Transthyretin amyloid cardiomyopathy (ATTR-CA) results from extracellular misfolded transthyretin deposition. Technetium-99 m pyrophosphate (99mTc-PYP) scintigraphy serves as the noninvasive diagnostic gold standard when Perugini grade 2-3 myocardial uptake accompanies characteristic infiltrative features and exclusion of light-chain amyloidosis (specificity ≈ 100%). Danon disease, an X-linked disorder caused by lysosome-associated membrane protein-2 gene mutations, manifests as vacuolar cardiomyopathy due to glycogen accumulation, mimicking ATTR-CA clinically but lacking amyloid fibrils. A 26-year-old male presented with exertional chest discomfort following his brother's sudden death. Laboratory studies revealed elevated creatine kinase (259 U/L) with normal serum free light chains. Electrocardiography showed Wolff-Parkinson-White syndrome. Echocardiography demonstrated concentric left ventricular hypertrophy (maximal wall thickness 13 mm), reduced global longitudinal strain (-15.1%) with apical sparing, and patchy hyperechogenicity. Cardiac MRI confirmed diffuse hypertrophy, mid-wall late gadolinium enhancement, elevated native T1 (1700 ms), and extracellular volume (52%). 99mTc-PYP scintigraphy revealed Perugini grade 3 uptake, initially suggesting ATTR-CA. Endomyocardial biopsy, however, identified glycogen-filled cytoplasmic vacuoles and Congo red negativity, confirming Danon disease. This case exposes a critical diagnostic pitfall: intense 99mTc-PYP uptake (Perugini grade 3) may occur in non-amyloid conditions like Danon disease, likely due to myocardial microcalcification, challenging scintigraphy's specificity for ATTR-CA. Key discriminators include younger age, Wolff-Parkinson-White syndrome, marked creatine kinase elevation, and neurocognitive impairment in Danon disease versus elderly male predominance, low-voltage QRS complexes, and refractory heart failure in ATTR-CA. Pathological confirmation remains essential for young patients with "ATTR-like" scintigraphy, particularly when atypical features (e.g., skeletal muscle involvement or preexcitation syndromes) are present. Comprehensive integration of demographic, electrocardiographic, biomarker, and imaging data is imperative to prevent misdiagnosis and ensure appropriate management.

Danon disease (DD) is an exceptionally uncommon X-linked dominant lysosomal glycogen storage disorder characterized by pronounced ventricular hypertrophy and cardiac insufficiency. The timely identification of cardiac impairment in individuals with DD holds significant clinical importance. We present a case of Danon Disease in a three-generation pedigree from Anhui Province, China. Clinical features and laboratory data were collected and analyzed for a 16-year-old male proband (III-1) and two affected female family members (II-2 and II-3). The proband exhibited Wolf-Parkinson-White syndrome, hypertrophic cardiomyopathy, abnormal cognitive function, and muscle weakness. Gene sequencing confirmed a mutation (c.963G > A) in the LAMP-2 gene. Patients with DD may present both dilated and hypertrophic cardiomyopathy. Comprehensive myocardial tissue characterization by MRI plays a key role in the diagnosis of the disease.

Successful therapy in a cohort with early onset Danon disease (DD) highlights the potential importance of earlier disease recognition. We present experience from the largest National Pediatric Center in Russia for cardiomyopathy patients. This report focuses on identification of early clinical features of DD in the pediatric population by detailed pedigree analysis and review of medical records. RESULTS: Nine patients (3 females) were identified with DD at the Russian National Medical Research Center of Children's Health ("National Pediatric Center") aged birth to 16 years. At presentation/evaluation: all patients had left ventricular hypertrophy (LVH), ECG features of Wolff-Parkinson-White (WPW), and an increase in hepatic enzymes (particularly lactate dehydrogenase (LDH)); three had marked increase in NT-proBNP; two had HCM with impaired LV function; one had LVH with LV noncompaction; five had arrhythmia with paroxysmal supraventricular and/or ventricular tachycardia. Two teenagers died at ages 16-17 from refractory heart failure and two underwent heart transplantation. 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. Retrospective review related to family background and earlier clinical evaluations revealed a definitive or highly suspicious family history of DD in 3, early clinical presentation with cardiac abnormalities (ECG, echo) in 3, and cerebral, hepatic and/or neuromuscular symptoms in 5. Abnormalities were detected 9,5 months to 5,8 years, median 3,5 years prior to referral to the National Pediatric Center. CONCLUSION: The earliest clinical manifestations of Danon disease occur in the first 12 years of life with symptoms of skeletal muscle and cerebral disease, raised hepatic enzymes, and evidence of cardiac disease on ECG/echo.

Danon disease is typically associated with cardiomyopathy and ventricular pre-excitation. The study aimed to characterize the clinical profile of Danon disease, analyze electrocardiographic (ECG) and electrophysiologic features, and investigate their association with Wolff-Parkinson-White (WPW) syndrome and fasciculoventricular pathways (FVPs). Clinical course, family history, ECG and electrophysiological data were collected from 16 patients with Danon disease. Over 0.4-8 years of follow up, 1 female patient died suddenly, and 5 male patients died of progressive heart failure by age 13-20 years. Family history analysis revealed that 3 mothers experienced hospitalization or death for heart failure at age 28-41 years. There was 100% penetrance for ECG abnormalities in 13 patients with original ECGs. Short PR intervals and delta waves were present in 9 and 8 patients, respectively. There were significant age-associated increases in the QRS complex width (r=0.556, P=0.048) and the number of leads with notched QRS (r=0.575, P=0.04). Four patients who underwent electrophysiological studies all had FVPs, and 2 of them still had left-side atrioventricular pathways. Danon disease causes a malignant clinical course characterized by early death caused by heart failure in both genders and progressive ECG changes as patients age. The pre-excited ECG pattern is related to FVPs and WPW, which is suggestive of extensive cardiac involvement.

This systematic review aimed to identify the most important social, environmental, biological, and/or genetic risk factors for intellectual disability (ID). Eligible were published prospective or retrospective comparative studies investigating risk factors for ID in children 4-18 years. Exclusions were single group studies with no comparator without ID and a sample size <100. Electronic databases (Medline, Cochrane Library, EMBASE, PsycInfo, Campbell Collaboration, and CINAHL) were searched for eligible publications from 1980 to 2020. Joanna Briggs Institute critical appraisal instruments, appropriate for study type, were used to assess study quality and risk of bias. Descriptive characteristics and individual study results were presented followed by the synthesis for individual risk factors, also assessed using GRADE. Fifty-eight individual eligible studies were grouped into six exposure topics: sociodemographic; antenatal and perinatal; maternal physical health; maternal mental health; environmental; genetic or biological studies. There were few eligible genetic studies. For half the topics, the certainty of evidence (GRADE) was moderate or high. Multiple studies have examined individual potential determinants of ID, but few have investigated holistically to identify those populations most at risk. Our review would indicate that there are vulnerable groups where risk factors we identified, such as low socioeconomic status, minority ethnicity, teenage motherhood, maternal mental illness, and alcohol abuse, may cluster, highlighting a target for preventive strategies. At-risk populations need to be identified and monitored so that interventions can be implemented when appropriate, at preconception, during pregnancy, or after birth. This could reduce the likelihood of ID and provide optimal opportunities for vulnerable infants. [https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=120032], identifier [CRD42019120032].