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RP-A501 (AAV9.LAMP2B)

Danon disease

Regulatory submission
BLA planned for late 2028
Last updated
300 sources

Product information and disease descriptionPlace of product in therapyDisease description

Natural history, survival, and mortality

36 evidence topics · 24 sources

Course by sex: consensus description

“Disease penetrance is likely 100% in both sexes.” (opens the source at this quote in a new tab)

“Male individuals typically manifest with a severe hypertrophic cardiomyopathy that progresses to end-stage in the second or third decade of life, whereas female individuals can present with either a hypertrophic or dilated cardiomyopathy that progresses more slowly, reaching the end stage a full decade or later than in male individuals.” (opens the source at this quote in a new tab)

“The median age at onset in male individuals is approximately 14 years, whereas in female individuals it ranges between 17 and 35 years.” (opens the source at this quote in a new tab)

“Nevertheless, very early onset in the first year of life has been described in both sexes, although mainly in male infants.” (opens the source at this quote in a new tab)

“Most patients with Danon disease will experience symptomatic heart failure. Male individuals generally present earlier than women and die of either heart failure or arrhythmia or receive a heart transplant by the third decade of life.” (opens the source at this quote in a new tab)

International Danon Disease Registry (116 participants, consent 2005 to 2022): cohort, age at diagnosis, and follow-up

“Data were from the International Danon Disease Registry and includes retrospective data on 116 patients who provided informed consent between 2005 and 2022.” (opens the source at this quote in a new tab)

“The analysis included 116 patients with DD (of which 20% [n=23] were international) and was stratified by sex: female (n=64, 55%) and male (n=52, 45%)” (opens the source at this quote in a new tab)

“Records were obtained from the first episode of care to the date of enrollment.” (opens the source at this quote in a new tab)

“Median age of diagnosis for the entire cohort was 15.2 years (10.0–25.2 years), and 21.9 years (15.0–34.9 years) and 12.4 years (7.1–15.6 years) for female and male patients, respectively.” (opens the source at this quote in a new tab)

“Median follow‐up time was 5.82 years (2.67–11.76 years) for the entire cohort, and 5.82 years (2.67–14.96 years) and 5.86 years (2.93–8.51 years) for female and male patients, respectively.” (opens the source at this quote in a new tab)

International Danon Disease Registry: heart transplantation, ventricular assist device, and death by sex
OutcomeMale participants: No.Male participants: IQR or %Female participants: No.Female participants: IQR or %Total: No.Total: IQR or %
Heart failure outcome“21”“40.4”“14”“21.9”“35”“30.2”
Heart transplant“17”“32.7”“13”“20.3”“30”“25.9”
Left ventricular assist device“2”“3.8”“2”“3.1”“4”“3.4”
Death“7”“13.5”“2”“3.1”“6”“5.2”
Age at heart failure outcome, years“19”“16–23”“26”“14–39”“20”“16–27”

“Outcome measures include heart transplantation, left ventricular assist device, and death.” (opens the source at this quote in a new tab)

“The incidence of the HF outcome was higher in male (40%, n=21) compared with female patients (22%, n=14)” (opens the source at this quote in a new tab)

“Additionally, the actuarial median age of HF outcome was younger in male compared with female patients with median time to HF outcome from birth being 25 years old in male and 63 years old in female patients” (opens the source at this quote in a new tab)

“While age of HF outcome in male patients (19 years [16–23 years]) was numerically lower compared with female patients (26 years [14–39 years]) who did experience HF outcome, this did not reach statistical significance” (opens the source at this quote in a new tab)

International Danon Disease Registry: two age groups of heart failure outcome among females

“Stratified analysis demonstrated 2 distinct groups of females: one who experienced HF outcome before 26 years of age and another group with this HF outcome after.” (opens the source at this quote in a new tab)

“Median age of HF outcome in female patients with HF outcome ≥26 years old (n=7) and <26 years old (n=7) was 39 (28–47 years) and 14 (11–20 years), respectively” (opens the source at this quote in a new tab)

“Notably, in time to event analyses comparing male patients with these female subgroups, median age of HF outcome was earliest in the female patients who experienced a HF outcome before the age of 26 years” (opens the source at this quote in a new tab)

“Notably, although all female patients who reached a HF outcome met criteria for LVH at some point during their life, patients in the <26 years old group developed more significant hypertrophy compared with those in the ≥26 years old (2.36 cm [2.30–3.26 cm] versus 1.4 cm (0.9–1.5 cm)” (opens the source at this quote in a new tab)

International Danon Disease Registry: echocardiograms available for longitudinal analysis

“A total of 95 (82%) patients had echocardiographic results, of which 75 (92%) had serial echocardiograms.” (opens the source at this quote in a new tab)

“Ages of first echocardiogram in patients with serial echocardiograms were 15.9 years (11.3–19.9 years) and 25.8 years (17.0–42.2 years) in male and female patients, respectively.” (opens the source at this quote in a new tab)

“Median time from first to last echocardiogram in all patients was 4.7 years (IQR, 1.1–8.9 years), and 4.2 years (IQR, 0.7–6.1 years) and 6.1 years (IQR, 1.2–11.3 years) in male and female patients, respectively.” (opens the source at this quote in a new tab)

“longitudinal analyses utilized data from 65% of the total patient population.” (opens the source at this quote in a new tab)

Untreated males: first and last echocardiographic measurements by heart failure outcome
MeasurementExaminationAll males: medianAll males: IQRHeart failure outcome: medianHeart failure outcome: IQRNo heart failure outcome: medianNo heart failure outcome: IQR
Left ventricular ejection fraction, %First“66”“57–71”“58”“50–68”“67”“62–76”
Left ventricular ejection fraction, %Last“55”“28–64”“33”“20–52”“58”“50–68”
Thickest left ventricular wall, cmFirst“1.2”“0.9–1.9”“1.7”“1.2–2.4”“1.1”“0.8–1.5”
Thickest left ventricular wall, cmLast“1.5”“1.0–2.5”“1.9”“1.6–2.5”“1.4”“1.0–2.3”
Left ventricular mass, gFirst“154”“87–413”“327”“209–541”“111”“80–163”
Left ventricular mass, gLast“275”“143–613”“596”“285–690”“161”“77–377”
Left ventricular end diastolic dimension, cmFirst“3.9”“3.4–4.6”“4”“3.6–4.6”“3.8”“3.4–4.7”
Left ventricular end diastolic dimension, cmLast“4.4”“3.7–5.3”“6.3”“4.8–6.6”“4”“3.7–4.7”

“Notably, in patients who experienced a HF outcome, LVEF from baseline to last echocardiogram decreased from 58% to 33%” (opens the source at this quote in a new tab)

Untreated females: first and last echocardiographic measurements by heart failure outcome
MeasurementExaminationAll females: medianAll females: IQRHeart failure outcome: medianHeart failure outcome: IQRNo heart failure outcome: medianNo heart failure outcome: IQR
Left ventricular ejection fraction, %First“61”“55–70”“57”“52–77”“61”“55–69”
Left ventricular ejection fraction, %Last“56”“35–65”“37”“23–47”“56”“47–66”
Thickest left ventricular wallFirst“1.1”“0.8–1.5”“1.1”“1.0–1.6”“1.1”“0.8–1.4”
Thickest left ventricular wallLast“1.2”“1.0–1.7”“1.2”“0.9–2.0”“1.2”“1.0–1.7”
Left ventricular mass, gFirst“165”“97–262”“296”“80–320”“157”“106–227”
Left ventricular mass, gLast“224”“140–272”“232”“218–288”“187”“132–272”
Left ventricular end diastolic dimensionFirst“4.3”“3.6–4.9”“4.4”“2.8–5.2”“4.3”“3.9–4.8”
Left ventricular end diastolic dimensionLast“4.7”“4.1–5.8”“5.9”“5.5–6.4”“4.5”“4.0–5.3”
Untreated males: change in echocardiographic parameters per year of age, by heart failure outcome
ParameterNo heart failure outcome: participants (n)No heart failure outcome: coefficientNo heart failure outcome: 95% CINo heart failure outcome: P valueHeart failure outcome: participants (n)Heart failure outcome: coefficientHeart failure outcome: 95% CIHeart failure outcome: P value
Left ventricular ejection fraction“20”“−0.888”“−1.521 to −0.254”“0.006”“12”“−2.461”“−3.026 to −1.898”“<0.001”
Left ventricular wall thickness“23”“0.101”“0.069 to 0.133”“<0.001”“13”“0.008”“−0.036 to 0.051”“0.734”
Left ventricular mass“20”“28.424”“19.094 to 37.755”“<0.001”“13”“34.183”“20.548 to 47.817”“<0.001”
Left ventricular end diastolic dimension“22”“0.123”“0.082 to 0.162”“<0.001”“14”“0.231”“0.176 to 0.287”“<0.001”

“Coefficients Derived from Mixed Effect Regression Models Represent the Magnitude of Change in the Parameter as Patient Ages” (opens the source at this quote in a new tab)

“Age was the fixed effect, and the individual patient the random effect.” (opens the source at this quote in a new tab)

“Specifically, mixed effects model coefficients in both male and female patients suggest a decrease in LVEF by ≈2.4% per year in patients who experience a HF outcome” (opens the source at this quote in a new tab)

Untreated females: change in echocardiographic parameters per year of age, by heart failure outcome
ParameterNo heart failure outcome: participants (n)No heart failure outcome: coefficientNo heart failure outcome: 95% CINo heart failure outcome: P valueHeart failure outcome: participants (n)Heart failure outcome: coefficientHeart failure outcome: 95% CIHeart failure outcome: P value
Left ventricular ejection fraction“34”“−0.832”“−1.164 to −0.500”“<0.001”“9”“−2.391”“−3.477 to −1.305”“<0.001”
Left ventricular wall thickness“33”“−0.012”“−0.022 to −0.003”“<0.009”“9”“−0.026”“−0.0372 to −0.016”“<0.001”
Left ventricular mass“29”“−0.631”“−2.482 to 1.219”“0.5037”“9”“1.868”“−3.342 to 7.078”“0.482”
Left ventricular end diastolic dimension“31”“0.05”“0.031 to 0.069”“<0.001”“9”“0.175”“0.109 to 0.240”“<0.001”
Trajectories identified by sex and heart failure outcome

“Trends in echocardiographic parameters over time indicate decreased left ventricular ejection fraction and increased left ventricular end diastolic dimension regardless of sex and heart failure (HF) outcome; however, rate of change was increased in patients who experienced a HF outcome in both sexes.” (opens the source at this quote in a new tab)

“Left ventricular wall hypertrophy continues in men who have not yet experienced a HF outcome and stabilizes before HF outcome, while females have progressive left ventricular thinning regardless of HF outcome.” (opens the source at this quote in a new tab)

“LV mass increases in male patients regardless of HF outcome and begins in childhood and continues through adulthood. In female patients, LV mass does not change significantly with age” (opens the source at this quote in a new tab)

“This suggests that eventual LVH stabilization may be a marker for end‐stage disease in male patients, particularly when paired with progressive LV dysfunction and dilation.” (opens the source at this quote in a new tab)

“Female patients who experience a HF outcome earlier in life have more severe LVH compared with female patients who experience a HF outcome later in life. Additionally, like male patients, their LV mass increases significantly over time.” (opens the source at this quote in a new tab)

Echocardiographic parameters proposed as surrogate end points, registry limitations, and funding

“The results from this study suggest that potential surrogate end points for therapeutic trials could include LVEF, LV mass, LVEDD, and LV wall thickness in male patients, and LVEF, LVEDD, and LV wall thickness in female patients.” (opens the source at this quote in a new tab)

“While this study reports outcomes from the largest cohort of patients with DD, the sample size remains small and limits generalizability.” (opens the source at this quote in a new tab)

“Patient registries often have problems with variability in data entry as well as the retrospective nature of the study and also standard of care data collection that spanned enrollment over several decades; therefore, data collection intervals and parameters were not consistent.” (opens the source at this quote in a new tab)

“Funding was provided by Muscular Dystrophy Association Grant 67 944. Investigator‐initiated sponsor research agreement with Rocket Pharmaceuticals.” (opens the source at this quote in a new tab)

International Danon Disease Registry, earlier analysis of 112 participants: ejection fraction, wall thickness, mass, and laboratory markers over time

“This study included 112 patients with a median follow up of 6.8 yrs (IQR: 2.5-12.8 yrs).” (opens the source at this quote in a new tab)

“At least mild ventricular dysfunction occurred in 30% of patients, and almost all patients had LV hypertrophy.” (opens the source at this quote in a new tab)

“Over time, LVEF decreased in both sexes and LV wall thickness did not increase, although LV mass increased in males only. BNP, CPK and AST did not change.” (opens the source at this quote in a new tab)

Untreated males: annual increase in left ventricular mass and BNP, unpublished registry data shown by the sponsor in October 2026

“LV Mass increases by 39.86 ± 4.01 g per year in untreated Danon males” (opens the source at this quote in a new tab)

“BNP increases by 42.17 ± 18.46 pg/mL per year in untreated Danon males” (opens the source at this quote in a new tab)

“Unpublished data from International Danon Disease Registry” (opens the source at this quote in a new tab)

Prospective study of nine males enrolled in 2019: cohort, censoring, and visit completion

“The cohort was comprised of 8 male pediatric and 1 male young adult patient, enrolled at the University of California, San Diego.” (opens the source at this quote in a new tab)

“The mean age of the cohort at study enrollment was 11.6 ± 4.5 years. The mean age of the cohort at diagnosis was 6.5 ± 5.2 years.” (opens the source at this quote in a new tab)

“Patient 7 received a heart transplant and patients 6 and 8 were enrolled in a Phase 1 gene therapy clinical trial, so data was censored after transplant and clinical trial enrollment respectively.” (opens the source at this quote in a new tab)

“Pre-COVID pandemic onset (March 2020), 80.1% of the expected 171 visits were attended (including baseline visits). Post-COVID pandemic, 19.7% of the 458 scheduled visits were attended.” (opens the source at this quote in a new tab)

“Regarding outcomes, one patient underwent transplantation during the study period at age 14. There were no deaths or ventricular assist device implantations.” (opens the source at this quote in a new tab)

Prospective study of nine males: echocardiographic change in pediatric participants over a mean of 24.5 months
ParameterAt baseline (n = 8)At last follow-up (n = 6)Average paired difference
Left ventricular ejection fraction, %“68.9 ± 4.8”“64.3 ± 8.5”“-5.9”
Maximum wall thickness, mm“14.1 ± 6.7”“15.6 ± 6.8”“+ 3.4”
Left ventricular mass, g“194.4 ± 131.1”“200.7 ± 88.9”“+ 64”
Left ventricular end-diastolic dimension, mm“37.9 ± 5.7”“36.5 ± 6.7”“-0.5”
Global longitudinal strain, %“-14.1 ± 2.9”“-15.2 ± 4.2”“+ 0.14”
ParameterAt baseline (n = 8)At last follow-up (n = 6)
Maximum wall thickness z-score“7.0 ± 6.0”“9.4 ± 7.6”
Left ventricular mass z-score“8.0 ± 6.2”“11.0 ± 12.0”
Left ventricular end-diastolic dimension z-score“-1.6 ± 1.8”“-2.1 ± 1.5”

“This is for the pediatric patients only” (opens the source at this quote in a new tab)

“None of the differences were statistically significant.” (opens the source at this quote in a new tab)

“After the mean follow-up time, all six pediatric patients with follow-ups had lower EF values (100%, n = 6).” (opens the source at this quote in a new tab)

“At last follow-up, wall thickness increased in all six pediatric patients (100%, n = 6).” (opens the source at this quote in a new tab)

“The adult patient had a baseline EF of 47% and at last follow-up 41%.” (opens the source at this quote in a new tab)

“For the young adult, he had an LV mass of 835.1 g at baseline and 789.1 g at follow-up after six months.” (opens the source at this quote in a new tab)

Prospective study of nine males: NT-proBNP and high-sensitivity troponin T at baseline and follow-up
ParameterMean, baseline (n = 9)Mean, follow-up (n = 9)Average paired differenceNormal range
NT-proBNP (pg/mL)“932.2 ± 1055.9”“1903.6 ± 1831.2”“+ 971.3”“< 125”
hs-cTnT (ng/L)“41.1 ± 51.5”“78.4 ± 51.2”“+ 37.3”“< 14”

“All patients completed the baseline laboratory measurements and follow-up with a mean follow-up time of 18.6 months.” (opens the source at this quote in a new tab)

“mean paired difference was 971.3 pg/mL and 37.3 respectively, which based on Wilcoxon signed-rank test was a significant increase in NT-proBNP, but not hs-cTnT” (opens the source at this quote in a new tab)

“Additionally, there was substantial inter- and intra-patient variability which led to high standard deviations and skewed means” (opens the source at this quote in a new tab)

Registry of 82 participants from 36 families (2011): age at onset, diagnosis, transplant, and death by sex

“We present data on 82 patients with Danon disease from 36 families, the largest series to date.” (opens the source at this quote in a new tab)

“The average age of onset and standard deviation of Danon disease symptoms was 12.1 (±6.5) years and 28.1 (±15) years in men and women, respectively.” (opens the source at this quote in a new tab)

“The average ages of diagnosis of disease, defined as skeletal or cardiac myopathy, cardiac preexcitation, or confirmed Danon disease (whichever occurred first), were 13.5 (±7.0) years and 31.4 (±15.4) years in men and women, respectively.” (opens the source at this quote in a new tab)

“In our cohort, the mean ages in years and standard deviations of cardiac transplantation, and death were 18.1 (±5.9) and 19.8 (±7.1) in men and 34.5 (±15.7) and 36.0 (±16.0) in women, respectively.” (opens the source at this quote in a new tab)

Registry of 82 participants (2011): values printed in the population table
CharacteristicMen (n=43)Women (n=39)
Symptomatic clinical disease“37 (94.9)”“31 (91.2)”
Cardiac transplant“13 (33.3)”“6 (17.6)”
Living“23 (59.0)”“23 (67.6)”
Mean age at first symptom, years“11.7”“26.8”
Mean age at diagnosis, years“13.1”“30.9”
Mean age at cardiac transplant, years“20.8”“32.3”
Mean age at death, years“20.1”“40.2”
Registry of 82 participants combined with 63 published cases: ages at events and proportion reaching transplant or death

“A PubMed search for reports on Danon disease where sufficient clinical data on these same parameters were provided yielded 63 additional cases (40 men and 23 women) from 20 published studies” (opens the source at this quote in a new tab)

“the mean ages in years (±standard deviation) of the first symptom, diagnosis of cardiac or skeletal myopathy, cardiac transplantation, and death were 12.1 (±6.8), 12.8 (±7.0), 17.9 (±7.2), and 19.0 (±8.0) in men and 27.9 (±14.5), 29.9 (±14.7), 33.7 (±16.1), and 34.6 (±15.5) in women, respectively.” (opens the source at this quote in a new tab)

“All together, 59.0% of men and 51.6% of women reached an endpoint of transplant or death.” (opens the source at this quote in a new tab)

“All pair-wise comparisons between men and women were significant (P < 0.001) by the log-rank test.” (opens the source at this quote in a new tab)

“If this atypical case is excluded, then the next oldest male in our study who did not reach a transplant or death endpoint was 25 years, highlighting the life-threatening nature of Danon disease in men by the third decade.” (opens the source at this quote in a new tab)

“Enhancements in cardiac treatment, transplant, and defibrillator therapy have likely improved overall outcomes in Danon disease, which could mean that survival chances today may be more favorable than our estimates herein, which included data from distantly deceased family members.” (opens the source at this quote in a new tab)

Systematic review of 146 published cases through October 2017: composite of death, transplant, or ventricular assist device

“Among 83 manuscripts in MEDLINE and EMBASE on DD cases published until October 2017, we identified 146 patients with positive genetic testing for DD or positive muscle biopsy in a relative of a genetically diagnosed proband.” (opens the source at this quote in a new tab)

“56 females and 90 males were identified.” (opens the source at this quote in a new tab)

“The composite outcome of death, heart transplant or ventricular assist devices occurred equally in both sexes (32% of females and 37% of males, p = 0.60) but later in females (median age 38 years) than in males (median age 21 years, p < 0.001).” (opens the source at this quote in a new tab)

European registry of 57 affected participants from 16 centers (2020): heart failure hospitalization, advanced therapies, and death

“The cohort comprised 30 male and 27 female patients.” (opens the source at this quote in a new tab)

“The age of first heart failure hospitalization was lower in men (18±6 versus 28±17 years; P<0.003).” (opens the source at this quote in a new tab)

“Heart failure was the leading cause of death (10 of 17; 59%), and LV systolic dysfunction predicted an adverse outcome.” (opens the source at this quote in a new tab)

“Eight men and 8 women (28%) underwent heart transplantation or received an LV assist device.” (opens the source at this quote in a new tab)

“Our cohort suggests better prognosis of female compared with male heart transplant recipients.” (opens the source at this quote in a new tab)

European registry, accepted manuscript: follow-up, age at death, deaths after transplant or assist device, and predictors of mortality

“Fifty-three of fifty-seven (93%) clinically affected patients were followed up for at least one year, comprising a total of 350 patient-years.” (opens the source at this quote in a new tab)

“The age at diagnosis was significantly lower in males: mean 13±9 years (range birth to 42), compared to 36±14 in affected females (range 2-65, p<0.01, Figure 1).” (opens the source at this quote in a new tab)

“Seventeen patients (30% of the cohort, 11 males and 6 females) died. The mean age of death was 23±19 years among men, and 45±18 in females (p=0.02, Figure 1).” (opens the source at this quote in a new tab)

“Five of the 8-heart transplant/assist device male recipients (62%) died within one year from the procedure.” (opens the source at this quote in a new tab)

“No death was reported among females receiving a heart transplant during a mean follow up of 10.6±5.6 years (range 4-17).” (opens the source at this quote in a new tab)

“Reduced left ventricular systolic function was also associated with mortality (71% vs. 31%, p=0.002), as were AV block >1st degree (25% vs. 3%, p=0.025) and atrial fibrillation (56% v. 28%, p=0.034).” (opens the source at this quote in a new tab)

“In an adjusted logistic model, which included variables that were significant in univariate analysis, only a hypokinetic left ventricle remained a significant predictor of mortality. This result did not change with the inclusion of age and gender in the multivariate model (OR 3.85, 95%CI 1.06-14.96, p=0.043, Table 4).” (opens the source at this quote in a new tab)

European registry, accepted manuscript: age of females at first heart failure hospitalization stated as 34 years in the body text

“Fifteen males and 15 females (53% of the entire cohort) had a heart failure hospitalization, at mean age 18 ± 6 compared to 34 ±13 years, p<0.003, Figure 1).” (opens the source at this quote in a new tab)

Spanish registry of 27 participants from 10 hospitals (2019): events and age at events by sex
EventMale participants (n=6)Female participants (n=21)
Admission for heart failure“2 (50)”“10 (47)”
Age at first heart-failure episode, y“23±16”“37±9”
Heart transplant“1 (20)”“6 (30)”
Age at heart transplant, y (n=7)“14”“32±9”
Death“3 (50)”“3 (14)”
Age at death, y (n=6)“23±13”“40±14”
Death or heart transplant“4 (57)”“9 (43)”
Age at death or heart transplant (n=13)“20±11”“36±20”

“Data were analyzed from a cohort of 27 patients with pathogenic mutations in the LAMP2 gene. Of the patients, only 6 were men (22%)” (opens the source at this quote in a new tab)

“Excluding patients diagnosed at postmortem, median follow-up was 4 years [interquartile range, 2-9].” (opens the source at this quote in a new tab)

“There were 3 male deaths (50%): 1 due to heart failure and 2 due to sudden cardiac death. Of the female deaths, 2 were due to advanced heart failure and 1 to sudden cardiac death.” (opens the source at this quote in a new tab)

“The data from our registry confirm that DD has a poor prognosis in both sexes and that without heart transplant male patients do not reach the age of 25 years.” (opens the source at this quote in a new tab)

Japanese nationwide survey of 39 participants from 20 families (2018): age at onset, age at death, and cause of death

“A total of 39 patients (17 males, 22 females) from 20 families were identified in the analysis.” (opens the source at this quote in a new tab)

“Ages at onset varied from 1 to 19 years in the 17 male patients, and from 6 to 36 years in seven female patients.” (opens the source at this quote in a new tab)

“Among the 21 patients (9 males and 12 females) who had died, 20 (95%) died of cardiac failure or sudden cardiac arrest, which is the main cause of death among patients.” (opens the source at this quote in a new tab)

“The mean age at death was 19 ± 5 years with a range of 13 to 26 years in seven male patients and 37 ± 11 years with a range of 20 to 52 years in seven female patients.” (opens the source at this quote in a new tab)

“No male patient survived beyond 26 years of age except for a 50-year-old man in Family 1.” (opens the source at this quote in a new tab)

“Only one female patient received a heart transplant, which is the most effective therapy.” (opens the source at this quote in a new tab)

Seven young participants with LAMP2 cardiomyopathy diagnosed at ages 7 to 17 (2009): outcomes by age 24

“Clinical course and outcome were assessed prospectively in 7 young LAMP2 patients (6 males) previously identified in our laboratory from the time of diagnosis (ages 7–17; median 14) to October 2008.” (opens the source at this quote in a new tab)

“At cardiac diagnosis, all patients were in New York Heart Association (NYHA) functional class I.” (opens the source at this quote in a new tab)

“Over 7.3 ± 3 (SD) years of follow-up, and by 12 to 24 years of age, the study patients developed LV systolic dysfunction (ejection fraction 25 ± 7[SD]%) and cavity enlargement, as well as particularly adverse clinical consequences including: progressive refractory heart failure and death (n = 4), sudden death (n = 1), aborted cardiac arrest (n = 1), or heart transplantation (n = 1).” (opens the source at this quote in a new tab)

“clinical deterioration was often rapid with the time interval from clinical stability with little or no symptoms and preserved systolic function to end-stage heart failure as brief as 6 months.” (opens the source at this quote in a new tab)

“Indeed, 7 female LAMP2 obligate carriers (age range 19–51 years) in 2 of the families remain asymptomatic, and at present have not developed LV hypertrophy or systolic dysfunction” (opens the source at this quote in a new tab)

Twenty males and 18 females from 13 families (2002): age at which each sex was affected

“The features of 20 affected men and 18 affected women in 13 families with genetically confirmed Danon disease were reviewed.” (opens the source at this quote in a new tab)

“Men were affected before age 20 years whereas most affected women developed cardiomyopathy in adulthood.” (opens the source at this quote in a new tab)

Age at symptom onset by sex and LAMP2 variant type: literature review through August 2013

“symptom onset is noted at an earlier age (13.3±8.0 years for males and 28.9±14.2 years for females; p=0.0008;” (opens the source at this quote in a new tab)

“Of the 68 LAMP2 mutations, 35 mutations had reported data on age of symptom onset providing data on 73 cases.” (opens the source at this quote in a new tab)

“Nonsense, frameshift, and large deletion/duplication mutations showed the earliest age of onset with mean and standard deviation of ages of symptom onset for males of 13.5±4.9 years, 12.1±8.4 years, and 12.3±7.5 years, respectively, and for females of 29.9±10.0 years and 21.6±11.9 years (no case report for females with large deletion/duplication), respectively.” (opens the source at this quote in a new tab)

“Missense mutations showed the latest age of onset compared to all other mutations at 47.6±19.1 years for males (p=0.015; n=5 males).” (opens the source at this quote in a new tab)

Global registry of 33 participants (2019 abstract): age at symptom onset, diagnosis, and transplant by sex

“A total of 33 patients (54.5% female) were included with the majority Caucasian (96.9%) and from the United States (78.8%).” (opens the source at this quote in a new tab)

“Irrespective of the organs involved, symptoms occurred earlier in males compared to females (5.5 (2.0-12.0) vs 16.0 (11.5-27.0) years, p = 0.002) and subsequently, the diagnosis of DD was made earlier in males (8.0 (4.0-12.0) vs 26.5 (13.0-41.0) years, p = 0.023).” (opens the source at this quote in a new tab)

“Heart transplantation (HTx) occurred in 4 (26.7%) males and in 7 (38.8%) females at similar median ages (18.0 (16.6-18.8) vs 17.0 (13.0-27.0) years, p = 1).” (opens the source at this quote in a new tab)

Transplant recipients (38 participants from 8 centers): age at transplant by sex

“The clinical phenotype and outcome data of patients with DD who underwent cardiac transplantation (n = 38; 19 males and 19 females) were obtained from 8 centers.” (opens the source at this quote in a new tab)

“The median age at transplant for the cohort was 20.2 years (15.8-27.9 years), with no difference in age between sexes.” (opens the source at this quote in a new tab)

“In an unpublished subanalysis of the same data that stratified by transplantation age groups <25 years old and ≥25 years old, comparison of median age in these 2 groups revealed 2 separate age cohorts in female individuals who had undergone transplantation: those with a median age of 16.9 years and those with a median age of 36.6 years (personal communication, September 2021).” (opens the source at this quote in a new tab)

Pediatric cohorts: transplant and death during follow-up

“We retrospectively analysed clinical and genetic data of 29 pediatric patients who visited our hospital for treatment or genetic counselling for DD from July 2014 to December 2023.” (opens the source at this quote in a new tab)

“During a median 2.7 years of follow-up, 2 male patients received heart transplants. One boy and 1 girl died of heart failure and sudden cardiac arrest, respectively.” (opens the source at this quote in a new tab)

“Nine patients (3 females) were identified with DD at the Russian National Medical Research Center of Children's Health” (opens the source at this quote in a new tab)

“Two teenagers died at ages 16-17 from refractory heart failure and two underwent heart transplantation.” (opens the source at this quote in a new tab)

Predictor of outcome: global longitudinal strain

“A total of 22 patients with DD (male 14 [63.6%], median age 16.5 years) had sufficient echocardiograms for analysis.” (opens the source at this quote in a new tab)

“The composite outcome occurred in a total of 7 patients, with 3 of them requiring heart transplantation and 4 requiring implatable cardioverter defibrillator (ICD) for secondary prevention.” (opens the source at this quote in a new tab)

“Univariable regression for GLS and composite outcome showed an odds ratio of 1.32 (95% CI, 1.02–1.71)” (opens the source at this quote in a new tab)

“An absolute GLS cutoff of 10.0% yielded a true positive rate of 85.7% and false positive rate of 13.3%.” (opens the source at this quote in a new tab)

“In the EF scatter plot, there was also a downward trend observed with time in males” (opens the source at this quote in a new tab)

“but the composite outcome occurred in patients despite a preserved EF” (opens the source at this quote in a new tab)

Predictor of outcome: Wolff-Parkinson-White pattern

“EKGs of 28 Danon Disease patients were assessed for WPW (PR interval ≤ 120 milliseconds, QRS interval ≥ 120 milliseconds, and delta wave) and ventricular hypertrophy (left, right or both).” (opens the source at this quote in a new tab)

“Time to transplant or VAD was shorter in WPW patients, with median time of 18.6 years (p=0.032).” (opens the source at this quote in a new tab)

“WPW is not sensitive for Danon Disease, but is a marker of severity and progression, with evidence of increased ventricular hypertrophy, higher rates of ICD implantation, and earlier requirement of advanced therapies (transplant or VAD) than those without WPW.” (opens the source at this quote in a new tab)

Predictor of outcome: left ventricular mass and late gadolinium enhancement on cardiac magnetic resonance

“A major adverse cardiac event (MACE) was a composite of death, ICD implantation for secondary prevention, and heart transplant.” (opens the source at this quote in a new tab)

“12 patients (5 males [42%], median age 13yrs [interquartile range (IQR) 5] were included.” (opens the source at this quote in a new tab)

“LGE was strongly associated with BNP (r=0.9, p=0.0021).” (opens the source at this quote in a new tab)

“Patients with MACE (6, median follow-up 2.9 yrs) had elevated left ventricular mass (241 +/- 63 g, p=0.032) and LGE (median mass 56 g [IQR 35], p=0.021) compared to those without (mass 155 +/- 56 g, LGE 0 g [IQR 8].” (opens the source at this quote in a new tab)

Progression from a hypertrophic to a dilated phenotype in two females: rates of change

“Two female patients initially described to have HCM developed DCM over a mean follow-up time of 9.6 yrs. These patients demonstrated an average rate of EF decline of 3.8%/year, loss of septal thickening and posterior wall thickening (1.0mm/year and 1.1mm/year), and mean increase in LVEDd of 2.7mm/year.” (opens the source at this quote in a new tab)

Literature survey of more than 500 reported cases (2020): prognosis in males

“We surveyed over 500 Danon disease patients reported in the literature from the first description to the present, in order to summarize the clinical, pathological and molecular data and treatment perspectives.” (opens the source at this quote in a new tab)

“in male patients, the prognosis is poor due to rapid progression towards heart failure, and only heart transplantation modifies the disease course.” (opens the source at this quote in a new tab)