Danon disease is X-linked, and much of the research to date has focused on males. In the latest episode of The Genetics Podcast, Patrick is joined by Jenny Hsieh, Co-Founder and President of the Danon Foundation. She argues that the male-focused picture is incomplete, and that women in her community are being dismissed or misdiagnosed as a result.
Jenny previously worked in biotech, including in breast cancer. She was diagnosed with Danon disease while asymptomatic, through testing during family planning. She then used IVF with PGD testing so as not to pass it on. She later learned she was already past the reported median survival age for females with Danon disease. She remains asymptomatic, with annual cardiology visits.
She co-founded the Foundation with Amy Atkinson. Amy's daughter Delaney was diagnosed with HCM at 4 and Danon disease at 5. Delaney later went into heart failure and did not wake up after a heart transplant.
Danon disease is linked to the LAMP2 gene. It is a lysosomal storage disorder that affects autophagy. It is also multisystemic, involving cardiomyopathy, eye disease, muscle weakness, and cognitive or learning issues.
Because the gene sits on the X chromosome, X-inactivation produces variable presentation in females. Jenny says the Foundation is working to change the narrative that severe disease is mainly a male experience.
About half of the Foundation's community is female. Around 60% of known members have had a heart transplant, a rate she describes as on par with males. Males often need a transplant around ages 18 to 22.
Severe disease in women does not always lead to a diagnosis. Jenny described a pattern where women's cardiac symptoms are attributed to other causes:
"Women often get dismissed in terms of their heart issues. Sometimes it's actually misdiagnosed as anxiety or other issues because it's not really presenting in the same way as males."
She also noted that women are often diagnosed only after their child, through cascade testing. For clinicians reviewing family history, unexplained sudden cardiac deaths are a signal to follow up.
Jenny calls this the "body part" problem. Clinicians treat the organ in front of them, and the pattern across organs goes unseen. Misdiagnosis as Wolff-Parkinson-White (WPW) syndrome is one example she gave, and she said LAMP2 is not believed to be on the ophthalmology panel.
The Foundation is working to change that panel gap. Her practical test for clinicians is simple:
"If cardiomyopathy plus anything else, you should definitely consider genetic testing."
The "anything else" can be eye disease, muscle weakness, or learning issues. Jenny said the community has higher rates of ADHD, autism, and learning issues, more pronounced in males. In her account, closing the gap depends less on new technology and more on clinicians pausing to ask what else is going on.
Jenny believes there is funding for Danon research. Her concern is what that work produces. Natural history studies need to generate learnings the community can use, and sex differences need to be understood before trials can be designed well.
The burden she wants studied extends beyond the heart. Retinal disease can affect driving, and caregiving falls on families. Trial participation adds its own costs, including lost wages and travel.
Consent is part of that burden. Jenny said consent forms can be overwhelming and full of jargon, and families often arrive in a state of panic. She asks industry partners to explain what the trial experience will be like, as well as the risks. She added that parents in rare disease are highly educated, so trial sites need to be ready for detailed questions.
One gene therapy for Danon disease is currently in clinical trials and could become the first FDA-approved therapy for the condition. Jenny would like to see more therapeutic attempts. She also expects an FDA-approved therapy to drive more diagnosis, as approvals tend to do in rare disease.
The Foundation has touched fewer than about 1,000 patients across more than 25 countries. With a community that size, Jenny's approach is "don't reinvent the wheel." The Foundation partners with Global Heart Hub, Rare Disease International, and EURORDIS.
The Foundation chose October 24 for the first-ever Danon Awareness Day, a nod to LAMP2's location at Xq24. Jenny's closing advice was directed at anyone who encounters an unusual presentation: if you see something, ask another question and ask why. For Danon disease, that extra question can be the difference between an anxiety label and a genetic test.
Listen to the full episode below.