Danon Disease (LAMP2)

Monogenic (Mendelian): 100%, pathogenic variants in LAMP2 (Xq24), most often truncating, frameshift or splice-site variants that abolish LAMP2 protein expression.^[2][3]

Mechanism: LAMP2 is required for fusion of autophagosomes with lysosomes; its absence causes accumulation of autophagic vacuoles in cardiomyocytes and skeletal muscle, a vacuolar myopathy (historically classified as glycogen storage disease type IIb, although glycogen content is not consistently raised).^[3]

Acquired or polygenic causes: none; the phenotype is exclusively monogenic.

Inheritance: X-linked dominant (LAMP2 gene on Xq24)

LAMP2 protein: Lysosomal-associated membrane protein 2, integral to cellular autophagy; absence/reduced expression leads to intracytoplasmic vacuoles containing autophagic material

Variant types^[2]:

• Stop codon or frameshift variants: 63.8% (most common)
• Splice-site variants: 24.6%
• Missense variants: 6.9%
• Most frequent mutation locations: exon 8 (34%), exon 6 (18%)
• Exon 9b variants (6.4%): severe skeletal myopathy with absent or mild cardiac involvement in males, but a woman from one such family died suddenly at 28 with HCM at autopsy, so female carriers still need cardiac surveillance^[2]

Males: Severe, early-onset disease (teenagers to 20s); full absence of LAMP2 protein; high early mortality

Females: Variable severity due to X-inactivation mosaicism; later onset (30s–40s); isolated cardiac disease in 73%^[2]

Rare, exact population prevalence unknown; may account for up to 5% of paediatric hypertrophic cardiomyopathy (HCM)^[2]

Systematic review of 146 confirmed cases (Brambatti et al 2019^[2]): 92.5% had cardiac abnormalities; 61.6% male, 38.4% female

More severe and earlier-onset in males (hemizygous, complete LAMP2 protein absence); females show variable severity (X-inactivation mosaicism)

Classic clinical triad (present in 42% of males, rarely in females^[2]):

• Cardiomyopathy (HCM phenotype predominant)
• Skeletal myopathy, proximal muscle weakness, elevated CK (present in 50.7%; mainly males)
• Cognitive impairment, mild to moderate in 55.6% of patients; predominantly males (80%)

Cardiac features (Brambatti et al 2019^[2]):

• Males: HCM phenotype in 96.2%; DCM at presentation 3.8%
• Females: HCM phenotype in 70.3%; DCM at presentation 29.3%, significantly higher than males (p<0.001)
• LVOT obstruction present in 26.2% of patients with the HCM phenotype
• End-stage cardiomyopathy (refractory to medical management) in 43.8% of patients with the HCM phenotype
• WPW pattern in 41.8%: accessory pathway pre-excitation with no clear gender difference
• Cardiac conduction abnormalities in 57.5%
• Late gadolinium enhancement (LGE) on CMR: present in 92.3% of males and 69.2% of females with available data

Non-cardiac features:

• Vision impairment (retinopathy, myopia) in 20.2%, onset median age 15 years
• Stroke/TIA (5 patients); fatal in 2/5 cases
• Elevated liver enzymes (AST, ALT), CK, and LDH in 61.9% of patients with available data

When to suspect:^[3]

• Marked LVH with ventricular pre-excitation in an adolescent or young adult male
• LVH with raised CK and transaminases, proximal weakness or learning difficulty
• A woman with HCM or DCM and a maternal-line family history of early transplant or sudden death; no male-to-male transmission

Differential diagnosis (LVH with pre-excitation or extracardiac features):^[1][3]

• PRKAG2 syndrome: LVH, pre-excitation and progressive conduction disease; autosomal dominant with male-to-male transmission; normal CK and no cognitive impairment
• Pompe disease: autosomal recessive; massive LVH with short PR in infancy, while late-onset disease is predominantly skeletal and respiratory
• Fabry disease: older presentation, short PR without pre-excitation, low native T1 on CMR, renal and neuropathic features
• Mitochondrial disease: maternal inheritance, raised lactate, multisystem involvement
• Sarcomeric HCM: usually asymmetric septal hypertrophy, pre-excitation uncommon, normal CK

No disease-modifying therapy is currently available: management is supportive and symptomatic.

1. General measures:

• Genetic counselling and family cascade testing (X-linked inheritance), see the Genetic Testing page

2. Medical therapy:

• Standard foundational medical therapy for heart failure (beta-blockers, ACE-I, MRA), though disease is often refractory to medical management; progression to end-stage HF occurs in 43.8%^[2]

3. Device therapy:

• 45% of patients received an ICD (76.5% for primary prevention)^[2]
• Consider ICD early, even with preserved LVEF, given high SCD risk in both sexes
• WPW with accessory pathway, electrophysiological study and ablation consideration

4. Advanced heart failure and/or transplant referral:

• Cardiac transplantation required in 19.9% (29/146 patients); males, in teens-to-20s; females, in 30s-40s
• Skeletal myopathy can progress post-transplant in males (profound muscle weakness reported in 4 patients post-HTx)
• Two male patients required re-transplantation due to allograft rejection

5. Emerging therapies:

• Gene therapy and substrate reduction approaches under investigation

• Rapidly progressive cardiomyopathy: with massive hypertrophy in males, leading to heart failure and early death, often before age 30, so transplant is frequently the only effective option^[2]
• Ventricular pre-excitation (WPW) and ventricular arrhythmia: with sudden death
• Multisystem involvement: skeletal myopathy, cognitive impairment and retinopathy

Composite outcome (death, heart transplant, or LVAD), Brambatti et al 2019^[2]:

• Overall: 34.9% of patients reached composite outcome
• Males: Composite outcome at median age 21 years (range: teens to 30s)
• Females: Composite outcome at median age 38 years (p<0.001 vs males)
• Cause of death (where reported): heart failure 45%, sudden cardiac death 40%, stroke 10%

No validated SCD risk model: the HCM Risk-SCD calculator is not validated in Danon disease or other phenocopies and should not be used to reassure.^[1][3]

Features associated with adverse outcome: male sex, extensive LGE, falling LVEF, NSVT or sustained VT, syncope, and pre-excitation with rapid accessory pathway conduction.^[2][3]

ICD: commonly considered even with preserved EF where high-risk features are present, recognising that Danon-specific evidence is limited and extrapolated. ICD therapy has failed to terminate ventricular arrhythmia in some patients with massive hypertrophy, so an ICD does not replace transplant assessment; because progression can be rapid, particularly in males, device decisions should be taken alongside early transplant assessment rather than in isolation.^[3][4]

Females: later onset and slower progression, but sudden death and end-stage heart failure still occur, so surveillance continues lifelong.^[2]

mWHO class II–III or above: refer to a Pregnancy Heart Team before conception (see Pregnancy).

Based on ESC 2023 Cardiomyopathy guidelines and Danon registry data^[1][2].

Advanced / complicated = any LVEF decline or symptomatic cardiomyopathy, note rapid progression, especially in males, warranting a low threshold for transplant assessment.

Genotype-positive / phenotype-negative (G+/P−) = a confirmed pathogenic-variant carrier with no overt disease expression yet.

	Genotype+ / Phenotype−	Uncomplicated / Stable	Advanced / Complicated
Frequency	Every 6–12 months (rapid conversion, esp. males)	Every 6 months	Every 3 months
Clinical review	Symptoms, neuromuscular & cognitive review	Symptoms, NYHA, neuromuscular & cognitive status	As above + transplant assessment
ECG	Each visit (pre-excitation, LVH)	Each visit (pre-excitation, conduction, LVH)	Each visit
Echocardiography	6–12 monthly	6-monthly	3-monthly
Holter / ambulatory	Periodic	6-monthly	3-monthly
CMR	Baseline + periodic	Baseline + periodic (LGE burden)	As clinically indicated
Transplant pathway	–	Early referral / listing discussion	Active evaluation

Disclaimer: This table is general guidance based on published guidelines and does not replace clinical judgement. The responsible clinician is accountable for determining the appropriate, individualised follow-up plan for each patient.

• Suspect in young males with severe LVH + pre-excitation + elevated CK; the classic triad is highly suggestive, but confirm with LAMP2 testing and consider phenocopies^[1][3]
• CMR clue: extensive LV free-wall LGE with relative septal sparing, together with extreme ECG voltages, points to Danon disease rather than sarcomeric HCM^[3]
• Females can present differently, up to 29.3% with DCM (not HCM); LAMP2 testing warranted in women with unexplained cardiomyopathy and a maternal-line family history^[2]
• Do NOT use the HCM Risk-SCD calculator: it is not validated in Danon disease^[1]
• Screen at-risk relatives according to the pedigree: the maternal line when the variant came through the mother, and all daughters of an affected man (who inherit his variant; his sons do not); female carriers can be affected, with milder, later-onset disease
• Rapidly progressive, early and proactive cardiac transplant evaluation is essential in males^[1][3]
• Multidisciplinary team involvement: cardiology, neurology/myology, ophthalmology, clinical genetics