What is the inheritance pattern of MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes)?

MELAS Inheritance Pattern

MELAS syndrome is inherited through maternal (mitochondrial) transmission, meaning only women can pass the disease to their children of either sex, with no male-to-male transmission possible. 1

Maternal Mitochondrial Inheritance

• MELAS follows a mitochondrial DNA inheritance pattern, which is exclusively transmitted through the maternal line 1, 2, 3, 4
• When women—but not men—transmit the disease to children of either sex, mitochondrial DNA mutations should be considered 1
• This is a maternally inherited mitochondrial disorder where affected males cannot pass the mutation to their offspring 2, 3, 4, 5, 6

Heteroplasmy and Disease Severity

• The proportion of mutant versus normal mitochondrial DNA (heteroplasmy level) inherited from the mother determines the severity of disease in affected children 7
• The threshold effect plays a crucial role in disease expression, where clinical manifestations emerge when mutant mtDNA exceeds a critical percentage, with high-energy organs being most vulnerable 7
• The degree of heteroplasmy in the patient's tissues and organs determines the variable clinical manifestations observed in MELAS syndrome 5

Genetic Counseling Implications

• Women with MELAS mutations face significant reproductive counseling challenges due to the unpredictable heteroplasmy levels that will be transmitted to offspring 7
• 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 7
• Pedigree analysis showing affected individuals only through maternal transmission, with no male-to-male transmission and presence of affected children of both sexes from affected mothers, confirms mitochondrial inheritance 1

Common Pitfalls to Avoid

• Do not assume autosomal dominant inheritance when seeing multiple affected family members—the absence of male-to-male transmission is the key distinguishing feature 1
• The most common mutation (A3243G in the MT-TL1 gene) is present in approximately 80% of MELAS patients, but genetic testing should still be pursued even with typical clinical presentation 7, 8, 4, 6