| Leigh syndrome | |
|---|---|
| Other names | Juvenile subacute necrotizing encephalomyelopathy, Leigh disease, infantile subacute necrotizing encephalomyelopathy, subacute necrotizing encephalomyelopathy (SNEM)[1] |
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| Detection of numerous ragged red fibers in a muscle biopsy | |
| Specialty | Neurology  |
Leigh syndrome (also calledLeigh disease andsubacute necrotizing encephalomyelopathy) is an inherited neurometabolic disorder that affects thecentral nervous system. It is named after Archibald Denis Leigh, a Britishneuropsychiatrist who first described the condition in 1951.[2] Normal levels ofthiamine,thiamine monophosphate, andthiamine diphosphate are 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]
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] Excesslactate may be seen in theurine,cerebrospinal fluid, andblood of a person with Leigh syndrome.[6]
As the disease progresses, themuscular system is debilitated throughout the body, as the brain cannot control the contraction of muscles.Hypotonia (lowmuscle tone and strength),dystonia (involuntary, sustained muscle contraction), andataxia (lack of control over movement) are often seen in people with Leigh disease. Theeyes are particularly affected; the muscles that control the eyes become weak, paralyzed, or uncontrollable in conditions calledophthalmoparesis (weakness or paralysis) andnystagmus (involuntary eye movements).[1] Slowsaccades are also sometimes seen.[7] Theheart andlungs 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;[1]asymmetric septal hypertrophy has 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 failure is 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]
Hypertrichosis is seen in Leigh syndrome caused by mutations in the nuclear geneSURF1.[7]
Mutations inmitochondrial DNA (mtDNA) and over 30 genes innuclear DNA (geneSURF1[10] and someCOX assembly 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 complexes 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 thebrain 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.[1]
Mitochondria are essentialorganelles ineukaryotic cells. Their function is to convert the potential energy ofglucose,amino acids, andfatty acids intoadenosine 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 theenzymes essential 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 mutation at nucleotide 8993 that changes athymine to 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-ND6 andMT-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 comprises most of thegenome of an organism and insexually 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 anautosomal 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 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 (BCS1L andNDUFA10);chromosome 5 (SDHA,NDUFS4,NDUFAF2, andNDUFA2);chromosome 8 (NDUFAF6),chromosome 10 (COX15);chromosome 11 (NDUFS3,NDUFS8, andFOXRED1);chromosome 12 (NDUFA9 andNDUFA12); 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]
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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 acidosis in 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 recessive Leigh 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]
The type of Leigh syndrome found at a much higher rate in theSaguenay–Lac-Saint-Jean region of Quebec is caused by a mutation in theLRPPRC gene, located on the small ('p') arm of chromosome 2.[9][16] Bothcompound heterozygosity andhomozygous 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 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 mildlydysmorphic facial features, includinghypoplasia of 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 carriers 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.[16]
The characteristic symptoms of Leigh syndrome are at least partially caused by bilateral, focallesions in thebrainstem,basal ganglia,cerebellum, and other regions of the brain. The lesions take on different forms, including areas ofdemyelination,spongiosis,gliosis,necrosis, andcapillary proliferation.[9] Demyelination is the loss of themyelin sheath around theaxons 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.[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 intoalanine viaalanine aminotransferase or converted into lactic acid bylactate dehydrogenase; both of these substances can then build up in the body.[7]
Leigh syndrome is suggested by clinical findings and confirmed with laboratory andgenetic testing.[7]
Dystonia,nystagmus, and problems with theautonomic nervous system suggest damage to thebasal ganglia andbrain stem potentially caused by Leigh syndrome. Other symptoms are also indicative of brain damage, such ashypertrichosis and neurologically causeddeafness. Laboratory findings of lactic acidosis or acidemia andhyperalaninemia (elevated levels ofalanine in the blood) can also suggest Leigh syndrome. Assessing the level of organic acids in urine can also indicate a dysfunction in themetabolic pathway.[7]
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. Whenhyperbilirubinemia is not treated withphototherapy, thebilirubin can accumulate in thebasal ganglia and cause lesions similar to those seen in Leigh syndrome. This is not common since the advent of phototherapy.[7]
Succinic acid has been studied, and shown effective for both Leigh syndrome, andMELAS syndrome.[17][18] 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 B1) may be given ifpyruvate dehydrogenase deficiency is 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.Dichloroacetate may also be effective in treating Leigh syndrome-associated lactic acidosis; research is ongoing on this substance.[6]Coenzyme Q10 supplements 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 Zhang and his team at New Hope Fertility Center in New York, USA, performed aspindle transfermitochondrial 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.[20]
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]
Leigh syndrome occurs in at least 1 of 40,000 live births, though certain populations have much higher rates. In theSaguenay–Lac-Saint-Jean region of centralQuebec, Leigh syndrome occurs at a rate of 1 in 2000 newborns.[1]
Leigh syndrome was first described byDenis Leigh in 1951[21] and distinguished from similarWernicke's encephalopathy in 1954.[9] In 1968, the disease's link with mitochondrial activity was first ascertained, though the mutations in cytochrome c oxidase and otherelectron transport chain proteins were not discovered until 1977.[7]