Leigh's Syndrome Diagnosis

Leigh's syndrome is a rare genetic disease that is caused by degenerative changes in the central nervous system, particularly in the brain, spinal cord, and optic nerve. It begins to manifest between the ages of three months and two years and is therefore also called infantile necrotizing encephalopathy.

In some cases, however, a Leigh-like syndrome occurs much later or even in adult life. The culprit is in most cases a genetic defect of the mitochondria which prevents adequate energy production by interfering with pyruvate metabolism or the electron transport chain which is responsible for mitochondrial respiration. In most cases it is autosomal recessive, but it may also be X-linked recessive or inherited from the mother by a mutation within the mitochondrial DNA.

Clinical Features

The diagnosis of Leigh's syndrome is based on clinical features confirmed by imaging tests. The symptoms in younger patients include loss of head control (the infant can no longer hold up the head) and failure to suck normally. In addition, there may be severe anorexia, repeated vomiting, intractable crying, and seizures.

Motor development is also delayed. In slightly older children, the manifestations also include reversal of motor as well as intellectual development (e.g. the child stops doing actions which were already learned, finds it difficult to speak, or becomes uncoordinated and clumsy), failure to thrive, tremors or spasms of the muscle, irritable temper, and convulsions. More advanced diseases show up as generalized weaknesses of the skeletal muscle with loss of tone, along with episodes of lactic acidosis seen as deterioration of breathing, as well as of heart and kidney function.

This syndrome in children is typically associated with breathing problems, including temporary apnea, dyspnea, hyperventilation, and Cheyne-Stokes pattern of respiration. Dysphagia, ocular muscle disability such as nystagmus, strabismus, paralysis of some ocular muscles, and slow pupil reactions may also occur. Atrophy of the optic nerve is often a cause of blindness in this condition.

Cardiac involvement may include hypertrophic cardiomyopathy or septal hypertrophy. Peripheral nerve development may also be affected over time which worsens the weakness of the limb muscles.

The same pattern is obvious in X-linked Leigh's syndrome, but a third variant which occurs in adult life is called subacute necrotizing encephalomyopathy. Though very rare, it begins with visual symptoms during the teenage or early adult period of life. Scotomas, color blindness, and progressive blindness are some common symptoms, due to optic atrophy. Neurological deficits are slow to develop in this variant, typically occurring after the age of 50 years as movement ataxia, spasticity of the muscles with weakness, clonus, seizures, and mental deterioration of some degree.

The diagnosis of this syndrome is therefore based upon the criteria which were stated by Rahman et al:

• Progressive degeneration of the central nervous system involving both muscular and mental development
• Damage to the brainstem and basal ganglia
• High lactic acid concentrations in the blood and cerebrospinal fluid (CSF) (though this is controversial given that this is not positive in all patients)
• Changes in the following:
  • Brain imaging by computed tomography (CT) or magnetic resonance imaging (MRI) shows specific changes such as cortical cerebral cysts in the cerebrum or other characteristic locations, manifesting as hypodense areas on CT and hyperintense signals on T2-weighted/ hypointense areas on T1-weighted MRI brain scanning
  • Neurons of affected systems both in the patient and in affected siblings

A new criterion added by newer studies is the proof of mitochondrial dysfunction. The presence of bilateral lesions with marked symmetry within the basal ganglia, thalamus, or brainstem—singly or in any combination–is also almost diagnostic of this condition when associated with typical clinical features.

Molecular Genetic Testing and Laboratory Testing

If the diagnostic criteria is fulfilled, then the next step is molecular genetic testing. This will help distinguish mtDNA mutations from nuclear DNA mutations in the etiology of Leigh's syndrome.

Some laboratory tests may be of use, such as high pyruvate and alanine levels, absence of pyruvate carboxylase in the liver, and thiamine triphosphate inhibitor in the serum and urine. Cytochrome C oxidase or pyruvate dehydrogenase may be significantly deficient in a subgroup of affected children.