SUCLA2-related mitochondrial DNA depletion syndrome

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.

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.

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.

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.