Lethal neonatal mitochondrial phenotype caused by a novel polymerase subunit gamma mutation: A case report

Area of Science:

• Genetics and Genomics
• Mitochondrial Biology
• Neonatal Medicine

Background:

• The Polymerase gamma (POLG) gene encodes the catalytic subunit of mitochondrial DNA polymerase, crucial for mitochondrial DNA replication.
• Mutations in POLG are linked to various clinical syndromes involving secondary mitochondrial DNA (mtDNA) defects, such as mtDNA depletion or mutation.
• These defects can impair cellular energy production, leading to severe consequences like Complex 1 deficiency.

Observation:

• A Saudi neonate born to consanguineous parents presented with severe hypotonia, respiratory distress, and dysmorphic features immediately after birth.
• The infant had a history of three siblings who died from similar clinical presentations during the neonatal period.
• The patient required mechanical ventilation and intensive care from birth until her death.

Findings:

• Molecular genetic testing identified novel compound heterozygous mutations in the POLG gene: c.680G>A (p.Arg227Gln) and c.3098C>T (p.Ala1033Val).
• These POLG mutations resulted in a complete failure of cellular energy production, specifically a Complex 1 respiratory chain defect.
• The infant succumbed to the condition at 5 months of age.

Implications:

• Mitochondrial respiratory chain defects should be strongly considered in neonates presenting with severe hypotonia, encephalopathy, and respiratory failure.
• Genetic counseling and molecular testing for POLG mutations are crucial, particularly in populations with high consanguinity rates.
• Early diagnosis and multidisciplinary management are vital for infants suspected of having mitochondrial disorders.