Overview of Mitochondrial Disorders

Mitochondria are special organelles inside cells. They have their own DNA (mtDNA) and RNA (mtRNA), and they are responsible for important physiological functions such as cellular energy metabolism, apoptosis, and redox balance. Mitochondrial dysfunction can cause a series of hereditary diseases, collectively called mitochondrial disorders. Mitochondrial disorders are a very complex and diverse group of diseases. They can affect multiple organ systems, manifesting as different clinical symptoms such as muscle weakness, muscle atrophy, deafness, vision impairment, headache, stroke-like episodes, consciousness disturbance, lactic acidosis, movement disorders, seizures, respiratory distress, developmental delay, and so on. These symptoms usually appear in childhood or adolescence, but they may also be discovered in adulthood. Mitochondrial disorders can be divided into two major categories: mtDNA-related and nuclear DNA-related. MtDNA-related diseases are caused by mutations or deletions of mtDNA itself, usually showing as maternal inheritance, that is, only mothers can pass the damaged mtDNA to their children, while fathers do not. Nuclear DNA-related diseases are caused by mutations or deletions of nuclear genes that encode mitochondrial proteins or participate in mitochondrial function regulation, usually showing as autosomal or sex-linked inheritance, that is, both parents may pass the damaged nuclear genes to their children. So far, many types of mitochondrial disorders have been discovered, some of which are more typical and common, such as MELAS syndrome (Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like Episodes), LHON syndrome (Leber's Hereditary Optic Neuropathy), Leigh syndrome, and so on. These diseases have their own different genetic mechanisms and clinical features, but they are all caused by mitochondrial dysfunction. In the next section, we will introduce these diseases' classification and clinical characteristics in detail.

MELAS Syndrome

MELAS syndrome is a rare genetic disease that affects the nervous system and muscles. It is caused by defects in the mitochondrial DNA, which is inherited from the mother. Mitochondrial DNA provides instructions for making proteins that are essential for the function of mitochondria, which are the energy-producing organelles of cells. When mitochondrial DNA is defective, mitochondria cannot produce enough energy for cells, especially those with high energy demands, such as neurons and muscles. The symptoms of MELAS syndrome usually start in childhood, after a period of normal development. The onset of symptoms can range from infancy to adulthood, but most commonly occurs between 2 and 10 years old. The symptoms vary depending on the type and severity of the mitochondrial DNA defect, but they typically include stroke-like episodes, seizures, headaches, muscle weakness, and lactic acidosis. Other symptoms of MELAS syndrome may include short stature, growth retardation, hearing loss, heart problems, kidney problems, diabetes, hormonal imbalances, and cognitive impairment.

The most common genetic variant of MELAS syndrome is a mutation called m.3243A>G on mitochondrial DNA. This mutation affects a molecule called tRNA(Leu(UUR)), which helps to assemble proteins that form mitochondria. Other variants on mitochondrial DNA may also cause MELAS syndrome. Genetic testing can confirm the presence of these mutations in blood or tissue samples.

The diagnosis of MELAS syndrome is based on clinical criteria, blood tests, imaging studies, and a muscle biopsy. The clinical criteria include having stroke-like episodes and two or more phenotypic features associated with mitochondria (such as deafness or epilepsy). The blood tests measure the levels of lactate and pyruvate (another byproduct of anaerobic respiration) in the blood or cerebrospinal fluid (CSF). The imaging studies show characteristic patterns of brain lesions on magnetic resonance imaging (MRI) or computed tomography (CT) scans. The muscle biopsy shows abnormal structures or reduced activity of mitochondria in muscle tissue. There is no cure for MELAS syndrome. The treatment aims to relieve symptoms and delay disease progression as much as possible. The treatment may involve a combination of drugs that affect different aspects of the disease. Gene therapy is a potential method to cure MELAS syndrome. It aims to repair or replace the defective mitochondrial DNA by using different techniques such as mitochondrial genome editing. The prognosis for MELAS syndrome is poor. The life expectancy of someone with MELAS syndrome is about five years from the onset of symptoms. The factors that affect the prognosis include brain atrophy (shrinkage), status epilepticus (prolonged seizures), and the use of drugs with high mitochondrial toxicity (such as valproic acid).

LHON Syndrome

LHON syndrome is a hereditary eye disease caused by mutations in mitochondrial DNA, mainly affecting the retinal ganglion cells and their axons, leading to acute or subacute bilateral central visual field loss. LHON syndrome is caused by one of three point mutations in mitochondrial DNA, namely 11778 G>A in the ND4 gene, 3460 G>A in the ND1 gene, and 14484 T>C in the ND6 gene. These mutations are asymptomatic until some unknown environmental or lifestyle factors trigger the onset of LHON syndrome. The main symptom of LHON syndrome is vision loss, usually occurring first in one eye and then in the other eye within weeks to months. Vision loss is usually accompanied by loss of color vision and a central scotoma. Retinal examination can reveal edema of the nerve fiber layer, dilated or tortuous peripapillary vessels, and other signs. LHON syndrome is diagnosed mainly based on family history, clinical manifestations, and mitochondrial DNA testing.

There is no specific treatment for LHON syndrome; it is mainly symptomatic and supportive treatment, such as avoiding smoking, alcohol, certain drugs, and other factors that may trigger or worsen LHON syndrome and supplementing antioxidants, coenzyme Q10, and other substances that may benefit mitochondrial function. Gene therapy is a potential treatment modality that is currently undergoing clinical trials. The principle of gene therapy is to provide normal mitochondrial DNA fragments to the damaged mitochondria, thereby restoring the activity of mitochondrial complex I, increasing energy production, and protecting retinal ganglion cells. Several gene therapy protocols have entered the clinical trial stage, such as GS010, rAAV2/2-ND4, rAAV2/2-ND1, etc. These protocols are delivered to the retinal ganglion cells by injection into the vitreous cavity, or macular area. Preliminary results show that these protocols have some visual improvement effects for some patients, but more data and long-term follow-up are needed to evaluate their safety and efficacy.

In summary, LHON syndrome is a hereditary eye disease caused by mutations in mitochondrial DNA, mainly manifested as bilateral central visual field loss. There is no specific treatment method at present, but gene therapy is a promising new technology that is undergoing clinical trials.

Leigh Syndrome

Leigh syndrome (also called Leigh disease and subacute necrotizing encephalomyelopathy) is a rare inherited neurometabolic disorder that affects the central nervous system. Leigh syndrome can be caused by mutations in mitochondrial DNA or by deficiencies in an enzyme called pyruvate dehydrogenase. Genetic mutations in mitochondrial DNA interfere with the energy sources that run cells in an area of the brain that plays a role in motor movements. These genetic mutations result in a chronic lack of energy in the cells, which affects the central nervous system and causes progressive degeneration of motor functions. There is also a form of Leigh syndrome (X-linked recessive inheritance) that is the result of mutations in a gene that produces another group of substances important for cell metabolism. This gene is only found on the X chromosome.

The symptoms of Leigh syndrome are classically described as beginning in infancy and leading to death within a span of several years; however, as more cases are recognized, it is apparent that symptoms can emerge at any age—including adolescence or adulthood—and patients can survive for many years following diagnosis. Symptoms are often first seen after a triggering event that taxes the body’s energy production, such as an infection or surgery. The general course of Leigh syndrome is one of episodic developmental regression during times of metabolic stress. Some patients have long periods without disease progression, while others develop progressive decline. Leigh syndrome can also affect the eyes, heart, and lungs. The muscles that control the eyes become weak, paralyzed, or uncontrollable in conditions called ophthalmoparesis (weakness or paralysis) and nystagmus (involuntary eye movements). Hypertrophic cardiomyopathy (thickening of part of the heart muscle) is also sometimes found and can cause death; asymmetric septal hypertrophy has also been associated with Leigh syndrome.

Leigh syndrome can be diagnosed by clinical examination, blood tests, urine tests, cerebrospinal fluid analysis, genetic testing, brain imaging, and muscle biopsy. The diagnosis can be confirmed by finding elevated levels of lactate in the body fluids or by identifying specific genetic mutations. There is no cure for Leigh syndrome, but some treatments may help manage the symptoms and improve the quality of life. The most common treatment for Leigh syndrome is thiamine, or Vitamin B1. Oral sodium bicarbonate or sodium citrate may be prescribed to manage lactic acidosis. Researchers are testing dichloroacetate to establish its effectiveness in treating lactic acidosis. In individuals with the X-linked form of Leigh syndrome, a high-fat, low-carbohydrate diet may be recommended. Gene therapy for Leigh Syndrome is still in its early stages and faces many challenges, such as safety, efficacy, delivery, and regulation. However, some promising results have been reported from animal models and human trials. For example, researchers have successfully used gene therapy to treat a mouse model of Leigh Syndrome caused by a mutation in the Ndufs4 gene, which encodes a subunit of complex I in the mitochondrial respiratory chain. They injected an adeno-associated virus (AAV) vector carrying a healthy copy of Ndufs4 into the brain ventricles of newborn mice and observed improved survival, motor function, brain pathology, and biochemical markers.

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