Leigh Disease
Disease Details
Family Health Simplified
- Description
- Leigh disease is a severe neurological disorder characterized by progressive loss of mental and movement abilities, typically resulting from genetic mutations that affect energy production in mitochondria.
- Type
- Leigh disease is a type of mitochondrial disorder. It is most commonly inherited in an autosomal recessive manner but can also be inherited in an X-linked recessive or mitochondrial DNA (maternal) manner.
- Signs And Symptoms
- The symptoms of Leigh syndrome were classically described as beginning in infancy and leading to death within a span of several years; however, as more cases are recognized, it is apparent that symptoms can emerge at any age—including adolescence or adulthood—and patients can survive for many years following diagnosis. Symptoms are often first seen after a triggering event that taxes the body's energy production, such as an infection or surgery. The general course of Leigh syndrome is one of episodic developmental regression during times of metabolic stress. Some patients have long periods without disease progression while others develop progressive decline.Infants with the syndrome have symptoms that include diarrhea, vomiting, and dysphagia (trouble swallowing or sucking), leading to a failure to thrive. Children with early Leigh disease also may appear irritable and cry much more than healthy babies. Seizures are often seen, with reported prevalence of seizures in Leigh syndrome that ranges from 40% to 79%. Excess lactate may be seen in the urine, cerebrospinal fluid, and blood of a person with Leigh syndrome.As the disease progresses, the muscular system is debilitated throughout the body, as the brain cannot control the contraction of muscles. Hypotonia (low muscle tone and strength), dystonia (involuntary, sustained muscle contraction), and ataxia (lack of control over movement) are often seen in people with Leigh disease. The eyes are particularly affected; the muscles that control the eyes become weak, paralyzed, or uncontrollable in conditions called ophthalmoparesis (weakness or paralysis) and nystagmus (involuntary eye movements). Slow saccades are also sometimes seen. The heart and lungs can also fail as a result of Leigh disease. Hypertrophic cardiomyopathy (thickening of part of the heart muscle) is also sometimes found and can cause death; asymmetric septal hypertrophy has also been associated with Leigh syndrome. In children with Leigh-syndrome associated ventricular septal defects, caused by pyruvate dehydrogenase deficiency, high forehead and large ears are seen; facial abnormalities are not typical of Leigh syndrome.However, respiratory failure is the most common cause of death in people with Leigh syndrome. Other neurological symptoms include peripheral neuropathy, loss of sensation in extremities caused by damage to the peripheral nervous system.Hypertrichosis is seen in Leigh syndrome caused by mutations in the nuclear gene SURF1.
- Prognosis
- Different genetic causes and types of Leigh syndrome have different prognoses, though all are poor. The most severe forms of the disease, caused by a full deficiency in one of the affected proteins, cause death at a few years of age. If the deficiency is not complete, the prognosis is somewhat better and an affected child is expected to survive 6–7 years, and in rare cases, to their teenage years.
- Onset
- Leigh disease, also known as Leigh syndrome, typically has an onset in infancy or early childhood, usually between the ages of 3 months and 2 years. In some cases, onset may occur later in childhood or even in adolescence.
- Prevalence
- Leigh disease is a rare, inherited neurodegenerative disorder. The prevalence is estimated to be approximately 1 in 40,000 live births.
- Epidemiology
- Leigh syndrome occurs in at least 1 of 40,000 live births, though certain populations have much higher rates. In the Saguenay–Lac-Saint-Jean region of central Quebec, Leigh syndrome occurs at a rate of 1 in 2000 newborns.
- Intractability
- Yes, Leigh disease, also known as Leigh syndrome, is considered to be intractable. It is a severe neurological disorder that typically leads to progressive loss of mental and movement abilities, and there are currently no cures. Treatment focuses on managing symptoms and providing supportive care.
- Disease Severity
- Leigh disease, also known as Leigh syndrome, is a severe neurological disorder that typically progresses rapidly and can be life-threatening. Most affected individuals experience symptoms beginning in infancy or early childhood, and the disease often leads to severe disability or death within a few years.
- Healthcare Professionals
- Disease Ontology ID - DOID:3652
- Pathophysiology
- The characteristic symptoms of Leigh syndrome are at least partially caused by bilateral, focal lesions in the brainstem, basal ganglia, cerebellum, and other regions of the brain. The lesions take on different forms, including areas of demyelination, spongiosis, gliosis, necrosis, and capillary proliferation. Demyelination is the loss of the myelin sheath around the axons of neurons, inhibiting their ability to communicate with other neurons. The brain stem is involved in maintaining basic life functions such as breathing, swallowing, and circulation; the basal ganglia and cerebellum control movement and balance. Damage to these areas therefore results in the major symptoms of Leigh syndrome—loss of control over functions controlled by these areas.The lactic acidosis sometimes associated with Leigh syndrome is caused by the buildup of pyruvate, which is unable to be processed in individuals with certain types of oxidative phosphorylation deficiencies. The pyruvate is either converted into alanine via alanine aminotransferase or converted into lactic acid by lactate dehydrogenase; both of these substances can then build up in the body.
- Carrier Status
-
Leigh disease is a severe neurological disorder usually caused by mutations in mitochondrial DNA or nuclear DNA affecting mitochondrial function. Carrier status typically applies to autosomal recessive forms of the disease, where a person may carry one mutated gene but be asymptomatic. These carriers can pass the gene to their offspring.
For "nan," if you are referring to natural antibodies (nAbs) or nanoparticle (NP) therapies, neither are specifically associated with carrier status in Leigh disease as of current medical knowledge. More context would be needed to provide specific information related to "nan." - Mechanism
-
Leigh disease, also known as Leigh syndrome, is a severe neurological disorder that usually arises in infancy or early childhood. It is characterized by progressive degeneration of the central nervous system.
**Mechanism:**
Leigh disease primarily affects the energy-producing structures in cells called mitochondria. These organelles are responsible for generating the bulk of cellular ATP through oxidative phosphorylation, a process that involves a series of enzyme complexes (complexes I-IV) in the mitochondrial inner membrane.
**Molecular Mechanisms:**
1. **Mitochondrial DNA Mutations:**
- Mutations in mitochondrial DNA (mtDNA) can impair the function of the respiratory chain complexes, leading to reduced ATP production and an increase in the production of reactive oxygen species (ROS). Common mutations include those in MT-ATP6, which affects complex V (ATP synthase).
2. **Nuclear DNA Mutations:**
- Mutations in nuclear genes responsible for the assembly and maintenance of the mitochondrial respiratory chain complexes also cause Leigh syndrome. These may include genes like SURF1 (involved in complex IV assembly) and NDUFS4 (a component of complex I).
3. **Pyruvate Metabolism Defects:**
- The pyruvate dehydrogenase complex (PDHC) converts pyruvate into acetyl-CoA, a critical substrate for the citric acid cycle and subsequent ATP production. Mutations in genes encoding components of the PDHC (e.g., PDHA1) can impair this conversion, leading to a buildup of lactate and a decrease in ATP levels.
4. **Coenzyme Q10 Deficiency:**
- Coenzyme Q10 (ubiquinone) is a crucial component of the electron transport chain. Deficiency in CoQ10 synthesis or function, due to mutations in genes like COQ2, can disrupt electron transport and ATP synthesis.
5. **Amino Acid Metabolism Defects:**
- Mutations in genes such as ECHS1 involved in mitochondrial fatty acid and amino acid metabolism can lead to the accumulation of toxic intermediates and impaired energy production.
The resultant biochemical dysfunction causes neuronal and muscular systems to be predominantly affected, leading to the clinical manifestations observed in Leigh disease. - Treatment
- Succinic acid has been studied, and shown effective for both Leigh syndrome, and MELAS syndrome. A high-fat, low-carbohydrate diet may be followed if a gene on the X chromosome is implicated in an individual's Leigh syndrome. Thiamine (vitamin B1) may be given if pyruvate dehydrogenase deficiency is known or suspected. The symptoms of lactic acidosis are treated by supplementing the diet with sodium bicarbonate (baking soda) or sodium citrate, but these substances do not treat the cause of Leigh syndrome. Dichloroacetate may also be effective in treating Leigh syndrome-associated lactic acidosis; research is ongoing on this substance. Coenzyme Q10 supplements have been seen to improve symptoms in some cases.Clinical trials of the drug EPI-743 for Leigh syndrome are ongoing.In 2016, John Zhang and his team at New Hope Fertility Center in New York, USA, performed a spindle transfer mitochondrial donation technique on a mother in Mexico who was at risk of producing a baby with Leigh disease. A healthy boy was born on 6 April 2016. However, it is not yet certain if the technique is completely reliable and safe.
- Compassionate Use Treatment
-
Leigh disease, also known as Leigh syndrome, is a severe neurological disorder. Due to its complexity and rarity, treatments are often limited. Here's an overview of compassionate use treatment, off-label, or experimental treatments for Leigh disease:
1. **Compassionate Use Treatment**:
- This generally involves access to investigational drugs or therapies that are still in the trial phase. Families can apply for compassionate use through the FDA or other regulatory agencies, depending on their country, for specific experimental treatments not yet approved for general use.
2. **Off-label Treatments**:
- **Antioxidants and Vitamins**: Supplements such as Coenzyme Q10, Vitamin B1 (thiamine), Vitamin B2 (riboflavin), and Vitamin E are sometimes used to support mitochondrial function.
- **Dichloroacetate (DCA)**: Used off-label to reduce lactate accumulation in the blood, which is a metabolic issue in Leigh disease.
3. **Experimental Treatments**:
- **Gene Therapy**: Research is ongoing into gene replacement or repair therapies targeted at the specific genetic mutations causing Leigh syndrome.
- **EPI-743 (Vincerinone)**: An experimental redox-active molecule shown to potentially improve mitochondrial function.
- **Rapamycin**: Studies are investigating its role in reducing neuroinflammation and mitochondrial stress.
These treatments are investigational and should be discussed thoroughly with a healthcare provider for potential risks and benefits, and evaluated on a case-by-case basis. - Lifestyle Recommendations
-
Leigh disease, also known as Leigh syndrome, is a severe neurological disorder that typically arises in infancy or early childhood. Here are some lifestyle recommendations for managing the condition:
1. **Nutritional Support**:
- High-fat, low-carbohydrate diets, like the ketogenic diet, may be beneficial for some patients as they provide an alternative energy source to glucose.
- Adequate hydration and balanced meals are essential.
2. **Regular Medical Follow-ups**:
- Frequent consultations with neurologists, geneticists, and other specialists.
- Monitoring of the disease progression and management of symptoms as they arise.
3. **Physical Therapy**:
- Engage in regular physical and occupational therapy to maintain muscle function and mobility as much as possible.
- Adaptive devices may be necessary to assist with mobility.
4. **Avoiding Illness**:
- Minimize exposure to infections by practicing good hygiene and avoiding sick contacts.
- Ensure all vaccinations are up-to-date, in consultation with healthcare providers.
5. **Environmental Adjustments**:
- Creating a safe living environment to prevent injury, considering the potential for motor coordination issues.
- Making home modifications to accommodate mobility aids if necessary.
6. **Energy Conservation**:
- Plan activities to avoid overexertion and fatigue.
- Ensure adequate rest and sleep.
7. **Support Networks**:
- Utilize support groups and counseling for the patient and family members to manage emotional and psychological stress.
- Seek assistance from social services when needed.
Adhering to these lifestyle recommendations can help manage symptoms and improve the quality of life for individuals affected by Leigh disease. - Medication
-
Leigh disease, also known as Leigh syndrome, is a severe neurological disorder. It's a mitochondrial disease typically affecting infants or young children. Treatment primarily focuses on managing symptoms and may include:
1. Thiamine (Vitamin B1): Sometimes used in high doses if there is a deficiency.
2. Coenzyme Q10: May be prescribed to support mitochondrial function.
3. Sodium Bicarbonate or Sodium Citrate: These can help manage lactic acidosis, a common feature of Leigh disease.
4. Dichloroacetate: Has been explored for treating lactic acidosis, but its use is still debated.
Management also involves a multidisciplinary approach including neurologists, geneticists, and nutritionists, among others. Because there is no definitive cure, treatments are highly individualized based on the patient's symptoms and specific genetic diagnosis. - Repurposable Drugs
-
Leigh disease, also known as Leigh syndrome, is a rare, inherited neurodegenerative condition. There is currently no definitive cure, but some repurposed drugs may provide symptomatic relief or slow disease progression. Potential repurposable drugs that have been studied include:
1. **Dichloroacetate (DCA)**: May help by stimulating the pyruvate dehydrogenase complex (PDC), although its efficacy can vary and it may have side effects.
2. **Coenzyme Q10 (CoQ10)**: Used to support mitochondrial function, sometimes combined with other antioxidants.
3. **Idebenone**: Similar to CoQ10, it's an antioxidant that may help improve cellular energy production.
4. **Thiamine (Vitamin B1)**: Sometimes used because it is a cofactor for several enzymes in energy metabolism.
These drugs do not cure Leigh disease but may offer some benefit to patients. It is important for patients to work closely with their healthcare providers to determine appropriate treatments. - Metabolites
- Leigh disease is a severe neurological disorder characterized by progressive loss of mental and movement abilities. Key metabolites involved in Leigh disease include lactate and pyruvate, which are typically elevated in blood and cerebrospinal fluid. Additionally, abnormalities in mitochondrial function can affect other metabolic intermediates in energy production pathways.
- Nutraceuticals
- Nutraceuticals have been explored as an adjunctive therapy for Leigh disease, although clinical evidence supporting their effectiveness is limited. Coenzyme Q10 (CoQ10), thiamine (vitamin B1), and L-carnitine are often used to support mitochondrial function and energy production in affected individuals. However, these supplements should be taken under medical supervision as part of a comprehensive treatment plan.
- Peptides
-
Leigh disease, also known as Leigh syndrome, is a rare genetic disorder that primarily affects the central nervous system. While the exact role of peptides in Leigh disease is not fully understood, research in the broader field of mitochondrial disorders does investigate peptide-based therapies as potential treatments. These peptides may influence mitochondrial function or assist in cellular protection.
In the context of nanotechnology (nan), nanoparticles are being explored as a means to deliver drugs or genetic material precisely to affected cells in Leigh disease. Researchers are investigating whether nanoparticles can cross the blood-brain barrier effectively to target the central nervous system, offering a new potential avenue for treatment.
Overall, the role of peptides and nanotechnology in Leigh disease is an area of ongoing research with promising potential, but more studies are required to fully establish their efficacy and safety.