SNP Shot: Genomic Insights

Leigh syndrome is a severe neurological disease that typically manifests in the first year of life. It's marked by a progressive decline in both mental and motor skills, known as psychomotor regression. Sadly, most individuals with Leigh syndrome die within two to three years, often due to respiratory failure. However, in some cases, symptoms may not appear until adulthood, or the condition may progress more slowly.

The earliest signs of Leigh syndrome in infants often include vomiting, diarrhea, and difficulty swallowing (dysphagia), which interferes with feeding. These problems frequently lead to a failure to grow and gain weight as expected (failure to thrive). Significant muscle and movement difficulties are also common. Affected individuals may experience weak muscle tone (hypotonia), involuntary muscle contractions (dystonia), and problems with coordination and balance (ataxia). Peripheral neuropathy, characterized by loss of sensation and weakness in the limbs, is also frequently observed, further contributing to movement difficulties.

Several other features can occur in individuals with Leigh syndrome. Many develop weakness or paralysis of the eye muscles (ophthalmoparesis), rapid, involuntary eye movements (nystagmus), or degeneration of the optic nerves, which transmit visual information to the brain (optic atrophy). Severe breathing problems are common and can worsen, leading to acute respiratory failure. Some individuals develop hypertrophic cardiomyopathy, a thickening of the heart muscle that makes it harder for the heart to pump blood. Additionally, an excess of lactate can accumulate in the body, often found in the blood, urine, or cerebrospinal fluid (the fluid surrounding the brain and spinal cord).

The symptoms of Leigh syndrome are partly due to areas of damaged tissue (lesions) that develop in the brain. Magnetic resonance imaging (MRI) reveals these characteristic lesions in specific brain regions. These areas include the basal ganglia, which control movement; the cerebellum, responsible for balance and coordination; and the brainstem, which connects the brain to the spinal cord and regulates vital functions like swallowing and breathing. Often, these brain lesions are accompanied by the loss of the myelin sheath around nerves (demyelination). This demyelination impairs the nerves' ability to activate muscles for movement and to transmit sensory information from the body to the brain.

Inheritance:

Leigh syndrome can be inherited in different ways. The most common inheritance pattern is autosomal recessive. This means that both copies of the relevant gene in each cell must have a mutation for the disorder to develop. This inheritance pattern is associated with most Leigh syndrome-related genes found in nuclear DNA, including SURF1. Parents of individuals with an autosomal recessive condition each carry one copy of the altered gene but usually don't show any symptoms of the condition.

In about 20% of cases, Leigh syndrome is inherited through a mitochondrial pattern. This pattern involves genes within mitochondrial DNA (mtDNA), such as MT-ATP6. Because only egg cells, and not sperm cells, contribute mitochondria to a developing embryo, children inherit these mtDNA mutations only from their mothers. Fathers cannot pass on traits linked to mtDNA changes to their children. However, when inherited from the mother, these disorders can appear in every generation of a family and affect both males and females. Each cell contains multiple copies of mtDNA. A mutation is often present in only some of these copies (heteroplasmy). The level of heteroplasmy can influence the severity of the condition. In some cases, a mutation is found in all mtDNA copies (homoplasmy).

In a small number of individuals with mutations in nuclear DNA, Leigh syndrome follows an X-linked recessive inheritance pattern. The associated gene is located on the X chromosome, one of the two sex chromosomes. In males, who have only one X chromosome, one altered copy of the gene in each cell is sufficient to cause the condition. In females, who have two X chromosomes, both copies of the gene would need to be mutated for the disorder to occur. As it's less likely for both copies to be altered, X-linked recessive disorders are more common in males. A key feature of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Rarely, Leigh syndrome arises from spontaneous genetic mutations with no prior family history of the condition.