Leigh’s disease is a rare mitochondrial disorder caused by the disruption of the mitochondrial respiratory chain or of an enzyme which feeds substrate into this chain. It may be transmitted via mutations in nuclear DNA or in the mitochondrial (maternal) DNA.
Following the diagnosis, the patient needs to be evaluated for his or her current developmental stage, neurologic signs, metabolic aberrations such as lactate or pyruvate elevation within the plasma and cerebrospinal fluid, and other organic acids in urine. Visual evaluation and ophthalmologic examination, assessment of the heart, and muscle involvement should all be documented.
Specific therapy for three forms of nuclear-mutation-induced Leigh-like syndrome are possible by biotin administration, namely for:
- Biotin-thiamine-responsive basal ganglia disease
- Biotinidase deficiency
- Coenzyme Q10 deficiency due to PDSS2 mutation
As with other mitochondrial disorders, there is no specific therapy for most other variants of Leigh syndrome. Treatment is primarily symptomatic and should be multidisciplinary—involving pediatricians, neurologists, cardiologists, ophthalmologists, audiologists, and psychologists, to assess and treat various manifestations of this disorder.
The most widespread recommendation in this situation is thiamine administration at 50-100 mg three times a day because of the partial and temporary improvement associated with it. Riboflavin and CoQ10 are other therapies that re often recommended.
If pyruvate dehydrogenase deficiency is present, a low carbohydrate diet that relies on fat to provide energy (a ketogenic diet) may be better.
Other symptomatic measures which may mitigate the suffering of the patient include:
- Treatment of seizures and anti-seizure prophylaxis
- Treatment of dystonia with benzhexol, baclofen, gabapentin and other similar drugs, or even botulinum toxin
- Supportive care for congestive heart failure in cardiomyopathy
- Advice on an appropriate nutritious diet and necessary feeding techniques to achieve adequate daily intake
- Acidosis that may be treated acutely with sodium bicarbonate or sodium citrate
Supportive services such as visual disability assistance may help patients cope with life situations better. Genetic counseling is also helpful in arriving at a better understanding of the condition and planning pregnancy in the family of the patient or, in adult patients with Leigh-like syndrome, the patients themselves.
Drugs such as sodium valproate and barbiturates (used to prevent seizures) should be avoided by inidividuals suffering from Leigh’s syndrome, unless they are in a lifesaving situation or admitted to facilities where anesthetics, full condition monitoring, and emergency treatment during respiratory difficulty or failure is available.
The patient should be scheduled for follow up every 6-12 months to assess the condition and to detect new symptoms in the nervous, visual, or cardiologic fields. To help the patients and their family cope better with their condition, psychologists should be involved in the treatment process early on.
Treatment Options for Leigh’s Syndrome
The use of dichloroacetate (DCA) was shown to have therapeutic effects in the treatment of Leigh’s syndrome. The chemical activates pyruvate dehydrogenase and thus causes a reduction in blood lactate levels. This process leads to some improvement in mt-DNA Leigh syndrome, but with possible toxicity to the peripheral nerves.
Meanwhile, investigational therapies include antioxidants, such as mitoQ, directed at the mitochondria to prevent toxicity due to oxidative stress. The process was based on the observed improvement in function and lifespan of cultured cells in one variant of the syndrome with the administration of Coenzyme Q10 analogs.
Another approach in treating Leigh’s syndrome is the administration of decanoic acid (an important end-product of the ketogenic diet) which seems to alleviate symptoms in mitochondrial myopathies. Such occurs because mitochondrial formation is stimulated by the acid; however, this treatment method is still at the experimental stage.
Gene therapy is also currently being studied as a therapeutic treatment for Leigh’s syndrome. Research shows that gene therapy could increase the percentage of normal mtDNA in the patient’s cells. One such technique associated with gene therapy is allotopic expression which recodes mtDNA genes in order to transfer them into the nucleus for further expression, thus enabling higher levels of ATP synthesis in affected individuals.
Another possible treatment is the use of a restriction endonuclease which targets the mitochondria and could break down mtDNA which contains the mutation, leaving the other wild type untouched. The use of adenoviruses to vector this enzyme into the mitochondrion has already been explored and appears to be successful in early studies.
Transcription activator-like effector nucleases (TALENs) which are modified to target the mitochondria selectively may also remove the mtDNA possessing the mutation from diseased cells in several variants. Like other presented treatment methods, this treatment is also currently under study. A technique called mtDNA heteroplasmy is also being explored at present. This method uses recombinant viruses to transduce muscles and brain cells and change the heteroplasmy, thus preventing or reversing clinical manifestations with some diseased forms of mtDNA.
Other techniques include the use of resveratrol and nicotinamide compounds to elevate NAD levels, both of which act via the PGC-1alpha pathway to stimulate the synthesis of mitochondria within the cells and increase the respiratory chain activity. Likewise, the use of such technique is strictly theoretical at present.
Studies are also focusing on organic acids such as alpha-ketoglutarate and aspartate could potentially push up substrate-level phosphorylation activity and thus increase ATP levels in affected cells.