Mitochondrial Disorders Overview, Blaylock on Mitochondria and Vaccines

GeneReviews

Initial posting: June 08, 2000.
Latest version: February 21, 2006.

Mitochondrial Disorders Overview
[Mitochondrial Encephalomyopathies, Mitochondrial Myopathies, Oxidative Phosphorylation Disorders, Respiratory Chain Disorders]
Patrick F Chinnery, MBBS, PhD, MRCP
Department of Neurology
University of Newcastle upon Tyne Medical School
Newcastle upon Tyne
p.f.chinnery@newcastle.ac.uk


View this article on the GeneTests Web site.

Summary

Disease 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 mutations of nuclear or mitochondrial DNA (mtDNA). Some mitochondrial disorders only affect a single organ (such as the eye in Leber hereditary optic neuropathy [LHON]), but many involve multiple organ systems and often present with prominent neurologic and myopathic features. Mitochondrial disorders may present at any age. In general terms, nuclear DNA mutations present in childhood and mtDNA mutations (primary or secondary to a nuclear DNA abnormality) present in late childhood or adult life. Many affected individuals 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. Common clinical features of mitochondrial disease include ptosis, external ophthalmoplegia, proximal myopathy and exercise intolerance, cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy, and diabetes mellitus. The central nervous system findings are often 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 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 muscle biopsy for histologic or histochemical evidence of mitochondrial disease, and molecular genetic testing for a mtDNA mutation.

Management. The management of mitochondrial disease is largely supportive. Management issues may include early diagnosis and treatment of diabetes mellitus, cardiac pacing, ptosis correction, and intraocular lens replacement for cataracts. Individuals with complex I and/or complex II deficiency may benefit from oral administration of riboflavin.

Genetic counseling. Mitochondrial disorders may be caused by defects of nuclear DNA or mtDNA. Nuclear gene defects may be inherited in an autosomal recessive manner or an 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 no significant risk to other family members. Mitochondrial DNA point mutations and duplications may be transmitted down the maternal line. The father of a proband is not at risk of having the disease-causing mtDNA mutation, but the mother of a proband (usually) has the mitochondrial mutation and may or may not have symptoms. A male does not transmit the mtDNA mutation to his offspring. A female harboring a heteroplasmic mtDNA point mutation may transmit a variable amount of mutant 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.

Definition

Mitochondrial diseases are a clinically heterogeneous group of disorders that arise as a result of dysfunction of the mitochondrial respiratory chain. The mitochondrial respiratory chain is the essential final common pathway for aerobic metabolism, and tissues and organs that are highly dependent upon aerobic metabolism are preferentially involved in mitochondrial disorders [Wallace 1999].

Over 70 different polypeptides interact on the inner mitochondrial membrane to form the respiratory chain. The vast majority of subunits are synthesized within the cytosol from nuclear gene transcripts, but 13 essential subunits are encoded by the 16.5-kb mitochondrial DNA (mtDNA) [Larsson & Clayton 1995]. Figure 1 illustrates the structure of the human mitochondrial genome. The 1.1 kb D-loop (noncoding region) is involved in the regulation of transcription and replication of the molecule and is the only region not directly involved in the synthesis of respiratory chain polypeptides. ND1-ND6 and ND4L encode seven subunits of complex I. Cyt b is the only mtDNA-encoded complex III subunit. COX I to III encode for three of the complex IV (cytochrome c oxidase, or COX) subunits, and the ATPase 6 and ATPase 8 genes encode for two subunits of complex V. Two ribosomal RNA genes (12S and 16S rRNA) and 22 transfer RNA genes are interspaced between the protein-encoding genes. These provide the necessary RNA components for intra-mitochondrial protein synthesis. OH and OL are the origins of heavy- and light-strand mtDNA replication.

Each human cell contains thousands of copies of mtDNA which at birth are usually all identical (homoplasmy). By contrast, individuals with mitochondrial disorders resulting from mtDNA mutations may harbor a mixture of mutant and wild-type mtDNA within each cell (heteroplasmy) (see, e.g., Holt et al 1988, Holt et al 1990). Single-cell studies and cybrid-cell studies have shown that the proportion of mutant mtDNA must exceed a critical threshold level before a cell expresses a biochemical abnormality of the mitochondrial respiratory chain (the threshold effect) [Schon et al 1997]. The percentage level of mutant mtDNA may vary among individuals within the same family, and also among organs and tissues within the same individual [Macmillan et al 1993]. This is one explanation for the varied clinical phenotype seen in individuals with pathogenic mtDNA disorders. For example, in individuals harboring the 8993T↓G mutation, higher percentage levels of mutated mtDNA are seen in individuals presenting with Leigh syndrome than in those presenting with neurogenic weakness with ataxia and retinitis pigmentosa (NARP) [Uziel et al 1997, White et al 1999].

Clinical Manifestations

Some mitochondrial disorders only affect a single organ, such as the eye in Leber hereditary optic neuropathy and the ear in nonsyndromic hearing loss with or without aminoglycoside sensitivity (see Mitochondrial Hearing Loss and Deafness); but many involve multiple organ systems and often present with prominent neurologic and myopathic features.

Mitochondrial disorders may present at any age [Leonard & Schapira 2000a, Leonard & Schapira 2000b]. In general terms, nuclear DNA abnormalities present in childhood and mtDNA abnormalities (primary or secondary to a nuclear DNA abnormality) present in late childhood or adult life.

Many individuals display a cluster of clinical features that fall into a discrete clinical syndrome (Table 2) [DiMauro & Schon 2001, Munnich & Rustin 2001], such as the Kearns-Sayre syndrome (KSS), chronic progressive external ophthalmoplegia (CPEO) [Moraes et al 1989], mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) [Hirano et al 1992], myoclonic epilepsy with ragged-red fibers (MERRF) [Hammans et al 1993], neurogenic weakness with ataxia and retinitis pigmentosa (NARP) [Holt et al 1990], or Leigh syndrome (LS) [Ciafaloni et al 1993]. However, there is often considerable clinical variability and many affected individuals do not fit neatly into one particular category.

Common clinical features of mitochondrial disease include ptosis, external ophthalmoplegia, proximal myopathy and exercise intolerance, cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy, and diabetes mellitus. Diabetes mellitus and deafness is also a well-recognized clinical phenotype [van den Ouweland et al 1992].

The central nervous system findings are often fluctuating encephalopathy, seizures, dementia, migraine, stroke-like episodes, ataxia, and spasticity. Chorea and dementia may also be prominent features [Nelson et al 1995].

A high incidence of mid- and late pregnancy loss is also a common feature which often goes unrecognized (see, e.g., Tay et al 2004).


Table 1. Clinical Syndromes of Mitochrondrial Diseases

Disorder Primary Features Additional Features

Chronic progressive external ophthalmoplegia (CPEO) External ophthalmoplegia
Bilateral ptosis
Mild proximal myopathy

Kearns-Sayre syndrome (KSS) PEO onset before age 20 years
Pigmentary retinopathy
One of the following: CSF protein greater than 1g/L, cerebellar ataxia, heart block
Bilateral deafness
Myopathy
Dysphagia
Diabetes mellitus
Hypoparathyroidism
Dementia

Pearson syndrome Sideroblastic anemia of childhood
Pancytopenia
Exocrine pancreatic failure
Renal tubular defects

Infantile myopathy and lactic acidosis (fatal and non-fatal forms) Hypotonia in the first year of life
Feeding and respiratory difficulties
Fatal form may be associated with a cardiomyopathy and/or the Toni-Fanconi-Debre syndrome

Leigh syndrome (LS) Subacute relapsing encephalopathy
Cerebellar and brain-stem signs
Infantile onset
Basal ganglia lucencies
Maternal history of neurologic disease or Leigh syndrome

Neurogenic weakness with ataxia and retinitis pigmentosa ( NARP ) Late-childhood or adult-onset peripheral neuropathy
Ataxia
Pigmentary retinopathy
Basal ganglia lucencies
Abnormal electroretinogram
Sensorimotor neuropathy

Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes ( MELAS ) Stroke-like episodes before age 40 years
Seizures and/or dementia
Ragged-red fibers and/or lactic acidosis
Diabetes mellitus
Cardiomyopathy (initially hypertrophic; later dilated)
Bilateral deafness
Pigmentary retinopathy
Cerebellar ataxia

Myoclonic epilepsy with ragged-red fibers ( MERRF ) Myoclonus
Seizures
Cerebellar ataxia
Myopathy
Dementia
Optic atrophy
Bilateral deafness
Peripheral neuropathy
Spasticity
Multiple lipomata

Leber hereditary optic neuropathy (LHON) Subacute painless bilateral visual failure
Males:females ~4:1
Median age of onset 24 years
Dystonia
Cardiac pre-excitation syndromes


Establishing the Diagnosis of a Mitochondrial Disorder

Mitochondrial dysfunction should be considered in the differential diagnosis of any progressive multisystem disorder. The diagnosis is most challenging when only one symptom is present and easier when two or more seemingly unrelated symptoms are present, involving more than one organ system. The investigation can be relatively straightforward if a person has a recognizable phenotype and if it is possible to identify a known pathogenic mtDNA mutation. The difficulty arises when no mtDNA defect can be found or when the clinical abnormalities are complex and not easily matched to those of more common mitochondrial disorders. In summary:

A full mitochondrial evaluation is often warranted in children with a complex neurologic picture or a single neurologic symptom and other system involvement.
When the presentation is classic for a maternally inherited mitochondrial syndrome, such as MELAS, MERRF, or Leber hereditary optic neuropathy, appropriate mtDNA studies should be obtained first.
When the clinical picture is classic for a nuclear DNA-inherited syndrome and the gene or linkage is known [such as mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), autosomal PEO with multiple secondary deletions, or Alpers-Huttenlocher syndrome], the clinician should proceed with molecular genetic studies.
When the clinical picture is nonspecific but highly suggestive of a mitochondrial disorder, the clinician should start with measurement of plasma or CSF lactic acid concentration, ketone bodies, plasma acylcarnitines, and urinary organic acids. If these studies are abnormal, the clinician should proceed with muscle biopsy and assessment of the respiratory chain enzymes. Normal plasma or CSF lactic acid concentration does not exclude the presence of a mitochondrial disorder.
Clinical tests are used to support a diagnosis of mitochondrial disease [Chinnery & Turnbull 1997].

Neuroimaging. Indicated in individuals with suspected CNS disease. CT may show basal ganglia calcification and/or diffuse atrophy. MRI may show focal atrophy of the cortex or cerebellum, or high signal change on T2-weighted images, particularly in the occipital cortex [Scaglia et al 2005]. There may also be evidence of a generalized leukoencephalopathy [Barragan-Campos et al 2005]. Cerebellar atrophy is a prominent feature in pediatric cases [Scaglia et al 2005].
Neurophysiologic studies. Electroencephalography (EEG) is indicated in individuals with suspected encephalopathy or seizures. Encephalopathy may be associated with generalized slow wave activity on the EEG. Generalized or focal spike and wave discharges may be seen in individuals with seizures.
Peripheral neurophysiologic studies are indicated in individuals with limb weakness, sensory symptoms, or areflexia. Electromyography (EMG) is often normal but may show myopathic features. Nerve conduction velocity (NCV) may be normal, or may show a predominantly axonal sensorimotor polyneuropathy.
Magnetic resonance spectroscopy and exercise testing (with measurement of blood concentration of lactate) may be used to detect evidence of abnormal mitochondrial function in a non-invasive manner.
Glucose. An elevated concentration of fasting blood glucose may indicate diabetes mellitus.
Cardiac. Both electrocardiography and echocardiography may indicate cardiac involvement (cardiomyopathy or atrioventricular conduction defects).
Magnetic resonance spectroscopy and exercise testing may also be of use to detect an elevated lactate level in brain or muscle at rest, or a delay in the recovery of the ATP peak in muscle after exercise.
Lactate/pyruvate

Measurement of blood lactate concentration is indicated in individuals with features of a myopathy or CNS disease.
Fasting blood lactate concentrations above 3.0 mm/L support a diagnosis of mitochondrial disease.
Measurement of CSF lactate concentration is indicated in individuals with suspected CNS disease.
Fasting CSF lactate concentrations above 1.5 mm/L support a diagnosis of mitochondrial disease.
Muscle biopsy. More specific tests of mitochondrial disease include a muscle biopsy that is analyzed for histologic or histochemical evidence of mitochondrial disease. The muscle biopsy should be carried out either in a center with special expertise or in close collaboration with such a center. Respiratory chain complex studies are then usually carried out on skeletal muscle or skin fibroblasts [Thorburn et al 2004].

Differential Diagnosis

Lactic acidosis. It is important to exclude other causes of lactic acidosis when interpreting these values. For example, the concentration of lactate may be elevated in the blood and CSF of affected individuals following a seizure. CSF lactate concentration may be elevated following an ischemic stroke.

White matter abnormalities. See Moroni et al 2002, Barkhof & Scheltens 2002.

Disorders of mitochondrial dysfunction. Mitochondrial dysfunction is also seen in a number of different genetic disorders, including dominant optic atrophy (mutations in OPA1) [Alexander et al 2000], Friedreich ataxia (FRDA) [Rotig et al 1997], hereditary spastic paraplegia (SPG7) [Casari et al 1998], and Wilson disease (ATP7B) [Lutsenko & Cooper 1998], and also as part of the aging process. These are not strictly mitochondrial disorders; the term "mitochondrial disorder" usually refers to primary disorders of mitochondrial metabolism affecting oxidative phosphorylation.

Disorders of mtDNA maintenance. Alpers-Huttenlocher syndrome, characterized by hypotonia, seizures, liver failure and renal tubulopathy, is caused by mutations in POLG1. Inheritance is autosomal recessive.

Prevalence

Mitochondrial disorders are more common than was previously thought (Table 2). Based upon the available data, a conservative estimate for the prevalence of all mitochondrial diseases is 11.5/100,000 (~1/8500). Arpa et al (2003) estimated the prevalence as 5.7/100,000 over age 14 years in Spain.


Table 2. Epidemiology of Mitochondrial Disease

Study Population Mutation or Disease Disease Prevalence/100,000 (95% C.I.) 1

Northern England;
point prevalence (8/97),
population size = 2,122,290
[Chinnery et al 2000] All mtDNA deletions 1.33 2
(0.76-1.89)
All mtDNA point mutations 5.24 2
(4.12-6.37)
G11778A & G3460A (LHON) 3.29 2
(2.39-4.18)
A3243G 0.95 2
(0.47-1.43)
A8344G 0.25 2
(0.01-0.5)
All mtDNA mutations 6.57 3
(5.30-7.83)
Northern Finland;
adult point prevalence,
population size = 245,201
[Majamaa et al 1998] A3243G 5.71
(4.53-6.89)
Western Sweden;
children <16 m =" maternal" s =" sporadic" ad =" autosomal" ar =" autosomal" xlr =" X" b =" cytochrome">G(8344) mutation and the syndrome of myoclonic epilepsy with ragged red fibres (MERRF). Relationship of clinical phenotype to proportion of mutant mitochondrial DNA. Brain 116 (Pt. 1993. 3):617-32. (PubMed)

Harding AE, Holt IJ, Sweeney MG, Brockington M, Davis MB. Prenatal diagnosis of mitochondrial DNA8993 T----G disease. Am J Hum Genet. 1992. 50:629-33. (PubMed)

Hirano M, Ricci E, Koenigsberger MR, Defendini R, Pavlakis SG, DeVivo DC, DiMauro S, Rowland LP. Melas: an original case and clinical criteria for diagnosis. Neuromuscul Disord. 1992. 2:125-35. (PubMed)

Holt IJ, Harding AE, Morgan-Hughes JA. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature. 1988. 331:717-9. (PubMed)

Holt IJ, Harding AE, Petty RK, Morgan-Hughes JA. A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. Am J Hum Genet. 1990. 46:428-33. (PubMed)

Larsson NG and Clayton DA. Molecular genetic aspects of human mitochondrial disorders. Annu Rev Genet. 1995. 29:151-78. (PubMed)

Leonard JV and Schapira AVH. Mitochondrial respiratory chain disorders I: mitochondrial DNA defects. Lancet. 2000a. 355:299-304. (PubMed)

Leonard JV and Schapira AVH. Mitochondrial respiratory chain disorders II: neurodegenerative disorders and nuclear gene defects. Lancet. 2000b. 355:389-94. (PubMed)

Lutsenko S and Cooper MJ. Localization of the Wilson's disease protein product to mitochondria. Proc Natl Acad Sci U S A. 1998. 95:6004-9. (PubMed)

Macmillan C, Lach B, Shoubridge EA. Variable distribution of mutant mitochondrial DNAs (tRNA(Leu[3243])) in tissues of symptomatic relatives with MELAS: the role of mitotic segregation. Neurology. 1993. 43:1586-90. (PubMed)

Majamaa K, Moilanen JS, Uimonen S, Remes AM, Salmela PI, Karppa M, Majamaa-Voltti KA, Rusanen H, Sorri M, Peuhkurinen KJ, et al. Epidemiology of A3243G, the mutation for mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes: prevalence of the mutation in an adult population. Am J Hum Genet. 1998. 63:447-54. (PubMed)

Moraes CT, DiMauro S, Zeviani M, Lombes A, Shanske S, Miranda AF, Nakase H, Bonilla E, Werneck LC, Servidei S, et al. Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome. N Engl J Med. 1989. 320:1293-9. (PubMed)

Moroni I, Bugiani M, Bizzi A, Castelli G, Lamantea E, Uziel G. Cerebral white matter involvement in children with mitochondrial encephalopathies. Neuropediatrics. 2002. 33:79-85. (PubMed)

Munnich A and Rustin P. Clinical spectrum and diagnosis of mitochondrial disorders. Am J Med Genet. 2001. 106:4-17. (PubMed)

Nelson I, Hanna MG, Alsanjari N, Scaravilli F, Morgan-Hughes JA, Harding AE. A new mitochondrial DNA mutation associated with progressive dementia and chorea: a clinical, pathological, and molecular genetic study. Ann Neurol. 1995. 37:400-3. (PubMed)

Poulton J and Turnbull DM. 74th ENMC International workshop: mitochondrial diseases 19-20 November 1999, Naarden, the Netherlands. Neuromuscul Disord. 2000. 10:460-2. (PubMed)

Poulton J, Macaulay V, Marchington DR. Mitochondrial genetics '98 is the bottleneck cracked? Am J Hum Genet. 1998. 62:752-7. (PubMed)

Rotig A, de Lonlay P, Chretien D, Foury F, Koenig M, Sidi D, Munnich A, Rustin P. Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia. Nat Genet. 1997. 17:215-7. (PubMed)

Scaglia F, Wong LJ, Vladutiu GD, Hunter JV. Predominant cerebellar volume loss as a neuroradiologic feature of pediatric respiratory chain defects. AJNR Am J Neuroradiol. 2005. 26:1675-80. (PubMed)

Schon EA, Bonilla E, DiMauro S. Mitochondrial DNA mutations and pathogenesis. J Bioenerg Biomembr. 1997. 29:131-49. (PubMed)

Servidei S. Mitochondrial encephalomyopathies:gene mutation. Neuromuscul Disord. 2002. 12:524-9. (PubMed)

Servidei S. Mitochondrial encephalomyopathies: gene mutation. Neuromuscul Disord. 2004. 14:107-16. (PubMed)

Shoubridge EA. Cytochrome c oxidase deficiency. Am J Med Genet. 2001. 106:46-52. (PubMed)

Skladal D, Halliday J, Thorburn DR. Minimum birth prevalence of mitochondrial respiratory chain disorders in children. Brain. 2003. 126:1905-12. (PubMed)

Taivassalo T, Shoubridge EA, Chen J, Kennaway NG, DiMauro S, Arnold DL, Haller RG. Aerobic conditioning in patients with mitochondrial myopathies: physiological, biochemical, and genetic effects. Ann Neurol. 2001. 50:133-41. (PubMed)

Tay SK, Shanske S, Kaplan P, DiMauro S. Association of mutations in SCO2, a cytochrome c oxidase assembly gene, with early fetal lethality. Arch Neurol. 2004. 61:950-2. (PubMed)

Thorburn DR and Dahl HH. Mitochondrial disorders: genetics, counseling, prenatal diagnosis and reproductive options. Am J Med Genet. 2001. 106:102-14. (PubMed)

Thorburn DR, Sugiana C, Salemi R, Kirby DM, Worgan L, Ohtake A, Ryan MT. Biochemical and molecular diagnosis of mitochondrial respiratory chain disorders. Biochim Biophys Acta. 2004. 1659:121-8. (PubMed)

Uziel G, Moroni I, Lamantea E, Fratta GM, Ciceri E, Carrara F, Zeviani M. Mitochondrial disease associated with the T8993G mutation of the mitochondrial ATPase 6 gene: a clinical, biochemical, and molecular study in six families. J Neurol Neurosurg Psychiatry. 1997. 63:16-22. (PubMed)

van den Ouweland JM, Lemkes HH, Ruitenbeek W, Sandkuijl LA, de Vijlder MF, Struyvenberg PA, van de Kamp JJ, Maassen JA. Mutation in mitochondrial tRNA(Leu)(UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness. Nat Genet. 1992. 1:368-71. (PubMed)

Wallace DC. Mitochondrial diseases in man and mouse. Science. 1999. 283:1482-8. (PubMed)

White SL, Collins VR, Wolfe R, Cleary MA, Shanske S, DiMauro S, Dahl HH, Thorburn DR. Genetic counseling and prenatal diagnosis for the mitochondrial DNA mutations at nucleotide 8993. Am J Hum Genet. 1999. 65:474-82. (PubMed)

White SL, Collins VR, Wolfe R, Cleary MA, Shanske S, DiMauro S, Dahl HH, Thorburn DR. Genetic counseling and prenatal diagnosis for the mitochondrial DNA mutations at nucleotide 8993. Am J Hum Genet. 1999. 65:474-82. (PubMed)

White SL, Shanske S, McGill JJ, Mountain H, Geraghty MT, DiMauro S, Dahl HH, Thorburn DR. Mitochondrial DNA mutations at nucleotide 8993 show a lack of tissue- or age-related variation. J Inherit Metab Dis. 1999. 22:899-914. (PubMed)

Chapter Notes

Revision History


21 February 2006 (me) Comprehensive update posted to live Web site
18 December 2003 (me) Comprehensive update posted to live Web site
8 June 2000 (tk, pb) Overview posted to live Web site
20 April 2000 (eh) Original submission



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Blaylock on Mitochondria and Vaccines
Mitochondria and VaccinesFrom Russell L. Blaylock M.D.As the person who first proposed the microglial/excitotoxin hypothesis (JANA 2003;6(4): 21-35 and J. Amer Phys Surg 2004; 9(2): 46-51) I feel I should explain the connection between microglia/excitotoxicity and mitochondrail dysfunction. My hypothesis was confirmed two years later by Vargis, et al in which they demonstrated chronic levels of inflammatory cytokines and chemokines as well as microglia and astrocytic activation in the brains of 11 autistics from age 5 years to 44 years, even though they never mentioned excitotoxicity as a final mechanism. I wish to address the mitochondrial issue, which has become of major interest with the appearance of the Hannah Poling’s case. In my original hypothesis, later expanded in a number of other articles, I explained that when the systemic immune system is overactivated, the brain’s special immune system, consisting of microglia and astrocytes, also becomes activated. The microglia normally remain in a quiescent state called ramified microglia. Upon activation, they swell, assume special immune receptors in their membranes and move within the extracellular space. In this activated state they act as immune presenting cells and can secrete a number of inflammatory chemicals, such as IL-1, IL-2, IL-6, IL-12 and IL-18, TNF-alpha, chemokines, complement and two excitotoxins called glutamate and quniolinic acid. They also generate a number of powerful free radicals and lipid peroxidation molecules.A number of studies have shown that when you use powerful immune adjuvants, as used in vaccines (especially when combined), this inflammatory/excitotoxic reaction within the brain is maximized. With the first vaccine (or natural infection) the brain’s microglia are in a semi-activated stated called primed. If you re-vaccinate the animal or person within 1 to 2 months, these primed microglia overreact intensely, pouring out even higher levels of the excitotoxins, inflammatory cytokines and free radicals. Each subsequent set of vaccinations worsens this process.These inflammatory/excitotoxic secretions damage the developing brain, which is undergoing its most active development at the very time the child is receiving 24 vaccines. This vaccine schedule exposes the child to a priming HepB vaccine at birth, 6 vaccines at age 2 months, then 5 vaccines at age 4 months, 7 vaccines at 6 months and finally 8 antigens at age one year. Each successive multi-dose barrage of vaccines intensely activates the brain’s microglial system and the microglia activate the astrocytes, which also secretes, inflammatory cytokines, free radicals and excitotoxins. Experiments in which this pattern of immune stimulation is simulated using a vaccine adjuvant, demonstrate that it produces significant disruption of brain development. The greatest damage in these experiments is to the cerebellum and frontal lobes, which is also the primary sites of damage in autism. Further, food allergins also act as brain microglial activators, thereby worsening and prolonging the original immune/excitotoxic effect produced by the vaccines.So, how does mercury play into all this. Mercury in extremely small concentrations (nanomolar concentrations) can activate microglia, trigger excitotoxicity and induce significant mitochondrial dysfunction. Blocking the glutamate receptors (that trigger excitotoxicity) also blocks most of the neurotoxic effect of mercury at these concentrations. That is, most of lower-dose effects of mercury in the brain are secondary to excitotoxicity. The mitochondria produce most of the energy used by neurons and a number of studies have shown that suppressing mitochondrial function by itself is not enough to alter brain function, but it is enough to magnify excitotoxic damage. That is, it is the excitotoxicity that is disrupting brain function and development. A newer study has shown conclusively, that mitochondrial activation using a vaccine adjuvant not only suppresses mitochondrial function but that the damage cause by this mitochondrial suppression is actually produced by excitotoxicity. Blocking excitotoxicity completely blocks the microglial-induced neurotoxicity and mitochondrial damage cause by the vaccine. A great number of studies have shown that activating the systemic immune system repetitively worsens neurological disorders caused by other things and can initiate neurodegeneration itself, that is prolonged. The inflammatory cytokines interact with glutamate receptors to dramatically increase excitotoxic damage. We know that autistic children have elevated CSF and blood levels of glutamate, which confirms the presence of the excitotoxic process. Basically, what we see is a process triggered by sequential, massive vaccination that primes and then activates the brain microglial/astrocytic system, triggering the release of massive amounts of inflammatory cytokines, chemokines and excitotoxins. This suppresses the mitochondria and the resulting energy loss further worsening the excitotoxic damage. Because of continued immune activation systemically, both by food allergies and natural infections, the brain’s immune system remains in an active state, leading to suppression of brain pathway development and neural function. This is why the change in the vaccine policy beginning in the mid-1980s, triggered the epidemic of autism. The mercury just aggravated the process.I warned a number of people and published my warning, that removing the mercury from vaccines would not stop the high incidence of autism, because it was just part of the picture. We must also appreciate that there are a great number of sources of mercury besides vaccine-mainly environmental and from dental amalgam.For more information on this mechanism you can read my original articles on my website –www.russellblaylockmd.com. Also I have written more papers on my website under the heading -Information. All the information is free. I have several newer articles appearing in Medical Veritas and the Journal of Alternative Therapeutics in Health and Medicine. Russell L. Blaylock, M.D.
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Labels: Mitochondrial Disorder, Russell Blaylock, Vaccine Injury