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Inherited Mitochondrial Diseases

Mitochondria are specialized compartments in all cells except red blood cells, which generate ninety percent of the energy the body uses.

They malfunction when mitochondria contain defective DNA and or defective proteins. The extent of DNA damage or defective protein level can vary between organs and the resulting symptoms or disease may be more noticeable in one organ or may involve multiple organs. Both mitochondrial and nuclear gene defects can cause inherited mitochondrial diseases and acquired mitochondrial DNA damage also causes mitochondrial degenerative diseases. In contrast damage to nuclear DNA is very efficiently repaired. These inherited diseases usually have their onset in childhood whereas acquired mitochondrial DNA diseases are mostly adult and elderly associated. Because of the key role of mitochondria in energy production mitochondrial diseases cause most damage to brain, endocrine, heart, kidney, liver, lungs and skeletal muscle.

Inherited mitochondrial diseases have an incidence of about one in three to four thousand individuals. They include more than fifty myopathies, neuropathies and metabolic diseases. The expression of disease varies by age and clinical severity varies in individual patients. Nuclear DNA damage can result in autosomal recessive diseases in which one quarter of offspring are affected or autosomal dominant transmitted diseases in which half of the offspring are affected. With mitochondrial DNA damage all offspring of the affected mother have the traits, though the symptoms and time of onset vary for each child. Besides maternally inherited and sporadic mitochondrial DNA mutations, there are also mendelian-inherited errors which damage mitochondrial DNA. These latter may cause either depletion of mitochondrial DNA by occurrence of deletions or quantitative depletion by affecting mitochondrial DNA replication.

Energy is produced and stored in a compound called adenosine triphosphate (ATP) by the oxidation of foodstuffs in the complex folded inner membrane of the mitochondria. Every muscle cell is filled with mitochondria, combining sugars or fats with oxygen to yield water and ATP. Mitochondria vary in the rates by which they produce energy and which foodstuffs they will use as substrate to produce energy in different organs. In liver cellls for example the role of energy production is lesser than in muscle cells. Depending upon the fraction of total mitochondria that are damaged, a mitochondrial disease can shut down some or all the mitochondria, cutting off this essential energy supply. Nerve cells in the brain and muscles require a great deal of energy, and thus appear to be particularly damaged when mitochondrial dysfunction occurs.

They are as many as several hundred to a few thousand mitochondria in each cell. Mitochondria contain multiple copies of loosely circular DNA and about three thousand proteins. Mitochondrial DNA is inherited almost exclusively via the maternal line. Mitochondrial DNA contains thirty-seven genes and only codes for thirteen proteins whereas the remainder of some three thousand proteins in mitochondria are coded for by nuclear genes. Proteins in the energy production line, referred to as the electron transport chain, include the thirteen mitchondrial gene derived proteins and also nuclear gene derived proteins. However most of the nuclear derived proteins are involved in other functions of mitochondria aside from energy production, such as calcium storage and regulation of apoptosis (programmed cell death), and their expression is specific to the particular cell type of the tissue they belong to. Unlike nuclear DNA, mitochondrial DNA has very limited repair abilities and fewer mechanisms to shield mitochondria from free radical damage.

About one in four thousand children will develop mitochondrial disease by the age of ten years. Mitochondrial diseases most frequently affect brain, muscles, heart, liver, nerves, eyes, ears, and kidneys. One or multiple organs may be affected.

Symptoms can range from extremely mild to severe, they can involve one or more body systems, and emerge at various ages. Most patients' symptoms fluctuate over the course of their illness - patients at some times experience no or few symptoms, and at other times have many and / or severe symptoms. Even family members with the same disorder can experience different symptoms. Symptoms associated with mitochondrial diseases occur affecting various organs: blindness, deafness, dementia, diabetic symptoms, droopy eyelids, heart failure or rhythm disturbances, limited mobility of the eyes, movement disorders, muscle weakness or exercise intolerance, seizures, stroke-like episodes and vomiting.

Mitochondrial disease in childhood can present as disease involving several organs simultaneously or several organ systems affected in sequence.

Common infections can be problematic. Some of the more common mitochondrial myopathies include Kearns-Sayre syndrome, Leigh’s disease, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes and myoclonus epilepsy with ragged-red fibers.

Individuals carrying mild mitochondrial DNA base substitutions manifest late onset diseases like Parkinson’s and Alzheimer’s diseases and familial deafness, whereas persons with moderately deleterious base substitutions develop Type II diabetes, Leber’s Hereditary Optic Neuropathy, Myclonic Epilepsy and Ragged Red Fiber Disease (MERRF). Individuals with severely deleterious base substitutions develop pediatric onset myopathies, dystonias and Leigh’s syndrome. Aging and common degenerative diseases are associated with energetic decline caused by oxidative phosphorylation (OXPHOS) gene defects and acquired somatic mutations. Mild mitochondrial deoxyribonucleic acid (DNA) rearrangements and duplications cause maternally inherited adult-onset diabetes and deafness. More severe rearrangements and deletions have been associated with adult-onset Chronic Progressive External Ophthalmoplegia (CPEO) and Kearns-Sayre Syndrome (KSS) and Pearson’s Marrow / Pancreas Syndrome. Primary oxidative phosphorylation (OXPHOS) diseases frequently have a delayed onset, organ selectivity and an episodic, progressive course. For example the A3243G mutation associated with mitochondrial encephalopathy, lactic acidemia, stroke-like episodes (MELAS) can cause a pure cardiomyopathy, pure diabetes and deafness, or pure external ophthalmoplegia.

Mitochondrial diseases are diagnosed by evaluating the patient's history and family history, performing a physical examination including a neurological examination, performing a metabolic examination that includes blood, urine, and optional cerebral spinal fluid tests and some other tests in individual patients. These tests may include: Magnetic resonance imaging (MRI) or scan (MRS) if neurological symptoms are present, retinal exam or electroretinogram if vision symptoms are present, electrocardiogram (EKG) or echocardiogram if heart disease symptoms are present, audiogram or brainstem auditory evoked potential (BAEP) if hearing symptoms are present, blood tests to detect thyroid dysfunction if thyroid problems are present, blood test to perform genetic DNA testing and skin or muscle biopsies.

Treatments for childhood mitochondrial diseases include B complex vitamins: thiamine (B 1), riboflavin (B 2), niacin (B 3), B 6, folate, B 12, biotin, pantothenic acid, Vitamin E, lipoic acid, selenium, and other antioxidants, Coenzyme Q10, L-carnitine and other supplements.

Mitochondrial diseases have provided tremendous research opportunity in recent decades because mitochondria are better understood component of cells than most others. These diseases involve medical needs from infants to elderly and findings in one area can open doors to understanding others.

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