• MeSH
• Chromosome Breakpoints * MeSH
• Alu Elements * MeSH
• Genomics * methods   MeSH
• Gene Rearrangement * MeSH
• Humans MeSH
• DNA Mutational Analysis methods   MeSH
• Polymerase Chain Reaction * methods   MeSH
• Sequence Deletion MeSH
• Check Tag
• Humans MeSH
• Publication type
• Letter MeSH
• Research Support, Non-U.S. Gov't MeSH

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.

• Keywords
• Advanced heart failure, Danon disease, Lysosomal-associated membrane protein type 2, Screening, White blood cells,
• MeSH
• Phenotype MeSH
• Glycogen Storage Disease Type IIb * complications   diagnosis   epidemiology   MeSH
• Cardiomyopathy, Hypertrophic * complications   diagnosis   epidemiology   MeSH
• Humans MeSH
• Lysosomal-Associated Membrane Protein 2 genetics   MeSH
• Heart Failure * diagnosis   epidemiology   etiology   MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• LAMP2 protein, human MeSH Browser
• Lysosomal-Associated Membrane Protein 2 MeSH

BACKGROUND: Spinal muscular atrophy (SMA) is an inherited neuromuscular disease affecting 1 in 8,000 newborns. The majority of patients carry bi-allelic variants in the survival of motor neuron 1 gene (SMN1). SMN1 is located in a duplicated region on chromosome 5q13 that contains Alu elements and is predisposed to genomic rearrangements. Due to the genomic complexity of the SMN region and genetic heterogeneity, approximately 50% of SMA patients remain without genetic diagnosis that is a prerequisite for genetic treatments. In this work we describe the diagnostic odyssey of one SMA patient in whom routine diagnostics identified only a maternal heterozygous SMN1Δ(7-8) deletion. METHODS: We characterized SMN transcripts, assessed SMN protein content in peripheral blood mononuclear cells (PBMC), estimated SMN genes dosage, and mapped genomic rearrangement in the SMN region. RESULTS: We identified an Alu-mediated deletion encompassing exons 2a-5 of SMN1 on the paternal allele and a complete deletion of SMN1 on the maternal allele as the cause of SMA in this patient. CONCLUSION: Alu-mediated rearrangements in SMN1 can escape routine diagnostic testing. Parallel analysis of SMN gene dosage, SMN transcripts, and total SMN protein levels in PBMC can identify genomic rearrangements and should be considered in genetically undefined SMA cases.

• Keywords
• SMN1, SMN2, Alu elements, spinal muscular atrophy,
• MeSH
• Gene Deletion * MeSH
• Alu Elements MeSH
• Genetic Testing methods   MeSH
• Leukocytes, Mononuclear metabolism   MeSH
• Humans MeSH
• RNA, Messenger genetics   metabolism   MeSH
• Child, Preschool MeSH
• Survival of Motor Neuron 1 Protein genetics   metabolism   MeSH
• Sequence Analysis, DNA methods   MeSH
• Muscular Atrophy, Spinal diagnosis   genetics   MeSH
• Blotting, Western methods   MeSH
• Check Tag
• Humans MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• RNA, Messenger MeSH
• Survival of Motor Neuron 1 Protein MeSH
• SMN1 protein, human MeSH Browser