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Disease Profile

Leigh syndrome

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

Age of onset

All ages

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ICD-10

G31.8

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

LS; Subacute necrotizing encephalopathy; SNE;

Categories

Congenital and Genetic Diseases; RDCRN

Summary

Leigh syndrome is a rare, inherited neurodegenerative condition. It usually becomes apparent in infancy, often after a viral infection. Rarely, it begins in the teenage or adult years. Signs and symptoms usually progress rapidly. Early symptoms may include poor sucking ability; loss of head control and motor skills; loss of appetite; vomiting; and seizures.[1] As the condition progresses, symptoms may include weakness and lack of muscle tone; spasticity; movement disorders; cerebellar ataxia; and peripheral neuropathy. Complications can lead to impairment of respiratory, heart and kidney function.[2] The term "Leigh-like syndrome" is often used for people with features that are strongly suggestive of Leigh syndrome but who do not meet the diagnostic criteria.[3] 

The inheritance of Leigh syndrome depends on where the responsible gene is located in each case. This is because it can be due to mutations in either mitochondrial DNA or nuclear DNA:[3][2][4]

Treatment is based on the symptoms present and depends on the type of Leigh syndrome a person has.[2][4] While life expectancy depends on the cause of Leigh syndrome in each person, most do not survive past mid-childhood or adolescence.[1]

Symptoms

The symptoms of Leigh syndrome vary greatly from person to person. Very rarely, affected people with near-normal neurologic findings have been reported. Most people with Leigh syndrome have central nervous system and peripheral nervous system abnormalities, without involvement of other body systems.[5]

Central nervous system abnormalities may include:[1][5]

Peripheral nervous system abnormalities may include polyneuropathy and myopathy.[1][5]

Although most people with Leigh syndrome only have neurological abnormalities, some people also have non-neurologic abnormalities. These may include:[5]

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Abnormality of movement
Movement disorder
Unusual movement

[ more ]

0100022
Ataxia
0001251
Cognitive impairment
Abnormality of cognition
Cognitive abnormality
Cognitive defects
Cognitive deficits
Intellectual impairment
Mental impairment

[ more ]

0100543
Decreased activity of mitochondrial respiratory chain
0008972
Muscular hypotonia
Low or weak muscle tone
0001252
Nystagmus
Involuntary, rapid, rhythmic eye movements
0000639
Respiratory insufficiency
Respiratory impairment
0002093
Strabismus
Cross-eyed
Squint
Squint eyes

[ more ]

0000486
30%-79% of people have these symptoms
Hemiplegia/hemiparesis
Paralysis or weakness of one side of body
0004374
Optic atrophy
0000648
Progressive ophthalmoplegia
0007650
Progressive spastic paraplegia
0007020
Seizure
0001250
Percent of people who have these symptoms is not available through HPO
Abnormal pattern of respiration
Abnormal respiratory patterns
Unusual breathing patterns

[ more ]

0002793
Autosomal recessive inheritance
0000007
CNS demyelination
0007305
Dysarthria
Difficulty articulating speech
0001260
Dystonia
0001332
Emotional lability
Emotional instability
0000712
Failure to thrive
Faltering weight
Weight faltering

[ more ]

0001508
Generalized hypotonia
Decreased muscle tone
Low muscle tone

[ more ]

0001290
Global developmental delay
0001263
Hepatocellular necrosis
Death of liver cells
0001404
Hyperreflexia
Increased reflexes
0001347
Hypertrichosis
0000998
Increased CSF lactate
0002490
Increased serum lactate
0002151
Infantile onset
Onset in first year of life
Onset in infancy

[ more ]

0003593
Intellectual disability
Mental deficiency
Mental retardation
Mental retardation, nonspecific
Mental-retardation

[ more ]

0001249
Lactic acidosis
Increased lactate in body
0003128
Mitochondrial inheritance
0001427
Ophthalmoplegia
Eye muscle paralysis
0000602
Pigmentary retinopathy
0000580
Progressive
Worsens with time
0003676
Psychomotor retardation
0025356
Ptosis
Drooping upper eyelid
0000508
Respiratory failure
0002878
Sensorineural hearing impairment
0000407
Spasticity
Involuntary muscle stiffness, contraction, or spasm
0001257

Cause

Leigh syndrome can be caused by mutations in any of more than 75 different genes. Most of our genes are made up of DNA in the cell's nucleus (nuclear DNA). Some of our genes are made up of DNA in other cell structures called mitochondria (mitochondrial DNA, or mtDNA). Most people with Leigh syndrome have a mutation in nuclear DNA, and about 20% have a mutation in mtDNA.

Most genes associated with Leigh syndrome are involved in the process of energy production in mitochondria (oxidative phosphorylation). Five protein complexes, named complex I through complex IV, are involved in this process. Many of the gene mutations associated with Leigh syndrome disrupt the function of proteins in these complexes, how the complexes form, or additional steps related to energy production. Researchers believe that impaired oxidative phosphorylation may cause cells to die because they don't have enough energy. The death of brain cells likely contributes to the neurologic features of the condition, while the death of cells in other tissues may lead to additional symptoms in other parts of the body.[2]

More information about the genes responsible for Leigh syndrome is available here on the Genetics Home Reference website.

Diagnosis

Leigh syndrome may be diagnosed by using the following criteria, defined by Rahman et al. in 1996:[3]

  • Progressive neurologic disease with motor and intellectual developmental delay
  • Signs and symptoms of brainstem and/or basal ganglia disease
  • Raised lactate concentration in blood and/or cerebrospinal fluid (CSF)
  • The presence of one or more of the following:
    • Characteristic features on brain imaging (CT scan or MRI)
    • Typical nervous system tissue changes
    • Typical nervous system tissue changes in a similarly affected sibling

After these criteria are met and a diagnosis of Leigh syndrome is made, molecular genetic testing can then differentiate between mtDNA-associated Leigh syndrome (caused by mutations in mtDNA) and nuclear gene-encoded Leigh syndrome (caused by mutations in nuclear DNA).[3] A diagnosis of nuclear gene-encoded Leigh syndrome can be made either by identifying a mutation in nuclear DNA, or by excluding the presence of a mutation in mtDNA.[4]

Because not all patients have increased lactate levels, recent studies proposed new diagnostic criteria excluding the raised lactate levels as a prerequisite. The remaining criteria are similar, but add mitochondrial dysfunction as a criterion.[3]

A diagnosis of Leigh-like syndrome may be considered in individuals who do not meet the strict diagnostic criteria but have features resembling Leigh syndrome.[3]

Testing Resources

  • The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.
  • Orphanet lists international laboratories offering diagnostic testing for this condition.

    Treatment

    Treatment of Leigh syndrome is directed toward the specific symptoms present in each person.[6]

    Supportive care for Leigh syndrome includes treatment of acidosis, seizures, dystonia, and cardiomyopathy, and attention to nutritional status.[4][3]

    Because anesthesia can potentially aggravate respiratory symptoms and bring on respiratory failure, careful consideration should be given to its use and close monitoring prior to, during, and after its use.[4][3]

    Progression and new symptoms should be monitored regularly (typically every 6-12 months). Evaluations with a neurologist, ophthalmologist, audiologist, and cardiologist are recommended.[4][3]

    Specific treatment is possible for the three nuclear gene-encoded Leigh-like syndromes (milder conditions with similar features). These include biotin-thiamine-responsive basal ganglia disease (BTBGD), biotinidase deficiency, and coenzyme Q10 deficiency caused by mutation of PDSS2.[4]

    Organizations

    Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

    Organizations Supporting this Disease

      Social Networking Websites

      • Visit the following Facebook groups related to Leigh syndrome:
        Leigh's Syndrome Parent Network
      • RareConnect has an online community for patients and families with this condition so they can connect with others and share their experiences living with a rare disease. The project is a joint collaboration between EURORDIS (European Rare Disease Organisation) and NORD (National Organization for Rare Disorders).

        Organizations Providing General Support

          Learn more

          These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

          Where to Start

            In-Depth Information

            • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
              Mitochondrial DNA-Associated Leigh Syndrome
              Nuclear Gene-Encoded Leigh Syndrome
            • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
            • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
            • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
            • PubMed is a searchable database of medical literature and lists journal articles that discuss Leigh syndrome. Click on the link to view a sample search on this topic.

              Selected Full-Text Journal Articles

                References

                1. Leigh's Disease Information Page. National Institute of Neurological Disorders and Stroke. December, 2011; https://www.ninds.nih.gov/disorders/leighsdisease/leighsdisease.htm.
                2. Leigh syndrome. Genetics Home Reference. June, 2016; https://ghr.nlm.nih.gov/condition/leigh-syndrome.
                3. Thronburn DR & Rahman S.. Mitochondrial DNA-Associated Leigh Syndrome and NARP. GeneReviews. April 17, 2014; https://www.ncbi.nlm.nih.gov/books/NBK1173/.
                4. Rahman S & Thorburn D. Nuclear Gene-Encoded Leigh Syndrome Overview. GeneReviews. October 1, 2015; https://www.ncbi.nlm.nih.gov/books/NBK320989/.
                5. Finsterer J. Leigh and Leigh-Like Syndrome in Children and Adults. Pediatr Neurol. 2008; https://www.ncbi.nlm.nih.gov/pubmed/18805359.
                6. Leigh Syndrome. NORD. 2016; https://rarediseases.org/rare-diseases/leigh-syndrome/.

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