Evicenter
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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

Clinical presentation - signs and symptoms

24 evidence topics · 25 sources

Multisystem presentation by sex: classic triad in males and isolated cardiac disease in females

“Whereas women present with isolated cardiac disease 73% of the time, in males DD was frequently multisystemic and presented as a triad of cognitive impairment, skeletal myopathy, and HCM in 42% of patients.” (opens the source at this quote in a new tab)

“Cumulatively, all males but only 10/27 females had at least 1 extracardiac manifestation (p<0.001).” (opens the source at this quote in a new tab)

“Male patients showed a high prevalence of extracardiac manifestations: myopathy (80%), learning disorders (83%), and visual alterations (60%), which were uncommon findings in women (5%, 0%, and 27%, respectively).” (opens the source at this quote in a new tab)

“Notably, although mild cognitive and muscular impairments may have been present since childhood, cardiovascular symptoms are often what trigger clinical evaluation.” (opens the source at this quote in a new tab)

Reported clinical characteristics by sex in a registry of 82 participants (percentage of those with data)
CharacteristicMen (n=26)Women (n=18)
Symptomatic heart disease“88.5”“77.7”
Chest pain“41.6”“37.5”
Palpitations“76.5”“68.8”
Hypertrophic cardiomyopathy“88”“33.3”
Dilated cardiomyopathy“12”“27.7”
Conduction abnormality“86.4”“80”
Wolff-Parkinson-White“68.2”“26.7”
Cardiac ablation“53.3”“30.8”
Defibrillator implantation“41.2”“31.3”
Learning and cognitive problems“100”“46.6”
Visual and retinal abnormalities“69.2”“64.2”
Symptomatic muscle disease“80”“50”
Muscle cramping“9.1”“15.3”
Neuropathy“9.1”“38.5”
Symptomatic respiratory disease“50”“16.7”
Symptomatic gastrointestinal disease“76.5”“50”
Earliest manifestations in children

“The earliest clinical manifestations of Danon disease occur in the first 12 years of life with symptoms of skeletal muscle and cerebral disease, raised hepatic enzymes, and evidence of cardiac disease on ECG/echo.” (opens the source at this quote in a new tab)

“The mean age at diagnosis was 7.2 ± 5.9 years for boys (n = 21) and 9.4 ± 5.0 years for girls (n = 8). Asymptomatic elevated liver transaminase or creatine kinase (CK) levels were initial manifestations detected in 10 male patients (48%) and absent in female patients.” (opens the source at this quote in a new tab)

Cardiac: hypertrophic and dilated phenotypes by sex

“92.5% of patients had cardiac abnormalities. Females presented with either hypertrophic cardiomyopathy (HCM, 70.3%) or dilated cardiomyopathy (DCM, 29.3%) whereas males presented with HCM 96.2% of the time.” (opens the source at this quote in a new tab)

“Cardiac involvement was observed in 96%.” (opens the source at this quote in a new tab)

“Left ventricular (LV) hypertrophy was reported in 73% of male and 74% of female patients. LV systolic dysfunction was reported in 40% of men (who had LV ejection fraction, 34±11%) and 59% of women (LV ejection fraction, 28±13%).” (opens the source at this quote in a new tab)

“All 17 male patients had cardiomyopathy. Most had hypertrophic cardiomyopathy, but two (12%) had dilated cardiomyopathy.” (opens the source at this quote in a new tab)

“Eleven (50%) had hypertrophic cardiomyopathy, six (27%) had dilated cardiomyopathy, and four (18%) had sudden cardiac arrest.” (opens the source at this quote in a new tab)

“Interestingly, in 12 patients in the registry (44%) the cardiomyopathy at the time of diagnosis was dilated cardiomyopathy (DCM), with a mean LVEF of 27±8%.” (opens the source at this quote in a new tab)

“At the time of diagnosis, 48% of female patients had DCM vs 33% of male patients” (opens the source at this quote in a new tab)

“Hypertrophic cardiomyopathy (HCM) was observed in 20 male patients (95%) and 7 female patients (88%), whereas dilated cardiomyopathy (DCM) was not detected.” (opens the source at this quote in a new tab)

Cardiac: magnitude of left ventricular hypertrophy

“LV hypertrophy was particularly marked (maximum ventricular septum, 29–65 mm; mean 44±15[SD]) including 2 patients with massive thickness of 60 mm and 65 mm at ages 23 and 15 years, respectively.” (opens the source at this quote in a new tab)

“Post-mortem examination of 2 hearts showed massive cardiac hypertrophy; heart weights were 1265 grams and 1425 grams with asymmetric LV wall thickening” (opens the source at this quote in a new tab)

“The average MWT at baseline for the pediatric patients was 13.6 ± 7.1 mm” (opens the source at this quote in a new tab)

“For the young adult, his MWT was 30.4 mm at baseline and 28.2 mm at last follow-up after six months.” (opens the source at this quote in a new tab)

“LV hypertrophy was reported in 73 % (n=22) of males, and 74% (n=20) of females with an average LV wall thickness of 20±8 and 17±6 (mm) respectively.” (opens the source at this quote in a new tab)

Cardiac: symptoms

“Most patients in the cohort reported cardiac related symptoms (78%, n = 7): dyspnea (33%, n = 3), palpitations (44%, n = 4), and chest pain (56%, n = 5).” (opens the source at this quote in a new tab)

“The cardiac symptoms shown by the DD patients were syncope (22% of patients), chest pain (22%), and heart failure (New York Heart Association functional class III-IV; 43%)” (opens the source at this quote in a new tab)

“Palpitations were the most universally reported cardiovascular complaint followed by chest pain.” (opens the source at this quote in a new tab)

Cardiac: pre-excitation and Wolff-Parkinson-White pattern, frequency across cohorts

“Regarding arrhythmia characteristics, 19.8% (n=23) of patients had Wolff‐Parkinson‐White, 18.1% (n=21) had atrial fibrillation, and 38.8% (n=45) of patients had a CIED throughout the study period” (opens the source at this quote in a new tab)

“Thirteen of 40 patients (32.5%) with Danon disease were found to have preexcitation (mean age 17.3 years; 38% women).” (opens the source at this quote in a new tab)

“A systematic analysis of available DD-patient ECGs in the registry revealed a preexcitation pattern in only 11 patients (48%), 4 of whom were male” (opens the source at this quote in a new tab)

“Nine (54%) of 17 males and four (22%) of 18 females showed WPW syndrome.” (opens the source at this quote in a new tab)

“Baseline ECG findings included: Wolff-Parkinson-White (WPW) (56%, n = 5), LV hypertrophy (44%, n = 4), biventricular hypertrophy (22%, n = 1), sinus bradycardia (11%, n = 1), and 1st degree atrioventricular (AV) block (11%, n = 1).” (opens the source at this quote in a new tab)

“Ventricular preexcitation (VP) was observed initially in 10 patients (36%) and in 15 (54%) at latest evaluation.” (opens the source at this quote in a new tab)

“Conduction abnormalities were reported in more than three quarters of men and women; 68% of men had a Wolff-Parkinson-White pattern on electrocardiography in comparison with 27% of women with a Wolff-Parkinson-White pattern.” (opens the source at this quote in a new tab)

Cardiac: electrophysiology studies of the pre-excitation pattern

“EPS performed in 9 of 13 patients (69%) demonstrated FVP only in 2 (22.2%), extranodal pathway without exclusion of FVP in 2 (22.2%), and both FVP and extranodal pathway in 5 (55.6%).” (opens the source at this quote in a new tab)

“In male patients, the initial QRS complex was characterized by a slurring upstroke and shortened PQ interval mimicking ventricular pre-excitation.” (opens the source at this quote in a new tab)

“However, the presence of an accessory pathway was excluded by an EP study in all patients.” (opens the source at this quote in a new tab)

Cardiac: atrial and ventricular arrhythmias

“Supraventricular tachycardias, including atrial flutter and atrial fibrillation, as well as ventricular arrhythmias, are common and occur in approximately 60% of individuals.” (opens the source at this quote in a new tab)

“Atrial fibrillation occurred more frequently in female compared with male patients” (opens the source at this quote in a new tab)

“Paroxysmal or permanent atrial fibrillation was more common in females (55% vs. 27% in males, p=0.02).” (opens the source at this quote in a new tab)

“whereas 4 women developed sustained ventricular tachycardia during follow-up (with the condition deteriorating to ventricular fibrillation in 1 patient), none of the male patients had these arrhythmias.” (opens the source at this quote in a new tab)

“Seven patients with Danon disease (4 males, 35.8 ± 10.8 years; 3 females, 51.3 ± 19.9 years) from 3 different families were studied.” (opens the source at this quote in a new tab)

“Asymptomatic ventricular tachyarrhythmias were documented in six of the seven patients. Moreover, 5 of the 7 patients suffered from atrial fibrillation (AF), with 1 of them experiencing thromboembolic stroke at the age of 30 years.” (opens the source at this quote in a new tab)

“However, sustained ventricular arrhythmias were not documented in any of the patients.” (opens the source at this quote in a new tab)

“Ten patients with Danon disease (30% male, average age 17.4 years) were identified. Seven patients (70%) had tachyarrhythmias including five with atrial arrhythmias and six with nonsustained ventricular tachycardia.” (opens the source at this quote in a new tab)

Cardiac: conduction disease

“High-degree heart block or sinus node dysfunction requiring pacemaker implantation is also highly prevalent and is reported to be between 35% and 50%.” (opens the source at this quote in a new tab)

“Overall, 50% of male patients (n=3) and 29% of women (n=6) experienced complete atrioventricular block, with no statistically significant differences between subgroups.” (opens the source at this quote in a new tab)

“Advanced atria-ventricular block was reported in 15% (n=4) of males and 14% (n=4) of the affected females.” (opens the source at this quote in a new tab)

Cardiac: sudden cardiac death and cardiac arrest

“Cardiac arrest and sudden arrhythmia death may be the first disease presentation in both sexes.” (opens the source at this quote in a new tab)

“Sudden cardiac death occurred in 3 female patients and was the first presentation of DD in one of them” (opens the source at this quote in a new tab)

“In our series, there were 3 instances of sudden cardiac death, in 2 male patients and 1 woman, none of whom had an ICD; 4 other patients (all women) had sustained ventricular tachycardia during follow-up.” (opens the source at this quote in a new tab)

“The combined rate of severe arrhythmia and sudden cardiac death in this cohort is high (26% of patients)” (opens the source at this quote in a new tab)

“We clinically followed and evaluated with echocardiography, cardiac magnetic resonance imaging (cMRI), and genetic testing a family affected by Danon disease in which 2 men and 6 women showed a severe arrhythmogenic phenotype.” (opens the source at this quote in a new tab)

“Four women died suddenly (1 aborted) at 37 to 54 years of age.” (opens the source at this quote in a new tab)

Cardiac: natriuretic peptide and troponin elevation

“Of note, cardiac biomarkers including N-terminal pro brain natriuretic peptide (NT-proBNP) and high sensitivity cardiac troponin T (hs-cTnT) were elevated at both baseline and follow-up.” (opens the source at this quote in a new tab)

“All patients tested (n=12) showed a generalized elevation of N-terminal pro-brain natriuretic peptide, with a tendency toward higher concentrations in male patients than in women: 1219 (511-10 984) pg/mL vs 916 (101-8245) pg/mL” (opens the source at this quote in a new tab)

“Defective autophagy impairs crucial biological functions in the relentlessly working cardiac muscle, leading to ongoing myocardial injury and sustained circulating troponin elevation.” (opens the source at this quote in a new tab)

Skeletal muscle: frequency and distribution of weakness

“Manifestations of skeletal muscle myopathy are usually mild, with weakness reported predominantly in proximal muscles, including pelvic girdle and axial muscles.” (opens the source at this quote in a new tab)

“All patients had cardiomyopathy, 18 of 20 male patients (90%) and 6 of 18 female patients (33%) had skeletal myopathy, and 14 of 20 male patients (70%) and one of 18 female patients (6%) had mental retardation.” (opens the source at this quote in a new tab)

“While 13 (76%) of the 17 male patients showed muscle weakness, the other four patients (24%) had no muscle weakness with mild myogenic changes on electromyography. In contrast, myopathy was observed in two (9%) of 22 female patients.” (opens the source at this quote in a new tab)

“All male and female patients remained ambulatory.” (opens the source at this quote in a new tab)

“Skeletal myopathy was clinically significant in 60% (n=18) of males but only in 3% (n=1) of females (p<0.001).” (opens the source at this quote in a new tab)

“Seven patients (78%) in our cohort reported neuromuscular symptoms at baseline: delay in motor milestones (67%, n = 6), difficulty running (67%, n = 6), difficulty walking (67%, n = 6), fatigue (67%, n = 6), weakness (67%, n = 6), joint pain (33%, n = 3), difficulty sitting (11%, n = 1), hypotonia (11%, n = 1), loss of range of motion (11%, n = 1), and abnormal gait (11%, n = 1).” (opens the source at this quote in a new tab)

“All limbs were found to be affected across the cohort: lower proximal limb (78%, n = 7), lower distal limb (67%, n = 6), upper proximal limb (56%, n = 5), upper distal limb (44%, n = 4).” (opens the source at this quote in a new tab)

“Skeletal myopathy was present in 87.9% of subjects and was more frequent in males (86.7% vs 64.3%).” (opens the source at this quote in a new tab)

Skeletal muscle: quantitative strength and timed function tests

“Four males (ages 10–34) and four females (ages 16–50) with the genetic markers of Danon disease were compared to eight healthy males (ages 22–34) and eight healthy females (ages 23–41) and previously reported norms.” (opens the source at this quote in a new tab)

“When compared to healthy males, affected males were 33.9% slower (p=0.006) on the TUG, 392% slower (p=0.007) on stair climbing, 290% slower (p=0.007) stair descent, and performed 47.4% fewer (p=0.006) STS in 30 seconds” (opens the source at this quote in a new tab)

“Overall, for generalized strength, males were 60.0±5% weaker than healthy males, while affected females were only 30.5±5% weaker than healthy females.” (opens the source at this quote in a new tab)

“The average NSAA total score at baseline was 28 ± 9 out of a max total of 34.” (opens the source at this quote in a new tab)

“Specifically, baseline mean 6MWT distance was 448.7 ± 64.7 m” (opens the source at this quote in a new tab)

“As a reference, several studies of healthy adolescents aged < 18 years old mean 6MWT was upwards of 600 m” (opens the source at this quote in a new tab)

“Our cohort’s mean stair ascent rate at baseline was only of 1.1 ± 0.4 stairs/sec, and while the majority of patients improved by last follow up, their rate remained below 2.2 stairs/sec.” (opens the source at this quote in a new tab)

“These results are consistent with DD preferentially affecting the proximal muscles.” (opens the source at this quote in a new tab)

Skeletal muscle: creatine kinase

“The CK value was 1086 ± 715 IU/L with a range of 77 to 2865 in all male patients and 148 ± 164 IU/L with a range of 40 to 643 in 12 female patients.” (opens the source at this quote in a new tab)

“Laboratory abnormalities present in many male patients included elevations of creatine kinase (1.8- to 7.4-fold over upper limits of normal), alanine aminotransferase (2.4- to 10.4-fold), and aspartate aminotransferase (3.9- to 12.4-fold).” (opens the source at this quote in a new tab)

“Creatine kinase values were normal in women with the exception of one woman who had a 2-fold elevation.” (opens the source at this quote in a new tab)

“Elevated creatine phosphokinase (>2 times normal limit) was reported in 80% (n=24) of males but not in women (p<0.001).” (opens the source at this quote in a new tab)

“significantly higher serum creatine kinase in male than in female patients (1255±1296 U/L vs 82±47 U/L” (opens the source at this quote in a new tab)

Skeletal muscle and hepatic laboratory values in nine males at baseline and follow-up
ParameterMean, baseline (n = 9)Mean, follow-up (n = 9)Normal range
CPK (U/L)“1393.8 ± 831.0”“1340.9 ± 794.5”“39–308”
Aldolase (units/L)“21.9 ± 7.7”“21.4 ± 9.0”“1.0–7.5”
AST (U/L)“407.0 ± 175.2”“361.9 ± 177.2”“0–40”
ALT (U/L)“259.7 ± 110.6”“301.3 ± 134.3”“0–41”
LDH (U/L)“1069.3 ± 346.1”“1223.3 ± 565.0”“140–280”
Neurocognitive: intellectual disability and learning difficulty by sex

“Mild cognitive impairment and learning difficulties have been reported in at least 80% of affected male individuals and between 6% and 47% of female patients.” (opens the source at this quote in a new tab)

“Learning or cognitive disorders were reported in 100% of men and, surprisingly, in approximately 50% of women.” (opens the source at this quote in a new tab)

“Mild mental retardation was present in eight (46%) of the 17 male patients and in two (9%) of the 22 female patients.” (opens the source at this quote in a new tab)

“The 5 patients with learning disorders were all male (83% of the male study population). Intellectual disability in these patients was mild to moderate, with all of them maintaining full autonomy in day-to-day activities.” (opens the source at this quote in a new tab)

“learning, neurological or psychiatric problems were quite common in males (n=22, 73%) but rare in females (n=3, 9%, p<0.001).” (opens the source at this quote in a new tab)

“Neurological involvement, primarily cognitive impairment, was documented in 86.7% of males and 61.1% of females with a similar age of onset (5.0 (4.0-10.0) vs 8.0 (7.0-15.0) years, p = 1).” (opens the source at this quote in a new tab)

Neurocognitive: standardized testing in pediatric males

“Six patients in the cohort completed the DAS-II at baseline.” (opens the source at this quote in a new tab)

“The mean at baseline for each domain in our cohort was: GCA, 67.0 ± 14.7; verbal, 66.3 ± 19.0; nonverbal, 70.5 ± 18.3; spatial, 68.7 ± 18.3.” (opens the source at this quote in a new tab)

“The mean at baseline for each domain in our cohort was: ABC, 68.9 ± 11.4; communication, 66.2 ± 18.5; daily living skills 74.0 ± 11.7; socialization, 69.4 ± 10.9” (opens the source at this quote in a new tab)

“DD patients in this cohort scored on average two standard deviations below the mean on cognitive and behavioral standardized testing, suggesting significant impairment.” (opens the source at this quote in a new tab)

Neurocognitive: intelligence testing in 13 adolescents and adults of both sexes

“The present cohort included 13 patients, 5 males and 8 females. At the time of the study the age of the participants ranged from 17 to 57 years (mean age = 36.23 y, SD = 16.06).” (opens the source at this quote in a new tab)

“The mean FSIQ score of the entire sample was 89.0 ± 12.4 points.” (opens the source at this quote in a new tab)

“Of the 12 participants that completed FSIQ assessment, 9 individuals (75%) had a score greater than 90, within the normal range of intelligence (ranging between 91 and 105 points).” (opens the source at this quote in a new tab)

“The results of the present study challenge earlier reports suggesting that mental retardation is a core constituent in DD.” (opens the source at this quote in a new tab)

Psychiatric: mood, anxiety, attention-deficit, and autism spectrum diagnoses

“At the time of psychiatric evaluation, 9 participants (69.2%) met criteria for at least one psychiatric disorder” (opens the source at this quote in a new tab)

“We observed high rates of mood disorders (found in 6 out of 13 participants, 46.15%), including: major depression disorder (MDD; n = 3), and dysthymia (n = 3). Similarly, 6 out of 13 individuals met criteria for an anxiety disorder (46.15%), including: general anxiety disorder (GAD; n = 3), social anxiety disorder (SAD; n = 2), panic disorder (n = 1), and specific phobia (n = 1).” (opens the source at this quote in a new tab)

“In our cohort, all patients (100%, n = 9) were affected by neuropsychological symptoms that included: learning difficulties (100%, n = 9), attention-deficit hyperactivity disorder (56%, n = 5), anxiety (44%, n = 4), depression (44%, n = 4), autism (22%, n = 2) and global developmental delay (11%, n = 1).” (opens the source at this quote in a new tab)

“Young individuals with the disease often carry the diagnosis of attention deficit disorder before receiving a definitive diagnosis of Danon disease.” (opens the source at this quote in a new tab)

Ophthalmic: retinopathy and visual acuity

“We identified 34 studies (25 case reports, 8 case series, and 1 retrospective cohort) describing 70 patients, aged 6 to 81 years. Retinal abnormalities were the most common finding (81%), typically midperipheral and peripheral salt-and-pepper pigmentary changes. Macular involvement was frequent (62%), usually presenting as nonspecific retinal pigment epithelium changes; a minority (13%) developed more severe pathology, including macular atrophy, bull's-eye maculopathy, or cystoid macular edema.” (opens the source at this quote in a new tab)

“Other ocular findings included myopia (16%) and lens opacities (13%).” (opens the source at this quote in a new tab)

“Detailed ocular examination in 10 patients with DD (3 males, 7 females) and a 45-year-old asymptomatic female somatic mosaic carrier of a LAMP2 disease-causing variant.” (opens the source at this quote in a new tab)

“All patients with manifest cardiomyopathy had pigmentary retinopathy with altered autofluorescence and diffuse visual field loss. Best corrected visual acuity (BCVA) was decreased (<0.63) in 8 (40%) out of 20 eyes.” (opens the source at this quote in a new tab)

“The BCVA was within the normal range for all patients (100%, n = 9).” (opens the source at this quote in a new tab)

“Of note, hyperreflective foci were identified at the level of the outer nuclear layer (ONL) and the border of the outer plexiform layer in six patients (67%, n = 6) in SD-OCT” (opens the source at this quote in a new tab)

“The 4 affected females demonstrated a peripheral pigmentary retinopathy. Lens changes, myopia, abnormal electroretinogram and visual fields were also found. The males demonstrated a near-complete loss of pigment in the retinal pigment epithelium.” (opens the source at this quote in a new tab)

Hepatic: transaminase elevation and hepatomegaly

“Elevated liver transaminases enzymes were found in 83% (n=25) of males and 6% (n=2) of females (p<0.001).” (opens the source at this quote in a new tab)

“In women, the average aminotransferase levels were normal to slightly elevated (<2-fold).” (opens the source at this quote in a new tab)

“Hepatomegaly has been reported and may occur in conjunction with elevated transaminases without hepatic synthetic dysfunction, which may be more indicative of myocyte and skeletal muscle involvement and not hepatocellular injury.” (opens the source at this quote in a new tab)

“Patients with advanced heart failure may experience congestive hepatopathy.” (opens the source at this quote in a new tab)

“Hepatic synthetic function is usually normal, although hepatomegaly was reported in 5/14 (35%) males in one study.” (opens the source at this quote in a new tab)

Gastrointestinal and respiratory symptoms

“Symptomatic respiratory disease was more frequent in men than women, with asthma being reported most often. Restrictive lung problems, possibly related to respiratory muscle weakness, were noted in just two male patients. Gastrointestinal complaints were more common in men and included chronic abdominal pain, constipation, and diarrhea.” (opens the source at this quote in a new tab)

“Most of our patients (89%, n = 8) had respiratory related problems: wheezing (44%, n = 4), dyspnea (33%, n = 3), cough (22%, n = 2), asthma allergies (11%, n = 1), and sleep apnea (11%, n = 1).” (opens the source at this quote in a new tab)

“At baseline, the average percent of predicted seated upright FVC was 74.6% ± 8.5% (2.3 ± 1.3 L)” (opens the source at this quote in a new tab)

Exercise capacity: peak oxygen uptake in pediatric males

“Our cohort had a baseline mean of 17.2 ± 4.4 ml/kg/min, which was lower than that what has been reported in healthy kids. In a study of healthy children, the peak VO2 range was 43.0–49.6 ml/kg/min for boys aged 10–14 years old” (opens the source at this quote in a new tab)

“It is worth noting that out of 10 total CPETs conducted, only 2 were terminated due to leg weakness (reached RQ >1.0), whereas the others were for shortness of breath or fatigue.” (opens the source at this quote in a new tab)