JennyLynn
10-19-2006, 11:28 AM
Mitochondrial diseases result from failures of the mitochondria, specialized compartments present 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 to sustain life and support growth. When they 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 becoming more and more common.
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.
When To Suspect Mitochondrial Dysfunction
There is no one identifying feature of mitochondrial disease. Patients can have combinations of problems whose onset may occur from before birth to late adult life. Mitochondrial diseases should be considered in the differential diagnosis when there are these unexplained features, especially when these occur in combination:
Encephalopathy
Seizures
Developmental Delay or Regression (including early and late-onset dementia)
Myoclonus
Movement Disorders (dystonia, dyskinesias, chorea, etc.)
Complicated Migraine
Stroke
Neuropathy
Cardiac Conduction Defects or Cardiomyopathy
Hearing Deficits
Short Stature
Disorders of Extraoccular muscles
ptosis
acquired strabismus
ophthalmoplegia
Diabetes
Renal tubular disease
Visual Loss
retinitis pigmentosa
optic atrophy
Lactic acidosis (may be mild)Problems Associated with Mitochondrial Cytopathies:
Organ SystemPossible Problems
Brain-Developmental delays, mental retardation, dementia, seizures, neuro-psychiatric disturbances, atypical cerebral palsy, migraines, strokes.
Nerves-Weakness (which may be intermittent), neuropathic pain, absent reflexes, gastrointestinal problem (gastroesophogeal reflux, delayed gastric emptying, constipation, pseudo-obstruction), fainting, absent or excessive sweating resulting in temperature regulation problems.
MuscleWeakness, hypotonia, cramping, muscle pain.KidneysProximal renal tubular wasting resulting in loss of protein, magnesium, phosphorous, calcium and other electrolytes.
HearCardiac conduction defects (heart blocks), cardiomyopathy.
Liver-Hypoglycemia (low blood sugar), liver failure.
Eyes-Visual loss and blindness.
Ears-Hearing loss and deafness.
Pancreas-Diabetes and exocrine pancreatic failure (inability to make digestive enzymes).
Systemic-Failure to gain weight, short statue, fatigue, respiratory problems including intermittent air hunger.
The Genetics of Mitochondrial Disease
Mitochondria are very complex organelles located in virtually all cells of the body. A large degree of the complexity is due to the fact that among the over 1000 proteins located in the mitochondria, 13 are encoded by the mitochondrial DNA (mtDNA), while the remainder are nuclear-encoded (on the chromosomes) and imported into mitochondria. Before launching into the inheritance of mitochondrial disease, I will define what this author defines as "mitochondrial disease". Herein, mitochondrial disease refers to any illness resulting from deficiency of any mitochondria-located protein which is involved in energy metabolism. Thus, deficiencies of the respiratory (electron transport) chain, either resulting from deficiency in one or more mitochondrial or nuclear-encoded proteins, are mitochondrial disorders. Also, by this definition, disorders of fatty acid (beta) oxidation, Krebs cycle and pyruvate dehydrogenase complex deficiency are mitochondrial disorders. Although the proteins involved are nuclear-encoded, they are located in the mitochondria and are involved in energy metabolism. Although genetically dissimilar, all of these disorders share clinical similarities in that they result in an energy deficient state.
Unfortunately, the multiple diseases classified as mitochondrial disorders are inherited in different manners. In fact, nearly every inheritance "model" known has been demonstrated to occur in mitochondrial disease. However, most mitochondrial disorders known to date are inherited in either an autosomal recessive or maternal manner. The model of inheritance is important in that it can be helpful in answering the following questions:
1. Are other family members, either existing or not yet born, at risk for developing mitochondrial disease?
2. What is the risk (percentage)?
3. When will other affected relatives become ill?
4. Will other affected relatives be as sick as my child/myself? Possibly even sicker?
5. What kinds of problems/diseases might other affected relatives suffer from?
As you will see, not all of these questions can be answered at the present time in all families where someone suffers from mitochondrial disease. The first step is to determine the inheritance model in your family. This can be done in two basic manners:
1. Based on a confirmed diagnosis: For example, if the individual caries the "MELAS" A3243G mtDNA mutation, your doctor can be sure that the inheritance model in your family is maternal. This is because this mtDNA mutation is maternally inherited, whether or not the mother shows any symptoms. MCAD and SURF1 deficiencies are always autosomal recessive in inheritance.
2. Based on the pedigree: Unfortunately, most of the time the exact defect cannot be found. However, in many cases we can give an educated guess of the inheritance model upon a careful look at the family history (pedigree). However, this only works if there are other family members affected with disease which likely is due to energy deficiency.
As you read through the inheritance models below, understand that all inheritance models involve nuclear genes/nuclear-encoded proteins except one. That exception is that maternal inheritance involves mitochondrial (mtDNA) genes/mitochondrial-encoded proteins. Although long and complex, the information presented here is actually just the basics, and important exceptions exist. This information should not be considered to be an alternative to individualized genetic counseling with a knowledgeable professional.
Treatment - At this time, there are no cures for these disorders.
Benefits of Treatment and Effectiveness of Therapies Vary
treatment may be beneficial and noted immediately in some disorders
benefit of treatment may take a few months to notice
benefit of treatment may never be noticed, but the treatment may be effective in delaying or stopping the progression of the disease
some patients may not benefit from therapy
Except where noted, the above excerpts were taken, with permission, from Mitochondrial Cytopathies: A Primer (http://www.umdf.org/MITOCYTO.PDF) written by Dr. Bruce Cohen, MD
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.
When To Suspect Mitochondrial Dysfunction
There is no one identifying feature of mitochondrial disease. Patients can have combinations of problems whose onset may occur from before birth to late adult life. Mitochondrial diseases should be considered in the differential diagnosis when there are these unexplained features, especially when these occur in combination:
Encephalopathy
Seizures
Developmental Delay or Regression (including early and late-onset dementia)
Myoclonus
Movement Disorders (dystonia, dyskinesias, chorea, etc.)
Complicated Migraine
Stroke
Neuropathy
Cardiac Conduction Defects or Cardiomyopathy
Hearing Deficits
Short Stature
Disorders of Extraoccular muscles
ptosis
acquired strabismus
ophthalmoplegia
Diabetes
Renal tubular disease
Visual Loss
retinitis pigmentosa
optic atrophy
Lactic acidosis (may be mild)Problems Associated with Mitochondrial Cytopathies:
Organ SystemPossible Problems
Brain-Developmental delays, mental retardation, dementia, seizures, neuro-psychiatric disturbances, atypical cerebral palsy, migraines, strokes.
Nerves-Weakness (which may be intermittent), neuropathic pain, absent reflexes, gastrointestinal problem (gastroesophogeal reflux, delayed gastric emptying, constipation, pseudo-obstruction), fainting, absent or excessive sweating resulting in temperature regulation problems.
MuscleWeakness, hypotonia, cramping, muscle pain.KidneysProximal renal tubular wasting resulting in loss of protein, magnesium, phosphorous, calcium and other electrolytes.
HearCardiac conduction defects (heart blocks), cardiomyopathy.
Liver-Hypoglycemia (low blood sugar), liver failure.
Eyes-Visual loss and blindness.
Ears-Hearing loss and deafness.
Pancreas-Diabetes and exocrine pancreatic failure (inability to make digestive enzymes).
Systemic-Failure to gain weight, short statue, fatigue, respiratory problems including intermittent air hunger.
The Genetics of Mitochondrial Disease
Mitochondria are very complex organelles located in virtually all cells of the body. A large degree of the complexity is due to the fact that among the over 1000 proteins located in the mitochondria, 13 are encoded by the mitochondrial DNA (mtDNA), while the remainder are nuclear-encoded (on the chromosomes) and imported into mitochondria. Before launching into the inheritance of mitochondrial disease, I will define what this author defines as "mitochondrial disease". Herein, mitochondrial disease refers to any illness resulting from deficiency of any mitochondria-located protein which is involved in energy metabolism. Thus, deficiencies of the respiratory (electron transport) chain, either resulting from deficiency in one or more mitochondrial or nuclear-encoded proteins, are mitochondrial disorders. Also, by this definition, disorders of fatty acid (beta) oxidation, Krebs cycle and pyruvate dehydrogenase complex deficiency are mitochondrial disorders. Although the proteins involved are nuclear-encoded, they are located in the mitochondria and are involved in energy metabolism. Although genetically dissimilar, all of these disorders share clinical similarities in that they result in an energy deficient state.
Unfortunately, the multiple diseases classified as mitochondrial disorders are inherited in different manners. In fact, nearly every inheritance "model" known has been demonstrated to occur in mitochondrial disease. However, most mitochondrial disorders known to date are inherited in either an autosomal recessive or maternal manner. The model of inheritance is important in that it can be helpful in answering the following questions:
1. Are other family members, either existing or not yet born, at risk for developing mitochondrial disease?
2. What is the risk (percentage)?
3. When will other affected relatives become ill?
4. Will other affected relatives be as sick as my child/myself? Possibly even sicker?
5. What kinds of problems/diseases might other affected relatives suffer from?
As you will see, not all of these questions can be answered at the present time in all families where someone suffers from mitochondrial disease. The first step is to determine the inheritance model in your family. This can be done in two basic manners:
1. Based on a confirmed diagnosis: For example, if the individual caries the "MELAS" A3243G mtDNA mutation, your doctor can be sure that the inheritance model in your family is maternal. This is because this mtDNA mutation is maternally inherited, whether or not the mother shows any symptoms. MCAD and SURF1 deficiencies are always autosomal recessive in inheritance.
2. Based on the pedigree: Unfortunately, most of the time the exact defect cannot be found. However, in many cases we can give an educated guess of the inheritance model upon a careful look at the family history (pedigree). However, this only works if there are other family members affected with disease which likely is due to energy deficiency.
As you read through the inheritance models below, understand that all inheritance models involve nuclear genes/nuclear-encoded proteins except one. That exception is that maternal inheritance involves mitochondrial (mtDNA) genes/mitochondrial-encoded proteins. Although long and complex, the information presented here is actually just the basics, and important exceptions exist. This information should not be considered to be an alternative to individualized genetic counseling with a knowledgeable professional.
Treatment - At this time, there are no cures for these disorders.
Benefits of Treatment and Effectiveness of Therapies Vary
treatment may be beneficial and noted immediately in some disorders
benefit of treatment may take a few months to notice
benefit of treatment may never be noticed, but the treatment may be effective in delaying or stopping the progression of the disease
some patients may not benefit from therapy
Except where noted, the above excerpts were taken, with permission, from Mitochondrial Cytopathies: A Primer (http://www.umdf.org/MITOCYTO.PDF) written by Dr. Bruce Cohen, MD