Leigh Syndrome

What is Leigh Syndrome?

Leigh Syndrome is a progressive neurological disorder and occurs at the early childhood, usually within a first year of the infant. The severity of this syndrome is high and associated with psychomotor regression or failure to mental abilities and body movement. Very rarely affected children get a slow progression of the disease and symptaggravated at their adulthood^1,2.

Symptoms

• At the initial stage of Leigh Syndrome, affected children usually experience vomiting, dysphagia (swallowing difficulty) and diarrhea, ultimately all these causes low appetite. Resulting of this causes weight loss and growth retardation. Muscle weakness gradually increasing and reach in peak level, which causes movement difficulty. Often the affected child has hypotonia (weak muscle tone), dystonia (uncontrolled muscle contractions), ataxia (disrupt body balancing).
• Numbness and weakness in the extremities due to peripheral neuropathy also cause movement difficulty.
• Muscular system problem causes eye involuntary, rapid eye movement, muscle paralysis. Eye muscle problem also spread to the optic nerve (nerve responsible for vision) and degenerate the nerve.
• Affected children also have seizures attack. In the advanced stage of Leigh Syndrome, affected patients also have the cardiac disorder, renal problem, breathing difficulty etc. Severe breathing problem worsens with time and often cause acute respiratory failure.
• Apart from skeletal muscle, cardiac muscle also becomes thicken and requires to forceful pumping and thus increase cardiac labor to pump out the blood.
• Lactate accumulation in the body and excess amount present in cerebrospinal fluid, blood, and urine.
• Lesions formation in some portion of the brain regions also found in Leigh syndrome. The included regions are basal ganglia (responsible for movement control), the cerebellum (responsible for body balancing and coordinated movement), the brainstem (connection between brain and spinal cord and regulate breathing and swallowing).
• Demyelination (defeat of the myelin coating around nerves) inhibits the nerves functioning to activates muscles and that cause movement abnormality and sensory information relay to the brain².

Frequency

Leigh syndrome is a very rare disorder and probably the ratio of incidence is in between 1:30,000 to 1: 40,000 population at birth. However, this ratio varies place to place like in the Saguenay-Lac-Saint-Jean region the ratio is almost 1:2000, whereas in the Faroe Islands this ratio is 1: 1,700.

Among the different type of Leigh syndrome, Mitochondrial DNA-associated Leigh syndrome is very rare and it’s about 1: 100,000 to 1: 140,000 births^1,3.

Causes

Leigh syndrome is a resultant of an abnormal genetic mutation. The abnormal genetic mutations may involve one to different 75 different genes. The involved gene in Leigh syndrome primarily associated with the production of energy in mitochondria. The abnormal gene mutation involve in Leigh syndrome may affect protein complexes or disrupt protein complexes engage in energy production and that leads to Leigh syndrome. There are five protein complexes engage in energy production in mitochondria. Among these, complex I disruption is most commonly associated with Leigh syndrome onset. Almost 25 genes present in complex I get abnormal mutation and leads to Leigh syndrome.

Approximately 15% of Leigh syndrome develops due to complex IV disruption. One of the primary gene SURF1, which is taking part in assembling of complex IV proteins become abnormally mutated and leads to Leigh syndrome.

Another important gene MT-ATP6, which is taking part in the formation of complex V is also abnormally mutated in some Leigh syndrome.

All the genetic abnormality associated with Leigh syndrome causes impaired mitochondrial energy production and deficit amount of energy supply to cellular level cause cell death and provide different characteristic features of Leigh syndrome².

Diagnosis

Diagnosis of Leigh Syndrome is a challenging work out.

• Medical history analysis, symptomatic assessment, physical examinations and hematological analysis provide an indication of the presence of Leigh Syndrome.
• Magnetic Resonance Imaging (MRI) also assists in detecting the location of the brain region where lesions develop and that also provide an indication of Leigh Syndrome^1,4.

Treatment

Leigh Syndrome usually non-curable disease. No specific treatment available for Leigh’s disease. Some supplementing medication can prescribe to slow down the progression of the syndrome. Vitamin B1 or thiamine most common supplement medication. Sodium bicarbonate or sodium citrate may administer orally to control lactic acidosis. Recent days, ongoing research are trying to establish the efficacy of dichloroacetate in the treatment of lactic acidosis. Low carb with high fat containing food usually recommended for an X-linked form of Leigh’s disease ( a specific type of Leigh’s disease, in which the involved gene is also present in  X chromosome)⁴.

Life Expectancy

Life expectancy of an affected child is very less. Due to respiratory failure usually, death occur within two to three years of the child life span. Very few children suffering from Leigh Syndrome stay alive until their adult age, as their symptoms are slowly progressive.

The poor prognosis of Leigh Syndrome is more prominent in involving complex IV mitochondrial energy deficit related Leigh Syndrome, in which affected child die within a few years of their life span. But an affected child with partial deficiencies has a better prognosis and may alive till their 6 to 7 years of age, whereas rarely patient can survive till their adolescent age^2,4.

References

1. Leigh syndrome; Genetic Home References; https://ghr.nlm.nih.gov/condition/leigh-syndrome
2. Leigh Syndrome; National Organization For Rare Disorders; https://rarediseases.org/rare-diseases/leigh-syndrome/
3. Leigh Syndrome; http://www.webmd.com/children/leighs-disease
4. Leigh’s Disease (Leigh’s Syndrome); http://www.medicinenet.com/leighs_syndrome_leighs_disease/page2.htm