Leigh syndrome

Leigh syndrome is a rare genetic neurometabolic disorder. It is characterized by degeneration of the central nervous system (i.e., the brain, spinal cord, and optic nerve). 

Symptoms of Leigh syndrome usually begin between three months and two years of age, but some patients develop symptoms only after several years. The symptoms are associated with progressive neurological deterioration and may include loss of previously acquired motor abilities, loss of appetite, vomiting, irritability, and/or seizure activity. As Leigh syndrome progresses, symptoms may also include generalized weakness, reduced muscle tone (hypotonia), and episodes of lactic acidosis, which may lead to impairment of respiratory and renal function. 

The syndrome, originally described more than 60 years ago, may be caused by several different genetically determined enzyme defects. Most individuals with Leigh syndrome have defects in mitochondrial energy metabolism, such as deficiency of an enzyme in the mitochondrial respiratory chain complex or the pyruvate dehydrogenase complex. In most cases, Leigh syndrome is inherited as an autosomal recessive trait. However, X-linked recessive inheritance and maternal inheritance due to mitochondrial DNA mutations are also possible modes of transmission.

Diagnosis

The diagnosis of Leigh syndrome may be confirmed by thorough clinical evaluation and a number of specialized tests, particularly advanced imaging techniques. Brain imaging using magnetic resonance imaging (MRI) or computed tomography (CT) may reveal abnormal areas in certain parts of the brain (i.e., the basal ganglia, brainstem, and gray matter). MRI uses a magnetic field and radio waves to produce cross-sectional images of specific organs and tissues. During CT scanning, a computer and X-rays are used to create images showing cross-sections of particular tissue structures.

In the cerebral cortex, small or large cysts may be present. Laboratory tests may reveal elevated levels of acidic waste products in the blood (lactic acidosis), as well as increased levels of pyruvate and alanine. Blood glucose (glucose) levels may be slightly lower than normal. The enzyme pyruvate carboxylase may be absent in the liver, and an inhibitor of thiamine triphosphate (TTP) production may be present in the blood and urine of affected individuals. Some children with Leigh syndrome may have detectable deficiencies in enzyme complexes such as pyruvate dehydrogenase or cytochrome C oxidase.

The classical form of Leigh syndrome develops in childhood (infantile necrotizing encephalopathy) and usually begins between 3 months and 2 years of age. This form of the disease affects males and females equally. In cases of Leigh syndrome inherited as an X-linked recessive trait, symptoms typically develop in childhood. In this form, males are affected almost twice as often as females. In some rare cases, Leigh syndrome may begin during late adolescence or early adulthood (subacute necrotizing encephalomyelopathy in adults). In these cases, which affect males about twice as often as females, progression of the disease is slower than in the classical form.

Researchers once believed that the classical form of Leigh syndrome accounted for approximately 80 percent of cases. In the medical literature, the prevalence of Leigh syndrome is estimated at 1 in 36,000–40,000 live births.

Several different types of genetically determined metabolic defects may lead to Leigh syndrome. This condition may be caused by deficiency of one or more different enzymes (e.g., mitochondrial respiratory chain enzymes or enzyme components of the pyruvate dehydrogenase complex). These enzyme deficiencies are caused by changes (mutations) in one of several different disease-related genes (genetic heterogeneity). These mutations may be inherited as an autosomal recessive trait, an X-linked recessive trait, or as a mutation located in mitochondrial DNA. In some cases of Leigh syndrome, no genetic cause can be identified.

Genetic information is contained in two types of DNA: nuclear DNA (nDNA) is located in the cell nucleus and is inherited from both biological parents. Mitochondrial DNA (mtDNA) is located in the mitochondria of cells and is inherited exclusively from the mother of the child. Genetic diseases resulting from mutations in nDNA (changes in genetic material) are determined by two genes, one inherited from the father and the other from the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one disease-causing gene, the person will be a carrier of the disease but will usually not show symptoms. The risk that two carrier parents will pass on the defective gene and have an affected child is 25% in each pregnancy. The risk of having a child who is a carrier like the parents is 50% in each pregnancy. The chance that a child will inherit normal genes from both parents and be genetically normal for this particular trait is 25%.

Additional enzyme deficiencies based on nDNA (i.e., NADH-CoQ and cytochrome c oxidase) have also been implicated as causes of some cases of autosomal recessive Leigh syndrome. These specific enzyme deficiencies are associated with several different genes. For example, mutations in the SURF1 gene located on chromosome 9 cause Leigh syndrome associated with cytochrome c oxidase deficiency. All these different genetic defects appear to have a common effect on the central nervous system, resulting in progressive neurological deterioration.

The medical literature also provides evidence for an X-linked recessive form of Leigh syndrome associated with nDNA. This form of the disease is associated with a specific defect in the gene known as the E1-alpha subunit of the pyruvate dehydrogenase complex, which is located on the short arm (p) of the X chromosome (Xp22.2–22.1). X-linked recessive disorders are conditions encoded on the X chromosome. Females have two X chromosomes, but males have one X chromosome and one Y chromosome. Therefore, in females, disease traits on one X chromosome may be masked by a normal gene on the other X chromosome. Because males have only one X chromosome, if they inherit the disease gene on the X chromosome, it will be expressed. Males with X-linked disorders pass the gene to all of their daughters, who are carriers, but never to their sons. Women who are carriers of an X-linked disorder have a 50% risk of passing the carrier trait to their daughters and a 50% risk of passing the disease to their sons.

In some cases, Leigh syndrome may be inherited from the mother as a mutation in mitochondrial DNA. Mitochondria, which are present in hundreds or thousands in almost every cell of the body, regulate cellular energy production and carry the genetic blueprint for this process in their own unique DNA (mtDNA). mtDNA from the father is carried by sperm, but during fertilization it is lost. As a result, all human mtDNA is inherited from the mother. An affected mother passes the trait to all her children, but only daughters transmit the mutation(s) to the next generation.

Genetic mutations present in mtDNA may outnumber normal copies of genes. Symptoms may not appear until mutations are present in a significant proportion of mitochondria. Uneven distribution of normal and mutant mtDNA in different tissues of the body may affect different organ systems in individuals within the same family and may result in different symptoms among affected family members. A specific mtDNA defect (mtDNA nt 8993), which may be responsible for some cases of Leigh syndrome, is associated with the gene known as ATPase 6 (complex V deficiency of the mitochondrial respiratory chain [ATPase deficiency]). These cases are sometimes referred to as maternally inherited Leigh syndrome (MILS) or Leigh syndrome associated with mtDNA.

Some researchers believe that cases of Leigh syndrome in adults may be inherited as an autosomal dominant trait due to mutation in nDNA. Dominant genetic disorders occur when only one copy of an abnormal gene is required for the expression of the disease. Because the condition is caused by a mutation in nDNA, the abnormal gene may be inherited from either parent or may result from a new mutation in the affected individual. The risk of transmitting the abnormal gene from an affected parent to offspring is 50% for each pregnancy, regardless of the sex of the child.

Therapy

There are no proven therapies for any form of Leigh syndrome. Treatment recommendations are based primarily on open studies, case reports, and personal observations. Treatment of Leigh syndrome is directed toward the specific symptoms present in each individual. Management may require the coordinated efforts of a team of specialists. Pediatricians, cardiologists, neurologists, specialists who evaluate and treat hearing problems (audiologists), ophthalmologists, and other healthcare professionals may need to systematically and comprehensively plan effective treatment for the affected child.

The most common treatment for Leigh syndrome is the administration of thiamine (vitamin B1) or thiamine derivatives. In some individuals with this disorder, temporary symptomatic improvement and a slight slowing of disease progression may occur. In patients with Leigh syndrome who also have deficiency of the pyruvate dehydrogenase enzyme complex, a high-fat, low-carbohydrate diet may be recommended.

Support services beneficial for individuals with visual impairment may also be helpful for some people with Leigh syndrome. Genetic counseling is recommended for families of affected individuals. Further treatment is symptomatic and supportive.

• progressive neurological disorder (onset between 3 months and 2 years of age)
• loss of previously acquired skills (loss of head control, poor sucking ability, loss of appetite, recurrent vomiting, irritability, persistent crying, possible seizures)
• failure to thrive
• if onset occurs later in childhood (after 2 years) – articulation problems (dysarthria) and ataxia (impaired coordination of voluntary movements)
• intellectual disability may occur
• reduced muscle tone, clumsiness, tremor, muscle spasms (spasticity), absence of tendon reflexes
• episodes of lactic acidosis may occur, characterized by abnormally high levels of lactic acid in the blood, brain, and other body tissues
• elevated carbon dioxide levels in the blood (hypercapnia) may also be present
• respiratory problems including temporary cessation of spontaneous breathing (apnea), breathing difficulties (dyspnea), abnormally rapid breathing (hyperventilation), and/or abnormal breathing patterns (Cheyne–Stokes respiration)
• some children may also have difficulty swallowing (dysphagia)
• visual problems may include abnormal rapid eye movements (nystagmus), sluggish pupils, crossed eyes (strabismus), paralysis of certain eye muscles (ophthalmoplegia), degeneration of the optic nerve (optic atrophy), and/or visual impairment leading to blindness
• possible cardiac involvement – abnormal enlargement of the heart (hypertrophic cardiomyopathy) and asymmetric septal hypertrophy
• a disorder affecting peripheral nerves (peripheral neuropathy) may occur, leading to progressive weakness of the arms and legs
• in some cases, color blindness or progressive vision loss
• in later life, varying degrees of dementia may occur