Leigh Syndrome (LS) is a severe, progressive neurological disorder that typically begins in infancy, profoundly affecting the central nervous system. It is classified as a neurometabolic condition because its root cause is a fundamental failure of the body’s energy production processes. This failure leads to the degeneration of brain tissue, particularly in areas like the brainstem and basal ganglia, which control basic motor and autonomic functions. The condition is genetically complex, arising from mutations in over 110 different genes found in two distinct parts of the cell.
The Underlying Cellular Failure
All forms of Leigh Syndrome share a common physiological problem: the inability to generate sufficient adenosine triphosphate (ATP), the cell’s universal energy currency. This energy production occurs mainly within the mitochondria, often referred to as the cell’s power plants. Mitochondria convert energy derived from nutrients, such as glucose, into ATP through a complex process.
The process begins with the breakdown of glucose into pyruvate, which is then converted into a usable fuel source. This fuel enters the inner mitochondrial membrane to feed the oxidative phosphorylation (OXPHOS) system. The OXPHOS system, also known as the electron transport chain (ETC), is a series of five protein complexes (Complexes I through V) that generate ATP. A defect in any one of these steps can disrupt the entire process, leading to an energy crisis.
When this energy pathway is blocked, cells suffer from an energy deficit, causing them to malfunction and eventually die. Since the brain consumes a disproportionately large amount of the body’s total energy supply, it is the most vulnerable organ to this cellular failure. The inability to properly process pyruvate also leads to a buildup of lactic acid, which further damages tissues and contributes to the progressive nature of the syndrome.
Genetic Causes Originating in Nuclear DNA
The majority of Leigh Syndrome cases (80% to 90%) are caused by mutations in genes found in the cell’s nucleus. These nuclear genes contain the instructions for building most of the protein components required by the mitochondria. Since a healthy cell needs two functional copies of a gene, most nuclear forms of LS are inherited in an autosomal recessive pattern, meaning both parents must carry a mutated copy.
One of the most frequent nuclear defects involves the Pyruvate Dehydrogenase Complex (PDHC), an enzyme group that links the breakdown of glucose to the mitochondrial energy cycle. PDHC deficiency prevents pyruvate from being converted into the acetyl-CoA needed to fuel the ETC, causing a metabolic traffic jam. Defects in the PDHA1 gene, which codes for a subunit of this complex, are common and are often inherited in an X-linked pattern.
Many other nuclear mutations affect the assembly or function of the five protein complexes that make up the electron transport chain. Complex I, the largest of the chain, is frequently impaired by nuclear gene defects and is the most common single cause of Leigh Syndrome. Another significant cause involves defects in Complex IV, often due to mutations in the SURF1 gene, which is necessary for the complex’s assembly. A SURF1 mutation results in the lack of a functional protein, which compromises Complex IV activity and is inherited in an autosomal recessive manner.
Genetic Causes Originating in Mitochondrial DNA
A smaller percentage of cases (approximately 10% to 20%) result from mutations in the mitochondrial DNA (mtDNA), which is separate from the nuclear DNA. mtDNA contains a small number of genes that code for some of the subunits of the ETC complexes. This form of the disorder is characterized by maternal inheritance because only the mother’s egg cell contributes mitochondria to the developing embryo.
The most common mtDNA mutation associated with Leigh Syndrome occurs in the MT-ATP6 gene, which codes for a subunit of Complex V, the final enzyme in the OXPHOS pathway that synthesizes ATP. These mutations are also associated with NARP (Neuropathy, Ataxia, and Retinitis Pigmentosa) syndrome. The severity of the disease is determined by the proportion of mutated mtDNA present.
This phenomenon is known as heteroplasmy, referring to the coexistence of both normal and mutated mtDNA within the same cell. For Leigh Syndrome to manifest, the proportion of mutated mtDNA must be extremely high, often above 90% to 95%. Lower levels of mutated mtDNA are associated with the milder NARP syndrome or may not cause symptoms at all, demonstrating a direct correlation between the genetic load and the clinical outcome.
Why Identifying the Specific Cause is Critical
Pinpointing the exact genetic mutation causing Leigh Syndrome is important for managing the disorder, moving beyond a simple diagnosis of energy failure. The specific gene affected offers insight into the likely course of the disease, as some mutations are associated with a more rapid and severe progression than others. For example, individuals with PDHC deficiencies or certain Complex I defects often have a poorer prognosis compared to those with SURF1 mutations.
Knowing the precise genetic origin is essential for providing accurate genetic counseling to families. The risk of recurrence for future children varies dramatically depending on the inheritance pattern—whether X-linked, autosomal recessive, or maternally inherited. This information allows parents to make informed decisions about family planning and prenatal testing options.
The genetic diagnosis can directly influence management strategies, even though there is currently no cure. Certain metabolic defects, such as PDHC deficiency, may show some response to high doses of cofactor supplements like thiamine or lipoic acid. While these supplements do not cure the condition, they may offer a therapeutic benefit by attempting to bypass or assist the dysfunctional enzyme complex.