SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria

Clinical characteristics: SUCLA2-related mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria (SUCLA2-related mtDNA depletion syndrome) is characterized by onset of the following features in infancy: developmental delay, hypotonia, dystonia, muscular atrophy, sensorineural hearing impairment, growth failure, and feeding difficulties. Other less frequent features include choreoathetosis, muscle weakness, recurrent vomiting, ptosis, and kyphoscoliosis. The median survival is age 20 years; approximately 30% of affected individuals succumb during childhood.

Diagnosis/testing: The diagnosis of SUCLA2-related mtDNA depletion syndrome is established in a proband with suggestive findings and biallelic pathogenic variants in SUCLA2 identified by molecular genetic testing.

Management: Treatment of manifestations: Appropriate early developmental support; physical therapy to maintain muscle function and prevent joint contractures; antiseizure medication for epileptic seizures; hearing aids / cochlear implantation for sensorineural hearing loss; gastrostomy tube placement as needed to assure adequate caloric intake; blepharoplasty for significant ptosis; low vision services as needed; chest physiotherapy, aggressive antibiotic treatment of chest infections, and consideration of respiratory aids; bracing to treat scoliosis or kyphosis.

Surveillance: Routine monitoring of development, growth, and hearing; periodic ophthalmologic evaluations; routine skeletal evaluations for kyphoscoliosis and joint contractures.

Genetic counseling: SUCLA2-related mtDNA depletion syndrome is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a SUCLA2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the SUCLA2 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing for SUCLA2-related mtDNA depletion syndrome are possible.