Mitochondrial Impact of Disease
Mitochondrial diseases are a wide variety of diseases that directly affect the mitochondria. High school students will have had the sentence “Mitochondria is the powerhouse of the cell” drilled into their heads so often that it is already an Internet meme. Since the mitochondria affect so many things in the cell, mitochondrial diseases manifest in many different ways, and as such, mitochondrial disease life expectancy is hard to predict as a general term.
Having an illness that affect the mitochondrial does not mean that the child should have autism or brain diseases. It only implies that the body cells have reduced capacity to turn food and oxygen into energy. One can find this type of ailment at any part of the body such as ears, eyes, muscle, kidney or brain. However, people with the ailment may be asymptomatic until they reach preschool years.[toc]
Transmission On the Maternal Side
You should consider the fact that illnesses involving mitochondria are most frequently transmitted by mother to offspring. Mitochondria of any human comes directly from mother, as sperm cell cannot give its mitochondria to egg cell because it is stored in tail, and that does not go inside the egg cell upon fertilization. Therefore, an easy diagnosis to determine if the disease is likely to be mitochondrial in nature is to look at the person’s family tree to see if they suffer from the same symptoms.
However, at times, the problem may lie in the nucleus, as mitochondria are reliant on nuclear products to function properly, so the problems may sometimes be inherited in the typical fashion. It must be added for females having illness involving mitochondria wanting to have children, it would be best to consult a doctor first.
Mitochondrial Illnesses Preview
Generally, prevalent ailments involving mitochondria include:
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)
The acronym’s meaning speaks for itself; presentations include problems with the brain, nervous system, muscles, and stroke-like episodes before the age of 40. The lactic acidosis raises the blood pH, leading to abdominal pain, vomiting, tiredness, muscle weakness, and difficulty in breathing. This condition must be seen to by a doctor aware of MELAS, as these symptoms can be misinterpreted as epilepsy or be misdiagnosed for something else.
Symptoms usually show before 20 years old, but can show from 4 to 40 years old. Sadly, MELAS can be treated but not cured. The current management paradigm is to treat the symptoms and help the patient as best as possible, even if difficult, but as of now it is fatal, with the life expectancy after the onset of symptoms at roughly five years. The best management as of now is for improving the patient’s quality of life as best as possible.
Myoclonic epilepsy with ragged red fibers (MERRF)
Myoclonic epilepsy with ragged red fibers (MERRF) takes its name from the muscle fibers looking ragged and red when stained with Gömöri trichrome stain and examined under a microscope. Apparent problems with the patient will include the four classical symptoms listed in GeneReviews as myoclonus, generalized epilepsy, ataxia, and the above-mentioned ragged red fibers.
Other symptoms include dementia, shortness, and exercise intolerance. The symptoms usually manifest at childhood. Seizures can be treated with traditional anticonvulsants, and again, the treatment involves treating the symptoms as they appear and alleviating the patient’s symptoms. Life expectancy is shortened and is very variable depending on the severity of the symptoms. At this point, the patient’s quality of life and their lack of suffering is the goal.
Diabetes mellitus and deafness (DAD) or maternally inherited diabetes and deafness (MIDD)
In this inherited disease, we see a combination of symptoms. DAD usually presents by having the hearing loss (specifically, loss of perception of higher frequencies) come before the diabetes. Thankfully, in this case the disease is not fatal, but the deafness and diabetes are great inconveniences. It has other names like NIDDM with deafness and Ballinger-Wallace syndrome.
Characteristically, it is passed on by the mother to the child. About 1% of all diabetes patients will have DAD. Diabetes can be type 1 or type 2. Hearing loss begins first and progresses to complete deafness. Mutation of the mitochondrial DNA can cause decreased consumption of oxygen in tissues in which replication rates are lesser such as muscle. It also affects the insulin secretion by the pancreas. Age is a significant player in this whole process.
Optic atrophy 1
This genetic defect is thankfully rare with an incidence of 1 in 50000. The optic nerve degenerates progressively resulting in vision impairment. The optical disc is pale and the person will experience impairment in detecting colors. Vision impairment will begin when the child is still young (6 – 7 years of age). The patient will develop tunnel vision.
People refer to optic atrophy 1 as autosomal dominant optic atrophy and Kjer type optic atrophy. The responsible gene participates in ATP synthesis, mitochondrial fusion regulation, apoptosis, and structure of the inner mitochondrial membrane. When this gene is affected, the person will experience loss of vision, hearing and muscle contraction. Cochlear implants find use in improving the levels of hearing thresholds for the affected people.
Leber’s hereditary optic atrophy (LHON)
In this mitochondrial disease, one sees the loss of central vision along with degeneration of the retina and optic nerve. It has genetic links and so it is passed on from mother to child. Males show a higher incidence of this ailment. It starts off as blurring or clouding of vision with the symptoms beginning in one eye and spreading to the other within a period of 12 – 15 days.
This loss of vision is permanent in most cases with the optic cells becoming dead over a period of time. The incidence of this is 1 in 30,000. However, it should be noted that the mutation of the genes does not always result in the person going blind. About 50% of the males and 85% of females remain asymptomatic even if they have mutated genes. Leber’s hereditary optic atrophy (LHON) follows the maternal mitochondrial inheritance pattern. The children of each generation are capable of developing symptoms. The father will not pass this down in his inheritance line.
This is a kind of inherited neuromuscular syndrome that results in gradual deterioration of the spinal cord and the brain. Friedreich Ataxia (FA, FRDA) is an ataxia of the autosomal recessive type. This type of ataxia covers more than half of all hereditary ataxia.
The gene mutation causes reduced expression of frataxin, a mitochondrial protein. Once the sensory nerves start to degenerate, the muscle movement in the legs and arms are affected. Spinal cord loses its girth; nerve cells lose their myelin sheath. General signs seen in patients are muscle weakness in arms and legs, slurred style of speaking, heart disorders such as tachycardia and atrial fibrillation, hearing loss, diabetes, loss of vision, deformity of the foot, less coordination and spine curvature.
Patients will show the symptoms before they reach 25 years of age. The gait of the person is stumbling with frequent falling. Other signs include cardiomegaly, quick eye movements, dysarthria, loss of vibratory sensation and absence of reflexes of the deep tendon. The mitochondrial disease life expectancy for Friedreich ataxia is not so good.
Mitochondrial Parkinson’s disease
Parkinson’s disease is a brain disorder that is progressive, chronic and degenerative. The person experiences tremors alongside slowed movements and rigidity of muscles. One variant of Parkinson’s disease is linked to the mitochondrial disease.
Symptoms of this ailment are reduced arm swinging during walking, rigid back, stooped posture, tremor, involuntary head nodding, loss of postural reflexes, trunk stiffness, difficulty in chewing and swallowing, impaired sense of smell, monotonous voice, skin problems, increased daytime sleepiness and increased urination in the night. Treatment methods using coenzyme CoQ10 and creatine have proved positive in experimental animal studies. These medicines improve the functioning of the DNA. One drug used in Russia as an antihistamine has been shown to improve thinking functions and improve functioning in Alzheimer patients.
One interesting observation is that the levels of mitochondrial DNA (mtDNA) in the blood and brain is indicative of the presence or absence of Parkinson’s disease. Though this biomarker is useful, research in this field is necessary to help differentiate it from those in other diseases like Alzheimer’s or Huntington’s disease.
Maternally Inherited Leigh Syndrome
Abnormalities found in mitochondrial diseases result in decreased energy production in cells. This multisystem genetic disorder Maternally Inherited Leigh Syndrome (MILS) and Neuropathy Ataxia and Retinitis Pigmentosa (NARP) are rare and form part of a spectrum of diseases. MILS shows elevated lactic acid levels in the body along with brain disease breathing abnormalities, heart disorders and seizures. It affects nerves within the central nervous system. NARP is a nervous disease that one sees outside the central nervous system. The patient shows impairment of voluntary movement and retinitis pigmentosa (RP). RP is an eye condition. Other abnormalities may be present. The prognosis in both the cases is poor. Children with the disease can expect to live 6 — 7 years. The brain stem, and regions of the brain including the cerebellum show lesions of various forms. Sometimes demyelination of neurons is seen resulting in the break of communication between the individual neurons.
Thus, damage to the brain stem and basal ganglia result in disruptions in the functioning of the auto nervous system, nystagmus, and dystonia. Brain damage might be indicated by other signs too such as hypertrichosis. Currently, there is no cure for this disease. A diet rich in fat and low in carbohydrates is given. Vitamin B1 may be given if needed. When lactic acidosis is present it is treated with diet supplements of sodium bicarbonate.
Wolfram Syndrome 2
By Wolfram Syndrome, we refer to a collection of conditions prominent among which is elevated blood sugar levels. This occurs due to the scarcity of insulin in the blood. Degeneration of the nerve that carries signal to the brain leads to loss of vision. Diabetes insipidus makes these people pass excess amounts of urine. Psychiatric disorders could be present along with urinary tract problems. Hypogonadism could occur whereby the males produce reduced levels of testosterone hormone. Inner ear changes could result in loss of hearing.
When the person is afflicted by diabetes insipidus, the pituitary gland ceases functioning. Due to this, the body balance of the body is disrupted. The person begins to pass urine excessively. About 50% of the people with this ailment will suffer from a neurological disorder. This typically will involve coordination and balance problems. About two-thirds of the patients will show sensorineural deafness.
There is no treatment currently available for Wolfram Syndrome 2. Efforts will go towards managing complications and making the patient comfortable. Since this is an autosomal recessive pattern of inheritance, both gene copies in each cell will show mutations. The parents will have only one copy and will not show signs of the ailment.
The Barth Syndrome is a rare, metabolic disorder of the neuromuscular type. The gene mutation responsible for this is passed on from mother to son and comes to light soon after childbirth. Muscles of the heart and skeletal muscles show abnormalities. Neutrophils, white blood cells in the body, are present in low levels. Growth retardation is present. Organic acids are present in blood and urine. The person will have a short stature normally. You could find increased thickness of the walls of the left ventricle of the heart. This occurs due to high amounts of collagenous fibers. As a result of this condition, the heart becomes unable to pump blood through to the lungs resulting in heart failure. Thus, it could be a reason for stillbirth. Further, mitochondria affected by this ailment will not produce enough of tetra linoleoyl-cardiolipin. This is a lipid that is vital for normal strength in mitochondria.
Most of the patients affected by Barth Syndrome will show cardiomyopathy. The symptoms come to light soon after birth in the form of deceleration in growth. Decreased muscle growth will result in decreased coordination of movement. The child will also show moderate to high learning disabilities as they grow older. Their height and weight too will be diminished. When they attain puberty, there is a spurt in growth and they attain full height. However, the mitochondrial disease life expectancy for this ailment remains poor.
Methyl Glutaconic Aciduria (MGA) is a disorder due to a gene mutation. This rare disorder is inherited and shows an excessive amount of unsynthesized 3- Methyl Glutaconic acid. This happens due to their inability to make energy. Neurological problems begin to show soon after the child develops from infancy. General symptoms will include but not limited to muscle cramping of involuntary nature, and optic atrophy. Mental skills and motor development become slow to progress. leading to weakness in the limbs. Speech delay is noticeable and spasms are present. The nerve that carries signals from the eye to the brain suffers extensive damage. There are instances when an adult in his or her 30s develops signs of MGA 4.
MGA 4 disorder shows symptoms common to both type 1 and type 3. In addition to reduced muscles tone, there is psychomotor retardation. As mentioned, there is increased level of 3-methylglutaconic acid in the urine and developmental delay. The person might experience seizures.
Incidence is more when you have more congenital marriages. The people living in insular areas are more prone to his ailment. While the parents have one copy of the autosomal gene, the children have both genes altered. The inheritance is through the X-chromosome and so fathers cannot pass the gene to their children.
Beta Ketothiolase deficiency
In this inherited mitochondrial disease, the body is unable to break down proteins of certain categories. In addition, processing of ketones is also not possible. Ketones help the body store energy. The organic acid condition Beta Ketothilase (BKT) results as the name suggest in excessive amounts of acid storage. However, this toxin amount could reach dangerous levels if not treated promptly. The onset of the disease will be seen within half year to two years from birth.
Typical symptoms will comprise of vomiting, extreme tiredness, and trouble with his or her breath. The child may also have dehydration and convulsions. These attacks typically occur when the organic acid levels begin to exceed a critical value. Triggers for this ailment include fasting or infection and in a few cases stress. When the blood becomes too acidic, the tissue functioning is impaired.
It also goes by the name of T2 deficiency or MAT deficiency.
The onset of this rare disorder occurs before the person reaches 20 years of age. Typical signs of the onset of disease will be manifested through pigmentary retinopathy. You also find ophthalmoparesis and occasionally cerebellar ataxia. Certain other conditions could also manifest such as proximal myopathy and cardiac conduction block.
Children affected by Kearns-Sayre Syndrome (KSS) will typically have a short stature and endocrinopathies such as Addison disease, hypoparathyroidism, and/or diabetes mellitus. They might also show raised CSF (cerebrospinal fluid) protein content.
As of now, there is no tangible way to rectify the defects in the abnormal mitochondrial mutations. Depending on how many organs are affected, the management will have to be done. Prognosis for KSS is poor.
Bottom Line on Length of Life
All in all, while mitochondrial disease life expectancy may be low depending on which disease it is, some are more easily managed than others. A defect in the mitochondria, appearing in several if not all of the body’s cells will invariably present with severe symptoms.
Making the patient comfortable with improved living conditions is highly desired. There, however, is no compulsion that the person must have a hasty death. People with mitochondrial disease sometimes surpass the normal average lifespan of healthy people.