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?
Children with Leigh syndrome are often weak and floppy, but this may not be obvious until they are several months old. Swallowing, breathing, movement and posture maybe particularly affected as the disorder involves parts of the brain responsible for these functions. Most children with this condition will gain developmental skills, such as rolling or sitting independently, only to lose them again. This is called developmental regression and typically occurs at times when children with Leigh syndrome are unwell with minor childhood illnesses such as ‘tummy bugs’ or ‘coughs and colds.’ This regression may be the first indication of the underlying mitochondrial problem, but other features such as recurrent vomiting and poor weight gain are often present. Following recovery from the illness, there may be recovery of some of the skills lost. Children with Leigh syndrome may deteriorate in this way over many years, or they may follow a more rapidly progressive decline over a period of months.
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 75 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:
AIFM1 / BCS1L / BTD / C12orf65 / COX10 / COX15 / DLAT / DLD / EARS2 / ECHS1 / ETHE1 / FARS2 / FBXL4 / FOXRED1 / GFM1 / GFM2 / GTPBP3 / / HIBCH / IARS2 / LIAS / LIPT1 / LRPPRC / MTFMT / NARS2 / NDUFA1 / NDUFA2 / NDUFA4 / NDUFA9 / NDUFA10 / NDUFA11 / NDUFA12 / NDUFAF2 / NDUFAF5 / NDUFAF6 / NDUFS1 / NDUFS2 / NDUFS3 / NDUFS4 / NDUFS7 / NDUFS8 / NDUFV1 / NDUFV2 / PDHA1 / PDHB / PDHX / PDSS2 / PET100 / PNPT1 / POLG / SCO2 / SDHA / SDHAF1 / SERAC1 / SLC19A3 / SLC25A19 / SUCLA2 / SUCLG1 / SURF1 / TACO1 / TPK1 / TRMU / TSFM / TTC19 / UQCRQ
Some examples of mitochondrial genes associated with Leigh syndrome include:
MT-ATP6 / MT-CO3 / 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.