Infantile encephalopathy associated with the MELAS A3243G mutation

Area of Science:

• Genetics and Molecular Biology
• Neurology
• Pediatrics

Background:

• MELAS syndrome (Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes) is a mitochondrial disorder.
• It is commonly associated with the A3243G point mutation in the mitochondrial DNA tRNALeu(UUR) gene.
• Typical presentation involves childhood-onset neurological deficits, seizures, and ragged red fibers.

Purpose of the Study:

• To report three unrelated children with the A3243G mutation presenting with atypical, early-onset severe psychomotor delay.
• To highlight the expanded phenotypic spectrum of the A3243G mutation beyond classic MELAS syndrome.
• To investigate the correlation between mutant mitochondrial DNA levels and neurological phenotype.

Main Methods:

• Clinical case series of three unrelated infants diagnosed with the A3243G mutation.
• Detailed clinical evaluation including neurological examinations, brain MRI, and muscle biopsy.
• Quantification of mutant mitochondrial DNA (mtDNA) proportion in muscle and blood samples.

Main Results:

• All three patients presented with severe psychomotor delay in early infancy, deviating from typical childhood onset.
• Clinical presentations included features resembling Leigh syndrome, refractory seizures, and atypical retinal changes.
• Low proportions of mutant mtDNA were found in peripheral tissues, with poor correlation to the neurological phenotype.

Conclusions:

• The A3243G mutation exhibits a broader phenotypic spectrum than previously recognized, including severe infantile psychomotor delay.
• Atypical presentations and early onset can occur despite low levels of mutant mtDNA in peripheral tissues.
• Factors beyond mutant mtDNA abundance in peripheral tissues likely influence the phenotypic expression of this mutation.