Who does it affect?
Leigh syndrome affects approximately 1 in 40,000 newborns, with symptoms usually starting in the first year of life. Though extremely rare, some people may not develop symptoms until early adult life, while others may have symptoms that develop more slowly in childhood.
What are the clinical features?
Symptoms of early onset Leigh Syndrome (3months +) often include poor sucking ability, loss of appetite and recurrent vomiting which may result in poor weight gain (failure to thrive). Young children may have poor head control and have bouts of unexplained irritability or continual crying. They may also experience delays in reaching developmental milestones.
Symptoms of later onset Leigh Syndrome (2 years+), may include difficulty coordinating movement (ataxia) or difficulty articulating words (dysarthria). Previously acquired intellectual and motor skills may be lost (developmental regression) and this typically occurs at times when children are unwell with minor childhood illnesses such as ‘tummy bugs’ or ‘coughs and colds.’
Abnormally high levels of lactic acid may be seen in the blood, brain and/or other tissues of the body. This is known as lactic acidosis and if left untreated can lead to respiratory, heart, or kidney impairment.
Leigh Syndrome can involve many systems but not all symptoms are seen with all patients.
Neurological problems may include generalized weakness, lack of muscle tone (hypotonia), clumsiness, tremors, muscle spasms (spasticity) or dystonia. Neurological development is often delayed, and intellectual disability is common.
Respiratory problems may include the temporary cessation of spontaneous breathing (apnea), difficulty breathing (dyspnea), abnormally rapid breathing (hyperventilation), and/or abnormal breathing patterns (Cheyne-Stokes). Some infants may also experience difficulty swallowing (dysphagia).
Visual problems may include abnormally rapid eye movements (nystagmus), sluggish pupils, crossed eyes (strabismus), paralysis of certain eye muscles (ophthalmoplegia), deterioration of the nerves of the eyes (optic atrophy), and/or visual impairment leading to blindness.
Heart problems may include abnormal enlargement of the heart (hypertrophic cardiomyopathy) and overgrowth of the fibrous membrane that divides the various chambers of the heart (asymmetric septal hypertrophy).
Nervous system problems may involve nerves outside of the central nervous system (peripheral neuropathy), causing progressive weakness of the arms and legs.
The symptoms of the adult-onset form of Leigh syndrome (a very rare form of the disorder), generally begin during adolescence or early adulthood. Initial symptoms are generally related to vision and may include such abnormalities as blurred “filmy” central visual fields (central scotoma), colour blindness, and/or progressive visual loss due to degeneration of the optic nerve (bilateral optic atrophy). The neurological problems associated with the disease progress slowly in this form of the disorder. At about 50 years of age, affected individuals may find it progressively difficult to coordinate voluntary movements (ataxia). Additional late symptoms may include partial paralysis and involuntary muscle movements (spastic paresis), sudden muscle spasms (clonic jerks), grand mal seizures, and/or varying degrees of dementia.
How is it diagnosed?
Specific patterns of brain involvement on an MRI scan along with typical clinical findings usually suggest the diagnosis. Lumbar puncture (a procedure used to collect a sample of spinal fluid) may also be helpful in confirming a disorder of mitochondrial function (raised cerebrospinal fluid lactate) and excluding other medical problems. Although less frequently performed now, muscle biopsy is often helpful in confirming that mitochondrial function is abnormal and may help direct more specific genetic testing.
What causes Leigh syndrome?
Leigh syndrome can be caused by genetic variations in over 100 different genes. These include nuclear genes (within the nuclear DNA) or mitochondrial genes (within the mitochondrial DNA).
All of the mutations disrupt the process of energy production by the mitochondria. One of the main jobs of mitochondria is to convert energy in food (carbohydrates and fats) into a form that can be used by the cell. There are five protein complexes (named complex I to complex V) that make up the energy chain needed for this process of energy conversion. Many of the genetic variations causing Leigh syndrome affect the proteins that make up these complexes or how they are put together.
What genes are associated with Leigh syndrome?
The most common genetic variants causing Leigh syndrome are found in genes needed to make complex I. These variations can occur in either the nuclear or mitochondrial DNA. Other variations in the genes needed to make complex IV and complex V are also common causes of Leigh syndrome. Sometimes the genetic variant will cause a fault that results in more than one complex being affected.
Some genetic variants causing Leigh syndrome disrupt other processes related to energy production. For example, Leigh syndrome can be caused by variants in genes that make the pyruvate dehydrogenase complex or coenzyme Q10. Variations in genes that are involved in making or repairing mtDNA can also affect energy production by the mitochondria and cause Leigh syndrome. Mitochondria have to bring in or ‘import’ lots of proteins that are essential for energy conversion. Variants in genes responsible for the import machinery can also cause Leigh syndrome.
Some examples of nuclear genes associated with Leigh syndrome include:
AARS2 / ACAD9 / ADCK3 / AIFM1 / ANT1 / BCS1L / BTD / CARS2 / C12orf65 / C10orf2 / COIII / COX10 / COX15 / DGOUK / DLAT / DLD / EARS2 / ECHS1 / ECSIT / ETHE1 / ELAC2 / FARS2 / FBXL4 / FOXRED1 / GFM1 / GFM2 / GTPBP3 / HIBCH / IARS2 / LARS / LIAS / LIPT1 / LRPPRC / MECR / MFN2 / MT01 / MPV17 / MRPL3 / MRPS22 / MTFMT / NARS2 / NDUFA1 / NDUFA2 / NDUFA4 / NDUFA9 / NDUFA10 / NDUFA11 / NDUFA12 / NDUFAF2 / NDUFAF3 / NDUFAF5 / NDUFAF6 / NDUFB3 / NDUFS1 / NDUFS2 / NDUFS3 / NDUFS4 / NDUFS7 / NDUFS8 / NDUFV1 / NDUFV2 / NUBPL / OPA1 / PDHA1 / PDHB / PDHX / PDP1 / PDSS2 / PET100 / PNPLA8 / PNPT1 / POLG / RARS2 / RMND1 / RRM2B / RTN4IP1 / SCO / SCO2 / SDHA / SDHB / SERAC1 / SDHD / SDHAF1 / SERAC1 / SLC19A3 / SLC25A1 / SLC25A19 / SUCLA2 / SUCLG1 / SURF1 / TACO1 / TANGO2 / TAZ / TK2 / TMEM126B / TMEM70 / TPK1 / TRIT1 / TRMU / TRTN1 / TSFM / TTC19 / TYMP / UQCRQ / WARS2 / YARS2
Some examples of mitochondrial genes associated with Leigh syndrome include:
MT-ATP6 / MT-CO3 / MT-FMT / MT-ND1 / MT-ND2 / MT-ND3 / MT-ND4 / MT-ND5 / MTND6 / MT-TI / MT-TK / MT-TL1 / MT-TV / MT-TW
How is Leigh syndrome inherited?
Leigh syndrome can be inherited in many different ways depending on which gene contains the variant that is causing the condition. It is most commonly inherited in an autosomal recessive pattern, meaning that an individual must inherit two copies of the faulty gene to develop the condition. Typically, both parents carry one copy of the faulty gene but do not show signs or symptoms of the condition themselves. There is a 1 in 4 chance of these parents having an affected child who inherits both copies of the faulty gene (one from each parent). This pattern of inheritance is seen for most of the nuclear genes associated with Leigh syndrome.
Leigh syndrome can also be inherited in a maternal pattern when the variant is found in a mitochondrial gene (within the mitochondrial DNA). This happens because only mothers who carry a faulty mitochondrial gene can pass this onto their children. Fathers who carry a faulty mitochondrial gene cannot pass this on. This means that both male and female children can be affected by the condition but only daughters can pass the faulty mitochondrial gene onto their own children. It is not possible to determine how many copies of the faulty mitochondrial gene will be passed from a mother to her children, however, which makes it very difficult to predict the extent to which her children will be affected by the condition. This is known as the ‘genetic bottleneck’ and can make genetic counselling challenging.
In a small number of cases, Leigh syndrome can be inherited in an X-linked recessive pattern when the variant is found in a nuclear gene located on the X chromosome (which is one of the two sex chromosomes). Because males carry only one X chromosome, one copy of the faulty gene is enough to develop the condition. In females who carry two X chromosomes, both copies of the gene must be faulty to develop the condition. This means that males are affected by X-linked recessive disorders more frequently than females. Fathers cannot pass X-linked recessive disorders to their sons.
Can Leigh syndrome be treated?
There is no specific treatment for Leigh syndrome.
Can Leigh syndrome be prevented?
If the genetic variant is present either in the nuclear or mitochondrial DNA then there is nothing that can be taken during pregnancy or given to the infant that will prevent Leigh syndrome occurring.
However, once a genetic variant that causes Leigh syndrome has been identified in either the nuclear or mitochondrial DNA, there are a number of reproductive options that can be offered in the next pregnancy. For people living in the UK, reproductive advice can be discussed with the doctors at any of the 3 highly specialised mitochondrial disease centres in Newcastle, London and Oxford. Referral to a specialised Mitochondrial Reproductive Advice Clinic in Newcastle is possible for those women with mitochondrial DNA variants.
One reproductive option is prenatal testing which involves testing cells from the baby in early pregnancy. This form of prevention is only suitable for those people who would consider termination and would usually be done after 10-12 weeks of the pregnancy by chorionic villus biopsy. The faulty gene is examined in this biopsy to see which copies have been inherited. If faulty copies of the gene have been inherited (with consideration given to the number of faulty copies if the mutation is in the mitochondrial DNA) then termination of the pregnancy is offered.
Preimplantation genetic diagnosis (PGD) is another reproductive option that can be offered once a genetic diagnosis has been made. This requires that the parents go through an IVF cycle to generate a number of early embryos that can be tested in the lab to determine if the faulty gene has been inherited (or the number of faulty copies if the mutation is in mitochondrial DNA). Only embryos that do not carry the faulty gene (or carry the faulty gene at low levels if the mutation is in the mitochondrial DNA) will be selected for transfer to the womb. It is important to note, however, that PGD may fail to identify any suitable embryos for transfer and even if an embryo is transferred to the womb, it may not result in a pregnancy.
If PGD is unsuitable for a woman who carries a genetic variant in her mitochondrial DNA, another reproductive option is mitochondrial donation. This is a new IVF-based treatment that can prevent a mitochondrial DNA variant being passed from a mother to her child. It involves using a donor egg with healthy mitochondrial DNA which is combined with the nuclear DNA from both parents, resulting in a child with a reduced risk of mitochondrial disease. There is only one centre in Newcastle that is currently licensed to perform mitochondrial donation and every patient wishing to use mitochondrial donation will also need regulatory approval.
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