Formal diagnostic criteria: statements that none are established

“Formal clinical diagnostic criteria for Danon disease have not been established.” (opens the source at this quote in a new tab)

“There are no internationally established diagnostic criteria for Danon disease.” (opens the source at this quote in a new tab)

Establishing the diagnosis by molecular genetic testing

“The diagnosis of Danon disease is established in a male with suggestive findings by identification of a hemizygous pathogenic (or likely pathogenic) variant in LAMP2 on molecular genetic testing” (opens the source at this quote in a new tab)
“The diagnosis of Danon disease is usually established in a female proband with cardiac pre-excitation and cardiomyopathy (either hypertrophic or dilated) by identification of a heterozygous pathogenic (or likely pathogenic) variant in LAMP2 on molecular genetic testing” (opens the source at this quote in a new tab)
“Identification of a hemizygous or heterozygous LAMP2 variant of uncertain significance does not establish or rule out the diagnosis.” (opens the source at this quote in a new tab)

“Although immunohistochemistry and other protein-based studies are feasible, from a practical standpoint the diagnosis of Danon disease is typically made on the basis of suggestive clinical features and detection of a pathogenic or likely pathogenic variant in LAMP2.” (opens the source at this quote in a new tab)
“All patients with suspected Danon disease should undergo genetic testing.” (opens the source at this quote in a new tab)

Consensus diagnostic algorithm for clinical Danon disease

Element	Quoted criterion
Genotype	“LAMP2 mutation (pathogenic or likely pathogenic)”
Clinical features required by sex	“Males: A or B or C; Females: A only”
A: cardiovascular	“Objective cardiovascular abnormality defined as any:”
A: left ventricular hypertrophy	“LVH: interventricular septal and posterior wall thickness age <18 y: z-score ≥2 age ≥18 y: ≥1.3 cm”
A: ejection fraction	“LVEF <50%”
A: electrocardiogram	“Electrocardiogram abnormalities: history of AF or AFL, VT, VF, or sudden cardiac death repolarization abnormalities, LVH/RVH, AV block pre-excitation pattern due to Wolff-Parkinson-White or fasciculoventricular pathways”
A: cardiac magnetic resonance	“Late gadolinium enhancement on cardiac MRI”
B: muscle	“Muscle abnormalities defined by any:”“Abnormal EMG, functional assessment (CPET, 6MWT), or timed tests”“Elevated CPK, AST, or ALT (>2 SD above the upper limit of normal)”
C: neurocognitive	“Intellectual disability, attention deficit disorder, or developmental delay”

“For individuals who carry pathogenic or likely pathogenic LAMP2 variants, diagnosis with clinical disease depends on the presence of cardiac, neuromuscular, or cognitive features of disease.” (opens the source at this quote in a new tab)
“extracardiac symptoms in male individuals automatically qualify them as having Danon disease.” (opens the source at this quote in a new tab)
“This is in contrast to female individuals, where penetrance is lower and thus, diagnosis requires the presence of cardiac manifestations.” (opens the source at this quote in a new tab)

Consensus algorithm: variants of uncertain significance

“In patients with a LAMP2 variant of unknown significance, regardless of sex, diagnosis requires RNA analysis to demonstrate radical defects or absence of LAMP-2 protein as determined by either leukocyte flow cytometry or tissue analysis.” (opens the source at this quote in a new tab)
“Supporting evidence includes cellular histologic analysis showing autophagic vacuoles with unique sarcolemmal features, as well as an X-linked inheritance pattern, and confirming a de novo mutation in the absence of a family history of diseases.” (opens the source at this quote in a new tab)

Japanese diagnostic criteria: clinical features, muscle pathology, and LAMP-2 evaluation

“The diagnostic criteria were approved by the Japan Society of Neurology.” (opens the source at this quote in a new tab)
“In fact, the three main criteria for diagnosis are (A) clinical features; (B) muscle pathology; and (C) evaluation of LAMP-2.” (opens the source at this quote in a new tab)

Clinical suspicion: red flags in an individual with hypertrophic cardiomyopathy

Domain	Quoted red flag
Extracardiac	“X-linked inheritance”“Developmental delay”“Pigmentary retinopathy”“Skeletal myopathy”“Elevated serum CK”
Electrocardiogram	“Short PR interval/ventricular pre-excitation”“AV block”“Voltage criteria for extreme LVH”
Echocardiography	“Extreme LVH”“Concentric distribution of LVH (especially in male individuals)”“Concomitant RVH”“Rapid progression (including progression to hypokinetic dilated phase)”
Cardiac magnetic resonance	“Extensive LGE with sparing of the midseptum”

“Family history of a cardiomyopathy with an X-linked hereditary pattern and multiorgan dysfunction that includes neurocognitive deficits, skeletal myopathy, and visual involvement is suggestive of Danon disease.” (opens the source at this quote in a new tab)

Clinical suspicion: red flags in the 2023 ESC cardiomyopathy guideline

Field	Quoted table text
Clinical red flags	“Short PR interval”“Massive LVH”“Skeletal myopathy”“Increased serum CK enzyme”“Intellectual disability”“X-linked inheritance”
Diagnosis	“NGS or target testing for LAMP-2 variants”
Specific cause	“Danon disease”

“An X-linked pattern of inheritance is typical of Danon disease (GSD IIb).” (opens the source at this quote in a new tab)
“Skeletal myopathy, in association with learning disability, retinal involvement and ventricular pre-excitation, has been detected in males affected by Danon disease, while the cardiac phenotype can be isolated in affected females.” (opens the source at this quote in a new tab)

Clinical suspicion: male adolescents with concentric hypertrophy, elevated enzymes, or pre-excitation

“Danon disease should be suspected in the male teenager with concentric LVH, especially with elevated serum hepatic enzymes and CK concentrations, and/or WPW syndrome with markedly increased voltage of the left ventricle.” (opens the source at this quote in a new tab)

“In this regard, a high index of suspicion should be raised for LAMP2 cardiomyopathy (and genetic testing) in young patients demonstrating massive LV hypertrophy and distinctive ECG patterns with greatly increased voltages.” (opens the source at this quote in a new tab)

Electrocardiography: pre-excitation, short PR interval, and high voltage

“Early manifestations include short PR and/or delta waves, which suggest accelerated atrioventricular nodal conduction and/or accessory pathways, high ECG voltage with repolarization abnormalities, and atrial and ventricular arrhythmias.” (opens the source at this quote in a new tab)
“Pre-excitation secondary to Wolff-Parkinson-White syndrome or fasciculoventricular pathways, which may be an early marker of disease, is common in both male (69%) and female individuals (27%) and occurs more frequently in Danon disease than in other forms of hypertrophic heart disease.” (opens the source at this quote in a new tab)

“In 6 patients, at study entry a ventricular pre-excitation pattern was associated with markedly increased voltages for maximum R- or S-wave (40–145 mm; mean 74±38mm), and deeply inverted T-waves.” (opens the source at this quote in a new tab)

“There was 100% penetrance for ECG abnormalities in 13 patients with original ECGs. Short PR intervals and delta waves were present in 9 and 8 patients, respectively.” (opens the source at this quote in a new tab)

Electrocardiography: frequency of pre-excitation differs across cohorts

“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)

“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)

“Pre-excitation was found in only 11 patients (49%).” (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)

Electrocardiography: features listed for Danon disease in the 2023 ESC cardiomyopathy guideline

Finding in hypertrophic cardiomyopathy	Specific diseases to be considered
“Short PR interval/pre-excitation”	“Glycogenosis”“Danon disease”“PRKAG2 cardiomyopathy”“Anderson–Fabry disease”“Mitochondrial disease”
“AV block”	“Amyloidosis”“Anderson–Fabry disease (late stage)”“Danon disease”“Sarcoidosis”“PRKAG2 cardiomyopathy”
“Extreme LVH”	“Danon disease”“Glycogenosis (e.g. Pompe disease)”“PRKAG2 cardiomyopathy”

Echocardiography: extreme concentric hypertrophy, outflow obstruction, and apical sparing strain

“Extreme concentric LVH (>30 mm) is an echocardiographic hallmark of Danon disease, but it is important to realize that only a minority of patients (more frequently male individuals) will exhibit this degree of hypertrophy.” (opens the source at this quote in a new tab)
“It is important to consider that left ventricular outflow tract obstruction can be present in one quarter of patients with Danon disease and should be actively searched for in patients with dyspnea.” (opens the source at this quote in a new tab)
“Decreased longitudinal strain with sparing of the apex, similar to cardiac amyloidosis, has recently emerged as a new echocardiographic feature.” (opens the source at this quote in a new tab)

Echocardiographic finding	Diseases listed
“Extreme concentric LVH (wall thickness ≥30 mm)”	“Danon disease, Pompe disease”

Cardiac magnetic resonance: late gadolinium enhancement sparing the mid septum

“Eleven DD had gadolinium-based contrast administered. Of these, 3 showed no LGE. All remaining (8, 73%) had various LGE patterns and distributions but LGE was always sparing the mid septum.” (opens the source at this quote in a new tab)
“Extensive LGE consistently sparing the mid septum may represent a specific sign of DD cardiomyopathy” (opens the source at this quote in a new tab)
“In DD males, LVH was typically concentric (3 in 4 males with LVH) with normal LV systolic function (ejection fraction [EF] 61 ± 5 %).” (opens the source at this quote in a new tab)
“Females presented with asymmetric LVH (5 in 6 with LVH), right ventricular hypertrophy and two different phenotypes: HCM (4 females) or DCM phenotype (2 females).” (opens the source at this quote in a new tab)

“The characteristic late gadolinium enhancement features included midbasal septum sparing (14 of 16; 88%) and apex involvement (16 of 16; 100%) with a base-to-apex increasing tendency, free wall involvement (15 of 16; 94%), and extensive subendocardium involvement (14 of 16; 88%).” (opens the source at this quote in a new tab)

“In Danon disease, late gadolinium enhancement is frequently present with extensive patchy and diffuse patterns.” (opens the source at this quote in a new tab)

Cardiac magnetic resonance: tissue characterization by sex in a 24-participant cohort

“Males predominantly developed hypertrophic cardiomyopathy (HCM: 73.3%), whereas females universally exhibited dilated cardiomyopathy (DCM: 88.9%) with preserved septal thickness.” (opens the source at this quote in a new tab)
“Cardiac MR revealed extensive LGE (21.9% ± 11.4%, diffuse free-wall involvement), elevated extracellular volume (ECV) (ECV: 38% ± 12%), and significantly prolonged T1/T2 values (1374 ± 60 ms/46.5 ± 5.4 ms; T1 was higher in females).” (opens the source at this quote in a new tab)

Laboratory findings: creatine kinase and transaminases

Sex	Supportive laboratory finding
Males	“Elevated creatine kinase (~5-fold increase)”
Males	“Elevated asparate aminotransferase (AST) (~7-fold increase) and alanine aminotransferase (ALT) (~6-fold increase) with preserved hepatic synthetic function”
Females	“Normal or mildly increased creatine kinase”
Females	“Normal or mildly increased AST and ALT with preserved hepatic synthetic function”

“Creatine kinase and transaminase levels are typically elevated in male individuals, suggesting ongoing myocyte injury.” (opens the source at this quote in a new tab)
“Although liver enzyme abnormalities and creatine kinase elevation can precede the diagnosis of cardiomyopathy, hepatic and pulmonary symptoms are often sequelae of progressive cardiac disease.” (opens the source at this quote in a new tab)

“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)

Muscle and endomyocardial biopsy: role in diagnosis

“Muscle biopsy is not required to make the diagnosis” (opens the source at this quote in a new tab)
“tissue staining demonstrating absence of the LAMP-2 protein can confirm the diagnosis, although this assay is not widely available on a clinical basis.” (opens the source at this quote in a new tab)

“Skeletal and myocardial tissue biopsies can be performed in circumstances when variants of unknown significance are identified in genetic testing and there is diagnostic uncertainty.” (opens the source at this quote in a new tab)

“Muscle histology revealed basophilic vacuoles that contain acid phosphatase-positive material within membranes that lack lysosome-associated membrane protein-2.” (opens the source at this quote in a new tab)

LAMP-2 immunostaining and western blot: results in males and in females

“Immunohistochemical and western blot analyses reveal the complete absence of LAMP-2 protein in skeletal muscle and cardiac muscle regardless of a specific LAMP2 gene mutation in male patients” (opens the source at this quote in a new tab)
“In female patients, LAMP-2 protein varies from deficient to normal, but LAMP-2 haploinsufficiency is also considered as a contributing factor” (opens the source at this quote in a new tab)

“In our female patient, muscle histopatholoy and LAMP-2 protein analysis was inconclusive, indicating that diagnosis in females requires mutation identification.” (opens the source at this quote in a new tab)

LAMP-2 protein assays in leukocytes by flow cytometry

“Although not widely available, functional gene protein assays such as flow cytometry testing and immunohistochemistry of peripheral leukocytes and immunofluorescence and western blot on skeletal and myocardial tissue can be used to quantify LAMP-2 protein expression and identify patients for genetic testing.” (opens the source at this quote in a new tab)

“We developed a flow cytometric assay for LAMP-2 expression that can serve as a rapid primary screening method to detect carriers of LAMP-2 deficiencies.” (opens the source at this quote in a new tab)

“Our observations of the mosaicism in the asymptomatic mother suggest that similarly affected females could be a potentially under-diagnosed Danon disease carrier group and that LAMP2 flow cytometry, because of its supreme sensitivity, can be an efficient method for pedigree screening.” (opens the source at this quote in a new tab)

“LAMP2 expression in peripheral white blood cells (WBC) was tested by flow cytometry (FC) in the remaining 45 female patients.” (opens the source at this quote in a new tab)

Genetic testing: sequence analysis followed by deletion or duplication analysis

“Sequence analysis of LAMP2 detects missense, nonsense, and splice site variants and small intragenic deletions/insertions. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.” (opens the source at this quote in a new tab)
“A cardiomyopathy or myopathy multigene panel that includes LAMP2 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype.” (opens the source at this quote in a new tab)

“However, it is imperative that clinicians also consider the less common copy number variants, which may be causative, and ensure that gene targeted deletion/duplication analysis is also performed.” (opens the source at this quote in a new tab)
“Sequencing with deletion/duplication analysis is the industry standard for most commercial laboratories at this time.” (opens the source at this quote in a new tab)
“LAMP2 is included in most hypertrophic and dilated cardiomyopathy gene panels.” (opens the source at this quote in a new tab)

Genetic testing: variants that sequencing can miss

“Additionally, because some rearrangements and copy-number variants in the LAMP2 gene may be missed by next-generation sequencing, if the result of genetic testing is negative and suspicion for Danon disease persists, then expression of LAMP-2 on leukocytes or on tissue obtained by biopsy should be performed as described earlier.” (opens the source at this quote in a new tab)

“In heterozygous female DD probands, the wild-type allele may hamper the identification of an eCNV even if it results in the complete abolition of LAMP2 transcription and/or translation.” (opens the source at this quote in a new tab)

Genetic testing: pediatric and adult indications in the consensus statement

“Genetic testing should be strongly considered for any individuals in a pediatric clinical setting who meet clinical diagnostic criteria suggestive of Danon disease (Table 3).” (opens the source at this quote in a new tab)
“For this reason, female sex should not be a factor that precludes an individual who meets the appropriate clinical criteria from genetic analysis.” (opens the source at this quote in a new tab)
“This reinforces the inclusion of LAMP2 on multigene panels for common inherited cardiomyopathy for both adult and pediatric populations.” (opens the source at this quote in a new tab)
“A multigene next-generation sequencing panel is the rule when an individual’s disease presentation is atypical, especially when one presents with isolated hypertrophic cardiomyopathy at <15 years of age.” (opens the source at this quote in a new tab)

Guideline: LAMP2 testing in the 2024 AHA/ACC hypertrophic cardiomyopathy guideline

“Systemic disorders include various metabolic and multiorgan syndromes such as RASopathies (variants in several genes involved in RAS-MAPK signaling); mitochondrial myopathies; glycogen and lysosomal storage diseases in children; and Fabry, amyloid, sarcoid, and Danon cardiomyopathies.” (opens the source at this quote in a new tab)
“Genes associated with HCM phenocopies may be included in first-tier genetic testing if there is clinical suspicion based on phenotype evaluation of a systemic disorder, including PRKAG2 (glycogen storage disease), LAMP2 (Danon disease), GLA (Fabry disease), transthyretin amyloid cardiomyopathy, and disease genes related to RASopathies.” (opens the source at this quote in a new tab)
“In some circumstances, the genetic test result may alter the management of the index case, such as enzyme replacement therapy in patients with Fabry disease or more aggressive clinical management of patients with Danon disease.” (opens the source at this quote in a new tab)
“Cascade genetic testing in the family identifies those who carry the disease-causing variant and require ongoing surveillance, while those who do not carry the variant can be released from lifelong clinical surveillance.” (opens the source at this quote in a new tab)

Typical presentation age	Systemic features	Possible etiology	Diagnostic approach
“Youth and adolescence”	“Skeletal muscle weakness or movement disorder”	“Friedreich’s ataxia”“Danon disease”“Mitochondrial disease”	“Biochemical screening”“Neuromuscular assessment”“Genetic testing”

Guidelines and statements: LAMP2 as a core gene in cardiomyopathy testing

“Beyond sarcomeric genes, core genes to screen in patients with HCM include GLA, PRKAG2, and LAMP2” (opens the source at this quote in a new tab)
“Large gene panels for cardiomyopathy may include genes that cause genetic syndromes associated with cardiomyopathy (eg, Fabry disease, Danon disease, Alström syndrome), neuromuscular conditions associated with cardiomyopathy (eg, limb girdle muscular dystrophies), or metabolic conditions.” (opens the source at this quote in a new tab)

“Four genes, all associated with metabolic storage phenotypes that can mimic HCM (GLA: Fabry disease, LAMP2: Danon disease, PRKAG2: PRKAG2 cardiomyopathy, and TTR: transthyretin amyloidosis), were classified as definitive.” (opens the source at this quote in a new tab)

Condition	Genes
“HCM, definitive syndromic genes for which isolated left ventricular hypertrophy can be seen”	“PLN, CACNA1C, DES, FHL1, FLNC, GLA, LAMP2, PRKAG2, PTPN11, RAF1, RIT1, TTR”

“Given the relatively rapid progression of disease and frequent involvement of treatment-refractory arrhythmias, early suspicion for Danon disease should be confirmed via LAMP2 gene testing whenever possible.” (opens the source at this quote in a new tab)

Age at diagnosis

“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)

“The age at diagnosis was birth to 42 years in men and 2 to 65 in women.” (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).” (opens the source at this quote in a new tab)

Characteristic, prospective study of 9 male participants	Value
“Mean age at diagnosis, years”	“6.5 ± 5.2”

“Although some females appear to be nearly as severely affected as typically affected males, the average age of diagnosis in females is reported to be 27.9 years.” (opens the source at this quote in a new tab)

“Male patients are diagnosed usually at teenage, whereas the diagnosis and events occurred approximately 15 years later in female than male patients.” (opens the source at this quote in a new tab)

Age at diagnosis among hypertrophic cardiomyopathy phenocopies in four European centres

“The study cohort comprised 818 patients with a clinical diagnosis of HCM [479 (62%) males, mean age 49 ± 21 years] referred to four European centres.” (opens the source at this quote in a new tab)
“Syndromic diseases such as Rasopathies, inherited metabolic disorders, and mitochondrial disorders were diagnosed in neonatal/early childhood (mean age 3 ± 2 years), whereas patients with Danon disease, Friedreich's ataxia, Noonan syndrome, and PRKAG2 cardiomyopathy were identified mostly during adolescence (mean age 16 ± 8 years).” (opens the source at this quote in a new tab)

Diagnostic delay: findings present before diagnosis

“Abnormalities were detected 9,5 months to 5,8 years, median 3,5 years prior to referral to the National Pediatric Center.” (opens the source at this quote in a new tab)
“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)

“A retrospective review of 29 DD cases suggests an underrecognised asymptomatic period in male DD patients, characterised by elevations in serum CK and transaminases.” (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)
“Thus, even if Danon disease is not initially suspected in a patient with cardiomyopathy, the diagnosis of Danon disease may be revealed to clinicians through the results of genetic testing.” (opens the source at this quote in a new tab)

Misdiagnosis as sarcomeric hypertrophic cardiomyopathy

“DD cardiomyopathy is often misclassified as sarcomeric hypertrophic cardiomyopathy (HCM) in young boys and underrecognized in females who can present with isolated HCM or dilated cardiomyopathy (DCM)” (opens the source at this quote in a new tab)

“Mutations in X-linked lysosome-associated membrane protein gene (LAMP2; Danon disease) produce a cardiomyopathy in young patients that clinically mimics hypertrophic cardiomyopathy (HCM) due to sarcomere protein mutations.” (opens the source at this quote in a new tab)

“The glycogen-storage cardiomyopathy produced by LAMP2 or PRKAG2 mutations resembles hypertrophic cardiomyopathy but is distinguished by electrophysiological abnormalities, particularly ventricular preexcitation.” (opens the source at this quote in a new tab)

“The two girls in contrast had clinical features that mimicked severe primary hypertrophic cardiomyopathy caused by mutations in genes encoding sarcomeric proteins.” (opens the source at this quote in a new tab)

Underdiagnosis in females

“Inasmuch as extracardiac manifestations are less prevalent and severe, the diagnosis of Danon disease is more challenging in female individuals and may be an unexpected finding from cardiomyopathy-panel or whole exome–based genetic testing.” (opens the source at this quote in a new tab)
“In the absence of an affected male in the family, misdiagnoses may occur in the absence of genetic testing.” (opens the source at this quote in a new tab)

“Clinical diagnosis and management is extremely challenging in women due to phenotypic diversity and the absence of extracardiac manifestations.” (opens the source at this quote in a new tab)

“Even though female patients are frequently the first affected individuals in DD families, many are identified retrospectively or even post-mortem after the diagnosis is established in their affected male relative(s) (brother or son).” (opens the source at this quote in a new tab)
“Danon disease is an underdiagnosed cause of AHF in young female patients.” (opens the source at this quote in a new tab)

Estimated diagnosis rate and genetic testing rates in cardiomyopathy, company presentation of October 2026

“Representing a current diagnosis rate under 10%” (opens the source at this quote in a new tab)

Population	Genetic testing rate
Adult HCM	“1.6%”
Adults with CM (<=40)	“2.6%”
Pediatric CM	“13.8%”

Differential diagnosis: selected genes and disorders

Gene	Disorder	Mode of inheritance	Cardiomyopathy	Skeletal muscle
GAA	“Pompe disease”	“AR”	“Severe early-onset hypertrophic cardiomyopathy”	“Rapidly progressive muscle weakness (infantile form only)”
PRKAG2	“Familial Wolff-Parkinson White syndrome (OMIM 194200)”	“AD”	“Wolff-Parkinson White syndrome w/or w/o hypertrophic cardiomyopathy”	“Normal”
VMA21	“X-linked myopathy w/excessive autophagy”	“XL”	“Hypertrophic cardiomyopathy (mild) in a minority of cases”	“Hypotonia & muscle atrophy”

“However, unlike Danon disease, these disorders are not known to be associated with intellectual disability or retinal disease.” (opens the source at this quote in a new tab)

Differential diagnosis: PRKAG2-related disease

“The inheritance pattern in PRKAG2 families is autosomal dominant. However, the combination of early-onset cardiac hypertrophy and pre-excitation makes PRKAG2 disease relevant to the differential diagnosis of Danon disease.” (opens the source at this quote in a new tab)
“Unlike in Danon disease, muscle weakness or myalgia was seldom reported in PRKAG2 (2% of patients), although 21% had mildly elevated creatine kinase levels.” (opens the source at this quote in a new tab)
“Additionally, PRKAG2 disease does not cause retinal disease or intellectual impairment.” (opens the source at this quote in a new tab)

Differential diagnosis: Pompe disease

“The phenotypic expression depends on the residual enzymatic activity, which is low in patients presenting at infancy and higher in patients presenting later in life.” (opens the source at this quote in a new tab)
“The infantile form is characterized by muscular hypotonia (floppy baby), macroglossia, hepatomegaly, and severe LVH that may be associated with left ventricular outflow tract obstruction.” (opens the source at this quote in a new tab)

“It resembles infantile Pompe disease with severe HCM but less pronounced skeletal myopathy, and it has additional problems of cardiac preexcitation, intellectual disabilities, and retinal pigmentary disease.” (opens the source at this quote in a new tab)

Differential diagnosis: Fabry disease

“Cardiac involvement appears in the third to fourth decades and later, with a hypertrophic phenotype characterized by biventricular hypertrophy that involves the papillary muscles, valvular thickening, and diastolic dysfunction.” (opens the source at this quote in a new tab)
“As such, Fabry disease, which also displays X-linked inheritance, can be considered in a differential diagnosis with Danon disease in male individuals.” (opens the source at this quote in a new tab)

Differential diagnosis: sarcomeric hypertrophic cardiomyopathy and inheritance clues

“Although the onset of the phenotype may occur in a relatively short time, progression toward massive LVH and systolic dysfunction is uncommon (<10%) and should raise suspicion of a rare genocopy such as Danon disease.” (opens the source at this quote in a new tab)
“Additionally, pre-excitation is rare and bradyarrhythmias are less frequent in hypertrophic cardiomyopathy.” (opens the source at this quote in a new tab)
“Although de novo LAMP2 mutations may occur, resulting in no contributory family history, male-to-male transmission or female-to-all-offspring patterns suggestive of mitochondrial disease should prompt consideration of other diagnoses.” (opens the source at this quote in a new tab)

Family cascade testing: consensus recommendations

“Genetic testing for relatives of an individual affected by Danon disease is imperative for proper risk assessment and determination of recurrence risk.” (opens the source at this quote in a new tab)
“For male individuals identified to have a pathogenic or likely pathogenic variant in the LAMP2 gene, only genetic testing of the patient’s mother is required because the affected X chromosome is inherited maternally.” (opens the source at this quote in a new tab)
“This is not the case for affected female individuals, and both parents should be tested once a pathogenic variant is identified in the affected proband.” (opens the source at this quote in a new tab)
“First, cascade genetic screening of relatives should be recommended at the time of diagnosis; second, family planning strategies should be introduced when a patient reaches reproductive age.” (opens the source at this quote in a new tab)
“Genetic counseling should be offered to all affected families to ensure they are aware of the inheritance pattern, reproductive risks, and technologies available to those who wish to pursue further testing before, during, and after pregnancy.” (opens the source at this quote in a new tab)

Family cascade testing: GeneReviews and Orphanet

“It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures.” (opens the source at this quote in a new tab)
“Once the LAMP2 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for Danon disease are possible.” (opens the source at this quote in a new tab)

“Identification of a LAMP2 pathogenic variant in a proband allows cascade testing of other at-risk relatives.” (opens the source at this quote in a new tab)

Screening of variant carriers without clinical findings

“Consequently, although both sexes should be screened during infancy (first year of life), yearly multidisciplinary follow-up care is recommended to begin at that time in boys, whereas girls can start annual follow-up visits around the age of 6 years.” (opens the source at this quote in a new tab)
“From the cardiac perspective, laboratory tests, 12-lead ECG, and echocardiography should detect early stages of involvement.” (opens the source at this quote in a new tab)
“CMR imaging might be helpful in identifying mild phenotypes and should be used upon clinical suspicion or when adequate echocardiographic images are not attainable.” (opens the source at this quote in a new tab)

Evaluation at diagnosis: consensus recommendations

“All individuals with a diagnosis of Danon disease should undergo a resting 12-lead ECG, echocardiogram, ambulatory Holter monitoring, and serum N-terminal pro-B-type natriuretic peptide (or B-type natriuretic peptide [BNP]) levels at baseline.” (opens the source at this quote in a new tab)
“Although this suggests that surveillance intervals should differ by sex, all LAMP2 variant carriers should undergo baseline multisystem evaluation to assess for the presence of any symptoms or signs of disease.” (opens the source at this quote in a new tab)
“It is recommended that patients with Danon disease be assessed and receive follow-up care at referral centers where a multidisciplinary team can provide a comprehensive management strategy.” (opens the source at this quote in a new tab)
“Ophthalmologic assessment for evidence of pigmentary retinopathy is recommended at initial evaluation and during follow-up care in all patients.” (opens the source at this quote in a new tab)
“Comprehensive developmental assessment with a view to initiating early educational support and interventions should be performed in all male individuals with Danon disease and in female individuals as clinically indicated.” (opens the source at this quote in a new tab)

Diagnostic tests, typical findings, and surveillance intervals: consensus table

Test	Typical findings	Frequency during follow-up care
Blood tests	“Raised NT-proBNP/troponin”“CK, AST, ALT, LDH”	“Yearly”
Electrocardiogram	“Pre-excitation, ventricular hypertrophy, extreme voltage, repolarization abnormalities, conduction disease”	“Yearly”
24-hour Holter	“Atrial fibrillation, ventricular arrhythmias”“Atrioventricular block”	“Yearly”“Every 6 mo if enlarged atria”
Echocardiography	“Extreme hypertrophy”“25% LVOTO”“Apical sparing strain pattern”	“Yearly”
Cardiac magnetic resonance	“Extensive and diffuse LGE with midseptal sparing”“Increased T1 and ECV”	“Every 2-3 y”
Neurologic evaluation	“Proximal muscle weakness”	“Yearly if symptoms, otherwise, every 3-4 y”
Development evaluation	“Intellectual disability”	“At baseline and if new manifestations appear”
Ophthalmologic evaluation	“Cone-rod dystrophy”“Peripheral pigmentation”	“Every 3-5 y”
Genetic counseling	“Cascade screening”“Family planning”	“At diagnosis and when needed”

Evaluations following initial diagnosis: GeneReviews

System or concern	Evaluation	Comment
Cardiac	“Electrocardiography”	“To evaluate for hypertrophy, arrhythmia, & conduction abnormalities”
Cardiac	“Echocardiography”	“Incl eval for left-ventricular outflow tract obstruction”
Cardiac	“Cardiac MRI”	“Late gadolinium enhancement indicates fibrosis & likely ↑ arrhythmia risk.”
Cardiac	“Cardiopulmonary exercise testing”	“Has not been formally studied in persons w/Danon disease”
Cardiac	“Brain natriuretic peptide level”	“As a baseline”
Neuromuscular	“Neurologic exam for signs of muscle disease”
Development	“Developmental assessment in males (& as indicated clinically in females)”	“To incl motor, adaptive, cognitive, & speech-language eval”
Retinopathy	“Retinal exam for evidence of cone-rod dystrophy”
Gastrointestinal	“Liver function tests”	“To incl AST, ALT, & LDH”
Other	“Consultation w/clinical geneticist &/or genetic counselor”	“To incl genetic counseling”

Recommended cardiac surveillance: GeneReviews

Evaluation	Frequency
“Electrocardiography”	“At least annually”
“Echocardiography”	“At least every 1-2 yrs, transitioning to every 6 mos once hypertrophy becomes moderate or if hypertrophy is rapidly progressive”
“Cardiac MRI”	“Consider every 1-2 yrs to evaluate progression of fibrosis.”
“Ambulatory arrhythmia monitoring”	“As needed for eval of symptoms consistent w/bypass track (e.g. palpitations, pre-syncope)”

Status of practice guidelines and funding of the consensus statement

“There are currently no consensus clinical practice guidelines and assessment, and management is largely based on expert opinion and extrapolation from hypertrophic cardiomyopathy guidelines.” (opens the source at this quote in a new tab)
“This paper represents the consensus opinions of the authors, borne from an International Advisory Board meeting funded by Rocket Pharmaceuticals, who also provided support for development of the Central Illustration.” (opens the source at this quote in a new tab)

“consensus management guidelines have not been published and evaluation and management is typically based on expert opinion.” (opens the source at this quote in a new tab)