Danon Disease

Monogenic (Mendelian): 100%, LAMP2 mutation^[2]

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 (Brambatti et al 2019^[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 mutations, notably associated with severe skeletal myopathy but absent or mild cardiac involvement in males; females carrying same mutations may die suddenly

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); can present with isolated cardiac disease in 73% of cases

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

ECG: WPW (delta wave, short PR, broad QRS) in 41.8%; LVH voltage criteria; conduction abnormalities; ventricular tachycardia (10% males, 3.6% females)

Echocardiography/CMR: Severe concentric LVH (often massively beyond typical HCM); assess LVEF, LVOT gradient, MR; CMR with LGE shows diffuse patchy pattern in the majority

Serum CK: Elevated (skeletal myopathy), also check LDH, AST, ALT

Genetic testing: LAMP2 full gene sequencing and deletion/duplication analysis; ClinVar pathogenicity assessment

Muscle biopsy: Vacuolar myopathy with autophagic vacuoles on electron microscopy (highly suggestive but less often required if genetic diagnosis confirmed)

Ophthalmology referral: For retinopathy/myopia assessment (20% affected)

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 GDMT 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%

High SCD risk: an ICD is commonly considered even with preserved EF where high-risk features are present, recognising that Danon-specific evidence is limited and extrapolated. Because progression can be rapid, particularly in males, device decisions should be taken alongside early transplant assessment rather than in isolation.

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 + WPW pattern + elevated CK, the classic triad is highly suggestive, but confirm with LAMP2 testing and consider phenocopies^[1]
• Females can present differently, up to 29.3% with DCM (not HCM); LAMP2 testing warranted in women with unexplained cardiomyopathy and family history^[2]
• Do NOT confuse with sarcomeric HCM, management and prognosis differ substantially
• Screen all first-degree female relatives, can be affected (milder, later onset)
• Rapidly progressive, early and proactive cardiac transplant evaluation is essential in males^[1]
• Multidisciplinary team involvement: cardiology, neurology/myology, ophthalmology, clinical genetics