SUCLG1-related mitochondrial DNA depletion syndrome

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.

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

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.

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.