LAMP2 flow cytometry in peripheral white blood cells is an established method that facilitates identification of heterozygous Danon disease female patients and mosaic mutation carriers

Sikora, Jakub; Majer, Filip; Kalina, Tomáš

doi:10.1016/j.jjcc.2014.12.014

Cited by 6 publications

(10 citation statements)

References 5 publications

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“…Leucocytes showed complete LAMP‐2 deficiency at immunoblot , flow cytometry and the smear technique . Lymphocytes from patients with splicing mutations showed trace amounts of LAMP‐2 .…”

Section: Tissue Pathology and Lamp‐2 Protein Testing In Male Patientsmentioning

confidence: 99%

“…Immunoblot analysis of leucocytes from a patient with random XCI pattern and from another asymptomatic patient showed normal LAMP‐2 amount , revealing that this test may be inconclusive in some patients. LAMP‐2 analysis using flow cytometry was useful in diagnosing asymptomatic female patients (15% in monocytes, 13% in granulocytes) .…”

Section: Tissue Pathology and Lamp‐2 Protein Testing In Female Patientsmentioning

confidence: 99%

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Review: Danon disease: Review of natural history and recent advances

Cenacchi

Papa

Pegoraro

et al. 2019

Neuropathology Appl Neurobio

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Danon disease is a severe multisystem disorder clinically characterized by hypertrophic cardiomyopathy, skeletal myopathy and mental retardation in male patients, and by a milder phenotype (predominantly involving cardiac muscle) in female patients. The disease is inherited as an X‐linked dominant trait. The primary deficiency of lysosome‐associated membrane protein‐2 (LAMP‐2) causes disruption of autophagy, leading to an impaired fusion of lysosomes to autophagosomes and biogenesis of lysosomes. We surveyed over 500 Danon disease patients reported in the literature from the first description to the present, in order to summarize the clinical, pathological and molecular data and treatment perspectives. An early molecular diagnosis is of crucial importance for genetic counselling and for therapeutic interventions: in male patients, the prognosis is poor due to rapid progression towards heart failure, and only heart transplantation modifies the disease course.

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Section: Tissue Pathology and Lamp‐2 Protein Testing In Male Patientsmentioning

confidence: 99%

Section: Tissue Pathology and Lamp‐2 Protein Testing In Female Patientsmentioning

confidence: 99%

Review: Danon disease: Review of natural history and recent advances

Cenacchi

Papa

Pegoraro

et al. 2019

Neuropathology Appl Neurobio

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“…XCI triggers mosaic expression of the wild-type and mutant LAMP2 alleles in tissues of female DD patients ( Figure 1B, C). 10,[12][13][14] Setting thresholds for skewing or extreme skewing of XCI is arbitrary. Importantly,~98% of females have WBC XCI ratios within the >5:95/<95:5 range.…”

Section: Danon Disease Screening Studiesmentioning

confidence: 99%

“…In specific pedigree situations, the test may also be modified to allow identification of individuals with extremely small LAMP2def populations (<1%) resulting from somatic mosaicism. 11,12 Sample collection is minimally invasive, the FC test uses commercially available reagents and the turnover time is short (<24 h). Flow cytometers are a standard laboratory equipment and the overall cost of the test is low.…”

Section: Laboratory Diagnostic Implicationsmentioning

confidence: 99%

“…Flow cytometric (FC) detection of LAMP2 in WBCs was first reported by Regelsberger et al 9 . Expanding these seminal studies, we optimized and presented a polychromatic FC protocol that allows quantitation of LAMP2def WBC populations not only in male DD patients but also in female DD patients and somatic mosaic carriers of LAMP2 mutations 10–12 …”

Section: Introductionmentioning

confidence: 99%

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Danon disease is an underdiagnosed cause of advanced heart failure in young female patients: a LAMP2 flow cytometric study

et al. 2020

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Aims Danon disease (DD) is a rare X-linked disorder caused by mutations in the lysosomal-associated membrane protein type 2 gene (LAMP2). DD is difficult to distinguish from other causes of dilated or hypertrophic cardiomyopathy (HCM) in female patients. As DD female patients regularly progress into advanced heart failure (AHF) aged 20-40 years, their early identification is critical to improve patient survival and facilitate genetic counselling. In this study, we evaluated the prevalence of DD among female patients with non-ischemic cardiomyopathy, who reached AHF and were younger than 40 years. Methods and results The study cohort comprised 60 female patients: 47 (78%) heart transplant recipients, 2 (3%) patients treated with ventricular assist device, and 11 (18%) patients undergoing pre-transplant assessment. Aetiology of the cardiomyopathy was known in 15 patients (including two DD patients). LAMP2 expression in peripheral white blood cells (WBC) was tested by flow cytometry (FC) in the remaining 45 female patients. Whole exome sequencing was used as an alternative independent testing method to FC. Five additional female DD patients (two with different novel LAMP2 mutations) were identified by FC. The total prevalence of DD in this cohort was 12%. HCM phenotype (57% vs. 9%, * P = 0.022) and delta waves identified by electrocardiography (43% vs. 0%, ** P = 0.002) were significantly more frequent in DD female patients. Conclusions Danon disease is an underdiagnosed cause of AHF in young female patients. LAMP2 expression testing in peripheral WBCs by FC can be used as an effective screening/diagnostic tool to identify DD in this patient population.

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LAMP2 exon‐copy number variations in Danon disease heterozygote female probands: Infrequent or underdetected?

Majer

Piherová

Řeboun

et al. 2018

American J of Med Genetics Pt A

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Danon disease (DD) is an X-linked disorder caused by mutations in the lysosomal-associated membrane protein 2 (LAMP2) gene (Xq24). DD is characterized by cognitive deficit, myopathy, and cardiomyopathy in male patients. The phenotype is variable and mitigated in females. The timely identification of de-novo LAMP2 mutated family members, many of whom are heterozygous females, remains critical for their treatment and family counseling. DD laboratory testing builds on minimally invasive quantification of the LAMP2 protein in white blood cells and characterization of the specific mutation. This integrative approach is particularly helpful when assessing suspect female heterozygotes. LAMP2 exon-copy number variations (eCNVs) were so far reported only in X-hemizygous male DD probands. 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. To document the likely underappreciated rate of occurrence and point out numerous potential pitfalls of detection of the LAMP2 eCNVs, we present the first two DD heterozygote female probands who harbor novel multi-exon LAMP2 deletions. Critical for counseling and recurrence prediction, we also highlight the need to search for somatic-germinal mosaicism in DD families.

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LAMP2 flow cytometry in peripheral white blood cells is an established method that facilitates identification of heterozygous Danon disease female patients and mosaic mutation carriers

Cited by 6 publications

References 5 publications

Review: Danon disease: Review of natural history and recent advances

Review: Danon disease: Review of natural history and recent advances

Danon disease is an underdiagnosed cause of advanced heart failure in young female patients: a LAMP2 flow cytometric study

LAMP2 exon‐copy number variations in Danon disease heterozygote female probands: Infrequent or underdetected?

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