Leigh Disease: Types, Causes, Symptoms, and Treatment

Introduction

Archibald Denis Leigh was a British physician who described Leigh's disease for the first time in 1951. He referred to the condition as subacute necrotizing encephalomyelopathy (SNE). Most medical professionals now refer to this disorder as Leigh syndrome or Leigh's disease. Leigh syndrome is a mitochondrial disorder characterized by progressive neurodegeneration that always results in death, generally in childhood. In this article, let's go into more detail about this condition.

What Is Leigh's Disease?

Leigh's disease is a rare inherited neurometabolic condition that affects the central nervous system. This progressive disease manifests itself in infants aged three months to two years. Occasionally, it might happen to teenagers and adults. Mitochondrial DNA mutations or abnormalities can cause Leigh's disease in an enzyme called pyruvate dehydrogenase. The signs and symptoms of this disease usually progress quickly. Seizures, developmental delays, cardiac problems, and breathing difficulties are all symptoms of this rare mitochondrial disorder. Sometimes it affects adults. There is no known cure for this fatal condition, however, treatments can lessen symptoms.

What Are the Other Names for Leigh's Disease?

• Leigh syndrome.

• Leigh disease.

• Infantile subacute necrotizing encephalopathy.

• Juvenile subacute necrotizing encephalopathy.

• Subacute necrotizing encephalomyelopathy.

What Are the Types of Leigh's Disease?

The various forms of Leigh syndrome include-

• Early- Onset (Infantile)- The most prevalent type of Leigh syndrome first manifests before age two. Doctors may also refer to it as infantile necrotizing encephalopathy or the classic Leigh syndrome. Both males and females both experience the condition.

• Late-Onset (Adult-Onset)- Symptoms begin after the age of two and may not manifest until adolescence or early adulthood. Adult-onset Leigh disease is uncommon. Males are more affected than females by this disease. The condition progresses more slowly than in infants.

• Leigh-Like Syndrome- An individual exhibits some Leigh syndrome symptoms, but imaging scans show no signs of the condition.

What Causes Leigh's Disease?

Mutations in more than 75 distinct genes can cause Leigh's disease. The mutated genes impact the body's capacity to produce ATP. Leigh syndrome affects 8 out of 10 children, and the gene mutation that causes it can be inherited in one of two ways-

• Autosomal Recessive Disorder- Every parent passes on the same gene mutation to their offspring. Despite carrying the altered gene, the parents are disease-free.

• X-linked Recessive Genetic Disorder- An X chromosomal gene alteration causes the disorder. It might come from either the biological mother or father. There is a 1 in 4 probability that a mother's child or daughter will inherit the mutant gene if one of her two X chromosomes carries the alteration. A boy who inherits the altered gene will experience Leigh syndrome; a girl will not. However, a daughter can pass on the faulty gene to her future children. A father can pass on a modified X chromosome to his daughter but not his son.

What Is the Inheritance Pattern of Leigh's Disease?

Leigh syndrome can have a variety of inheritance patterns. It is usually inherited in an autosomal recessive form, which means that both copies of the gene in each cell are mutated. Most nuclear DNA-encoded Leigh syndrome-related genes, including SURF1, follow this inheritance pattern. The parents with an autosomal recessive condition have one copy of the defective gene, although they usually do not have the condition. Leigh's disease is inherited in an X-linked recessive pattern in a small subset of those who are affected and have mutations in their nuclear DNA. This form of inheritance occurs when the defective gene is placed on the X chromosome, one of the two sex chromosomes.

Leigh syndrome is inherited in a mitochondrial pattern, commonly referred to as maternal inheritance. Several mtDNA genes, including MT-ATP6, follow this pattern of inheritance. Children can only receive mtDNA mutation-related disorders from their mother since only egg cells, not sperm cells, give mitochondria to the growing embryo. Although both males and females can be affected by these conditions, fathers do not convey traits connected to mtDNA alterations to their offspring.

What Are the Symptoms of Leigh's Disease?

Signs of Leigh syndrome usually arise within the first two years of an infant's life. Initially, the baby may achieve expected development milestones, such as holding their head up. They begin to regress, losing their abilities or displaying physical or developmental impairments. Early-onset Leigh syndrome symptoms include-

• Swallowing difficulties (dysphagia).

• Poor sucking or issues in feeding.

• Poor reflexes and head control.

• Irritability and persistent crying.

• Hypotonia (low muscular tone).

• Vomiting and diarrhea.

As the disease progresses, other symptoms could appear. Late-onset Leigh's disease can cause the following symptoms-

• Dementia.

• Muscle stiffness or spasms.

• Seizures.

• Partial paralysis.

• Movement and balance problems like ataxia.

• Dysarthria (difficulty producing words).

• Dystonia (involuntary muscular contractions).

• Peripheral neuropathy.

• Slowed physical development.

What Are the Complications of Leigh's Disease?

Lactic acidosis can occur due to Leigh syndrome, which causes an accumulation of lactic acid in the child's bloodstream. As oxygen levels in cells become insufficient to facilitate metabolism, the human body produces lactic acid (the breakdown of carbohydrates into energy). There could also be an excess of carbon dioxide in their blood. Increased carbon dioxide levels and lactic acidosis can result in the following complications-

• Kidney problems.

• Heart problems such as hypertrophic cardiomyopathy (thickened heart muscle).

• Respiratory problems such as rapid breathing (hyperventilation), shortness of breath (dyspnea), and apnea (pauses in breathing).

What Are the Conditions Associated With Leigh's Disease?

• Weakness.

• Paralysis of the eye-moving muscles (ophthalmoparesis).

• Rapid, uncontrollable eye motions (nystagmus).

• Degeneration of the nerves (optic atrophy).

• Acute respiratory failure.

• Hypertrophic cardiomyopathy.

How Is Leigh's Disease Diagnosis Made?

Leigh's disease diagnosis includes the following-

• Medical History- The first step in diagnosing any medical condition is to obtain the patient's medical history by asking pertinent questions. Doctors may also discuss current and previous drugs, allergies, family medical history, and the outcomes of previous tests and procedures.

• Physical Exam- The doctors perform a physical examination to assess the patient's vital signs, neurological system, and any abnormalities.

• Laboratory Tests- The doctor collects blood, urine, or body tissue samples to examine for indications of a medical condition. The findings aid in identifying the condition and creating a management strategy.

• Imaging Tests- Magnetic resonance imaging (MRI) is one of the imaging methods used to detect damaged areas of brain tissue (lesions) and accurately diagnose the condition.

• Investigations- Brain activity is studied using techniques like Electroencephalogram (EEG), which may aid the physician in making an accurate diagnosis.

• Genetic Testing- A type of blood test is advised to check for any DNA alterations that may be linked to a disease or other health problems.

How to Treat Leigh's Disease?

Leigh syndrome has no known cure. The goal of treatments is to keep the child comfortable by reducing symptoms. Healthcare providers may use a combination of treatments to manage the symptoms and slow down the progression of the disease. It includes the following-

• Vitamin supplements, including L- carnitine or vitamin B1.

• Eye medicine to improve vision.

• Breathing support.

• Antiepileptic drugs to treat seizures.

• Medications for movement issues.

• Lactic acidosis is treated with sodium bicarbonate or citric acid (sodium citrate).

• Thiamine (vitamin B1) injections can delay disease development.

• A high-fat, low-carbohydrate diet may benefit children with specific enzyme deficiencies. Some children who have trouble eating can require tube feeding (enteral nutrition).

How to Prevent Leigh's Disease?

Some prevention methods for Leigh's disease include the following-

• A genetic test can establish whether the patient and their partner have a gene mutation that causes Leigh syndrome if they have a child with it.

• They might choose to consult a genetic counselor to discuss strategies for reducing the likelihood of transferring the defective gene to future generations.

What Is the Prognosis of Leigh's Disease?

People with Leigh syndrome have a poor prognosis (outlook). It is frequently fatal during the first few years after development, usually due to breathing difficulties. A child with early-onset Leigh syndrome has a low chance of surviving till adolescence. The condition known as Leigh syndrome can appear in people after the age of 50. The prognosis is worst for infants that do not have complex IV activity in their mitochondria.

Conclusion

A child's body can be affected by Leigh syndrome in several ways, including the brain, eyes, heart, and kidneys. Hence, it is essential to consult with multiple specialists. In addition, it is beneficial to seek care from experienced specialists with the condition when the child has a rare, life-limiting disease. These professionals can assist in managing symptoms and connecting with supportive services so that people can enjoy their time with the child.