View source for Leigh syndrome

{{short description|Metabolic disease }}
{{Infobox medical condition (new)
| name            = Leigh syndrome
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| caption         = Detection of numerous ragged red fibers in a muscle biopsy
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| synonyms        = Juvenile subacute necrotizing encephalomyelopathy, Leigh disease, infantile subacute necrotizing encephalomyelopathy, subacute necrotizing encephalomyelopathy (SNEM)<ref name=GHR/>
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'''Leigh syndrome''' (also called '''Leigh disease''' and '''subacute necrotizing encephalomyelopathy''') is an inherited neurometabolic disorder that affects the [[central nervous system]]. It is named after Archibald Denis Leigh, a British [[neuropsychiatry|neuropsychiatrist]] who first described the condition in 1951.<ref>{{cite journal |doi=10.1192/pb.22.10.648 |title=Denis Archibald Leigh |journal=Psychiatric Bulletin |volume=22 |issue=10 |pages=648–9 |year=2018 |last1=Noble |first1=Peter |doi-access=free }}</ref> Normal levels of [[thiamine]], [[thiamine monophosphate]], and [[thiamine diphosphate]] are commonly found, but there is a reduced or absent level of [[thiamine triphosphate]]. This is thought to be caused by a blockage in the enzyme [[thiamine-diphosphate kinase]], and therefore treatment in some patients would be to take thiamine triphosphate daily.<ref>{{cite journal |doi=10.1001/archneur.1974.00490400034002 |title=Leigh Disease: Biochemical Characteristics of the Inhibitor |journal=Archives of Neurology |volume=31 |issue=4 |pages=220–7 |year=1974 |last1=Murphy |first1=Jerome V }}</ref><ref>{{cite journal |pmid=1206418 |pmc=492163 |year=1975 |last1=Murphy |first1=J. V |title=Leigh's disease: Significance of the biochemical changes in brain |journal=Journal of Neurology, Neurosurgery, and Psychiatry |volume=38 |issue=11 |pages=1100–3 |last2=Craig |first2=L |doi=10.1136/jnnp.38.11.1100 }}</ref> While the majority of patients typically exhibit symptoms between the ages of 3 and 12 months, instances of adult onset have also been documented.<ref>{{Cite journal |last1=Gerards |first1=Mike |last2=Sallevelt |first2=Suzanne C.E.H. |last3=Smeets |first3=Hubert J.M. |date=March 2016 |title=Leigh syndrome: Resolving the clinical and genetic heterogeneity paves the way for treatment options |url=http://dx.doi.org/10.1016/j.ymgme.2015.12.004 |journal=Molecular Genetics and Metabolism |volume=117 |issue=3 |pages=300–312 |doi=10.1016/j.ymgme.2015.12.004 |pmid=26725255 |issn=1096-7192|url-access=subscription }}</ref>

==Signs and symptoms==
The symptoms of Leigh syndrome were classically described as beginning in infancy and leading to death within a span of several years;<ref name=GHR/> however, as more cases are recognized, it is apparent that symptoms can emerge at any age—including adolescence or adulthood—and patients can survive for many years following diagnosis.<ref name=NINDS/> Symptoms are often first seen after a triggering event that taxes the body's energy production, such as an infection or surgery. The general course of Leigh syndrome is one of episodic developmental regression during times of metabolic stress. Some patients have long periods without disease progression while others develop progressive decline.<ref name=pmid23772060/>

Infants with the syndrome have symptoms that include [[diarrhea]], [[vomiting]], and [[dysphagia]] (trouble swallowing or sucking), leading to a [[failure to thrive]].<ref name=GHR/> Children with early Leigh disease also may appear irritable and cry much more than healthy babies. Seizures are often seen, with reported prevalence of seizures in Leigh syndrome that ranges from 40% to 79%.<ref>{{Cite journal |last1=Sofou |first1=Kalliopi |last2=De Coo |first2=Irenaeus F M |last3=Isohanni |first3=Pirjo |last4=Ostergaard |first4=Elsebet |last5=Naess |first5=Karin |last6=De Meirleir |first6=Linda |last7=Tzoulis |first7=Charalampos |last8=Uusimaa |first8=Johanna |last9=De Angst |first9=Isabell B |last10=Lönnqvist |first10=Tuula |last11=Pihko |first11=Helena |last12=Mankinen |first12=Katariina |last13=Bindoff |first13=Laurence A |last14=Tulinius |first14=Már |last15=Darin |first15=Niklas |date=2014 |title=A multicenter study on Leigh syndrome: disease course and predictors of survival |journal=Orphanet Journal of Rare Diseases |volume=9 |issue=1 |pages=52 |doi=10.1186/1750-1172-9-52 |pmid=24731534 |pmc=4021638 |issn=1750-1172 |doi-access=free }}</ref> Excess [[lactic acid|lactate]] may be seen in the [[urine]], [[cerebrospinal fluid]], and [[blood]] of a person with Leigh syndrome.<ref name=NINDS/>

As the disease progresses, the [[muscular system]] is debilitated throughout the body, as the brain cannot control the contraction of muscles. [[Hypotonia]] (low [[muscle tone]] and strength), [[dystonia]] (involuntary, sustained muscle contraction), and [[ataxia]] (lack of control over movement) are often seen in people with Leigh disease. The [[eyes]] are particularly affected; the muscles that control the eyes become weak, paralyzed, or uncontrollable in conditions called [[ophthalmoparesis]] (weakness or paralysis) and [[nystagmus]] (involuntary eye movements).<ref name=GHR/> Slow [[saccades]] are also sometimes seen.<ref name=pmid23772060/> The [[heart]] and [[lungs]] can also fail as a result of Leigh disease. [[Hypertrophic cardiomyopathy]] (thickening of part of the heart muscle) is also sometimes found and can cause death;<ref name=GHR/> [[Hypertrophic cardiomyopathy#Obstructive and non-obstructive|asymmetric septal hypertrophy]] has also been associated with Leigh syndrome.<ref name=OMIM/> In children with Leigh-syndrome associated [[ventricular septal defect]]s, caused by pyruvate dehydrogenase deficiency, high forehead and large ears are seen; facial abnormalities are not typical of Leigh syndrome.<ref name=pmid23772060/>

However, [[respiratory failure]] is the most common cause of death in people with Leigh syndrome. Other neurological symptoms include [[peripheral neuropathy]], loss of sensation in extremities caused by damage to the [[peripheral nervous system]].<ref name=GHR>{{cite web |url = https://medlineplus.gov/genetics/condition/leigh-syndrome/ |title = Leigh syndrome |work = Genetics Home Reference |publisher = National Institute of Health |access-date = 16 October 2013 |date = 23 September 2013}}</ref>

[[Hypertrichosis]] is seen in Leigh syndrome caused by mutations in the nuclear gene [[SURF1]].<ref name=pmid23772060/>

==Genomics==
[[Image:Mitochondria, mammalian lung - TEM.jpg|thumb|250px|right|Two healthy mitochondria from mammalian lung tissue as shown by electron microscopy]]

[[Mutation]]s in [[mitochondrial DNA]] (mtDNA) and over 30 genes in [[nuclear DNA]] (gene ''[[SURF1]]''<ref name=pmid17908801>{{cite journal |doi=10.1136/jcp.2007.051060 |pmid=17908801 |pmc=2571978 |title=Light and electron microscopy characteristics of the muscle of patients with SURF1 gene mutations associated with Leigh disease |journal=Journal of Clinical Pathology |volume=61 |issue=4 |pages=460–6 |year=2008 |last1=Pronicki |first1=M |last2=Matyja |first2=E |last3=Piekutowska-Abramczuk |first3=D |last4=Szymanska-Debinska |first4=T |last5=Karkucinska-Wieckowska |first5=A |last6=Karczmarewicz |first6=E |last7=Grajkowska |first7=W |last8=Kmiec |first8=T |last9=Popowska |first9=E |last10=Sykut-Cegielska |first10=J }}</ref> and some [[Cytochrome c oxidase|COX]] assembly factors) have been implicated in Leigh disease.<ref name=GHR/>

Disorders of [[oxidative phosphorylation]], the process by which cells produce their main energy source of [[adenosine triphosphate]] (ATP), may be caused by mutations in either mtDNA or in nuclear encoded genes. The latter account for the majority of Leigh disease, although it is not always possible to identify the specific mutation responsible for the condition in a particular individual. Four out of the five [[protein complex]]es involved in oxidative phosphorylation are most commonly disrupted in Leigh syndrome, either because of malformed protein or because of an error in the assembly of these complexes. Regardless of the genetic basis, it results in an inability of the complexes affected by the mutation to perform their role in oxidative phosphorylation. In the case of Leigh disease, crucial cells in the [[brain stem]] and basal ganglia are affected. This causes a chronic lack of energy in the cells, which leads to cell death and in turn, affects the central nervous system and inhibits motor functions. The heart and other muscles also require a significant amount of energy and are affected by cell death caused by chronic energy deficiencies in Leigh syndrome.<ref name=GHR/>

===Mitochondrial DNA mutations===
[[Mitochondria]] are essential [[organelle]]s in [[eukaryote|eukaryotic]] cells. Their function is to convert the potential energy of [[glucose]], [[amino acid]]s, and [[fatty acid]]s into [[adenosine triphosphate]] (ATP) in a process called [[oxidative phosphorylation]]. Mitochondria carry their own [[DNA]], called mitochondrial DNA (mtDNA). The information stored in the mtDNA is used to produce several of the [[enzyme]]s essential to the production of ATP.<ref name=GHR/>

Between 20 and 25 percent of Leigh syndrome cases are caused by mutations in mitochondrial DNA. The most common of these mutations is found in 10 to 20 percent of Leigh syndrome and occurs in [[MT-ATP6]], a gene that codes for a protein in the last complex of the oxidative phosphorylation chain, [[ATP synthase]], an enzyme that directly generates ATP. Without ATP synthase, the electron transport chain will not produce any ATP.<ref name=GHR/> The most common MT-ATP6 mutation found with Leigh syndrome is a [[point mutation]] at nucleotide 8993 that changes a [[thymine]] to a [[guanine]]. This and other point mutations associated with Leigh syndrome destabilize or malform the protein complex and keep energy production down in affected cells.<ref>{{cite web |url = https://medlineplus.gov/genetics/gene/mt-atp6/ |title = MT-ATP6 |work = Genetics Home Reference |publisher = NIH |date = 19 November 2013 |access-date = 25 November 2013}}</ref> Several mitochondrial genes involved in creating the first complex of the oxidative phosphorylation chain can be implicated in a case of Leigh syndrome, including genes [[MT-ND2]], [[MT-ND3]], [[MT-ND5]], [[MT-ND6]] and [[MT-CO1]].<ref name=OMIM/><ref name=Poole2019>{{cite journal |last1=Poole |first1=Olivia V. |last2=Everett |first2=Chris M. |last3=Gandhi |first3=Sonia |last4=Marino |first4=Silvia |last5=Bugiardini |first5=Enrico |last6=Woodward |first6=Cathy |last7=Lam |first7=Amanda |last8=Quinlivan |first8=Ros |last9=Hanna |first9=Michael G. |last10=Pitceathly |first10=Robert D.S. |title=Adult-onset Leigh syndrome linked to the novel stop codon mutation m.6579G>A in MT-CO1 |journal=Mitochondrion |date=July 2019 |volume=47 |pages=294–297 |doi=10.1016/j.mito.2019.02.004 |pmid=30743023 |s2cid=73445211 |url=http://discovery.ucl.ac.uk/10068646/ |url-access=subscription }}</ref>

Mitochondrial DNA is passed down matrilineally in a pattern called [[maternal inheritance]]—a mother can transmit the genes for Leigh syndrome to both male and female children, but fathers cannot pass down mitochondrial genes.<ref name=GHR/>

===Nuclear DNA mutations===
[[File:Autosomal recessive - en.svg|thumb|250px|right|The autosomal recessive pattern of inheritance seen in some cases of Leigh syndrome]]

[[Nuclear DNA]] comprises most of the [[genome]] of an organism and in [[sexual reproduction|sexually reproducing]] organisms is inherited from both parents, in contrast to mitochondrial DNA's maternal pattern of inheritance. Leigh syndrome caused by nuclear DNA mutations is inherited in an [[autosomal recessive]] pattern. This means that two copies of the mutated gene are required to cause the disease, so two unaffected parents, each of whom carries one mutant [[allele]], can have an affected child if that child inherits the mutant allele from both parents.<ref name=GHR/>

75 to 80 percent of Leigh syndrome is caused by mutations in nuclear DNA; mutations affecting the function or assembly of the fourth complex involved in oxidative phosphorylation, [[cytochrome c oxidase]] (COX), cause most cases of Leigh disease. Mutations in a gene called [[SURF1]] (surfeit1) are the most common cause of this subtype of Leigh syndrome. The protein that SURF1 codes for is terminated early and therefore cannot perform its function, shepherding the subunits of COX together into a functional protein complex. This results in a deficit of COX protein, reducing the amount of energy produced by mitochondria.<ref name=GHR/> SURF1 is located on the long arm of [[chromosome 9]].<ref>{{cite web |url = https://medlineplus.gov/genetics/gene/surf1/ |title = SURF1 |publisher = NIH |work = Genetics Home Reference |date = 19 November 2013 |access-date = 25 November 2013}}</ref> Some types of SURF1 mutations cause a subtype of Leigh syndrome that has a particularly late onset but similarly variable clinical course.<ref name=pmid23772060/> Another nuclear DNA mutation that causes Leigh syndrome, gene [[Dihydrolipoamide dehydrogenase|DLD]], affects another protein complex in the mitochondria, the [[pyruvate dehydrogenase complex]].<ref name="GHR" /><ref name="OMIM" />

Other nuclear genes associated with Leigh syndrome are located on [[chromosome 2]] ([[BCS1L]] and [[NDUFA10]]); [[chromosome 5]] ([[SDHA]], [[NDUFS4]], [[NDUFAF2]], and [[NDUFA2]]); [[chromosome 8]] ([[NDUFAF6]]), [[chromosome 10]] ([[COX15]]); [[chromosome 11]] ([[NDUFS3]], [[NDUFS8]], and [[FOXRED1]]); [[chromosome 12]] ([[NDUFA9]] and [[NDUFA12]]); and [[chromosome 19]] ([[NDUFS7]]). SDHA is the only nuclear-coded protein present in the mitochondrial electron transport chain (as complex II), and [[Mitochondrial complex II deficiency]], in its biallelic form, causes Leigh syndrome.<ref name="Fullerton">{{cite journal |vauthors=Fullerton M, McFarland R, Taylor RW, Alston CL |title=The genetic basis of isolated mitochondrial complex II deficiency |journal=Mol Genet Metab |volume=131 |issue=1–2 |pages=53–65 |date=2020 |pmid=33162331 |pmc=7758838 |doi=10.1016/j.ymgme.2020.09.009 }}</ref> Many of these genes affect the first oxidative phosphorylation complex.<ref name=OMIM>{{OMIM|256000|Leigh Syndrome}}</ref>

===X-linked Leigh syndrome===
[[File:X-linked recessive (carrier mother).svg|thumb|250px|right|The [[X-linked recessive]] pattern of inheritance seen occasionally in cases of Leigh syndrome]]

Leigh syndrome can also be caused by deficiency of the [[Pyruvate dehydrogenase complex|pyruvate dehydrogenase complex (PDHC)]], the x-linked gene being [[Pyruvate dehydrogenase (lipoamide) alpha 1|PDHA1]].<ref name="OMIM" /> In general, there are two major presentations of [[Pyruvate dehydrogenase deficiency|PDH deficiency]], metabolic and neurologic, which occur at equal frequency.<ref name=":0">{{Cite journal |last1=Brown |first1=G. K. |last2=Otero |first2=L. J. |last3=LeGris |first3=M. |last4=Brown |first4=R. M. |date=1994-11-01 |title=Pyruvate dehydrogenase deficiency. |url=https://jmg.bmj.com/content/31/11/875 |journal=Journal of Medical Genetics |language=en |volume=31 |issue=11 |pages=875–879 |doi=10.1136/jmg.31.11.875 |issn=0022-2593 |pmid=7853374|pmc=1016663 }}</ref> The metabolic form presents as severe [[lactic acidosis]] in the newborn period, and many die as newborns.<ref name=":0" /> Patients with the neurologic presentation are [[Hypotonia|hypotonic]] (low muscle tone), feed poorly, lethargic, and develop seizures, mental retardation, microcephaly, blindness and spasticity secondary to contractures.<ref name=":0" /> "Between these two extremes, there is a continuous spectrum of intermediate forms...A number of patients with primarily neurological symptoms fit into the category of Leigh's syndrome."<ref name=":0" />

[[X-linked recessive]] Leigh syndrome affects male children far more often than female children because they only have one copy of the [[X chromosome]]. Female children would need two copies of the faulty gene to be affected by X-linked Leigh syndrome.<ref name=GHR/>

===French Canadian Leigh syndrome===
The type of Leigh syndrome found at a much higher rate in the [[Saguenay–Lac-Saint-Jean]] region of Quebec is caused by a mutation in the [[LRPPRC]] gene, located on the small ('p') arm of chromosome 2.<ref name=OMIM/><ref name=LSFC-OMIM>{{cite web |url = http://omim.org/entry/220111 |title = Leigh Syndrome, French Canadian type |work = Online Mendelian Inheritance in Man |date = 1 December 2011 |publisher = Johns Hopkins University |access-date = 25 December 2013}}</ref> Both [[compound heterozygosity]] and [[homozygous]] mutations have been observed in French Canadian Leigh syndrome. This subtype of the disease was first described in 1993 in 34 children from the region, all of whom had a severe deficiency in [[cytochrome c oxidase]] (COX), the fourth complex in the mitochondrial [[electron transport chain]]. Though the subunits of the protein found in affected cells were functional, they were not properly assembled. The deficiency was found to be almost complete in brain and liver tissues and substantial (approximately 50% of normal enzyme activity) in [[fibroblast]]s (connective tissue cells) and [[skeletal muscle]]. Kidney and heart tissues were found to not have a COX deficiency.<ref name=LSFC-OMIM/>

French Canadian Leigh syndrome has similar symptoms to other types of Leigh syndrome. The age of onset is, on average, 5 months and the median age of death is 1 year and 7 months. Children with the disease are [[Developmental disability|developmentally delayed]], have mildly [[dysmorphism|dysmorphic]] facial features, including [[hypoplasia]] of the midface and wide [[nasal bridge]], chronic [[metabolic acidosis]], and [[hypotonia]] (decreased muscular strength). Other symptoms include [[tachypnea]] (unusually quick breathing rate), poor sucking ability, [[hypoglycemia]] (low blood sugar), and [[tremor]]s. Severe, sudden metabolic acidosis is a common cause of mortality.<ref name=LSFC-OMIM/>

Estimates of the rate of [[genetic carrier]]s in the Saguenay–Lac-Saint-Jean region range from 1 in 23 to 1 in 28; the number of children born with the disease has been estimated at 1 in 2063 to 1 in 2473 live births. Genealogic studies suggest that the responsible mutation was introduced to the region by early European settlers.<ref name=LSFC-OMIM/>

==Pathophysiology==
The characteristic symptoms of Leigh syndrome are at least partially caused by bilateral, focal [[lesion]]s in the [[brainstem]], [[basal ganglia]], [[cerebellum]], and other regions of the brain. The lesions take on different forms, including areas of [[demyelination]], [[spongiosis]], [[gliosis]], [[necrosis]], and [[capillary]] proliferation.<ref name=OMIM/> Demyelination is the loss of the [[myelin sheath]] around the [[axon]]s of neurons, inhibiting their ability to communicate with other neurons. The brain stem is involved in maintaining basic life functions such as breathing, swallowing, and circulation; the basal ganglia and cerebellum control movement and balance. Damage to these areas therefore results in the major symptoms of Leigh syndrome—loss of control over functions controlled by these areas.<ref name=GHR/>

The lactic acidosis sometimes associated with Leigh syndrome is caused by the buildup of [[pyruvate]], which is unable to be processed in individuals with certain types of oxidative phosphorylation deficiencies. The pyruvate is either converted into [[alanine]] via [[alanine aminotransferase]] or converted into lactic acid by [[lactate dehydrogenase]]; both of these substances can then build up in the body.<ref name=pmid23772060/>

==Diagnosis==
Leigh syndrome is suggested by clinical findings and confirmed with laboratory and [[genetic testing]].<ref name=pmid23772060/>

===Clinical findings===
Dystonia, [[nystagmus]], and problems with the [[autonomic nervous system]] suggest damage to the [[basal ganglia]] and [[brain stem]] potentially caused by Leigh syndrome. Other symptoms are also indicative of brain damage, such as [[hypertrichosis]] and neurologically caused [[deafness]]. Laboratory findings of lactic acidosis or acidemia and [[hyperalaninemia]] (elevated levels of [[alanine]] in the blood) can also suggest Leigh syndrome. Assessing the level of organic acids in urine can also indicate a dysfunction in the [[metabolic pathway]].<ref name=pmid23772060/>

===Differential diagnosis===
Other diseases can have a similar clinical presentation to Leigh syndrome; excluding other causes of similar clinical symptoms is often a first step to diagnosing Leigh syndrome. Conditions that can appear similar to Leigh disease include [[perinatal asphyxia]], [[kernicterus]], [[carbon monoxide poisoning]], [[methanol toxicity]], [[thiamine deficiency]], [[Wilson's disease]], [[biotin-thiamine-responsive basal ganglia disease]] (BTBGD), and some forms of [[encephalitis]]. Perinatal asphyxia can cause bilateral ganglial lesions and damage to the [[thalamus]], which are similar to the signs seen with Leigh syndrome. When [[hyperbilirubinemia]] is not treated with [[phototherapy]], the [[bilirubin]] can accumulate in the [[basal ganglia]] and cause lesions similar to those seen in Leigh syndrome. This is not common since the advent of phototherapy.<ref name=pmid23772060/>

==Treatment==
[[Succinic acid]] has been studied, and shown effective for both Leigh syndrome, and [[MELAS syndrome]].<ref>{{cite journal |doi=10.1038/ncomms12317 |pmid=27502960 |pmc=4980488 |title=Cell-permeable succinate prodrugs bypass mitochondrial complex I deficiency |journal=Nature Communications |volume=7 |article-number=12317 |year=2016 |last1=Ehinger |first1=Johannes K |last2=Piel |first2=Sarah |last3=Ford |first3=Rhonan |last4=Karlsson |first4=Michael |last5=Sjövall |first5=Fredrik |last6=Frostner |first6=Eleonor Åsander |last7=Morota |first7=Saori |last8=Taylor |first8=Robert W |last9=Turnbull |first9=Doug M |last10=Cornell |first10=Clive |last11=Moss |first11=Steven J |last12=Metzsch |first12=Carsten |last13=Hansson |first13=Magnus J |last14=Fliri |first14=Hans |last15=Elmér |first15=Eskil |bibcode=2016NatCo...712317E }}</ref><ref name=pmid15206559>{{cite journal |doi=10.2169/internalmedicine.43.427 |pmid=15206559 |title=Successful Treatment with Succinate in a Patient with MELAS |journal=Internal Medicine |volume=43 |issue=5 |pages=427–31 |year=2004 |last1=Oguro |first1=Hiroaki |last2=Iijima |first2=Kenichi |last3=Takahashi |first3=Kazuo |last4=Nagai |first4=Atsushi |last5=Bokura |first5=Hirokazu |last6=Yamaguchi |first6=Shuhei |last7=Kobayashi |first7=Shotai |doi-access=free }}</ref> A high-fat, [[low-carbohydrate diet]] may be followed if a gene on the X chromosome is implicated in an individual's Leigh syndrome. [[Thiamine]] (vitamin B<sub>1</sub>) may be given if [[pyruvate dehydrogenase deficiency]] is known or suspected. The symptoms of lactic acidosis are treated by supplementing the diet with [[sodium bicarbonate]] (baking soda) or [[sodium citrate]], but these substances do not treat the cause of Leigh syndrome. [[Dichloroacetate]] may also be effective in treating Leigh syndrome-associated lactic acidosis; research is ongoing on this substance.<ref name=NINDS/> [[Coenzyme Q10]] supplements have been seen to improve symptoms in some cases.<ref name=OMIM/>

Clinical trials of the drug EPI-743 for Leigh syndrome are ongoing.<ref>{{cite web |url=http://www.mitoaction.org/epi743 |title=EPI743 &#124; Mitochondrial Disease Action Committee - MitoAction |access-date=2013-07-24 |url-status=dead |archive-url=https://web.archive.org/web/20130819052414/http://www.mitoaction.org//epi743 |archive-date=2013-08-19 }}</ref>

In 2016, [[John Zhang (scientist)|John Zhang]] and his team at New Hope Fertility Center in New York, USA, performed a [[spindle transfer]] [[mitochondrial donation]] technique on a mother in Mexico who was at risk of producing a baby with Leigh disease. A healthy boy was born on 6 April 2016. However, it is not yet certain if the technique is completely reliable and safe.<ref>{{Cite news|url=https://www.bbc.co.uk/news/health-37485263|title=First 'three person baby' born using new method|last=Roberts|first=Michelle|date=2016-09-27|newspaper=BBC News|language=en-GB|access-date=2016-09-28}}</ref>

== Prognosis ==
Different genetic causes and types of Leigh syndrome have different prognoses, though all are poor. The most severe forms of the disease, caused by a full deficiency in one of the affected proteins, cause death at a few years of age. If the deficiency is not complete, the prognosis is somewhat better and an affected child is expected to survive 6–7 years, and in rare cases, to their teenage years.<ref name=NINDS>{{cite web |url = http://www.ninds.nih.gov/disorders/leighsdisease/leighsdisease.htm |title = NINDS Leigh's Disease Information Page |publisher = NIH |work = National Institute of Neurological Diseases and Stroke |date = 16 December 2011 |access-date = 25 November 2013 |archive-url = https://web.archive.org/web/20131203053441/http://www.ninds.nih.gov/disorders/leighsdisease/leighsdisease.htm |archive-date = 3 December 2013 |url-status = dead }}</ref>

==Epidemiology==
Leigh syndrome occurs in at least 1 of 40,000 live births, though certain populations have much higher rates. In the [[Saguenay–Lac-Saint-Jean]] region of central [[Quebec]], Leigh syndrome occurs at a rate of 1 in 2000 newborns.<ref name=GHR/>

==History==
Leigh syndrome was first described by [[Denis Leigh]] in 1951<ref name=pmid14874135>{{cite journal |doi=10.1136/jnnp.14.3.216 |pmid=14874135 |pmc=499520 |title=Subacute Necrotizing Encephalomyelopathy in an Infant |journal=Journal of Neurology, Neurosurgery & Psychiatry |volume=14 |issue=3 |pages=216–21 |year=1951 |last1=Leigh |first1=D }}</ref> and distinguished from similar [[Wernicke's encephalopathy]] in 1954.<ref name=OMIM/> In 1968, the disease's link with mitochondrial activity was first ascertained, though the mutations in cytochrome c oxidase and other [[electron transport chain]] proteins were not discovered until 1977.<ref name=pmid23772060>{{cite journal |doi=10.1136/jnnp-2012-304426 |pmid=23772060 |title=A guide to diagnosis and treatment of Leigh syndrome |journal=Journal of Neurology, Neurosurgery & Psychiatry |volume=85 |issue=3 |pages=257–65 |year=2013 |last1=Baertling |first1=F |last2=Rodenburg |first2=R. J |last3=Schaper |first3=J |last4=Smeitink |first4=J. A |last5=Koopman |first5=W. J. H |last6=Mayatepek |first6=E |last7=Morava |first7=E |last8=Distelmaier |first8=F |s2cid=45323262 }}</ref>

==See also==
* [[Joseph Maraachli case]]
* [[Neuropathy, ataxia, and retinitis pigmentosa]]

==References==
{{Reflist}}

==Further reading==
* [https://www.ncbi.nlm.nih.gov/books/NBK1173/  GeneReviews/NCBI/NIH/UW entry on Mitochondrial DNA-Associated Leigh Syndrome and NARP]
* [https://omim.org/search?index=entry&start=1&limit=10&search=omim/256000,516000,516001,516002,516003,516005,516006,516050,516060,551500,590050,590060,590095,590105,256000,516000,516001,516002,516003,516005,516006,516050,516060,551500,590050,590060,590095,590105&sort=score+desc&field=number  OMIM entries on Mitochondrial DNA-Associated Leigh Syndrome and NARP]
* {{RareDiseases|6877|Leigh syndrome}}

== External links ==
{{Medical resources
|  DiseasesDB      = 30792
|  ICD10           = {{ICD10|G|31|8|g|30}}
|  ICD9            = {{ICD9|330.8}}
|  ICDO            =
|  OMIM            = 256000
|  MedlinePlus     =
|  eMedicineSubj   =
|  eMedicineTopic  =
|  MeshID          = D007888
}}
{{Diseases of the nervous system}}
{{Mitochondrial diseases}}
{{Disorders of TCA and ETC}}

[[Category:Mitochondrial diseases]]
[[Category:Neurological disorders]]
[[Category:Neurological disorders in children]]
[[Category:Rare syndromes]]
[[Category:TCA and ETC metabolism disorders]]
[[Category:Diseases named after discoverers]]