Diseases caused by abnormal function of Mitochondria Krishna Sairam G 2015B1PS810H Diseases caused by abnormal function of Mitochondria Diseases mainly discussed: Leigh Syndrome Kearns Sayre Syndrome

Leigh Syndrome Named after  Archibald Denis Leigh(a British neuropsychiatrist) Leigh’s Disease is a severe neurometabolic disorder that usually becomes apparent in infancy or childhood, but can also occur in teens and adults The general course of Leigh disease is one of rapid developmental regression Child often appears normal at birth but begins displaying symptoms within a three months to two years of age. Symptoms are often seen after triggering event that taxes body’s energy production such as viral infection or major surgery  It is mainly identified on MRI by visible dead or dying tissue(lesions) on the brain, particularly in the midbrain(basal ganglia,cerebellum) and brainstem.

Frequency Leigh syndrome affects 1 in 40,000 new borns. The condition is more common in certain populations. For example, the condition occurs in approximately 1 in 2,000 newborns in the Quebec region , Canada and in approximately 1 in 1,700 individuals on the Faroe Islands.  However, this may be an underestimate since mitochondrial diseases tend to be under-diagnosed and misdiagnosed.

Symptoms The first signs of Leigh syndrome seen in infancy are usually vomiting, diarrhea, and difficulty swallowing , which disrupts eating ,resulting in inability to grow and gain weight in expected value(failure to thrive) Excess lactate may be seen in the urine, cerebrospinal fluid, and blood of a person. – A TEST FOR LEIGH SYNDROME Severe muscle and movement problems , weak muscle tone (hypotonia), involuntary muscle contractions (dystonia),peripheral neuropathy and problems with movement and balance (ataxia) are common with leigh syndrome  Many individuals with this condition develop weakness or paralysis of the muscles that move the eyes (ophthalmoparesis)

Breathing problems are common and when becomes severe can also lead to acute respiratory failure Some Individuals may develop thickening of heart muscle , that forces heart to work harder to pump blood The signs and symptoms of Leigh syndrome are caused in part by patches of damaged tissue (lesions) that develop in the brains of people with this condition The brain lesions are accompanied by loss of the myelin coating around nerves, which reduces the ability of the nerves to activate muscles used for movement or relay sensory information.

Cause of the disease Leigh syndrome can be caused by mutations in one of more than 75 different genes, Although exact mechanism is unclear ,researchers believe that impaired oxidative phosphorylation lead to cell death because of decreased energy available in the cell As we know , most genes are found in nuclear DNA , but however some genes are found in DNA of Mitochondria , known as mitochondrial DNA or mtDNA About 20 percent of people affected by leigh syndrome have a mutation in mtDNA Five protein complexes (complex1,complex2,complex3,4,5) drive production of ATP,through transfer of electrons in oxidative phosphorylation ----- Many mutations reduce or eliminate activity of these complexes

Disruption of complex I, also called NADH:ubiquinone oxidoreductase, causes nearly one third of cases of the condition. At least 25 genes involved in the formation of complex I, found in either nuclear or mitochondrial DNA, have been associated with Leigh syndrome Disruption of complex IV, also called cytochrome c oxidase or COX, is causing approximately 15 percent of cases This COX or complex 4 is involved in the last step of electron transfer in oxidative phosphorylation, provides the energy that will be used in the next step of the process to generate ATP SURF1 (gene in nuclear DNA) which assembles the COX protein complex mutates(broken down) into abnormally short SURF1 , resulting in the absence of functional SURF1 protein

Mutation of  MT-ATP-6 gene, which provides instructions for making a piece of complex V, also known as the ATP synthase protein complex is a common cause for Leigh disease. Other gene mutations decrease the activity of one or more oxidative phosphorylation protein complexes .Ex. Mutations in genes that form pyruvate dehydrogenase complex or coenzyme Q10. Tests and Treatment Test of Lactose in blood and urine Problems with autonomous nervous system(basal ganglia and cerebellum No Curative treatment. progression of periventricular white matter abnormality(inside brain of a 3-year old boy.

Inheritance Patterns Leigh syndrome can have different inheritance patterns. It is most commonly inherited in an autosomal recessive pattern , which means both copies of the gene in each cell have mutations – (SURF1). The parents each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition In approximately 20 percent of people with Leigh syndrome, the condition is inherited in mitochondrial pattern, which is also known as maternal inheritance - (MT-ATP-6). Fathers do not pass traits associated with changes in mtDNA to their children In a small number of affected individuals with mutations in nuclear DNA, Leigh syndrome is inherited in an X- linked recessive pattern. The condition has this pattern of inheritance when the mutated gene is located on the X-Chromosome, which is one of the two sex chromosomes.

Recent Experiments in this area In 2015, the United Kingdom became the first country in the world to permit techniques designed to eradicate the transmission of serious mitochondrial diseases from mother to child. In 2015, the United Kingdom Parliament said it would be legal. But we have to get a licence from the authorities to do it. UK law says it can be used only in cases of severe mitochondria.

Kearns Sayre Syndrome (KSS) Kearns-Sayre syndrome is a condition that affects many parts of the body, especially the eyes Usually appear before the age of 20 years People with KSS have progressive external ophthalmoplegia, which is weakness of eye muscles that disables eye movement and causes drooping eyelids People with KSS also have pigmentary retinopathy, which results from breakdown of the light-sensing tissue at the back of the eye or retina KSS Victims have muscle weakness in their limbs, deafness, kidney problems, or a deterioration of cognitive functions

The muscle cells of victims when stained and viewed under microscope, appear abnormal , as they contain excess of mitochondria and are known as ragged-red fibers Ragged Red Fibers Frequency of KSS is 1 to 3 in 100,000 individuals

Symptoms The first symptom of this disease is a unilateral ptosis, or difficulty opening the eyelids, that gradually develops to bilateral ptosis. Pigmentary retinopathy, which results from breakdown of the light- sensing tissue at the back of the eye or retina Cardiac conduction abnormalities Usually seen years after ptosis and retinopathy Creates atrioventricular block , which is complete blockage of electrical conduction from atrium to ventricle pigmentory retinopathy mid-stage

Causes for KSS People with Kearns-Sayre syndrome have a single, large deletion of mtDNA , ranging from 1,000 to 10,000 DNA nucleotides. The cause of the deletion in affected individuals is unknown. The mtDNA deletions that cause Kearns-Sayre syndrome result in the loss of genes important for mitochondrial protein formation and oxidative phosphorylation The most common deletion removes 4,997 nucleotides, which includes twelve mitochondrial genes. Deletions of mtDNA result in impairment of oxidative phosphorylation and a decrease in cellular energy production. Regardless of which genes are deleted, all steps of oxidative phosphorylation are affected.

Researchers have not determined how these deletions lead to symptoms of Kearns-Sayre syndrome, although the features of the condition are probably related to a lack of cellular energy. It has been suggested that eyes are commonly affected by mitochondrial defects because they are especially dependent on mitochondria for energy A neuro-ophthalmologist ,based on clinical exam findings ,suspects KSS in an individual  Suspicion of myopathies should be increased in patients whose ophthalmoplegia does not match a particular set of cranial nerve palsies (oculomotor nerve palsy e.t.c) Diagnosis is confirmed with muscle biopsy, and supplemented with PCR determination of mtDNA mutations  Cross-section of muscle fibers stained with trichrome strain is viewed using light microscopy Diagnosis

Management and treatment Currently,There is no curative treatment to KSS  As KSS is rare , there are only few case reports of treatments with very little data to support their effectiveness Several promising discoveries have been reported which may support the discovery of new treatments with further research Could mtDNA be restored to muscle tissue by encouraging muscle regeneration?

“There should be no boundaries to human endeavour “There should be no boundaries to human endeavour . However bad life may seem, there is always something you can do, and succeed at. While there's life, there is hope” - Stephen Hawking