Lee (Leia) syndrome: what is it, symptoms, treatment, prognosis

What is Leigh Syndrome?

Lee syndrome (Leigh's syndrome) Is a rare genetic neurometabolic disease. It is characterized by degeneration of the central nervous system (i.e., the brain, spinal cord, and optic nerve). Symptoms of Lee syndrome usually begin between three months and two years of age, but in some patients, signs and symptoms do not appear until several years later.

Symptoms are associated with progressive neurological deterioration and may include loss of earlier acquired motor skills, loss of appetite, vomiting, irritability and / or convulsive activity. As Leigh's syndrome progresses, symptoms may also include generalized weakness, absence muscle tone (hypotension) and episodes of lactic acidosis, which can lead to respiratory and renal impairment functions.

Leigh's syndrome can be caused by several different genetically determined enzyme defects, originally described over 60 years ago. Most people with Lee syndrome have defects in mitochondrial energy production, such as a deficiency in an enzyme of the mitochondrial respiratory chain complex or a pyruvate dehydrogenase complex. In most cases, Lee syndrome is inherited in an autosomal recessive manner. However, X-linked recessive and maternal inheritance due to mitochondrial DNA mutation are additional transmission routes.

Signs and symptoms

Symptoms of classic Lee syndrome (infantile necrotizing encephalopathy), a rapidly progressive neurological disorder, usually begin between 3 months and 2 years of age. In most children, the first noticeable sign is loss of previously acquired motor skills. When the disease has an early onset (i.e., 3 months), loss of head control and poor sucking ability may be the first noticeable symptoms. It can be accompanied by deep loss of appetite, intermittent vomiting, irritability, constant crying and possible seizures. Delays in reaching milestones can also occur. Affected children may not grow and gain weight at the expected rate (failure to develop).

If Lee syndrome appears later in childhood (for example, after 24 months), the child may have difficulty with the formulation of words (dysarthria) and the coordination of voluntary movements such as walking or running (ataxia). Previously acquired intellectual skills may diminish and intellectual disabilities may also occur.

The progressive neurological deterioration associated with Leigh's syndrome is characterized by a variety of symptoms, including:

• generalized weakness;
• lack of muscle tone (hypotension);
• clumsiness;
• tremor;
• muscle spasms (spasticity) that result in slow, stiff leg movements and / or lack of tendon reflexes

Further neurological development is delayed.

Episodes of lactic acidosis, which are characterized by abnormally high levels of lactic acid in the blood, brain, and other body tissues, may occur. Periodically, the level of carbon dioxide in the blood may also be abnormally high (hypercapnia). Lactic acidosis and hypercapnia can lead to psychomotor regression and respiratory, heart, or kidney problems.

Children with Lee syndrome usually have breathing problems, including temporary cessation of spontaneous breathing (apnea), labored breathing (dyspnea), abnormally fast breathing (hyperventilation) and / or abnormal Cheyne-Stokes breathing. Some children may also have difficulty swallowing (dysphagia). Vision problems can include abnormally fast eye movements (nystagmus), sluggish pupils, strabismus, paralysis of certain eye muscles (ophthalmoplegia), deterioration of the nerves in the eyes (visual atrophy), and / or visual impairment leading to blindness.

Lee syndrome can also affect the heart. Some children with this disorder may have abnormal enlargement of the heart (hypertrophic cardiomyopathy) and proliferation of the fibrous membrane that separates the various chambers of the heart (asymmetric septal hypertrophy). Over time, a disorder may develop that affects nerves outside the central nervous system (peripheral neuropathy), causing progressive weakness in the arms and legs.

The symptoms of the X-linked infantile form of Leigh syndrome are similar to those of the classic Leigh syndrome. Symptoms of Lee syndrome in adults (subacute necrotizing encephalomyelopathy), a very rare form of the disorder, usually begin in adolescence or early adulthood. Initial symptoms are usually vision related and may include abnormalities such as a blurred central visual field (central scotoma), color blindness and / or progressive vision loss due to optic nerve degeneration (bilateral optic atrophy). In this form of the disorder, the neurological problems associated with the disease progress slowly. At about 50 years old, it becomes more difficult for sick people to coordinate voluntary movements (ataxia).

Additional late symptoms may include partial paralysis and involuntary muscle movements (spastic paresis), sudden muscle spasms (clonic twitching), generalized tonic-clonic convulsions and / or dementia varying degrees of severity.

Causes

Several different types of genetically determined metabolic defects can lead to Lee syndrome. The condition can be caused by a deficiency of one or more different enzymes (for example, enzymes of the mitochondrial respiratory chain or enzyme components of the pyruvate dehydrogenase complex). These enzyme deficiencies are caused by changes (mutations) in one of several different disease genes (genetic heterogeneity). These mutations can be inherited as an autosomal recessive trait, an X-linked recessive trait, or as a mutation found in mitochondrial DNA. In some cases of Leigh syndrome, the genetic cause cannot be identified.

Genetic information is contained in two types of DNA: Nuclear DNA (nDNA) is contained in the cell nucleus and is inherited from both biological parents. Mitochondrial DNA (mtDNA) is found in the mitochondria of cells and is inherited exclusively from the baby's mother. Genetic diseases caused by nDNA mutations (changes in genetic material) are determined by two genes, one from the father and the other from the mother. Recessive genetic disorders occur when a person inherits the same abnormal gene for one trait from each parent. If a person receives one normal gene and one gene for the disease, the person will be a carrier of the disease, but usually asymptomatic. The risk that two carrier parents will both pass on the defective gene and therefore infect the baby is 25% with each pregnancy. The risk of having a child who will be a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for this particular trait is 25%.

Other deficiencies in nDNA-based enzymes (eg, NADH-CoQ and cytochrome c oxidase) are also responsible for some cases of autosomal recessive Lee syndrome. These specific enzyme deficiencies have been associated with several different genes. For example, gene mutations SURF1, located on chromosome 9, cause Lee syndrome associated with a deficiency of cytochrome c-oxidase. All of these various genetic defects appear to have a common effect on the central nervous system, resulting in progressive neurological impairment.

The medical literature also contains data on the recessive form of Leigh's syndrome linked to the X chromosome of nDNA. This form of the disease has been associated with a specific gene defect known as the E1 alpha subunit of the pyruvate dehydrogenase complex located on the short arm (p) of the X chromosome (Xp22.2-22.1). X-linked recessive disorders are conditions that are encoded on the X chromosome. Women have two X chromosomes, while men have one X chromosome and one Y chromosome. Consequently, in women, signs of disease on the X chromosome may be masked by a normal gene on the other X chromosome. Since males only have one X chromosome, if they inherit the gene for a disease present on X, it will be expressed. Men with X-linked disorders pass the gene on to all their daughters, who will carry the disease, but never to their sons. Women who are carriers of X-linked disorder have a 50 percent risk of passing the carrier condition to their daughters and a 50 percent risk of passing the disease on to their sons.

In some cases, Lee syndrome can be inherited from the mother as a mutation found in mitochondrial DNA. Found in hundreds or thousands in virtually every cell in the body, mitochondria regulate production cellular energy and carry the genetic blueprints of this process in their own unique DNA (mtDNA). MtDNA is carried by sperm from the father. However, in the process of fertilization, the father's mtDNA is lost. As a result, all human mtDNA comes from the mother. The affected mother will pass on the traits to all of her children, but only the daughters will pass on the mutation (s) to the next generation.

Genetic mutations that are present in mtDNA can outnumber normal gene copies. Symptoms may not appear until mutations appear in a significant percentage of mitochondria. Uneven distribution of normal and mutant mtDNA in different tissues of the body can affect different organ system in people from the same family and may cause different symptoms in affected members of the same families.

A specific mtDNA defect that may be responsible for some cases of Leigh's syndrome (mtDNA nt 8993), associated with a gene known as ATPase 6 (deficiency of the V complex of the mitochondrial respiratory chain [deficiency ATPases]). These cases are sometimes referred to as hereditary Lee syndrome or mtDNA-related Leigh syndrome.

Some researchers believe that cases of Lee syndrome in adults can be inherited as an autosomal dominant trait due to nDNA mutations. Dominant genetic disorders occur when only one copy of an abnormal gene is needed for a disease to appear. Since this condition is associated with an nDNA mutation, the abnormal gene may be inherited from either parent or may be the result of a new nDNA mutation in the affected individual. The risk of passing the abnormal gene from the affected parent to the offspring is 50 percent with every pregnancy, regardless of the sex of the child.

Affected populations

The classic form of Lee syndrome develops in infancy (necrotizing encephalopathy in children) and usually begins between 3 months and 2 years of age. This form of the disease affects men and women in equal numbers.

In cases of Lee syndrome that are inherited as an X-related recessive trait, symptoms usually develop in infancy. This form of the disease affects almost twice as many men as women.

In some rare cases, Leigh's syndrome can begin in late adolescence or early adulthood (subacute necrotizing encephalomyelopathy in adults). In these cases, which affect twice as many men as women, the disease progresses more slowly than the classic form of the disease.

Researchers once believed that the classic form of Lee's syndrome accounted for about 80 percent of cases. In the medical literature, the prevalence of Lee syndrome is estimated at 1 in 36,000–40,000 live births.

Symptomatic disorders

Symptoms of the following disorders may be similar to those of Lee's syndrome. Comparisons can be useful for differential diagnosis:

• Wernicke's syndrome and Korsakoff syndrome Are related disorders that often arise from thiamine deficiency (vitamin b1). Wernicke syndrome, also known as Wernicke encephalopathy, is a neurological disease characterized by the clinical triad of confusion, inability to coordinate voluntary movements (ataxia), and visual impairment eye. Korsakoff syndrome is a neurological disorder characterized by a disproportionate loss of memory in relation to other mental aspects. When these two disorders occur together, the term is used Wernicke-Korsakoff syndrome. Most cases occur in alcoholics. Some researchers believe that Wernicke and Korsakoff syndromes are separate but related disorders; others believe they are different stages of the same disorder or spectrum of diseases. Wernicke's syndrome is considered an acute phase with a shorter duration and more severe symptoms. Korsakoff's syndrome is considered a chronic phase and is a long-term condition.
• Batten's disease Is a rare genetic disorder that belongs to a group of progressive degenerative neurometabolic disorders known as neuronal ceroid lipofuscinosis. These disorders have certain similar symptoms and differ in part in the age at which such symptoms appear. Batten's disease is considered a juvenile form of neuronal ceroid lipofuscinosis (NCL). SCLs are characterized by an abnormal accumulation of certain fatty, granular substances (i.e., pigmented lipids [lipopigments] ceroid and lipofuscin) in the nerve cells (neurons) of the brain, as well as in other tissues of the body, which can lead to progressive deterioration (atrophy) of certain areas of the brain, neurological disorders and other characteristic symptoms, and physical signs. Symptoms of Batten's disease usually appear between the ages of 5 and 15, when progressive vision loss develops, epilepsy and progressive neurological degeneration. In some cases, the initial symptoms may be more vague and include clumsiness, problems with balance, and changes in behavior or personality. Batten's disease is inherited as an autosomal recessive trait and occurs most commonly in families of Northern European or Scandinavian descent.
• Tay-Sachs disease Is a rare neurodegenerative disease in which a lack of an enzyme (hexosaminidase A) results in excessive accumulation of certain fats (lipids) known as gangliosides in the brain and nerves cells. This abnormal accumulation of gangliosides leads to progressive dysfunction of the central nervous system. This disorder refers to lysosomal storage disease. Lysosomes are the main digestive units in cells. Enzymes in lysosomes break down or "digest" nutrients, including some complex carbohydrates and fats. Symptoms associated with Tay-Sachs disease may include an exaggerated startle response to sudden noises, lethargy, loss of previously acquired skills (i.e. psychomotor regression) and severely reduced muscle tone (hypotension). As the disease progresses, affected infants and children may develop cherry red spots in the middle layer of the eyes, gradual loss of vision and deafness, increased muscle stiffness and limitation of movement, possible paralysis, uncontrolled electrical disturbances in the brain (epilepsy), and impairment of cognitive processes (dementia). The classic form of Tay-Sachs disease occurs in infancy; the adult form (late-onset Tay-Sachs disease) can occur at any time from adolescence to the mid-30s. Tay-Sachs disease is inherited in an autosomal recessive manner.
• Syndrome of neuropathy, ataxia and retinitis pigmentosa is a rare genetic disorder. It is characterized by nervous diseases affecting nerves outside the central nervous system (peripheral neuropathy), impaired the ability to coordinate voluntary movements (ataxia), an eye condition known as retinitis pigmentosa (PR), and many additional anomalies. PD is a general term for a group of visual impairments that cause progressive degeneration of the membrane that lines the eye (retina), resulting in impaired vision. The specific symptoms of the syndrome in each person vary greatly from case to case. The disease is a maternal hereditary mitochondrial disorder. The syndrome is caused by a specific mutation affecting a mitochondrial gene known as the ATPase 6 gene. This mutation can also cause a specific subtype of Lee syndrome.

Diagnostics

The diagnosis of Leigh's syndrome can be confirmed by careful clinical evaluation and a variety of specialized tests, in particular advanced imaging techniques. Brain scans using magnetic resonance imaging (MRI) or computed tomography (CT) can identify abnormal areas in specific parts of the brain (i.e., basal ganglia, brainstem, and seromas substance). MRI uses a magnetic field and radio waves to produce cross-sectional images of individual organs and tissues in the body. During a CT scan, a computer and an X-ray are used to create a film showing cross-sectional images of specific tissue structures. Small or large cysts can be found in the cerebral cortex.

Laboratory tests can reveal high levels of acidic waste products in the blood (lactic acidosis), as well as elevated levels of pyruvate and alanine. Blood sugar (glucose) may be slightly lower than normal. The enzyme pyruvate carboxylase may be absent in the liver, and an inhibitor of thiamine diphosphate production may be present in the blood and urine of patients. Some children with Lee syndrome may have a deficiency in the enzymes of the pyruvate dehydrogenase complex or cytochrome c oxidase.

Standard treatments

There are no proven treatments for any type of Lee syndrome. Treatment recommendations are based primarily on open-label studies, case reports and personal observations. Treatment for Lee syndrome focuses on the specific symptoms that each person experiences. Treatment may require a coordinated team of specialists. Pediatricians, Cardiologists, Neurologists, Hearing Evaluation and Treatment Professionals (Audiologists), Ophthalmologists and other health care providers may need systematic and comprehensive planning for effective treatment child.

The most common treatment for Leigh's syndrome is the administration of thiamine (vitamin B1) or its derivatives. Some people with this disorder may experience temporary symptomatic improvement and a slight slowdown in the progression of the disease. For those patients with Lee syndrome who also have a deficiency of the enzyme complex pyruvate dehydrogenase, a diet high in fat and low in carbohydrates.

Forecast

The prognosis of Lee's syndrome is poor, the life expectancy of most patients is low, up to several years.