SUCLG1-related mitochondrial DNA (mtDNA) depletion syndrome is an inherited disorder that affects the early development of the brain. Signs and symptoms typically appear soon after birth. Most affected children develop severe brain dysfunction and muscle weakness (encephalomyopathy). Infants with SUCLG1-related mtDNA depletion syndrome often have weak muscle tone (hypotonia). They typically have difficulty eating and may require a feeding tube. Additional features may include liver abnormalities and thickening of the heart muscle (hypertrophic cardiomyopathy). In affected individuals, a substance called methylmalonic acid typically builds up in the blood and urine.

People with SUCLG1-related mtDNA depletion syndrome can have serious health complications, which result in a shortened lifespan. Individuals with SUCLG1-related mtDNA depletion syndrome typically do not survive past childhood.

Some infants with SUCLG1-related mtDNA depletion syndrome develop a toxic buildup of acids in the body in the first few days of life. This form of the disorder is called fatal infantile lactic acidosis. Infants with fatal infantile lactic acidosis typically only survive for a few days after birth.

SUCLG1-related mtDNA depletion syndrome is caused by variants (also called mutations) in the SUCLG1 gene. The SUCLG1 gene provides instructions for making one part (the alpha subunit) of an enzyme called succinyl-CoA ligase. This enzyme plays an important role in mitochondria, which are the energy-producing centers inside the cell. Succinyl-CoA ligase is involved in producing and maintaining the molecules that make up mtDNA, which is essential for the normal function of mitochondria.

Variants in the SUCLG1 gene lead to the production of an altered version of the alpha subunit, which disrupts the normal function of succinyl-CoA ligase. A shortage (deficiency) of the normal enzyme leads to problems with the production and maintenance of mtDNA.

A reduction in the amount of mtDNA (known as mtDNA depletion) impairs energy production in many of the body's cells and tissues. These problems lead to hypotonia, muscle weakness, and the other characteristic features of SUCLG1-related mtDNA depletion syndrome.

Normal Function

The SUCLG1 gene provides instructions for making one part, the alpha subunit, of an enzyme called succinate-CoA ligase. Two slightly different versions of this enzyme are made with the alpha subunit: ADP-forming succinate-CoA ligase (A-SUCL) and GDP-forming succinate-CoA ligase (G-SUCL). A-SUCL is most active in tissues that require a large amount of energy, such as those of the brain and muscles. G-SUCL is most active in other tissues, particularly in the liver and kidneys.

Both versions of succinate-CoA ligase play a critical role in mitochondria, which are structures inside cells that convert the energy from food into a form that cells can use. Within mitochondria, these enzymes are likely involved in a series of chemical reactions known as the citric acid cycle or Krebs cycle. These reactions allow cells to use oxygen and generate energy.

Mitochondria each contain a small amount of DNA, known as mitochondrial DNA or mtDNA. Studies suggest that succinate-CoA ligase interacts with another enzyme, nucleoside diphosphate kinase, to produce and maintain the building blocks of mitochondrial DNA. Having an adequate amount of mitochondrial DNA is essential for normal energy production within cells.

Health Conditions Related to Genetic Changes

Succinate-CoA ligase deficiency

At least two mutations in the SUCLG1 gene have been identified in people with succinate-CoA ligase deficiency. One mutation has been found to cause a very severe form of the condition known as fatal infantile lactic acidosis. Children with this condition usually live only a few days after birth. The mutation responsible for fatal infantile lactic acidosis deletes a small amount of genetic material from the SUCLG1 gene, which completely eliminates the activity of both versions of succinate-CoA ligase.

At least one other SUCLG1 gene mutation results in a somewhat less severe form of succinate-CoA ligase deficiency that is characterized by very weak muscle tone (severe hypotonia), uncontrolled movements, hearing loss, and delayed development. This mutation changes a single protein building block (amino acid) in succinate-CoA ligase, which reduces but does not eliminate the activity of both A-SUCL and G-SUCL.

A shortage (deficiency) of succinate-CoA ligase leads to problems with the production and maintenance of mitochondrial DNA. A reduction in the amount of mitochondrial DNA (known as mitochondrial DNA depletion) impairs mitochondrial function in many of the body's cells and tissues. A total loss of succinate-CoA ligase activity appears to have more severe effects than a partial loss of enzyme activity.

Leigh syndrome

MedlinePlus Genetics provides information about Leigh syndrome

Other Names for This Gene

• FLJ21114
• G-ALPHA
• SUCA_HUMAN
• succinate-CoA ligase, alpha subunit
• succinate-CoA ligase, GDP-forming alpha subunit
• SUCLA1

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell must have a variant to cause the disorder. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.

• Muscle weakness
• Difficulty feeding
• Inability to sit or hold the head up
• Hearing loss
• Poor growth (failure to thrive)
• Difficulty breathing due to muscle weakness
• Developmental delay
• Cognitive impairment

• Neurologist
• Gastroenterologist
• Orthopedist
• Physical therapist
• Medical geneticist
• Ear, nose, and throat physician
• Cardiologist
• Ophthmologist
• Audiologist
• Dietician

Approximately 40 people with SUCLG1-related mtDNA depletion syndrome have been reported in the medical literature.