Leigh's Disease

Clinical presentation of Leigh's disease (also called infantile necrotizing encephalopathy) is characterized by rapid deterioration of the central nervous system functions, beginning within months after birth. Neurological symptoms include cognitive impairment, hypotonia, ataxia, tremor, polyneuropathy, hyporeflexia, seizures, as well as generalized weakness. Ocular symptoms, including nystagmus, retinitis, optic atrophy and paresis may be encountered in these patients, which can eventually progress to blindness [8]. Constitutional symptoms, such as malaise, fatigue, anorexia and failure to thrive are present in many patients, while respiratory and gastrointestinal disturbances such as hypoxia and tachypnea, vomiting, and dysphagia are frequently encountered. Other accompanying illnesses may be present, such as hypertrophic cardiomyopathy, presence of ventricular septal defects, diabetes mellitus, nephrotic syndrome, as well as thyroid dysfunction [9].

If the onset of the symptoms is delayed, dysarthria and mental retardation may be observed.

The diagnosis of Leigh's disease is achieved through a detailed workup involving biochemical tests and neuroimaging studies.

Biochemical findings, such as indirect markers of energy utilization, including lactate levels, should be investigated to identify the underlying defect, and levels of pyruvate may be evaluated in the cerebrospinal fluid (CSF) together with lactate, both usually having increased values. Liver and muscle enzymes should also be evaluated, including transaminases (AST and ALT), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH).

Neuroimaging studies are performed to assess the severity of the lesions in the central nervous system. Magnetic resonance imaging (MRI) of endocranium typically reveals symmetric lesions of the brain stem and basal ganglia, including cerebral atrophy and leukodystrophy, while infarctions may be observed in severe cases.

Currently, the treatment of Leigh's disease comprises supportive management that improves levels of ATP and suppression of lactate levels, as well as other accompanying disorders. Thiamine (vitamin B1) has been used in a number of patients due to a reported slight improvement of the neurological status, while riboflavin (vitamin B2) is also administered, presumably because of its role of aiding in ATP production.

Ketogenic diets, and the use of intravenous soya bean oil has been shown to improve the metabolic status of patients, particularly in those with respiratory failure, while other strategies to manage lactic acidosis includes administration of oral sodium citrate and sodium bicarbonate. Dystonia frequently occurs in these patients, and the use of gabapentin and baclofen is indicated in such circumstances, and in severe cases, botulinum toxin is used, while antiepileptic drugs are also frequently given because of epilepsy [10].

The prognosis of patients with Leigh's disease is quite poor, and most patients die within the first few years of life. The severity of the disease depends on the type of the mutation, and which enzymes are affected. Individuals with PDH deficiency, as well as those lacking activity of the mitochondrial complex IV have the worst prognosis, while those with partial enzyme deficiencies may live up to 6 or 7 years [7]. Rarely have individuals lived until their teenage years, and this rapidly progressive disorder is universally fatal.

This disease occurs due to heterogenous genetic malformations both in mitochondrial and nuclear DNA, which makes this syndrome quite complex, because it can cause only one, or several mutations of enzymes in the metabolic pathway [3]. Hallmarks of this disease include mutations of the mitochondrial respiratory chain, cytochrome C oxidase [4], coenzyme Q, pyruvate dehydrogenase, as well as other enzymes and parts of the metabolism that are critical for energy utilization and ATP formation. The mutation that is most commonly encountered in Leigh's disease is the disruption of complex IV mitochondrial chain, or cytochrome C oxidase, which is involved in the last step of electron transfer during oxidative phosphorylation. Another commonly encountered mutation includes genes that are responsible for the production of complex V, also known as the ATP synthase complex, which is responsible for the generation of ATP at the end of the electron transport chain, and it is found in 10-20% of patients with Leigh's disease [5].

So far, autosomal recessive and X-linked patterns of inheritance have been observed since nuclear DNA contains genes from both parents, while mitochondrial DNA is transferred only from maternal genes. However, causes of this syndrome and the resulting mutations have not yet been identified.

This genetic disorder is considered rare. Although prevalence rates vary, it is estimated that it occurs in approximately 1 in 36,000 individuals. The majority of the patients develop symptoms within the first year of life and the disease rarely has a delayed onset. The diagnosis is almost always confirmed when patients are between three months and two years old. Predilection for gender or race is not established.

Mutations in this genetic disorder target enzymes and other parts of the metabolic pathway that are essential for the production of the energy that supplies the body. The production of adenosine triphosphate (ATP) is not possible without the activity of enzymes such as pyruvate dehydrogenase (PDH), coenzyme Q, or the mitochondrial respiratory chain. When mutations in the mitochondrial and nuclear DNA occur, which is the case in this disease, the electron transport chain, oxidative phosphorylation, as well as tricyclic acid cycle, are all unable to replenish ATP and cellular energy sources, leading to generalized energy deficiency [6]. As a result, cells are not able to perform their functions, and once their reserves are depleted, generalized cellular damage occurs, eventually leading to their death. These changes are most prominent in the central nervous system, where neurons need constant replenishment of ATP through aerobic glycolysis to sustain their metabolic needs.

Although specific mutations in this inherited genetic disorder have been identified, its cause remains unknown, and prevention is currently not possible.

Leigh's disease is a rare genetic disorder of energy metabolism primarily affecting the central nervous system. This disorder occurs as a result of mutations in mitochondrial and nuclear DNA, which leads to impaired energy metabolism. Deficiency of various enzymes including pyruvate dehydrogenase (PDH), coenzyme Q, or defects in the mitochondrial chain complex are documented, which are of essential value in the tricyclic acid cycle, oxidative phosphorylation and energy utilization. Both autosomal recessive and X-linked inheritance patterns can be observed in these patients [1], but its actual cause is still unknown. This rare disease is estimated to occur in 1 per 36,000 live births, and symptoms usually start before the age of 12 months, but they may appear later in childhood. The onset usually occurs between three months and two years of age.

Since this disease leads to inability to create sufficient energy through metabolism, rapid cellular deterioration occurs, particularly in the central nervous system, which results in symptoms such as psychomotor retardation, ataxia, dystonia, atrophy of the optic nerves, as well as symptoms of peripheral nervous system involvement, such as polyneuropathy [2]. Additionally, loss of appetite, vomiting, seizures, diabetes, and other constitutional symptoms may appear, eventually leading to an impaired respiratory and renal function. The diagnosis of Leigh's disease is made through biochemical blood findings and neuroimaging studies of the endocranium, which shows symmetric lesions of the basal ganglia and the brain stem. Apart from supportive therapy which includes thiamine, riboflavin, and management of complications (such as lactic acidosis, epilepsy, etc.) specific therapy for this disorder does not exist. The prognosis is very poor, and depends on the severity of disease, but the majority of patients live only for a few years.

Leigh's disease is a rare inherited disorder that affects primarily the central nervous system. This disorder occurs as a result of DNA mutations which impair the parts of the metabolism responsible for energy production. As a result, the majority of cells in the body are unable to perform their metabolic functions, consequently leading to progressive deterioration and death of cells throughout the body. This disorder is rapidly progressive, and it is most commonly observed in children between three months and two years of life. It carries a very poor prognosis, with only a few patients reaching adolescence, making this disorder a universally fatal disease.

Leigh's disease primarily causes damage to the brain, specifically the basal ganglia, which are involved in motor functions, as well as the brain stem, which performs numerous vital functions. The most common symptoms are generalized weakness, failure to thrive, psychomotor retardation, anorexia, muscle atrophy, absence of reflexes, and sometimes seizures. Patients may have accompanying diseases such as congenital heart defects, diabetes, kidney or thyroid problems. Breathing problems are common, and both kidney and lung functions are severely impaired in patients with Leigh's disease.

The diagnosis is made by obtaining levels of lactate and pyruvate in the cerebrospinal fluid through a lumbar puncture, while a magnetic resonance imaging SCAN (MRI) of the brain is performed to assess the damage of the central nervous system.

Treatment is mainly supportive, since there is no cure for this disorder. Thiamine (vitamin B1) is believed to provide some degree of improvement in terms of neurological complaints, while other treatment is aimed at correcting the accompanying issues, such as lactic acidosis, hypoxia, kidney failure, and seizures. In patients with a certain type of mutation, a high-fat and low-carbohydrate diet may be recommended, to prevent lactic acidosis.

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