MITOCHONDRIAL DISEASE

Mitochondrial diseases are caused by defects in the processes of the mitochondria. Mitochondria are organelles, or specialized compartments in every cell of the body except red blood cells. Mitochondria are responsible for creating more than 90% of the energy needed by the body. When mitochondria fail, less and less energy is generated within the cell. Cell injury and even cell death follow. If this process is repeated throughout the body, whole systems begin to fail, and the life of the person in whom this is happening is severely compromised. The disease primarily affects children, but adult onset is not uncommon.

Diseases of the mitochondria appear to cause the most damage to cells of the brain, heart, liver, skeletal muscles, kidney and the endocrine and respiratory systems.

Depending on which cells are affected, symptoms may include loss of motor control, muscle weakness and pain, gastro-intestinal disorders and swallowing difficulties, poor growth, cardiac disease, liver disease, diabetes, respiratory complications, seizures, visual/hearing problems, lactic acidosis, developmental delays and susceptibility to infection. There are over 40 known types of mitochondrial disease. The relationship between clinical findings and the genetic basis of these diseases is not entirely clear at this point in time.

Scientists believe that the aging process itself may be due to a lifetime of damage to the mitochondria. Research also suggests that genetic defects in the mitochondria may be linked to many chronic diseases associated with age-related degenerative diseases such as cancer, Alzheimer's, Parkinson's, and heart disease.
The incidence of diseases of aging outnumbers the incidence of mitochondrial diseases in children by about 5,000 to 1. From a scientific point of view, studying mitochondrial disease in children generally offers more clarity than the study of disease in adults, since adults have had a lifetime of exposure to environmental agents and other factors.

Biochemical Detail: The mitochondrial respiratory chain, which is capable of transferring electrons from reduced pyridine and flavin nucleotides to oxygen, is a highly organized system located in the inner mitochondrial membrane. This membrane can be treated with detergents to release 5 complexes which together make up the respiratory chain and phosphorylating systems: complex I (NADH-coenzyme Q reductase); complex II (succinate coenzyme Q reductase); complex III, (coenzyme Q H2-cytochrome c reductase); complex IV (cytochrome c oxidase); and complex V (ATP synthetase). Each of these complexes consists of multiple polypeptides and some of the polypeptides, except for those in complex II, are encoded by the mitochondrial genome. Complex I, for example, comprises 25 polypeptide subunits of which 7 are encoded by mitochondrial DNA. Complex II has 4 or 5 polypeptides, all encoded by the nuclear genome. Complex III has 9 or 10 complexes, 1 of which is encoded by the mitochondrial chromosome. Complex IV has 13 subunits, 3 of which are mitochondrially coded. Complex V has 12 to 14 components, of which 2 are encoded by the mitochondrial genome

LEIGH'S SYNDROME:

Symptoms
The symptoms found in a study of LS patients were as follows:

Developmental Delay, 100% YES
Lactate raised, 91% NO
Hypotonia, 86%
CT/MRI typical (for Leigh’s), 83% MOST RECENT CT/MRI NORMAL
Respiratory disturbance, 71% YES
Reflexes increased, 66% NO
Weakness, 57% YES
Spasticity, 54% OCCAISIONAL
Bulbar problems, 49%
Failure to thrive, 49% YES
Nystagmus, 46%
Poor feeding, 46%
Seizures, 40% YES: MYOCLONIC, ABSENCE
Ataxia, 37%
Ophthalmoplegia/squint, 34% NO
Optic atrophy, 34% NO
Unexplained vomiting, 34% UNDETERMINED
Involuntary movements, 29% YES, MYOCLONIS
Dystonia, 20%
Reflexes decreased, 17% NO
Ptosis, 17%
CT/MRI normal, 12% YES
Cranial nerve palsies, 9% NO
Peripheral neuropathy, 6%
Cardiac problems, 6% NONE TO DATE
Lactate normal, 3% NORMAL

Causes: LS was confirmed in 35 patients and specific biochemical or DNA defects were identified in 80% of these patients. LS was suspected in the remaining 32 patients and specific biochemical or DNA defects were identified in 41% of them.

Specific point mutations in the mitochondrial DNA were found in 11 of the cases at positions 8993 (T to G [NARP] and T to C) and 8344 (A to G). One case had a large mitochondrial DNA deletion (4-kb). Enzyme defects were found in 29 of the patients: 13 in complex I of the respiratory chain; 9 in complex IV (COX) of the respiratory chain; and 7 in the pyruvate dehydrogenase complex.

Inheritance: Less than half of the patients were thought to have an autosomal type of inheritance. Mitochondrial DNA point mutations (11 cases) and deletions (1 case) are maternally inherited or occur randomly. X-linked inheritance was found in 6 of the cases (PDHC E1alpha). The enzyme defects were thought to be divided among maternal and autosomal recessive.

Gender specificity: They found male patients outnumbered females, three to two. (This has also been observed in other studies.) They attribute part of this difference to the X-linked nature of some cases, but note that this is also true for non-X-linked cases.

Prognosis: The article includes a chart with survival plotted against age (through 21 years). For Leigh’s patients, it shows a 50% survival rate to 3 years of age, decreasing to less than 20% by mid-teens. The survival rate for Leigh’s-like patients never falls below 60%.

Other Observations: The researchers were surprised at the high numbers of complex I related cases (more than one third of those with enzyme defects). They attribute this to improved techniques used to analyze this complex. They recommend testing for complex defects I and mitochondrial DNA mutations in cases older than 3 years.

They found that the intensity of symptoms appears more dependent upon the area of brain involvement than a specific genetic mutation.

Complex II Deficiency

Long Name: Succinate dehydrogenase deficiency.
Alternative Name: Succinate CoQ Reductase Deficiency

Symptoms: Encephalomyopathy and various manifestations, including failure to thrive, developmental delay, hyoptonia, lethargy, respiratory failure, ataxia, myoclonus. Lactic acidosis common. May cause Leigh Syndrome.

Cause: Probably autosomal recessive.

CLINICAL SYNOPSIS
Neuro :
Progressive encephalomyopathy
Dementia
Myoclonic seizures

Growth :
Short stature

Lab :
Deficient muscle mitochondrial complex II, or succinate coenzyme Q reductase
Normal succinate dehydrogenase activity
Normal NADH-cytochrome c reductase and cytochrome oxidase

INHERITANCE::
Autosomal recessive
Complex II has 4 or 5 polypeptides, all coded by the nuclear genome