Please log in.

Lost your password?

Create an account

Diagnosis and Treatment

Clinical Features

Signs associated with Leigh syndrome range from a near absence of abnormalities to severe neurologic problems. Central nervous system is frequently affected. The clinical signs include motor and /or intellectual retardation/regression, brainstem dysfunction, including respiratory abnormalities and abnormal eye movement (nystagmus and ophthalmoparesis) [1,2].

Sometimes, atypical neurologic abnormalities present to suggest Leigh syndrome, and this condition is known as Leigh-like syndrome ; endocrine abnormalities, cardiac abnormalities, and gastroenterologic problem are some examples [1].

A diagnosis of Leigh syndrome is based on clinical signs and symptoms, metabolic abnormalities, and neuroimaging findings [3]. Leigh syndrome is characterized by almost identical brain changes: focal, bilateral symmetric lesions associated with demyelination, vascular proliferation and gliosis [3].

Pathological Changes

The gray matter
The abnormal histopathology in central gray matter is a major indication of Leigh syndrome. Lesions are most consistently observed in the brain stem gray matter and usually occur in both sides. They are delineated and spread into the white matter. These lesions are spongy and show an intense capillary proliferation. Vacuoles enclosed by membrane(s) also present in lesions. The most severe lesions can lead to cavitation and tissue collapse [4].

The white matter
White matter is well preserved in most cases, but abnormal white matter can be found in cerebra and cerebellum. The abnormalities include sponginess, deficient myelin formation, myelin loss, abundant presence of lipid-laden macrophages, capillary proliferation, prominent gliosis, and eventually axonal loss. Myelin sheaths and dendrites degenerate before axons and cell bodies do. The optic nerves and tracts are often demyelinated and scarred up [4].

The muscle
Ragged red fibers are usually associated with mitochondrial disease and can be found in some Leigh syndrome patients. Mitochondria accumulate in skeletal muscle fibers when oxygen level is abnormally low. The staining with Gomori modified Trichrome gives the red color [4].


Diagnostic Imaging

Modern imaging techniques give diagnostic support to Leigh Syndrome by showing some characteristic abnormalities in brain.

Computed Tomography (CT) uses special x-ray equipment to obtain cross-sectional pictures of the brain.
In patients with cytochrome c oxidase deficiency, symmetric lesions scatter between the basal ganglia, brainstem, and cerebellum are present [1].

Magnetic Resonance Imaging (MRI) uses magnets and radio waves to create the images, generating images similar to those of a CAT scan but with much more details in the soft tissues.
Bilateral, symmetric focal hyperintensities in the basal ganglia, thalamus, substantia nigra, nucleus rubber, brainstem cerebellar white matter, cerebellar cortex, cerebral white matter, or spinal cord on T2 images are the most common findings [1].

Lactate and Pyruvate Level

Lactate and pyruvate levels increase in both blood and cerebrospinal fluid (CSF) in most Leigh syndrome cases. In Leigh syndrome individuals with mitochondrial malfunction, Krebs-cycle intermediates, including lactate, are excreted in urine. On the other hand, individuals with non-mitochondrial Leigh syndrome may have increased 3-methyl-glutaconic acid or 3-methyl-glutaric acid in urine [1].

Biochemical Analysis of Enzymes

In 50% of Leigh syndrome patients, biochemical abnormalities in mitochondria of the skeletal muscle can be detected. Deficiency of one or more of the complexes I, II, IV, or V of mitochondria electron transport chain is frequently observed [1].

Muscle Biopsy

The results can range from normal, slightly abnormal to markedly abnormal. Deficiency of cytochrome C oxidase, lipid accumulation, and size and arrangement of muscle fibres are most commonly observed [1].

Genetic Testing

Leigh syndrome is not only associated with diverse clinical signs but also multiple genes. There is no genetic screen readily available.

However, a 2008 study shows that preimplantation genetic diagnosis (PGD) can be used to diagnose Leigh syndrome if the gene changes are known in advance. After in vitro fertilization, genetic testing is performed on one cell from a resulting 3-day-old embryo. Cytochrome c oxidase (COX) deficiency is the most common cause of Leigh syndrome, and the change of SURF1 gene is most frequently observed in this category. (Please read the Research section for more details about the relation between genes and different inheritance patterns.) Changes can locate in different regions of SURF1 gene, and most of them result in premature proteins that may be degraded before performing any function. In their study, Unsal et al. examined the mutation in the 769th nucleotide and selected a non-affected embryo. A healthy baby girl was born [5].


YouTube Preview Image

PGD provides hope to couples with similar conditions, but there are some general challenges. First, the causes of Leigh syndrome in a large proportion of patients are unknown. Knowing the changes of genes is necessary for a successful PGD application.
Second, multiple genes and different changes in one gene can contribute to Leigh syndrome. Not all of them can be identified, and it makes the diagnosis even more difficult. A single unidentified gene/change can lead to Leigh syndrome.
Third, Leigh syndrome causing gene changes can arise spontaneously in an embryo that doesn’t have any family history.
Fourth, there is very little genetic material in the single cell used for genetic testing, and scientists may not be able to use this material to identify the changes of genes due to technical difficulties.

Nuclear genes

DNA-base prenatal diagnosis is possible when the defect in the family is known and the following criteria are met: it is a mitochondrial defect, is encoded by a nuclear gene, and shows an autosomal recessive mode of inheritance. However, Leigh syndrome with PDC deficient is an exception. The gender of the PDC deficient fetus must be considered [4].

X-linked Leigh syndrome is frequent in PDC deficient Leigh syndrome, and the affected male fetuses are likely to have a similar condition to that of previous affected brothers. However, X chromosome inactivation in female fetal brain cannot be predicted, so does the condition of the fetus [4].

X inactivation

YouTube Preview Image

Although this video uses calico cat as an example, the X chromosom inactivation is the same in the female calico cat and female human. (Fun Fact: There is no male calico cat! You can always get a free beer by betting on the gender of a calico cat you see.)

Mitochondrial genes

A reliable prediction from prenatal diagnosis is impossible when dealing with changes in mitochondrial genes. Some mitochondria may not carry the diseased change while others do when a mother passes mitochondria to her children. These mitochondria distribute in different proportion in different tissues within the embryo and can change over time [4].

Although ATP synthase 6 gene is also a mitochondrial gene, examination of its changes provides a good prediction of Leigh syndrome [4].

Therapy for Leigh Syndrome

There is no established treatment for Leigh syndrome, but there are some successful reports on symptom management. Treatments for patients with Mitochondrial Leigh Syndrome aim to improve adenosine triphosphate (ATP- the energy currency) production and to lower the lactate level [3]. Thiamine (vitamin B1) has been reported to improve the neurological status in some patients, while riboflavin has been reported to normalize the ATP production [3]. Intravenous soya bean oil (ketogenic emulsion) has been shown to improve clinical and biochemical perspectives in patients with acute central respiratory failure [3].

Oral sodium bicarbonate/sodium citrate is used to treat lactic acidosisDichloroacetate is currently being tested to treat lactic acidosis [6].

High fat and low carbohydrate diet is recommended for those with X-linked form of Leigh Syndrome [6].

Benzhexol, baclofen, tetrabenezine, and gabapentin, alone or in combination, may be used to treat dystoniaBotulinum toxin (more commonly known as Botox) injection is sometimes used to treat severe dystonia [7]. Antiepileptic drugs may be administered to treat seizures [7].


1. Finsterer J,. Leigh and Leigh-like syndrome in children and adults . Pediatr Neurol 2008 Oct; 39(4):223-235.
2. Rahman S, Blok RB, Dahl HH, et al.,. Leigh syndrome: clinical features and biochemical and DNA abnormalities . Ann Neurol 1996 Mar; 39(3):343-351.
3. Shrikhande DY, Kalakoti P, Syed MM, et al.,. A rare mitochondrial disorder: Leigh syndrome–a case report . Ital J Pediatr 2010 Sep 15; 36:62.
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.Unsal E, et al.. Successful application of preimplantation genetic diagnosis for Leigh syndrome. Fertility and Sterility 2008 Nov Vol.90, No.5.
6.  National Institute of Neurological Disorders and Stroke [homepage on the Internet]. [updated 2011 Dec 16; cited 2012 Jun 4]; Available from:
7. Thornburn DR, Rahman S. Mitochondrial DNA-Associated Leigh Syndrome and NARP. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2003 Oct 30 [updated 2011 May 03; cited 2012 Jun 4]. Available from: