SUCLA2-related mitochondrial DNA (mtDNA) depletion syndrome is an inherited disorder that affects the early development of the brain. Affected infants typically develop weak muscle tone (hypotonia) in the first few months of life. In these infants, hypotonia can delay the development of motor skills such as lifting the head and rolling over. Children with SUCLA2-related mtDNA depletion syndrome typically have difficulty eating and may require a feeding tube; as a result, they have difficulty growing and gaining weight as expected (failure to thrive).

Additional features of SUCLA2-related mtDNA depletion syndrome can include uncontrolled movements (dystonia), hearing loss, muscle wasting (atrophy), and intellectual disabilities. In most affected children, a substance called methylmalonic acid builds up in the blood.

People with SUCLA2-related mtDNA depletion syndrome typically have a shortened lifespan. Approximately 30 percent of individuals with SUCLA2-related mtDNA depletion syndrome do not survive past childhood.

SUCLA2-related mtDNA depletion syndrome is caused by variants (also called mutations) in the SUCLA2 gene. The SUCLA2 gene provides instructions for making one part (the beta 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 SUCLA2 gene lead to the production of an altered version of the beta 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 the characteristic features of SUCLA2-related mtDNA depletion syndrome.

Normal Function

The SUCLA2 gene provides instructions for making one part (a beta subunit) of an enzyme called succinate-CoA ligase. The body makes two slightly different versions of this enzyme: ADP-forming succinate-CoA ligase (A-SUCL) and GDP-forming succinate-CoA ligase (G-SUCL). Only A-SUCL contains the beta subunit produced from the SUCLA2 gene. This version of the enzyme is most active in tissues that require a large amount of energy, such as those of the brain and muscles.

Succinate-CoA ligase plays 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, this enzyme is 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 four mutations in the SUCLA2 gene have been identified in people with succinate-CoA ligase deficiency. Each of these mutations alters the structure of A-SUCL, reducing the enzyme's activity. However, SUCLA2 gene mutations do not affect the other version of succinate-CoA ligase, G-SUCL. Studies suggest that the activity of G-SUCL may be able to compensate for a loss of A-SUCL in some tissues.

A shortage (deficiency) of A-SUCL leads to problems with the production and maintenance of mitochondrial DNA in the brain, muscles, and other tissues that require a large amount of energy. A reduction in the amount of mitochondrial DNA (known as mitochondrial DNA depletion) impairs mitochondrial function and the production of energy within cells. These problems lead to weak muscle tone (hypotonia), delayed development, and the other characteristic features of succinate-CoA ligase deficiency.

Leigh syndrome

MedlinePlus Genetics provides information about Leigh syndrome

Other Names for This Gene

• A-BETA
• ATP-specific succinyl-CoA synthetase, beta subunit
• renal carcinoma antigen NY-REN-39
• SCS-betaA
• SUCB1_HUMAN
• succinate-CoA ligase beta subunit
• succinate-CoA ligase, ADP-forming, beta subunit

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.

Approximately 60 people with SUCLA2-related mtDNA depletion syndrome have been reported in the medical literature. This condition occurs more frequently among people from the Faroe Islands in the North Atlantic Ocean.