analysis necessitates understanding the breadth of mitochondrial DNA mutation types, the relative merits and drawbacks of the various analytic methods available, and the appropriate tissue for testing in a given patient. The types of mitochondrial DNA abnormalities that can be causative of human mitochondrial disease include single basepair point mutations, several basepair insertions or deletions, large scale deletions on the order of 100s to 1000s of
mtDNA sequencing microarray
The latest version of the Affymetrix oligonucleotide resequencing microarray (MitoChip 2.0) provides a method that yields sequence data on the complete coding region and 15,452 of the 15,569 bp. mtDNA [128]. It reduces the possibility of amplifying pseudogenes by first amplifying mtDNA in three long overlapping fragments that are not present in the nDNA. In addition, it now appears to be able to detect heteroplasmy down to about 2–5% [129].
ESI-TOF mass spectrometry
A variety of mass spectrometry platforms are suitable
Summary
An in-depth evaluation of mitochondrial disease is possible and indeed warranted to obtain a clear diagnosis for individual patients. This is necessary to minimize cost of duplicate investigations, correct misinformation to families and health care providers, and provide accurate prognostic and recurrence risk counseling. Recognized mitochondrial diagnostic centers working in close collaboration with referring clinicians can successfully navigate the complexities of the diagnostic evaluation
Acknowledgments
The authors thank Drs. Salvatore DiMauro, Wolfgang Sperl, and Jan Smeitink for their helpful comments on this manuscript.
References (188)
- et al.
Mitochondrial encephalomyopathies: an update
Neuromuscul. Disord.
(2005) The problem of interlab variation in methods for mitochondrial disease diagnosis: enzymatic measurement of respiratory chain complexes
Mitochondrion
(2004)Assessment of precision and concordance of quantitative mitochondrial DNA assays: a collaborative international quality assurance study
J. Clin. Virol.
(2003)Techniques and pitfalls in the detection of pathogenic mitochondrial DNA mutations
J. Mol. Diagn.
(2003)- et al.
Pyruvate dehydrogenase phosphatase deficiency: orphan disease or an under-diagnosed condition?
Mol. Cell Endocrinol.
(2006) Non-ketotic hyperglycinemia is usually not detectable by tandem mass spectrometry newborn screening
Mol. Genet. Metab.
(2007)Mitochondrial DNA deletion in a patient with mitochondrial myopathy, lactic acidosis, and stroke-like episodes (MELAS) and Fanconi’s syndrome
Pediatr. Neurol.
(1995)- et al.
A biochemical perspective on the use of tandem mass spectrometry for newborn screening and clinical testing
Clin. Biochem.
(2005) Metabolomic approaches to mitochondrial disease: correlation of urine organic acids
Mitochondrion
(2004)Deficiency of mitochondrial ATP synthase of nuclear genetic origin
Neuromuscul. Disord.
(2006)
Phenotypic heterogeneity in the syndromes of 3-methylglutaconic aciduria
J. Pediatr.
Quantification of free carnitine, individual short- and medium-chain acylcarnitines, and total carnitine in plasma by high-performance liquid chromatography
Anal. Biochem.
Immunocytochemical localization of N-acetyl-aspartate with monoclonal antibodies
Neuroscience
In vivo 1H MRS choline: correlation with in vitro chemistry/histology
Life Sci.
Quantitative 1H and 31P MRS of PCA extracts of postmortem Alzheimer’s disease brain
Neurobiol. Aging
Efficacy of proton magnetic resonance spectroscopy in neurological diagnosis and neurotherapeutic decision making
NeuroRx
Exercise testing as a diagnostic entity in mitochondrial myopathies
Mitochondrion
Respiratory chain enzyme analysis in muscle and liver
Mitochondrion
A homoplasmic mitochondrial transfer ribonucleic acid mutation as a cause of maternally inherited hypertrophic cardiomyopathy
J. Am. Coll Cardiol.
Pathology of skeletal muscle in mitochondrial disorders
Mitochondrion
Optical imaging techniques (histochemical, immunohistochemical, and in situ hybridization staining methods) to visualize mitochondria
Methods Cell Biol.
Focal cytochrome c oxidase deficiency in various neuromuscular diseases
J. Neurol. Sci.
Mitochondrial encephalomyopathies in childhood. I. Biochemical and morphologic investigations
J. Pediatr.
Biochemical and molecular diagnosis of mitochondrial respiratory chain disorders
Biochim. Biophys. Acta
An evaluation of the measurement of the activities of complexes I–IV in the respiratory chain of human skeletal muscle mitochondria
Biochem. Med. Metab. Biol.
Reference charts for respiratory chain activities in human tissues
Clin. Chim. Acta
Endomyocardial biopsies for early detection of mitochondrial disorders in hypertrophic cardiomyopathies
J. Pediatr.
Multiple defects of the mitochondrial respiratory chain in a mitochondrial encephalopathy (MERRF): a clinical, biochemical and molecular study
J. Neurol. Sci.
Evaluation of mitochondrial respiratory function in small biopsies of liver
Anal. Biochem.
Activities of mitochondrial oxidative phosphorylation enzymes in cultured amniocytes
Clin. Chim. Acta
In vivo control of respiration by cytochrome c oxidase in human cells
Free Radic. Biol. Med.
Oxidative phosphorylation analysis: assessing the integrated functional activity of human skeletal muscle mitochondria–case studies
Mitochondrion
A case of mitochondrial encephalomyopathy associated with a muscle coenzyme Q10 deficiency
J. Neurol. Sci.
Quinone-responsive multiple respiratory-chain dysfunction due to widespread coenzyme Q10 deficiency
Lancet
Impaired mitochondrial pyruvate importation in a patient and a fetus at risk
Mol. Genet. Metab.
Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation
Am. J. Hum. Genet.
Coenzyme Q(10) – Its role as a prooxidant in the formation of superoxide anion/hydrogen peroxide and the regulation of the metabolome
Mitochondrion
Infantile and pediatric quinone deficiency diseases
Mitochondrion
A mutation in para-hydroxybenzoate-polyprenyl transferase (COQ2) causes primary coenzyme Q10 deficiency
Am. J. Hum. Genet.
The evidence basis for coenzyme Q therapy in oxidative phosphorylation disease
Mitochondrion
Metabolism and function of coenzyme
Q. Biochim. Biophys. Acta
Age-related changes in plasma coenzyme Q10 concentrations and redox state in apparently healthy children and adults
Clin. Chim. Acta
Simultaneous determination of ubiquinol and ubiquinone in skeletal muscle of pediatric patients
Anal. Biochem.
Mitochondrial disease: a practical approach for primary care physicians
Pediatrics
Diagnostic criteria for respiratory chain disorders in adults and children
Neurology
Mitochondrial disorders: a proposal for consensus diagnostic criteria in infants and children
Neurology
Diagnosis of mitochondrial disorders: clinical and biochemical approach
J. Inherit. Metab. Dis.
Diagnostic accuracy of blood lactate-to-pyruvate molar ratio in the differential diagnosis of congenital lactic acidosis
Clin. Chem.
Leigh syndrome associated with a mutation in the NDUFS7 (PSST) nuclear encoded subunit of complex I
Ann. Neurol.
Thiamin and the brain
Annu. Rev. Nutr.
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