プラダー･ウィリ症候群

Mutations that enhance type I interferon (IFN-I) activity cause monogenic autoinflammatory disorders termed type I interferonopathies. Along with the typical neurologic and rheumatologic manifestations, severe pulmonary disease is increasingly recognized yet poorly understood. We studied three siblings presenting with early-onset, life-threatening pulmonary alveolar proteinosis (PAP) and autoinflammatory stigmata. Genetic analysis uncovered a novel homozygous variant (R223Q) in STAT2, a key mediator of IFN-I signaling, which also facilitates feedback inhibition via USP18. R223Q STAT2 preserved signal transduction and viral control in vitro. However, cells homozygous for the R223Q variant failed to terminate IFN-I responses, owing to impaired localization of USP18. Unlike in classical forms of PAP, GM-CSF signaling remained intact. Instead, persistent IFN-I signaling antagonized monocyte migration toward chemokines essential for lung trafficking. Informed by these findings, the youngest sibling received JAK inhibitor and anti-IFN-I receptor therapy with marked clinical improvement. Collectively, type I interferonopathy by mutation of STAT2 (TIMS2) compromises monocyte chemotaxis and underlies a novel mechanism of PAP.

OBJECTIVE: Aim: The study evaluates the effectiveness of wearable biometric devices, geofencing systems, and artificial intelligence algorithms in improving the quality of life and autonomy of individuals with Prader-Willi syndrome. It analyses the impact of digital ecosystems on reducing caregiver burden and personalizing therapy through objective data analysis. PATIENTS AND METHODS: Materials and Methods: A systematic literature review was conducted in PubMed, Web of Science, and the Cochrane Library databases since 2019. Research focused on metabolic monitoring, the use of gamification and virtual reality in rehabilitation, and the implementation of smart home technologies for patients with rare genetic syndromes. Analysis indicates that data from wearable devices enables the detection of prodromal states, mitigating episodes of hyperphagia and aggression. Geofencing systems provide a safe environment for autonomous physical activity, improving cardiovascular fitness and reducing caregiver anxiety. Artificial intelligence algorithms, by personalizing the energy balance with a precision of 10 kilocalories, significantly optimize weight reduction. CONCLUSION: Conclusions: The digital support ecosystem redefines the care paradigm for Prader-Willi syndrome. Replacing human supervision with autonomous algorithmic control promotes behavioural stabilization and allows for greater patient self-determination. This process increases biological safety and significantly reduces the burden on caregivers, forming the basis of modern, individualized therapy.

Prader-Willi syndrome (PWS; MIM# 176270) is a rare neurodevelopmental disorder characterized by clinical manifestations across multiple body systems. PWS represents an atypical form of obesity-associated metabolic disease in which extreme adiposity coexists with a comparatively attenuated risk of insulin resistance and hepatic complications. The genetic basis of PWS leads to impaired lipid storage and oxidation capacity in adipocytes, with downstream consequences for hepatic lipid burden. Systemic lipidomic and metabolomic profiling further supports the existence of a distinct metabolic signature in PWS, showing consistent qualitative alterations in circulating phospholipids that may, in turn, influence hepatic lipid export and the risk of steatosis. Hepatic involvement in PWS seems to be shaped by intrinsic alterations in lipid handling and endocrine signaling rather than by adiposity. Finally, metabolic dysfunction-associated steatotic liver disease (MASLD) remains less prevalent in PWS. Among the currently available models derived from induced pluripotent stem cells (iPSCs), hepatocyte-like cells (HLCs) and iPSC-derived organoids, have emerged as valuable tools for investigating rare genetic liver disorders and as powerful strategies to dissect tissue-specific mechanisms underlying PWS phenotype, because they bridge the gap between molecular epigenetic mechanisms and organism-level metabolic phenotypes in PWS. Their ability to capture patient-specific epigenetic regulation and tissue-specific metabolic dysfunction positions them as indispensable tools for advancing both mechanistic understanding and therapeutic development in PWS.

BACKGROUND: Dual molecular diagnoses involving concurrent monogenic variants and imprinting disorders are increasingly recognized in complex phenotypes, yet systematic approaches to elucidate such convergence remain limited. METHODS: We report a 46,XY proband with disorders of sex development (DSD), global developmental delay, and clinical features suggestive of Prader-Willi syndrome (PWS). We performed whole-exome sequencing (WES) to identify sequence-level variants. Upon detection of copy-neutral loss of heterozygosity (CN-LOH), we used methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) to assess imprinting status and performed single-nucleotide polymorphism (SNP) microarray to characterize the extent and allelic architecture. RESULTS: WES identified a maternally inherited heterozygous deletion spanning exons 2-7 of NR5A1, classified as likely pathogenic based on its predicted loss-of-function impact on this dosage-sensitive transcription factor. WES also detected a 13.95 Mb CN-LOH at 15q21.1q21.3. MS-MLPA revealed a methylation profile consistent with maternal uniparental disomy of chromosome 15 (UPD(15)), confirming PWS. SNP microarray detected a larger 32.7 Mb CN-LOH across 15q14-q21.3. The combined data support maternal UPD(15) involving mixed heterodisomy and isodisomy, likely arising from meiotic nondisjunction followed by trisomy rescue. CONCLUSIONS: An integrated genomic strategy resolved dual etiologies-NR5A1 haploinsufficiency and maternal UPD(15)-underlying complex neurodevelopmental and reproductive features. Demonstrating how integrated analysis of sequence variation, epigenetic regulation, and genome-wide allelic architecture can uncover coexisting monogenic and imprinting mechanisms, this case highlights a diagnostic strategy warranting further evaluation in broader cohorts.

BACKGROUND: Intellectual Disability-Obesity-Brain Malformations-Facial Dysmorphism Syndrome (IDOB-FMD) is a rare genetic disorder characterized by moderate to severe intellectual disability, microcephaly, and brain abnormalities such as a thin corpus callosum, cerebellar hypoplasia, and cerebral white matter hypoplasia, often observed on MRI scans. Additional features include obesity and craniofacial dysmorphism. IDOB-FMD is inherited in an autosomal recessive manner, attributed to Trafficking Protein Particle Complex Subunit 9 (TRAPPC9) deficiency, with a prevalence of less than 1 in 1,000,000. This syndrome shares clinical similarities with Prader-Willi syndrome (PWS). RESULTS: In our study, we conducted a clinical evaluation of two Tunisian siblings suspected of having Prader-Willi-like syndrome (PWLS) based on their clinical presentation. Whole-exome sequencing (WES) was employed to identify genetic variants associated with the phenotype. Variant interpretation and segregation analysis were performed to ascertain the pathogenicity of the identified variants. WES revealed a homozygous mutation in the TRAPPC9 gene in both siblings. The variant was predicted to be pathogenic and segregated with the phenotype within the family. Clinical examination was consistent with PWLS, including intellectual disability, microcephaly, and dysmorphism. CONCLUSIONS: Our findings emphasize the importance of genetic testing in patients presenting with PWLS features, highlighting a TRAPPC9 mutation that expands the known mutational spectrum. This study, the second investigation of PWLS in Tunisia, reports a pathogenic variant in the TRAPPC9 gene underlying the observed phenotype in this family, offering valuable insights into clinical management and genetic counseling. Our identification of this variant not only reveals genetic heterogeneity but also prompts further research to elucidate the genotype-phenotype correlations and molecular mechanisms underlying TRAPPC9-related disorders.