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What Causes Leigh Syndrome?

A number of inborn errors related to energy turnover can lead to Leigh syndrome. Frequent causes include deficiency of pyruvate dehydrogenase complex and respiratory chain complexes of mitochondria. In addition, a point mutation in the tRNA gene is also identified in a few patients [1].

Pyruvate Dehydrogenase Complex (PDC)

Pyruvate dehydrogenase complex is a complicated enzyme with multiple components and regulators. It is responsible for converting pyruvate to acetyl CoA in the mitochondrial matrix. The malfunction of PDC will decrease the available fuel, acetyl-CoA, for mitochondria. Consequently, fewer ATPs can be produced and pyruvates are shunted to lactate production pathway, increasing lactate level.

Pyruvate dehydrogenase (E1) is a component of PDC, and its subunit E1α is encoded by PDHA1, locating on the X chromosome. Mutations in PDHA1 are most often associated with PDC deficiency, and the corresponding Leigh syndrome shows an X-linked inheritance pattern.  This condition is also known as X-linked Leigh syndrome [2].


Mitochondria are interesting structures within cells.
First, we get our mitochondria only from our mother, not father.

Maternal Inheritance of Mitochondrial DNA

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Second, mitochondria have a separate set of genes that are different than those found in cell nucleus.

Moreover, proteins present in a mitochondrion can be encoded by both mitochondrial located genes and nucleus located genes.

Last but not least, mitochondria are often called the power house of cells. They produce ATP, an energy currency, to meet the energy requirement of an organism. The respiratory chain in a mitochondrion is important in producing ATP. Five protein complexes (complex I, complex II, complex III, complex IV and complex V) are involved in the process of oxidative phosphorylation, which eventually produce ATP.
Abnormalities of mitochondria in skeletal muscle are found in about 50% of individuals with Leigh syndrome. The abnormalities are diverse, and many different components in mitochondria can be affected [3]. The gene mutations related to Leigh syndrome affect proteins in complex I, II, IV or V, or can disturb the assembly of these complexes [3]. Therefore, the activities of these complexes are disrupted or reduced, ultimately leading to Leigh syndrome.

Cellular Respiration (Respiratory Chain of Mitochondria)

Complex I (NADH dehydrogenase) deficiency, complex II (succinate dehydrogenase, which is not shown in the video) deficiency, complex III (cytochrome bc1 complex), complex IV (cytochrome oxidase) deficiency, and complex V (ATP synthase) deficiency can all contribute to Leigh syndrome.
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Complex I

Complex I passes electrons from NADH to ubiquinone while pumping hydrogen ions out of the mitochondrial matrix into the space between the two membranes. It has 35 nuclear-encoded subunits and 7 mitochondrial-encoded subunits. Consequently, Leigh Syndrome with mutations in the nuclear-encoded subunits shows an autosomal recessive inheritance pattern while Leigh syndrome with mutations in the mitochondrial-encoded subunits shows a maternal inheritance pattern [4].

Complex II

Complex II is involved in the Krebs cycle, converting succinate to fumerate and passing electrons to the ubiquinone in the respiratory chain. All four subunits of complex II are encoded by nuclear DNA, and the Leigh syndrome with Complex II deficiency has an autosomal recessive inheritance [4].

Complex III

Complex III transfers electrons from succinate and nicotinamide adenine dinucleotide-linked dehydrogenases to cytochrome c. The protein underlying Complex III deficiency facilitates the assembly of complex III. It is encoded by BCS1L gene on chromosome 2, and the associated Leigh syndrome is relatively rare [1] [5].  The observed cases suggest an autosomal recessive inheritance.

Complex IV

The most common cause of Leigh syndrome is mutations in complex IV (also called cytochrome c oxidase or COX). Complex IV transfers electrons from cytochrome c to oxygen. It has 10 nuclear-encoded subunits and 3 mitochondrial-encoded subunits. Although autosomal recessive inheritance is more common for COX deficiency, no mutation has been found in the 10 nuclear-encoded subunits.  In fact, the underlying genetic defects are unknown in the majority of the patients [4].

The gene most frequently mutated in COX-deficient Leigh syndrome is SURF1, which is found in nuclear DNA and contributes to the assembly of the COX complex. In cellular respiration, the COX complex provides energy for the next step that would generate ATP. Mutations in the SURF1 gene lead to the production of abnormal SURF1 proteins that would reduce the formation of COX complexes, thus impairing mitochondrial ATP production [3].

The French Canadian type of Leigh Syndrome (LSFC) is associated with COX deficiency, which is particularly severe in the liver [6].  LRPPRC gene variation(s) underlies LSFC, and LSFC is inherited in an autosomal recessive mode.

Complex V

Subunit 6 of Complex V (aka. ATP synthase) is encoded by mitochondrial DNA and its defects can contribute to Leigh syndrome.  Consequently, the related Leigh syndrome shows a maternal mode of inheritance. The most common mutation is on the 8993th amino acid, a change from threonine to glycine [4].


Mutations in genes encoding mitochondrial tRNA proteins were found in a few patients and associated with myoclonus epilepsy and ragged red fibers (MERRF) [1].

Coenzyme Q10 deficiency is also associated with Leigh syndrome [1].

Animal Model for Leigh Syndrome

Breathing problem is common in individuals with Leigh syndrome (LS) and a major cause of mortality. However, little is known about the nature of these problems in early stages of LS. The understanding of early breathing problems might provide a target for treatment [7].

In a mouse model, Surf1 gene (a main cause of COX deficiency) is disrupted and loses its function. These mice have a higher frequency of breathing and abnormal responses to low oxygen level, suggesting the need to develop therapeutic strategies to protect patients with COX deficiency from low oxygen content [7].


  1. OMIM Entry – #256000 – LEIGH SYNDROME; LS.
  2. OMIM Entry – #308930 – LEIGH SYNDROME, X-LINKED.
  3. Finsterer J,. Leigh and Leigh-like syndrome in children and adults . Pediatr Neurol 2008 Oct; 39(4):223-235.
  4. van der Knapp, Marjo S and Valk, Jaap. Leigh Syndrome and Mitochondrial leukoencephalopathies. Magnetic Resonance of Myelination and Myelin Disorders; 2005 Chapter 28:224 – 244.
  5. de Lonlay et al. A mutant mitochondrial respiratory chain assembly protein causes complex III deficiency in patients with tubulopathy, encephalopathy and liver failure – Nature Genetics ; 2012(4/17/2012).
  7. Stettner GM, Viscomi C, Zeviani M, et al.,. Hypoxic and hypercapnic challenges unveil respiratory vulnerability of Surf1 knockout mice, an animal model of Leigh syndrome . Mitochondrion 2010 Dec 15 PMID: 21167962.