Wikipedia

Leigh syndrome

Leigh syndrome(also calledLeigh diseaseandsubacute necrotizing encephalomyelopathy) is an inherited neurometabolic disorder that affects thecentral nervous system.It is named after Archibald Denis Leigh, a Britishneuropsychiatristwho first described the condition in 1951.[2]Normal levels ofthiamine,thiamine monophosphate,andthiamine diphosphateare commonly found, but there is a reduced or absent level ofthiamine triphosphate.This is thought to be caused by a blockage in the enzymethiamine-diphosphate kinase,and therefore treatment in some patients would be to take thiamine triphosphate daily.[3][4]While the majority of patients typically exhibit symptoms between the ages of 3 and 12 months, instances of adult onset have also been documented.[5]

Leigh syndrome
Other namesJuvenile subacute necrotizing encephalomyelopathy, Leigh disease, infantile subacute necrotizing encephalomyelopathy, subacute necrotizing encephalomyelopathy (SNEM)[1]
Detection of numerous ragged red fibers in a muscle biopsy
SpecialtyNeurologyEdit this on Wikidata

Signs and symptoms

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The symptoms of Leigh syndrome were classically described as beginning in infancy and leading to death within a span of several years;[1]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.[6]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.[7]

Infants with the syndrome have symptoms that includediarrhea,vomiting,anddysphagia(trouble swallowing or sucking), leading to afailure to thrive.[1]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%.[8]Excesslactatemay be seen in theurine,cerebrospinal fluid,andbloodof a person with Leigh syndrome.[6]

As the disease progresses, themuscular systemis debilitated throughout the body, as the brain cannot control the contraction of muscles.Hypotonia(lowmuscle toneand strength),dystonia(involuntary, sustained muscle contraction), andataxia(lack of control over movement) are often seen in people with Leigh disease. Theeyesare particularly affected; the muscles that control the eyes become weak, paralyzed, or uncontrollable in conditions calledophthalmoparesis(weakness or paralysis) andnystagmus(involuntary eye movements).[1]Slowsaccadesare also sometimes seen.[7]Theheartandlungscan 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;[1]asymmetric septal hypertrophyhas also been associated with Leigh syndrome.[9]In children with Leigh-syndrome associatedventricular septal defects,caused by pyruvate dehydrogenase deficiency, high forehead and large ears are seen; facial abnormalities are not typical of Leigh syndrome.[7]

However,respiratory failureis the most common cause of death in people with Leigh syndrome. Other neurological symptoms includeperipheral neuropathy,loss of sensation in extremities caused by damage to theperipheral nervous system.[1]

Hypertrichosisis seen in Leigh syndrome caused by mutations in the nuclear geneSURF1.[7]

Genomics

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Two healthy mitochondria from mammalian lung tissue as shown by electron microscopy

Mutationsinmitochondrial DNA(mtDNA) and over 30 genes innuclear DNA(geneSURF1[10]and someCOXassembly factors) have been implicated in Leigh disease.[1]

Disorders ofoxidative phosphorylation,the process by which cells produce their main energy source ofadenosine 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 fiveprotein complexesinvolved 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 thebrain stemand 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.[1]

Mitochondrial DNA mutations

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Mitochondriaare essentialorganellesineukaryoticcells. Their function is to convert the potential energy ofglucose,amino acids,andfatty acidsintoadenosine triphosphate(ATP) in a process calledoxidative phosphorylation.Mitochondria carry their ownDNA,called mitochondrial DNA (mtDNA). The information stored in the mtDNA is used to produce several of theenzymesessential to the production of ATP.[1]

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 inMT-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.[1]The most common MT-ATP6 mutation found with Leigh syndrome is apoint mutationat nucleotide 8993 that changes athymineto aguanine.This and other point mutations associated with Leigh syndrome destabilize or malform the protein complex and keep energy production down in affected cells.[11]Several mitochondrial genes involved in creating the first complex of the oxidative phosphorylation chain can be implicated in a case of Leigh syndrome, including genesMT-ND2,MT-ND3,MT-ND5,MT-ND6andMT-CO1.[9][12]

Mitochondrial DNA is passed down matrilineally in a pattern calledmaternal inheritance—a mother can transmit the genes for Leigh syndrome to both male and female children, but fathers cannot pass down mitochondrial genes.[1]

Nuclear DNA mutations

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The autosomal recessive pattern of inheritance seen in some cases of Leigh syndrome

Nuclear DNAcomprises most of thegenomeof an organism and insexually reproducingorganisms 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 anautosomal recessivepattern. This means that two copies of the mutated gene are required to cause the disease, so two unaffected parents, each of whom carries one mutantallele,can have an affected child if that child inherits the mutant allele from both parents.[1]

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 calledSURF1(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.[1]SURF1 is located on the long arm ofchromosome 9.[13]Some types of SURF1 mutations cause a subtype of Leigh syndrome that has a particularly late onset but similarly variable clinical course.[7]Another nuclear DNA mutation that causes Leigh syndrome, geneDLD,affects another protein complex in the mitochondria, thepyruvate dehydrogenase complex.[1][9]

Other nuclear genes associated with Leigh syndrome are located onchromosome 2(BCS1LandNDUFA10);chromosome 5(SDHA,NDUFS4,NDUFAF2,andNDUFA2);chromosome 8(NDUFAF6),chromosome 10(COX15);chromosome 11(NDUFS3,NDUFS8,andFOXRED1);chromosome 12(NDUFA9andNDUFA12); andchromosome 19(NDUFS7). SDHA is the only nuclear-coded protein present in the mitochondrial electron transport chain (as complex II), andMitochondrial complex II deficiency,in its biallelic form, causes Leigh syndrome.[14]Many of these genes affect the first oxidative phosphorylation complex.[9]

X-linked Leigh syndrome

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TheX-linked recessivepattern of inheritance seen occasionally in cases of Leigh syndrome

Leigh syndrome can also be caused by deficiency of thepyruvate dehydrogenase complex (PDHC),the x-linked gene beingPDHA1.[9]In general, there are two major presentations ofPDH deficiency,metabolic and neurologic, which occur at equal frequency.[15]The metabolic form presents as severelactic acidosisin the newborn period, and many die as newborns.[15]Patients with the neurologic presentation arehypotonic(low muscle tone), feed poorly, lethargic, and develop seizures, mental retardation, microcephaly, blindness and spasticity secondary to contractures.[15]"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."[15]

X-linked recessiveLeigh syndrome affects male children far more often than female children because they only have one copy of theX chromosome.Female children would need two copies of the faulty gene to be affected by X-linked Leigh syndrome.[1]

French Canadian Leigh syndrome

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The type of Leigh syndrome found at a much higher rate in theSaguenay–Lac-Saint-Jeanregion of Quebec is caused by a mutation in theLRPPRCgene, located on the small ('p') arm of chromosome 2.[9][16]Bothcompound heterozygosityandhomozygousmutations 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 incytochrome c oxidase(COX), the fourth complex in the mitochondrialelectron 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) infibroblasts(connective tissue cells) andskeletal muscle.Kidney and heart tissues were found to not have a COX deficiency.[16]

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 aredevelopmentally delayed,have mildlydysmorphicfacial features, includinghypoplasiaof the midface and widenasal bridge,chronicmetabolic acidosis,andhypotonia(decreased muscular strength). Other symptoms includetachypnea(unusually quick breathing rate), poor sucking ability,hypoglycemia(low blood sugar), andtremors.Severe, sudden metabolic acidosis is a common cause of mortality.[16]

Estimates of the rate ofgenetic carriersin 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.[16]

Pathophysiology

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The characteristic symptoms of Leigh syndrome are at least partially caused by bilateral, focallesionsin thebrainstem,basal ganglia,cerebellum,and other regions of the brain. The lesions take on different forms, including areas ofdemyelination,spongiosis,gliosis,necrosis,andcapillaryproliferation.[9]Demyelination is the loss of themyelin sheatharound theaxonsof 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.[1]

The lactic acidosis sometimes associated with Leigh syndrome is caused by the buildup ofpyruvate,which is unable to be processed in individuals with certain types of oxidative phosphorylation deficiencies. The pyruvate is either converted intoalanineviaalanine aminotransferaseor converted into lactic acid bylactate dehydrogenase;both of these substances can then build up in the body.[7]

Diagnosis

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Leigh syndrome is suggested by clinical findings and confirmed with laboratory andgenetic testing.[7]

Clinical findings

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Dystonia,nystagmus,and problems with theautonomic nervous systemsuggest damage to thebasal gangliaandbrain stempotentially caused by Leigh syndrome. Other symptoms are also indicative of brain damage, such ashypertrichosisand neurologically causeddeafness.Laboratory findings of lactic acidosis or acidemia andhyperalaninemia(elevated levels ofalaninein the blood) can also suggest Leigh syndrome. Assessing the level of organic acids in urine can also indicate a dysfunction in themetabolic pathway.[7]

Differential diagnosis

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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 includeperinatal asphyxia,kernicterus,carbon monoxide poisoning,methanol toxicity,thiamine deficiency,Wilson's disease,biotin-thiamine-responsive basal ganglia disease(BTBGD), and some forms ofencephalitis.Perinatal asphyxia can cause bilateral ganglial lesions and damage to thethalamus,which are similar to the signs seen with Leigh syndrome. Whenhyperbilirubinemiais not treated withphototherapy,thebilirubincan accumulate in thebasal gangliaand cause lesions similar to those seen in Leigh syndrome. This is not common since the advent of phototherapy.[7]

Treatment

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Succinic acidhas been studied, and shown effective for both Leigh syndrome, andMELAS syndrome.[17][18]A high-fat,low-carbohydrate dietmay be followed if a gene on the X chromosome is implicated in an individual's Leigh syndrome.Thiamine(vitamin B1) may be given ifpyruvate dehydrogenase deficiencyis known or suspected. The symptoms of lactic acidosis are treated by supplementing the diet withsodium bicarbonate(baking soda) orsodium citrate,but these substances do not treat the cause of Leigh syndrome.Dichloroacetatemay also be effective in treating Leigh syndrome-associated lactic acidosis; research is ongoing on this substance.[6]Coenzyme Q10supplements have been seen to improve symptoms in some cases.[9]

Clinical trials of the drug EPI-743 for Leigh syndrome are ongoing.[19]

In 2016,John Zhangand his team at New Hope Fertility Center in New York, USA, performed aspindle transfermitochondrial donationtechnique 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.[20]

Prognosis

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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.[6]

Epidemiology

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Leigh syndrome occurs in at least 1 of 40,000 live births, though certain populations have much higher rates. In theSaguenay–Lac-Saint-Jeanregion of centralQuebec,Leigh syndrome occurs at a rate of 1 in 2000 newborns.[1]

History

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Leigh syndrome was first described byDenis Leighin 1951[21]and distinguished from similarWernicke's encephalopathyin 1954.[9]In 1968, the disease's link with mitochondrial activity was first ascertained, though the mutations in cytochrome c oxidase and otherelectron transport chainproteins were not discovered until 1977.[7]

See also

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References

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  1. ^abcdefghijklmnopq"Leigh syndrome".Genetics Home Reference.National Institute of Health. 23 September 2013.Retrieved16 October2013.
  2. ^Noble, Peter (2018)."Denis Archibald Leigh".Psychiatric Bulletin.22(10):648–9.doi:10.1192/pb.22.10.648.
  3. ^Murphy, Jerome V (1974). "Leigh Disease: Biochemical Characteristics of the Inhibitor".Archives of Neurology.31(4):220–7.doi:10.1001/archneur.1974.00490400034002.
  4. ^Murphy, J. V; Craig, L (1975)."Leigh's disease: Significance of the biochemical changes in brain".Journal of Neurology, Neurosurgery, and Psychiatry.38(11):1100–3.doi:10.1136/jnnp.38.11.1100.PMC492163.PMID1206418.
  5. ^Gerards, Mike; Sallevelt, Suzanne C.E.H.; Smeets, Hubert J.M. (March 2016)."Leigh syndrome: Resolving the clinical and genetic heterogeneity paves the way for treatment options".Molecular Genetics and Metabolism.117(3):300–312.doi:10.1016/j.ymgme.2015.12.004.ISSN1096-7192.PMID26725255.
  6. ^abcd"NINDS Leigh's Disease Information Page".National Institute of Neurological Diseases and Stroke.NIH. 16 December 2011. Archived fromthe originalon 3 December 2013.Retrieved25 November2013.
  7. ^abcdefghijBaertling, F; Rodenburg, R. J; Schaper, J; Smeitink, J. A; Koopman, W. J. H; Mayatepek, E; Morava, E; Distelmaier, F (2013). "A guide to diagnosis and treatment of Leigh syndrome".Journal of Neurology, Neurosurgery & Psychiatry.85(3):257–65.doi:10.1136/jnnp-2012-304426.PMID23772060.S2CID45323262.
  8. ^Sofou, Kalliopi; De Coo, Irenaeus F M; Isohanni, Pirjo; Ostergaard, Elsebet; Naess, Karin; De Meirleir, Linda; Tzoulis, Charalampos; Uusimaa, Johanna; De Angst, Isabell B; Lönnqvist, Tuula; Pihko, Helena; Mankinen, Katariina; Bindoff, Laurence A; Tulinius, Már; Darin, Niklas (2014)."A multicenter study on Leigh syndrome: disease course and predictors of survival".Orphanet Journal of Rare Diseases.9(1): 52.doi:10.1186/1750-1172-9-52.ISSN1750-1172.PMC4021638.PMID24731534.
  9. ^abcdefghiOnline Mendelian Inheritance in Man(OMIM):Leigh Syndrome - 256000
  10. ^Pronicki, M; Matyja, E; Piekutowska-Abramczuk, D; Szymanska-Debinska, T; Karkucinska-Wieckowska, A; Karczmarewicz, E; Grajkowska, W; Kmiec, T; Popowska, E; Sykut-Cegielska, J (2008)."Light and electron microscopy characteristics of the muscle of patients with SURF1 gene mutations associated with Leigh disease".Journal of Clinical Pathology.61(4):460–6.doi:10.1136/jcp.2007.051060.PMC2571978.PMID17908801.
  11. ^"MT-ATP6".Genetics Home Reference.NIH. 19 November 2013.Retrieved25 November2013.
  12. ^Poole, Olivia V.; Everett, Chris M.; Gandhi, Sonia; Marino, Silvia; Bugiardini, Enrico; Woodward, Cathy; Lam, Amanda; Quinlivan, Ros; Hanna, Michael G.; Pitceathly, Robert D.S. (July 2019)."Adult-onset Leigh syndrome linked to the novel stop codon mutation m.6579G>A in MT-CO1".Mitochondrion.47:294–297.doi:10.1016/j.mito.2019.02.004.PMID30743023.S2CID73445211.
  13. ^"SURF1".Genetics Home Reference.NIH. 19 November 2013.Retrieved25 November2013.
  14. ^Fullerton M, McFarland R, Taylor RW, Alston CL (2020)."The genetic basis of isolated mitochondrial complex II deficiency".Mol Genet Metab.131(1–2):53–65.doi:10.1016/j.ymgme.2020.09.009.PMC7758838.PMID33162331.
  15. ^abcdBrown, G. K.; Otero, L. J.; LeGris, M.; Brown, R. M. (1994-11-01)."Pyruvate dehydrogenase deficiency".Journal of Medical Genetics.31(11):875–879.doi:10.1136/jmg.31.11.875.ISSN0022-2593.PMC1016663.PMID7853374.
  16. ^abcd"Leigh Syndrome, French Canadian type".Online Mendelian Inheritance in Man.Johns Hopkins University. 1 December 2011.Retrieved25 December2013.
  17. ^Ehinger, Johannes K; Piel, Sarah; Ford, Rhonan; Karlsson, Michael; Sjövall, Fredrik; Frostner, Eleonor Åsander; Morota, Saori; Taylor, Robert W; Turnbull, Doug M; Cornell, Clive; Moss, Steven J; Metzsch, Carsten; Hansson, Magnus J; Fliri, Hans; Elmér, Eskil (2016)."Cell-permeable succinate prodrugs bypass mitochondrial complex I deficiency".Nature Communications.7:12317.Bibcode:2016NatCo...712317E.doi:10.1038/ncomms12317.PMC4980488.PMID27502960.
  18. ^Oguro, Hiroaki; Iijima, Kenichi; Takahashi, Kazuo; Nagai, Atsushi; Bokura, Hirokazu; Yamaguchi, Shuhei; Kobayashi, Shotai (2004)."Successful Treatment with Succinate in a Patient with MELAS".Internal Medicine.43(5):427–31.doi:10.2169/internalmedicine.43.427.PMID15206559.
  19. ^"EPI743 | Mitochondrial Disease Action Committee - MitoAction".Archived fromthe originalon 2013-08-19.Retrieved2013-07-24.
  20. ^Roberts, Michelle (2016-09-27)."First 'three person baby' born using new method".BBC News.Retrieved2016-09-28.
  21. ^Leigh, D (1951)."Subacute Necrotizing Encephalomyelopathy in an Infant".Journal of Neurology, Neurosurgery & Psychiatry.14(3):216–21.doi:10.1136/jnnp.14.3.216.PMC499520.PMID14874135.

Further reading

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