Brief overview of mitochondrial disorders and dysfunction
By A. Minocha MD, author: Guide to Alternative Medicine and the Digestive System
- Multi-system disorders affecting in varying proportions the nervous system, heart, muscles, vision, hearing and kidneys etc.
- Symptoms may wax and wane.
- Manifest in a variety of ways and neurodevelopmental problems like mental or growth retardation and seizures occur only in some but not all cases. Likewise the severity of symptoms varies.
- Even family members with the same disorder can experience vastly different symptoms.
- Usually seen during childhood although they may in some cases manifest during adult life.
- Patients partially fulfilling criteria for mitochondrial disorders are frequently termed as mitochondrial dysfunction.
Are mothers to blame for mitochondrial disorders/dysfunction
- Contrary to popular misconception mitochondrial diseases are inherited not just from the mother; rather they represent complex inheritance patterns including mutations, most of which are not in the mitochondrial DNA.
- Disorders occurring as a results of mutations in mitochondrial DNA are of course derived from mother only.
- Mitochondrial disorders may also occur as a result of environmental factors like infections and toxins that may “poison” the mitochondrial functional processes.
Outcome and prognosis of mitochondrial disorders
- Not curable
- Therapy is aimed at control of symptoms and disabilities
Therapeutic options/strategies
- Avoiding trigger like stress etc.
- Medications
- Nutritional supplements tend to help in many cases.
Diagnosis of mitochondrial disorders/dysfunctiom
According to Dr. Rodenburg from the Nijmegen Center for Mitochondrial Disorders (NCMD), Department of Pediatrics, Department of Laboratory Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. as reported in the journal Journal of Inherit and Metabolic diseases, “The diagnostic examination of patients requires a multi-disciplinary clinical and laboratory evaluation in which the biochemical examination of the mitochondrial functional state often plays a central role. In most cases, a muscle biopsy provides the best opportunity to examine mitochondrial function".
Diagnostic strategies for mitochondrial disorders/dysfunction
- One should not oversimplify the diagnosis of a mitochondrial disorder. Broadly, the diagnostic criteria may be classified into Clinical, Biochemical and Genetic. Presence of more than two abnormal tests makes the diagnosis more likely.
- There is no single test to diagnose mitochondrial disease. There is dearth of less invasive, specific and sensitive diagnostic tools based on serum biomarkers.
- An experienced integrated approach is necessary for accurate diagnosis and relies on a combination of clinical observations, laboratory evaluation, brain imaging, and muscle biopsies
- Blood levels of lactate are frequently used as a screening tool. An abnormal test invariably calls for further investigation. , however, a normal test does not exclude the diagnosis.
- A battery of tests that can be performed include analysis of on blood, urine and spinal fluid to look for presence of mitochondrial dysfunction.
- For example, an abnormal genetic test on a blood sample may not be adequate for diagnosis of mitochondrial disorder and may require muscle biopsy for confirmation in many cases.
- A comprehensive portrait of mitochondrial energy-generating system can be obtained by tests performed on of muscle biopsy including evaluation of individual oxidative phosphorylation enzymes, mitochondrial respiration, substrate oxidation and rate of ATP synthesis.
Role of muscle biopsy for diagnosis
- Muscle tissue is subjected to comprehensive analysis including histology, genetic and enzyme testing.
- Although a muscle biopsy is frequently touted as the "gold standard" for diagnosis of mitochondrial disorders, it is fraught with its own shortcomings.
- The enzyme testing on a tissue sample is especially difficult and has not been standardized making interpretations subject to interpretation.
- Muscle biopsy makes results of research studies on mitochondrial disorders more trustworthy.
What is muscle biopsy
- Muscle biopsy is a simple, low risk surgical procedure involving skeletal muscle. The analysis on the on other hand tends to be complex and varies with laboratories.
- Muscle biopsy is usually performed under local anesthetic.
- All muscle biopsy are not the same.
- May be Open versus Needle Biopsy. The open biopsy involves use of sharp scissors/scalples. An open biopsy, a 2-to-3-inch incision is made and tissue is taken and sutures may be used to close the incision. In a needle biopsy, tissue is collected with a large bore needle.
- Typically two to three pieces are taken. One is analyzed as fresh specimen, while other is analyzed as fixed tissue. Still another piece is used for analysis of enzyme and genetic testing. Analysis may be undertaken on fresh or frozen samples.
Tests done on muscle biopsy
Tests performed on muscle biospy include but are not limited to:
- H&E stain for routine histology
- Nicotinamide adenine dinucleotide tetrazolium reductase (NADH) staining for assessment of NADH enzymes seen in mitochondria and endoplasmic reticulum.
- Staining for myofibers
- Modified Gomori trichrome stain
- Fat stains to assess for presence of fat in muscle
- Human leukocyte antigen class by immunohistochemistry
- The lab may also use electron microscopy to get very high magnification views of the cellular structure, which can confirm structural abnormalities.
- Enzyme testing may be undertaken on the ground up muscle tissue or from the mitochondria extracted from the muscle. Although controversial, analysis of fresh tissue sample may have advantages over frozen tissue analysis.
- Although mutations can be detected by blood sample, DNA analysis may be needed on a muscle sample to test for mitochondrial DNA mutations.
Contraindications of muscle biopsy
- High risk of intractable bleeding or presence of infection at the biopsy site.
Caution about muscle biopsy for mitochondrlal disorders/dysfunction
Undertaking a muscle biopsy and it’s comprehensive analysis should not be undertaken lightly.
- A diagnosis of mitochondrial disorder/dysfunction has limited impact on long-term outcome. The benefits and its limitations of muscle biopsy should also be weighed with the surgical risks although small.
- The cost associated with it which can easily be north of $10,000 should be a matter for serious consideration for most people.
- Because of limited impact on outcome, many physicians do not insist on muscle biopsy for a diagnosis.
- A muscle biopsy may not always be necessary in cases where diagnosis can be made based on identification of a genetic mutation associated with mitochondrial function along with clinical manifestations consistent with it.
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