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Infantile encephalopathy associated with the MELAS A3243G mutation
1Departments of Neurology and Pediatrics, College of Physicians and Surgeons of Columbia University, New York, New York, USA.
Abstract:
MELAS syndrome is typically characterized by normal early development and childhood-onset recurrent neurologic deficits (stroke-like episodes), seizures, short stature, lactic acidosis, and ragged red fibers on muscle biopsy specimens. It is usually, but not invariably, associated with the A3243G point mutation in the mitochondrial DNA tRNALeu(UUR) gene. We report 3 unrelated children with the A3243G mutation who presented with severe psychomotor delay in early infancy. One patient's clinical picture was more consistent with Leigh syndrome, with apneic episodes, ataxia, and bilateral striatal lesions on brain magnetic resonance imaging (MRI). The second patient had generalized seizures refractory to treatment and bilateral occipital lesions on brain MRI. The third child had atypical retinal pigmentary changes, seizures, areflexia, and cerebral atrophy on brain MRI. All patients had several atypical features in addition to early onset: absence of an acute or focal neurologic deficit, variable serum and cerebrospinal fluid lactate levels, lack of ragged red fibers in muscle biopsy specimens. The proportion of mutant mtDNA in available tissues was relatively low (range, 5% to 51% in muscle; 4% to 39% in blood). These observations further extend the phenotypic expression of the A3243G "MELAS" mutation. Our findings confirm previous observations that there is poor correlation between abundance of mutant mtDNA in peripheral tissues and neurologic phenotype. This suggests that other factors contribute to the phenotypic expression of this mutation.
Insights
The A3243G mitochondrial DNA mutation, typically linked to MELAS syndrome, can cause severe early-onset psychomotor delay in infants. This 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.