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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

Definition and etiology

23 evidence topics · 21 sources

Definition: X-linked LAMP2 deficiency with cardiomyopathy, skeletal myopathy, and cognitive impairment

“Danon disease is a rare X-linked autophagic vacuolar cardioskeletal myopathy associated with severe heart failure that can be accompanied with extracardiac neurologic, skeletal, and ophthalmologic manifestations.” (opens the source at this quote in a new tab)

“It is caused by loss of function variants in the LAMP2 gene and is among the most severe and penetrant of the genetic cardiomyopathies.” (opens the source at this quote in a new tab)

“Clinically, the disease is characterized by the classic triad of severe cardiomyopathy, skeletal myopathy, and cognitive impairment, reflecting the fact that the myocardium, skeletal muscle, and brain have the most abundant expression of LAMP-2 (Central Illustration).” (opens the source at this quote in a new tab)

“A rare X-linked genetic condition due to deficiency of the lysosomal-associated membrane protein 2 (LAMP2) characterized by severe cardiomyopathy and variable degrees of muscle weakness, frequently associated with intellectual deficits (in males).” (opens the source at this quote in a new tab)

“Danon disease is a multisystem condition with predominant involvement of the heart, skeletal muscles, and retina, with overlying cognitive dysfunction.” (opens the source at this quote in a new tab)

First description in 1981 and identification of primary LAMP-2 deficiency in 2000

“In 1981 Morris Danon described 2 patients with severe hypertrophic cardiomyopathy resembling Pompe syndrome but with normal acid maltase levels” (opens the source at this quote in a new tab)

“Here we report ten unrelated patients, including one of the patients from the original case report, who have primary deficiencies of LAMP-2, a principal lysosomal membrane protein.” (opens the source at this quote in a new tab)

“From these results and the finding that LAMP-2-deficient mice manifest a similar vacuolar cardioskeletal myopathy, we conclude that primary LAMP-2 deficiency is the cause of Danon disease.” (opens the source at this quote in a new tab)

“To our knowledge this is the first example of human cardiopathy-myopathy that is caused by mutations in a lysosomal structural protein rather than an enzymatic protein.” (opens the source at this quote in a new tab)

LAMP2 gene: chromosomal location and exon structure

“Danon disease is caused by a critical deficiency of expression of the lysosomal-associated membrane 2 (LAMP-2) protein, encoded by the LAMP2 gene, which is localized to the X-chromosome (Xq24).” (opens the source at this quote in a new tab)

“LAMP2 is composed of nine exons, with exons 1–8 and part of exon 9 constituting the lumenal domain and the remainder of exon 9 constituting both the transmembrane and cytoplasmic domains.” (opens the source at this quote in a new tab)

“Selective splicing of exon 9 results in 9A/9B/9C, with three isoforms, LAMP-2A/2B/2C, respectively.” (opens the source at this quote in a new tab)

Three LAMP-2 isoforms and the isoforms affected by pathogenic variants

“Three isoforms, LAMP-2A, LAMP-2B, and LAMP-2C, are created by alternative splicing of the terminal exon 9, each with varying roles in autophagy.” (opens the source at this quote in a new tab)

“Most pathogenic variants detected affect all three isoforms, although several reported pathogenic variants appear to affect only the LAMP-2B isoform” (opens the source at this quote in a new tab)

“The majority of LAMP2 pathogenic variants are loss-of-function alterations that predict an absence or severe reduction in LAMP-2 proteins.” (opens the source at this quote in a new tab)

“Given that all known mutations affect at least the LAMP-2B isoform, LAMP-2B deficiency seems to be a necessary and central feature to the pathogenesis of Danon disease.” (opens the source at this quote in a new tab)

Variant types: proportion detected by sequence analysis and by deletion or duplication analysis
MethodProportion of pathogenic variants identified by the method
Sequence analysis“~95%”
Gene-targeted deletion/duplication analysis“~5%”

“The vast majority of pathogenic variants reported to date are nonsense, frameshift, splicing, and small insertion-deletion variants. A minority of pathogenic variants are due to large gene deletions, duplications, or rearrangements.” (opens the source at this quote in a new tab)

“The majority of reported cases of Danon disease are associated with nonsense, frameshift, splicing, and small indel variants detected in the LAMP2 gene, accounting for approximately 95% of all pathogenic and likely pathogenic variants detected.” (opens the source at this quote in a new tab)

“A small proportion of affected individuals have copy number variants, which include the LAMP2 gene in the form of large deletions, duplications, and structural rearrangements.” (opens the source at this quote in a new tab)

“Variants that portend a loss of LAMP-2 protein expression (nonsense, frameshift, and insertion/deletion variants) represent the spectrum of Danon disease–causing genetic findings.” (opens the source at this quote in a new tab)

Variant types: counts of described LAMP2 germline variants by classification, 2026 review

“The LAMP2 gene has approximately 681 germline variants described, including 140 PV, 254 variants of uncertain significance (VUS), and 287 benign. Among the 140 PV, 89% (n=125/140) are loss of function, 6 missense or in-frame indels, and 9 non-coding.” (opens the source at this quote in a new tab)

“Among the VUS, the vast majority, 80% (n=204/254), are missense or in-frame indels.” (opens the source at this quote in a new tab)

Variant types: 68 variants in a 2014 literature and registry review

“At the time of this review, 68 LAMP2 mutations are reported in the English literature (62) and unpublished data from our registry (6)” (opens the source at this quote in a new tab)

“Most mutations are nonsense or frameshift mutations predicted to truncate the LAMP2 protein, resulting in absence of the transmembrane and cytoplasmic domains and likely disabling its function as a lysosomal membrane protein.” (opens the source at this quote in a new tab)

“Splicing, large deletion, large duplication, insertion/deletion, and missense mutations that cause LAMP2 deficiency of all isoforms have also been described.” (opens the source at this quote in a new tab)

“The exon-skipping mutation c.928G>A (skips exon 7) is the most frequent mutation reported in the LAMP2 gene” (opens the source at this quote in a new tab)

Variant types in Japanese families: 2018 nationwide survey and 2024 update

“Currently, we have identified 22 different LAMP2 mutations in 26 families” (opens the source at this quote in a new tab)

“The distribution of mutations widely ranged from exon 1 to 9.” (opens the source at this quote in a new tab)

“All mutations were either nonsense or frame-shift mutations that are predicted to cause truncation of the protein, except for the exon 6 skipping mutation in Family 5.” (opens the source at this quote in a new tab)

Genotype and phenotype: age at symptom onset by variant type

“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)

“Splicing mutations showed a trend of presenting later with ages of symptom onset for males and females of 15.4±8.1 years (p=0.31) and 37.3±12.3 years (p=0.059), 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)

Genotype and phenotype: no confirmed correlation for loss-of-function variants; milder phenotypes with exon 9B and missense variants

“To date, no specific genotype-phenotype correlations for pathogenic loss-of-function variants have been confirmed.” (opens the source at this quote in a new tab)

“A small number of pathogenic missense variants and pathogenic variants confined to exon 9B of the LAMP-2B protein isoform have been reported in association with mild or atypical phenotypes” (opens the source at this quote in a new tab)

“In some cases the onset of cardiac features is later in males (e.g., after the 4th decade) and rare males have been reported without overt hypertrophic or dilated cardiomyopathies.” (opens the source at this quote in a new tab)

“We found four families with mutations in exon 9B (c.1097_1098 delAA) that encodes LAMP-2B, which is considered genetically important.” (opens the source at this quote in a new tab)

“Recently, we reported that male patients over 50 years of age with mutations in exon 9B showed very mild clinical symptoms, including cardiomyopathy” (opens the source at this quote in a new tab)

“Over 160 separate LAMP2 variants cause Danon Disease and genotype-phenotype correlation is yet to be clarified.” (opens the source at this quote in a new tab)

De novo variants: reported share of cases

“Additionally, more than one third of Danon disease cases are de novo mutations.” (opens the source at this quote in a new tab)

“In one study, the frequency of de novo pathogenic variants was estimated at 40%” (opens the source at this quote in a new tab)

“Half of the probands showed de novo mutations.” (opens the source at this quote in a new tab)

“Of the 20 families, 16 probands were male and four probands were female. Ten of the 20 mothers were symptomatic (50%).” (opens the source at this quote in a new tab)

“All patients were found to have a pathogenic/likely pathogenic variant in the LAMP2 gene, six patients had no family history and a de novo evolvement was documented in 4/6 of those available for genetic tested.” (opens the source at this quote in a new tab)

De novo variant, prospective study of 9 male participantsParticipantsPercent
Yes“4”“44%”
No“5”“56%”
Germline and somatic mosaicism

“Germline mosaicism for LAMP2 pathogenic variants has been described but the frequency of mosaicism is currently unknown” (opens the source at this quote in a new tab)

“Here, we describe the first molecularly documented evidence of somatic mosaicism for a LAMP2 mutation, identified in the asymptomatic mother of a boy with Danon disease caused by the frameshift mutation c.808dupG (p.A270Gfx3) within exon 6.” (opens the source at this quote in a new tab)

“Critical for counseling and recurrence prediction, we also highlight the need to search for somatic-germinal mosaicism in DD families.” (opens the source at this quote in a new tab)

Inheritance pattern and transmission risk

“Danon disease is inherited in an X-linked manner.” (opens the source at this quote in a new tab)

“If the mother of the proband has a LAMP2 pathogenic variant, the chance of transmitting it in each pregnancy is 50%.” (opens the source at this quote in a new tab)

“Males who have a pathogenic variant in LAMP2 will transmit the pathogenic variant to all of their daughters and none of their sons.” (opens the source at this quote in a new tab)

“Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygous and may have features of Danon disease.” (opens the source at this quote in a new tab)

“Owing to its X-linked dominant inheritance, disease expression differs by sex, with female individuals often presenting with disease manifestations later in life and often with isolated cardiac symptoms.” (opens the source at this quote in a new tab)

“However, in practical terms, male individuals with Danon disease are often too medically sick to father children.” (opens the source at this quote in a new tab)

Recurrence risk when the variant is not detected in a parent

“If the proband represents a simplex case (i.e., a single occurrence in a family) and if the LAMP2 pathogenic variant cannot be detected in the leukocyte DNA of the mother, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of maternal germline mosaicism.” (opens the source at this quote in a new tab)

“If a woman has more than one affected child and no other affected relatives and if the LAMP2 pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.” (opens the source at this quote in a new tab)

Penetrance by sex

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

“The penetrance in Danon disease is age dependent and has not been well studied in the literature.” (opens the source at this quote in a new tab)

“Given the severity of the cardiac phenotype, the penetrance is estimated as high or nearly complete in males by the second decade.” (opens the source at this quote in a new tab)

“Females appear to also have a high cardiac penetrance that is later in onset compared to males.” (opens the source at this quote in a new tab)

Disease classification: from glycogen storage disease to a disorder of autophagy

“The condition was originally described as a glycogen storage disease due to similarities noted on pathologic studies, however LAMP-2 does not appear to have enzymatic activity nor directly affect glycogen storage or degradation.” (opens the source at this quote in a new tab)

“Given all of the above, Danon disease is now considered a condition of pathologic autophagy with histologic features of abnormal cytoplasmic trafficking manifest with vacuolar myopathy and elevated glycogen staining.” (opens the source at this quote in a new tab)

“As histological findings of glycogen buildup in muscle tissue similar to those seen in Pompe disease were noted, the condition was originally considered to be a lysosomal storage disease and was termed glycogen storage disease type IIb.” (opens the source at this quote in a new tab)

“Danon disease was originally classified as a glycogen storage disease (GSD), but is distinct from other GSDs, which are caused by a deficient enzyme of glycogen metabolism.” (opens the source at this quote in a new tab)

Disease classification: grouping with glycogen storage disorders in cardiomyopathy guidelines

“Glycogen storage disorders (GSDs) represent a heterogeneous group of metabolic diseases, including infantile-onset Pompe disease (GSD, type IIa), Danon disease (GSD, type IIb), and PRKAG2 disease.” (opens the source at this quote in a new tab)

“Those most commonly associated with an HCM phenotype include GSD type II (Pompe disease), Danon disease (formerly referred to as GSD type IIb), and PRKAG2 cardiomyopathy.” (opens the source at this quote in a new tab)

Disease classification: autophagic vacuolar myopathy

“Among the autophagic vacuolar myopathies (AVMs), a subgroup is characterized pathologically by unusual autophagic vacuoles with sarcolemmal features (AVSF) and includes Danon disease and X-linked myopathy with excessive autophagy.” (opens the source at this quote in a new tab)

“This disease is one of the autophagy-related muscle diseases.” (opens the source at this quote in a new tab)

Outdated names for Danon disease
FieldQuoted term
Outdated term“X-linked vacuolar cardiomyopathy and myopathy”
Outdated term“Glycogen storage disease IIb”
Outdated term“X-Linked pseudoglycogenosis II”
Outdated term“Antopol disease”
Outdated term“Lysosomal glycogen storage disease without acid maltase deficiency”
ICD-10-CM code E74.05: proposal presented in September 2022

“A specific ICD-10-CM code for Danon disease will facilitate patient identification for appropriate treatments as well as for clinical trials, and will facilitate better understanding of prevalence, onset, and disease progression, as well as supporting further research in the evaluation and treatment of Danon disease.” (opens the source at this quote in a new tab)

“A proposal to create a specific code for Danon disease was received from University of Colorado, Adult Medical Genetics Program.” (opens the source at this quote in a new tab)

Proposed tabular modificationQuoted text
Subcategory“E74.0 Glycogen Storage Disorders”
New code“E74.05 Lysosome-associated membrane protein 2 [LAMP2] deficiency”
Inclusion term added“Danon disease”
ICD-10-CM code E74.05: effective October 1, 2023

“2024 (effective 10/1/2023): New code” (opens the source at this quote in a new tab)

“E74.05 is a billable/specific ICD-10-CM code that can be used to indicate a diagnosis for reimbursement purposes.” (opens the source at this quote in a new tab)

“In 2023, Rocket secured an ICD-10 code from the Centers for Medicare and Medicaid Services (CMS) to document patients with LAMP2 deficiency in Danon disease.” (opens the source at this quote in a new tab)

“ICD-10 code for Danon available from Q4 2023.” (opens the source at this quote in a new tab)

OMIM entries for the disease and the gene
Entry typeQuoted entry
Disease“300257 DANON DISEASE”
Gene“309060 LYSOSOME-ASSOCIATED MEMBRANE PROTEIN 2; LAMP2”
Orphanet entry: identifiers and classification
FieldQuoted record
ORPHAcode“ORPHA:34587”
Classification level“Disorder”
Inheritance“X-linked dominant”
Age of onset“Childhood”
ICD-10“E74.0”
ICD-11“5C51.3”
OMIM“300257”