Menkes disease with discordant phenotype in female monozygotic twins

Area of Science:

• Genetics
• Neuroscience
• Pediatrics

Background:

• Menkes disease (MD) is a rare, X-linked recessive neurodegenerative disorder.
• It results from mutations in the ATP7A gene, affecting copper distribution and enzyme function.
• MD primarily impacts males, with affected females being exceptionally rare.

Observation:

• This study reports on clinically discordant female monozygotic twins (MZT) carrying a heterozygous ATP7A mutation.
• One twin remained healthy, while the other developed classical MD.
• The affected twin showed transient stabilization with copper histidine treatment before succumbing at age 3.

Findings:

• The discordant phenotype in MZT girls suggests skewed X inactivation may lead to MD.
• Skewed X inactivation was hypothesized but not definitively demonstrated in available tissues (blood, buccal mucosa).
• This case represents a rare instance of an affected female with MD and highlights discordant phenotypes in MZT.

Implications:

• This case underscores the potential for skewed X inactivation to cause severe X-linked disorders in heterozygous females.
• It emphasizes the importance of considering X inactivation patterns in understanding phenotypic variability in female carriers.
• Further research into X inactivation mechanisms in MZT may elucidate disease discordance in X-linked conditions.