How MELAS Syndrome is Inherited
MELAS syndrome is inherited through maternal (mitochondrial) transmission, where only women pass the disease to children of either sex, with no male-to-male transmission possible. 1
Inheritance Pattern
Maternal inheritance occurs because mitochondrial DNA mutations are exclusively transmitted through the maternal line. 1 When evaluating a family pedigree, suspect mitochondrial DNA mutations when women—but not men—transmit the disease to children of either sex. 1
Key Genetic Features
The A3243G mutation in mitochondrial DNA is the most common cause, present in approximately 80% of MELAS patients. 2, 3 This mutation occurs in the tRNA leucine gene (MT-TL1), affecting mitochondrial protein synthesis. 2, 4
The severity of disease in an affected child depends on the proportion of mutant versus normal mitochondrial DNA (heteroplasmy level) inherited from the mother. 2 High-energy organs like brain, muscle, heart, liver, and kidney are most vulnerable. 2
Clinical manifestations emerge when mutant mtDNA exceeds a critical percentage (threshold effect). 2 This explains why disease severity varies even among siblings who inherit the mutation from the same mother.
Distinguishing from Other Inheritance Patterns
When constructing a family pedigree, MELAS differs from other patterns: 1
- Autosomal dominant: Affected individuals in every generation, transmission from either parent including male-to-male, 50% risk to offspring
- X-linked: Males only or most severely affected, no male-to-male transmission
- Autosomal recessive: Both parents unaffected and consanguineous
- Mitochondrial (MELAS): Only maternal transmission to children of either sex
Reproductive Counseling Implications
Women with MELAS mutations face significant reproductive counseling challenges. 2 Newer mitochondrial replacement techniques (MRTs) involving transfer of nuclear genetic material into donor oocytes with healthy mitochondria are being developed, though currently only permitted in the UK. 2
Genetic counseling is an important component of patient management in MELAS. 5 The heteroplasmy level and threshold effect make predicting disease severity in offspring difficult but critical for family planning discussions.