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Leigh Syndrome (mtDNA mutation)

MedGen UID:
833803
Concept ID:
CN230159
Disease or Syndrome

Definition

Several other features may occur in people with Leigh syndrome. Many individuals with this condition develop weakness or paralysis of the muscles that move the eyes (ophthalmoparesis); rapid, involuntary eye movements (nystagmus); or degeneration of the nerves that carry information from the eyes to the brain (optic atrophy). Severe breathing problems are common, and these problems can worsen until they cause acute respiratory failure. Some affected individuals develop hypertrophic cardiomyopathy, which is a thickening of the heart muscle that forces the heart to work harder to pump blood. In addition, a substance called lactate can build up in the body, and excessive amounts are often found in the blood, urine, or the fluid that surrounds and protects the brain and spinal cord (cerebrospinal fluid) of people with Leigh syndrome.

The signs and symptoms of Leigh syndrome are caused in part by patches of damaged tissue (lesions) that develop in the brains of people with this condition. A medical procedure called magnetic resonance imaging (MRI) reveals characteristic lesions in certain regions of the brain. These regions include the basal ganglia, which help control movement; the cerebellum, which controls the ability to balance and coordinates movement; and the brainstem, which connects the brain to the spinal cord and controls functions such as swallowing and breathing. The brain lesions are often accompanied by loss of the myelin coating around nerves (demyelination), which reduces the ability of the nerves to activate muscles used for movement or relay sensory information from the rest of the body back to the brain.

The first signs of Leigh syndrome seen in infancy are usually vomiting, diarrhea, and difficulty swallowing (dysphagia), which disrupts eating. These problems often result in an inability to grow and gain weight at the expected rate (failure to thrive). Severe muscle and movement problems are common in Leigh syndrome. Affected individuals may develop weak muscle tone (hypotonia), involuntary muscle contractions (dystonia), and problems with movement and balance (ataxia). Loss of sensation and weakness in the limbs (peripheral neuropathy), common in people with Leigh syndrome, may also make movement difficult.

Leigh syndrome is a severe neurological disorder that usually becomes apparent in the first year of life. This condition is characterized by progressive loss of mental and movement abilities (psychomotor regression) and typically results in death within two to three years, usually due to respiratory failure. A small number of individuals do not develop symptoms until adulthood or have symptoms that worsen more slowly. [from MedlinePlus Genetics]

Professional guidelines

PubMed

Na JH, Lee YM
Acta Neurol Scand 2022 Apr;145(4):414-422. Epub 2021 Dec 7 doi: 10.1111/ane.13566. PMID: 34877647
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J Neurol Neurosurg Psychiatry 2014 Mar;85(3):257-65. Epub 2013 Jun 14 doi: 10.1136/jnnp-2012-304426. PMID: 23772060

Recent clinical studies

Etiology

Ibañez K, Polke J, Hagelstrom RT, Dolzhenko E, Pasko D, Thomas ERA, Daugherty LC, Kasperaviciute D, Smith KR; WGS for Neurological Diseases Group, Deans ZC, Hill S, Fowler T, Scott RH, Hardy J, Chinnery PF, Houlden H, Rendon A, Caulfield MJ, Eberle MA, Taft RJ, Tucci A; Genomics England Research Consortium
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Schon KR, Horvath R, Wei W, Calabrese C, Tucci A, Ibañez K, Ratnaike T, Pitceathly RDS, Bugiardini E, Quinlivan R, Hanna MG, Clement E, Ashton E, Sayer JA, Brennan P, Josifova D, Izatt L, Fratter C, Nesbitt V, Barrett T, McMullen DJ, Smith A, Deshpande C, Smithson SF, Festenstein R, Canham N, Caulfield M, Houlden H, Rahman S, Chinnery PF; Genomics England Research Consortium
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Ganetzky RD, Stendel C, McCormick EM, Zolkipli-Cunningham Z, Goldstein AC, Klopstock T, Falk MJ
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Wong LJ
Semin Neurol 2012 Feb;32(1):55-61. Epub 2012 Mar 15 doi: 10.1055/s-0032-1306387. PMID: 22422207

Diagnosis

Schon KR, Horvath R, Wei W, Calabrese C, Tucci A, Ibañez K, Ratnaike T, Pitceathly RDS, Bugiardini E, Quinlivan R, Hanna MG, Clement E, Ashton E, Sayer JA, Brennan P, Josifova D, Izatt L, Fratter C, Nesbitt V, Barrett T, McMullen DJ, Smith A, Deshpande C, Smithson SF, Festenstein R, Canham N, Caulfield M, Houlden H, Rahman S, Chinnery PF; Genomics England Research Consortium
BMJ 2021 Nov 3;375:e066288. doi: 10.1136/bmj-2021-066288. PMID: 34732400Free PMC Article
Ganetzky RD, Stendel C, McCormick EM, Zolkipli-Cunningham Z, Goldstein AC, Klopstock T, Falk MJ
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Pronicka E, Piekutowska-Abramczuk D, Ciara E, Trubicka J, Rokicki D, Karkucińska-Więckowska A, Pajdowska M, Jurkiewicz E, Halat P, Kosińska J, Pollak A, Rydzanicz M, Stawinski P, Pronicki M, Krajewska-Walasek M, Płoski R
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Valero T
Curr Pharm Des 2014;20(35):5507-9. doi: 10.2174/138161282035140911142118. PMID: 24606795
Baertling F, Rodenburg RJ, Schaper J, Smeitink JA, Koopman WJ, Mayatepek E, Morava E, Distelmaier F
J Neurol Neurosurg Psychiatry 2014 Mar;85(3):257-65. Epub 2013 Jun 14 doi: 10.1136/jnnp-2012-304426. PMID: 23772060

Therapy

Zilber S, Woleben K, Johnson SC, de Souza CFM, Boyce D, Freiert K, Boggs C, Messahel S, Burnworth MJ, Afolabi TM, Kayani S
Orphanet J Rare Dis 2023 Sep 4;18(1):264. doi: 10.1186/s13023-023-02886-0. PMID: 37667390Free PMC Article
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Schon KR, Horvath R, Wei W, Calabrese C, Tucci A, Ibañez K, Ratnaike T, Pitceathly RDS, Bugiardini E, Quinlivan R, Hanna MG, Clement E, Ashton E, Sayer JA, Brennan P, Josifova D, Izatt L, Fratter C, Nesbitt V, Barrett T, McMullen DJ, Smith A, Deshpande C, Smithson SF, Festenstein R, Canham N, Caulfield M, Houlden H, Rahman S, Chinnery PF; Genomics England Research Consortium
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Valero T
Curr Pharm Des 2014;20(35):5507-9. doi: 10.2174/138161282035140911142118. PMID: 24606795

Prognosis

Lopriore P, Gomes F, Montano V, Siciliano G, Mancuso M
Int J Mol Sci 2022 Oct 30;23(21) doi: 10.3390/ijms232113216. PMID: 36362003Free PMC Article
van de Wal MAE, Adjobo-Hermans MJW, Keijer J, Schirris TJJ, Homberg JR, Wieckowski MR, Grefte S, van Schothorst EM, van Karnebeek C, Quintana A, Koopman WJH
Brain 2022 Mar 29;145(1):45-63. doi: 10.1093/brain/awab426. PMID: 34849584Free PMC Article
Schon KR, Horvath R, Wei W, Calabrese C, Tucci A, Ibañez K, Ratnaike T, Pitceathly RDS, Bugiardini E, Quinlivan R, Hanna MG, Clement E, Ashton E, Sayer JA, Brennan P, Josifova D, Izatt L, Fratter C, Nesbitt V, Barrett T, McMullen DJ, Smith A, Deshpande C, Smithson SF, Festenstein R, Canham N, Caulfield M, Houlden H, Rahman S, Chinnery PF; Genomics England Research Consortium
BMJ 2021 Nov 3;375:e066288. doi: 10.1136/bmj-2021-066288. PMID: 34732400Free PMC Article
Valero T
Curr Pharm Des 2014;20(35):5507-9. doi: 10.2174/138161282035140911142118. PMID: 24606795
Baertling F, Rodenburg RJ, Schaper J, Smeitink JA, Koopman WJ, Mayatepek E, Morava E, Distelmaier F
J Neurol Neurosurg Psychiatry 2014 Mar;85(3):257-65. Epub 2013 Jun 14 doi: 10.1136/jnnp-2012-304426. PMID: 23772060

Clinical prediction guides

Baide-Mairena H, Marti-Sánchez L, Marcé-Grau A, Cazurro-Gutiérrez A, Sanchez-Montanez A, Delgado I, Moreno-Galdó A, Macaya-Ruiz A, García-Arumí E, Pérez-Dueñas B; Childhood Basal Ganglia Disease Group
Dev Med Child Neurol 2022 Jun;64(6):743-752. Epub 2022 Jan 5 doi: 10.1111/dmcn.15125. PMID: 34988976
Ganetzky RD, Stendel C, McCormick EM, Zolkipli-Cunningham Z, Goldstein AC, Klopstock T, Falk MJ
Hum Mutat 2019 May;40(5):499-515. Epub 2019 Mar 4 doi: 10.1002/humu.23723. PMID: 30763462Free PMC Article
Valero T
Curr Pharm Des 2014;20(35):5507-9. doi: 10.2174/138161282035140911142118. PMID: 24606795
Baertling F, Rodenburg RJ, Schaper J, Smeitink JA, Koopman WJ, Mayatepek E, Morava E, Distelmaier F
J Neurol Neurosurg Psychiatry 2014 Mar;85(3):257-65. Epub 2013 Jun 14 doi: 10.1136/jnnp-2012-304426. PMID: 23772060
Carrozzo R, Piemonte F, Tessa A, Lucioli S, Rizza T, Meschini MC, Fattori F, Santorelli FM
Biosci Rep 2007 Jun;27(1-3):105-12. doi: 10.1007/s10540-007-9039-y. PMID: 17486440

Recent systematic reviews

Chang X, Wu Y, Zhou J, Meng H, Zhang W, Guo J
Medicine (Baltimore) 2020 Jan;99(5):e18634. doi: 10.1097/MD.0000000000018634. PMID: 32000367Free PMC Article
Cruz ACP, Ferrasa A, Muotri AR, Herai RH
Mitochondrion 2019 May;46:345-360. Epub 2018 Sep 13 doi: 10.1016/j.mito.2018.09.005. PMID: 30218715
Fassone E, Rahman S
J Med Genet 2012 Sep;49(9):578-90. doi: 10.1136/jmedgenet-2012-101159. PMID: 22972949

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