Rare LAMP2 Variants Behind Severe Heart Disease in Two Young Women Misdiagnosed as Amyloidosis

Two young Chinese women whose severe heart disease was initially mistaken for cardiac amyloidosis have been diagnosed with Danon disease, a rare X-linked lysosomal storage disorder caused by mutations in the LAMP2 gene, according to a case report and literature review published in Frontiers in Cardiovascular Medicine. The patients, aged 23 and 21 at presentation, both developed primarily cardiac symptoms in adulthood and were ultimately confirmed to carry two rare LAMP2 variants, one classified as a variant of uncertain significance and the other as likely pathogenic. Both underwent heart transplantation and remained alive at follow-up, at 53 months and 19 months after surgery respectively.

Danon disease results from loss-of-function mutations in the gene encoding lysosome-associated membrane protein 2, a lysosomal protein essential for cellular waste disposal. The classic clinical triad comprises cardiomyopathy, skeletal myopathy, and intellectual disability, but the presentation is often heterogeneous and can be mistaken for other forms of cardiomyopathy. The condition was first described in 1981 in two 16-year-old boys who showed the full triad, with muscle biopsy and electron microscopy revealing intralysosomal glycogen accumulation despite normal acid alpha-glucosidase activity. Although its prevalence in the general population remains uncertain, Danon disease accounts for approximately 4 percent of childhood hypertrophic cardiomyopathy cases and up to 17 percent of cases featuring left ventricular hypertrophy with ventricular pre-excitation syndrome.

The first patient, a 23-year-old woman, reported exertional palpitations for more than a year, accompanied by dizziness and weakness in both lower limbs. In October 2020 she experienced syncope after intense exercise, and over the following months her symptoms recurred and worsened with physical exertion. Local evaluation showed elevated myocardial enzymes and echocardiographic myocardial hypertrophy, and she was referred with a suspected diagnosis of cardiac amyloidosis. On admission in October 2021, laboratory tests revealed a constellation of abnormalities: creatine kinase of 148 IU/L, creatine kinase isoenzyme of 6.42 ng/mL, troponin T of 61.0 ng/L, lactate dehydrogenase of 686.0 IU/L, hydroxybutyrate dehydrogenase of 646.0 IU/L, aspartate aminotransferase of 85.0 IU/L, and NT-proBNP of 2840.0 ng/L. Tests for immunoglobulins, serum free light chains, immunofixation electrophoresis, and urine light chains were unremarkable.

Cardiac magnetic resonance imaging in this patient revealed cardiomegaly driven mainly by left ventricular enlargement, diffuse thickening of the left ventricular wall with a maximum end-diastolic thickness of approximately 2.4 centimeters, and patchy mid-myocardial late gadolinium enhancement most prominent in the lateral wall. Her left ventricular ejection fraction was 57.4 percent, a value within the preserved range. Despite medical therapy she remained in NYHA functional class III, and after the diagnosis was established through clinicopathological and genetic testing she underwent orthotopic heart transplantation in March 2022, an informed decision made despite her preserved ejection fraction.

The second patient, a 21-year-old woman, presented with paroxysmal palpitations lasting more than a month. In September 2023, cardiac amyloidosis was suspected at a local hospital based on electrocardiographic findings suggestive of pre-excitation syndrome and echocardiographic cardiomegaly. Radiofrequency ablation was performed and she was treated with metoprolol, dapagliflozin, sacubitril/valsartan, and spironolactone, but her palpitations worsened. When referred in March 2024, laboratory testing showed elevated IgA, elevated lambda light chain, and a decreased kappa/lambda free light chain ratio, findings that required differentiation from cardiac amyloidosis and reinforced the value of a timely endomyocardial biopsy. Her cardiac MRI showed biventricular enlargement with thickening of the interventricular septum and left ventricular free wall, multiple perfusion defects, and extensive late gadolinium enhancement. Critically, her left ventricular ejection fraction was severely reduced at 19.17 percent and her right ventricular ejection fraction was just 3.76 percent. She underwent heart transplantation in January 2025 after Danon disease was confirmed by biopsy and genetic analysis.

The pathological findings from biopsy and explanted heart tissue were striking. The explanted hearts weighed 450 grams and 440 grams, well above the normal range of 230 to 280 grams, with diffuse or asymmetric left ventricular wall thickening reaching approximately 2.9 and 2.8 centimeters respectively, and multiple small myocardial scars. Microscopic examination showed hypertrophied cardiomyocytes with architectural disarray, vacuolar degeneration, enlarged hyperchromatic irregular nuclei, and multifocal fibrosis. Periodic acid Schiff staining demonstrated glycogen accumulation within some cells, while Masson staining revealed fibrosis between cardiomyocytes. Congo Red staining showed no amyloid deposition, excluding amyloidosis. Immunohistochemistry indicated partial loss of LAMP2 protein expression, in contrast to the cytoplasmic positivity seen in control hypertrophic cardiomyocytes.

Electron microscopy added further diagnostic weight. In the first patient, it demonstrated myofibrillar disorganization, autophagic vacuoles with sarcolemmal features-like structures, and subsarcolemmal glycogen granules. In the second, autophagic vacuole-like structures and myelin-like figures resembling zebra bodies were observed. These ultrastructural changes reflect the underlying biology of the disease: LAMP2 deficiency disrupts autophagy, leading to massive accumulation of undigested material within lysosomes. The LAMP2 gene at Xq24 encodes 410 amino acids, and alternative splicing of exon 9 yields three isoforms. LAMP2b, which is highly expressed in the heart, skeletal muscle, and brain, mediates macroautophagy, and its deficiency leads to accumulation of autophagic vacuoles containing glycogen and cytoplasmic debris, contributing to cardiomyocyte hypertrophy. More than 250 pathogenic LAMP2 variants have been identified to date, predominantly nonsense or splicing mutations.

Genetic testing identified two rare heterozygous variants. In the first patient, c.3G>T in exon 1 disrupts the canonical initiation codon. Under the American College of Medical Genetics and Genomics framework incorporating ClinGen Sequence Variant Interpretation recommendations, the variant was absent from population and disease databases, and PVS1 was applied at Moderate rather than Very Strong strength because translation may reinitiate downstream; the nearest in-frame methionine is Met48, and pathogenic variants have been reported between Met1 and Met48. It was therefore classified as a variant of uncertain significance. In the second patient, the frameshift variant c.446del in exon 4 is predicted to introduce a premature termination codon and trigger nonsense-mediated mRNA decay, meeting PVS1 at Very Strong; combined with absence from databases, it was classified as likely pathogenic. Neither variant was detected in the probands’ mothers, although the authors note that testing was not performed on all available relatives, so de novo status could not be conclusively established.

The report also compiled a literature review of Danon disease in Chinese patients. As of August 2026, 115 Chinese cases had been reported, with ages ranging from 0.25 to 52 years, a median onset age of 15 years, and a male-to-female ratio of 4.2 to 1. Among 59 cases with documented mental status, 20 patients had intellectual disability, all of them male. Ventricular pre-excitation was reported in 46 cases, and among 74 patients with follow-up data, 16 had died, 15 of them male. The most frequently affected genomic region was exon 8, accounting for 32 cases or 27.8 percent, followed by exon 3 and exon 6. Including the two present cases, only 15 cases involving exon 1 or exon 4 variants have been reported in China, all in young patients, underscoring the rarity of the variants described here.

The authors emphasize that Danon disease is challenging to recognize because of its rarity and nonspecific early manifestations, and that it is typically misdiagnosed without genetic testing. Differential diagnoses include amyloidosis, Fabry disease, Pompe disease, and mitochondrial cardiomyopathy, each with distinct pathological signatures: amyloidosis shows Congo red positivity and randomly oriented 10-nanometer fibrils, Fabry disease shows concentric lamellar myelin figures with 4.5-nanometer periodicity, Pompe disease shows glycogen accumulation from alpha-glucosidase deficiency, and mitochondrial cardiomyopathy shows mitochondrial proliferation or depletion. In patients whose initial presentation is primarily cardiac, endomyocardial biopsy may serve as a useful diagnostic adjunct, while genetic testing is required for definitive confirmation. The study’s limitations include incomplete familial testing, purely in silico pathogenicity assessment without functional validation, and the retrospective, publication- and referral-bias-prone nature of the literature review. The authors highlight that these rare LAMP2 variants expand the known mutational spectrum of Danon disease and underscore the need for genetic counseling.

Subject of Research: Danon disease in two young women initially misdiagnosed as cardiac amyloidosis, with two rare LAMP2 variants identified

Article Title: Two young women with severe Danon disease initially suspected to have cardiac amyloidosis: a case report and literature review

Article References: Yu, T., Xie, X., Pan, X., Yu, T., Su, Y., Li, Y., Chen, Y., & Chen, X. (2026). Two young women with severe Danon disease initially suspected to have cardiac amyloidosis: a case report and literature review. Frontiers in Cardiovascular Medicine, 13, Article 1934783. https://doi.org/10.3389/fcvm.2026.1934783

Image Credits: AI Generated

DOI: 10.3389/fcvm.2026.1934783

Keywords: Danon disease, LAMP2, cardiac amyloidosis, cardiomyopathy, endomyocardial biopsy, genetic testing, heart transplantation, lysosomal storage disorder, autophagy, genetic counseling, case report, young