Danon disease: when the retina reveals a life-threatening cardiac disorder

Danon disease is a rare, multisystem X-linked genetic disorder caused by variants in the LAMP2 gene. In children and young adults, it is defined overwhelmingly by its effects on the heart. What is far less appreciated is that the eye is frequently involved and that the retinal findings can appear before the systemic diagnosis is established.

"The aim of our group led by Demetrios G. Vavvas, MD, PhD, and Nimesh A. Patel, MD, is to get Danon disease onto the ophthalmologist's differential, and ultimately onto the genetic panels we order when a patient presents with unexplained retinal findings, where LAMP2 is still not routinely included," said Maria Emfietzoglou, MD, a Research Fellow at the Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston. Vavvas is the Solman and Libe Friedman Professor of Ophthalmology at Harvard Medical School and Director of the Retina Service at Massachusetts Eye and Ear, and Patel is Director of Pediatric Retina at Massachusetts Eye and Ear and Massachusetts General Hospital and Assistant Professor of Ophthalmology at Harvard Medical School, all in Boston.

Differences between males and females

Danon disease is a multisystem disorder that, beyond the eye, involves the heart, skeletal muscle, and brain, and the cardiac disease drives its serious prognosis.^1,2 Males are typically affected earlier and far more severely, presenting with hypertrophic cardiomyopathy in early childhood that often requires heart transplantation or defibrillator placement in young adulthood to prevent sudden death, Emfietzoglou said. Females have a more variable, often later-onset course, ranging from asymptomatic carriers to severe disease.

Bringing the ophthalmic picture into focus

Ocular findings in Danon disease have long been recognized but rarely studied systematically. To characterize them, Emfietzoglou and colleagues conducted a systematic review of PubMed and EMBASE to identify patients with genetically or clinically confirmed Danon disease, publishing their findings in the American Journal of Ophthalmology.³ The search yielded 34 studies (25 case reports, eight case series, and one retrospective cohort) comprising 70 patients ranging in age from 6 to 81 years.

Retinal abnormalities were the most common ocular finding, appearing in 81% of cases, typically as midperipheral or peripheral salt-and-pepper mottling (about 60%), with near-complete pigment loss in a minority. Macular involvement was also frequent (62%), usually as nonspecific RPE change, while a smaller group (13%) developed more severe pathology such as macular atrophy, bull's-eye maculopathy, or cystoid macular edema.³

Critically, the eye was not always a late or incidental feature. Ophthalmic findings were the first or only manifestation of Danon disease in 11 of 70 patients (16%). In some, retinal changes appeared years before systemic disease was recognized; in others, all female carriers or mosaics, the eye remained the only affected site; and in a few, the eye examination itself prompted the workup that led to the diagnosis.³

A commonly misdiagnosed retinopathy

These patterns help explain why Danon disease has been misclassified in the past. Prior reports have variously labeled it "cone dystrophy," "cone-rod dystrophy," or "retinitis pigmentosa," labels the authors consider misleading, since the features that define those diagnoses are typically absent in Danon disease.

On OCT, a telling signal in the outer nuclear layer

Optical coherence tomography (OCT) images were available in about half of the patients in the review, and the most frequent findings were disruption of the RPE and ellipsoid zone (85%) and hyperreflectivity of the outer nuclear layer (ONL) (61%).³

That ONL signal was intriguing enough to warrant its own study. In a separate paper, Emfietzoglou and colleagues singled out ONL hyperreflectivity as a strikingly consistent OCT feature.⁴ Combining a single-center, retrospective observational case series with a literature search of confirmed Danon disease patients who had undergone macular OCT, they analyzed 52 macular scans from 29 patients and reported, "Evidence of ONL hyperreflectivity appeared in 39 macular scans (75%)." When the analysis was limited to evaluable foveal scans, the figure rose to 97.5%.

The finding was most evident in younger patients whose outer retina was otherwise intact, which may point to early retinal involvement, although longitudinal data are lacking to prove that it precedes other changes. The authors hypothesized that it "could reflect mitochondrial accumulation secondary to impaired mitophagy," and framed it as a potential early, non-invasive marker whose prognostic value future longitudinal studies will need to confirm.⁴

From imaging sign to diagnosis

The practical power of that signal is not hypothetical. It was the unexplained fundus findings and the ONL hyperreflectivity that led Patel to a Danon diagnosis in a young girl who had no other signs of disease.

"One practical lesson is the value of saving images of your interesting cases. It helps with recall, and it builds the pattern recognition that lets you connect a new patient to one you've seen before. I would also keep Danon disease in mind whenever you see pigmentary change without atrophy, which is exactly the kind of finding that's easy to overlook," he said.

Reported as part of the published case series, the patient was a 7-year-old girl referred for retinal pigmentary changes, with no family history and no systemic features of Danon disease; earlier genetic testing for inherited retinal dystrophies had been unrevealing. Macular OCT demonstrated a preserved foveal contour with ONL hyperreflectivity and outer plexiform layer granularity, and targeted LAMP2 testing confirmed the diagnosis, making her the youngest patient reported to date to be diagnosed with Danon disease retinopathy in the absence of family history or systemic findings.⁴

What eye care clinicians should order

For clinicians who encounter these findings, Emfietzoglou and colleagues propose a standardized multimodal evaluation for any patient with suspected or confirmed Danon disease: fundus photography to document pigmentary changes, fundus autofluorescence to assess RPE health, spectral-domain OCT to detect outer retinal abnormalities including ONL hyperreflectivity, and electroretinography guided by visual symptoms, the presence of atrophy, and availability.

When to suspect it

Danon disease belongs in the differential for unexplained pigmentary retinopathy, particularly in a young patient or one with a family history of cardiomyopathy or arrhythmia. Helpful features distinguishing it from retinitis pigmentosa include the absence of optic disc pallor, bone-spicule pigmentation, and a flat ERG. Notably, conditions that share Danon's cardiac differential, such as PRKAG2 syndrome and Pompe disease, are not typically associated with retinal involvement, which makes the eye examination a potentially discriminating adjunct in the workup.³

"Eye care clinicians should be aware of the potential for Danon disease, because they may be the first clinician in a position to suspect it," Emfietzoglou commented. "If a patient has ocular findings, clinicians should ask about systemic problems, especially in a young patient or someone with a family history of cardiomyopathy or arrhythmias. Picking it up can lead to genetic testing, cardiac workup, and family screening."

Why it matters

The stakes are twofold. First, the eye can make the diagnosis, and because Danon disease is life-threatening, that recognition can be lifesaving. Even in female carriers, spotting retinal anomalies can flag disease before it progresses to frank cardiac involvement, Emfietzoglou emphasized.

Second, the retinal disease itself can threaten sight. Patients should be aware that current cardiac gene therapy approaches, based on cardiotropic AAV9 vectors, do not target the eye, so retinal degeneration may progress despite systemic improvement.

Vavvas commented, "Multidisciplinary care is central to managing Danon disease, ophthalmic evaluation is often overlooked in practice and there is still much to be learned about how the disease affects the eyes and what the eye findings can teach us about the systemic condition. As these patients are now diagnosed earlier and live longer, more thorough eye and retinal assessment becomes essential to better serve our patients."

Danon Foundation

The Danon Foundation in Madison, NJ, is a nonprofit organization with the stated goal of "empowering people living with Danon disease by providing trusted information, support and resources to navigate life with this rare condition… improving access to genetic testing, supporting the newly diagnosed, building community, and engaging in research initiatives to advance the development of therapies for Danon disease." Information is available at danonfoundation.org.

“As a foundation rooted in the lived experience of Danon disease, we know it is often defined by its cardiac impact but it affects far more than the heart. Eye-related issues can persist and affect the quality of life for patients and families. Recognizing ocular involvement and establishing clear guidelines around ophthalmologic findings could meaningfully improve diagnosis and inform care for people living with this rare disease,”Jenny Hsieh, Co-Founder and President, Danon Foundation, said.

References

1. Taylor MRG, Adler ED. Danon disease. GeneReviews [Internet]. Updated March 5, 2020. https://www.ncbi.nlm.nih.gov/books/NBK554742/
2. MedlinePlus. Danon disease. https://medlineplus.gov/genetics/condition/danon-disease/
3. Emfietzoglou M, Sakuno G, Awh C, et al. Ophthalmic manifestations of Danon disease: a systematic review. Am J Ophthalmol. Published online March 25, 2026. doi:10.1016/j.ajo.2026.03.026
4. Emfietzoglou M, Sakuno G, Hoyek S, et al. Outer nuclear layer hyperreflectivity as an optical coherence tomography finding in Danon disease. Acta Ophthalmol. Published online February 10, 2026. doi:10.1111/aos.70098