Search Results (8)

Background/Objectives: Artificial intelligence and large language models like ChatGPT and Google’s Gemini are promising tools with remarkable potential to assist healthcare professionals. This study explores ChatGPT and Gemini’s potential utility in assisting clinicians during the first evaluation of patients with suspected neurogenetic disorders. Methods: By analyzing the model’s performance in identifying relevant clinical features, suggesting differential diagnoses, and providing insights into possible genetic testing, this research seeks to determine whether these AI tools could serve as a valuable adjunct in neurogenetic assessments. Ninety questions were posed to ChatGPT (Versions 4o, 4, and 3.5) and Gemini: four questions about clinical diagnosis, seven about genetic inheritance, estimable recurrence risks, and available tests, and four questions about patient management, each for six different neurogenetic rare disorders (Hereditary Spastic Paraplegia type 4 and type 7, Huntington Disease, Fragile X-associated Tremor/Ataxia Syndrome, Becker Muscular Dystrophy, and FacioScapuloHumeral Muscular Dystrophy). Results: According to the results of this study, GPT chatbots demonstrated significantly better performance than Gemini. Nonetheless, all AI chatbots showed notable gaps in diagnostic accuracy and a concerning level of hallucinations. Conclusions: As expected, these tools can empower clinicians in assessing neurogenetic disorders, yet their effective use demands meticulous collaboration and oversight from both neurologists and geneticists. Full article

Rare diseases are heterogeneous diseases characterized by various symptoms and signs. Due to the low prevalence of such conditions (less than 1 in 2000 people), medical expertise is limited, knowledge is poor and patients’ care provided by medical centers is inadequate. An accurate diagnosis is frequently challenging and ongoing research is also insufficient, thus complicating the understanding of the natural progression of the rarest disorders. This review aims at presenting the multimodal approach supported by the integration of multiple analyses and disciplines as a valuable solution to clarify complex genotype–phenotype correlations and promote an in-depth examination of rare disorders. Taking into account the literature from large-scale population studies and ongoing technological advancement, this review described some examples to show how a multi-skilled team can improve the complex diagnosis of rare diseases. In this regard, Facio-Scapulo-Humeral muscular Dystrophy (FSHD) represents a valuable example where a multimodal approach is essential for a more accurate and precise diagnosis, as well as for enhancing the management of patients and their families. Given their heterogeneity and complexity, rare diseases call for a distinctive multidisciplinary approach to enable diagnosis and clinical follow-up. Full article

FacioScapuloHumeral muscular Dystrophy (FSHD) is one of the most prevalent inherited muscle disorders and is linked to the inappropriate expression of the DUX4 transcription factor in skeletal muscles. The deregulated molecular network causing FSHD muscle dysfunction and pathology is not well understood. It has been shown that the hypoxia response factor HIF1α is critically disturbed in FSHD and has a major role in DUX4-induced cell death. In this study, we further explored the relationship between DUX4 and HIF1α. We found that the DUX4 and HIF1α link differed according to the stage of myogenic differentiation and was conserved between human and mouse muscle. Furthermore, we found that HIF1α knockdown in a mouse model of DUX4 local expression exacerbated DUX4-mediated muscle fibrosis. Our data indicate that the suggested role of HIF1α in DUX4 toxicity is complex and that targeting HIF1α might be challenging in the context of FSHD therapeutic approaches. Full article

The HOXB1 gene encodes a homeobox transcription factor pivotal in the development of rhombomere 4. Biallelic pathogenic variants in this gene are associated with congenital facial paresis type 3 (HCFP3). Only seven single nucleotide variants have been reported in the literature to date. Here, we report a 27-year-old female with a unique presentation of HCFP3 with two novel compound-heterozygous missense variants: c.763C>G, p.(Arg255Gly), which arose de novo and an inherited c.781C>T, p.(Arg261Cys) variant. The patient exhibited HCFP3 symptoms with mild upward esodeviation and lacked the documented ear malformations common in HCFP. For many years, she was misdiagnosed with facio-scapulo-humeral muscular dystrophy, due to complaints of shoulder girdle and neck muscle weakness. No alternative genetic or acquired causes of neck and shoulder girdle weakness were found, suggesting its potential inclusion in the phenotypic spectrum. Full article

The study describes a protocol for methylation analysis integrated with Machine Learning (ML) algorithms developed to classify Facio-Scapulo-Humeral Dystrophy (FSHD) subjects. The DNA methylation levels of two D4Z4 regions (DR1 and DUX4-PAS) were assessed by an in-house protocol based on bisulfite sequencing and capillary electrophoresis, followed by statistical and ML analyses. The study involved two independent cohorts, namely a training group of 133 patients with clinical signs of FSHD and 150 healthy controls (CTRL) and a testing set of 27 FSHD patients and 25 CTRL. As expected, FSHD patients showed significantly reduced methylation levels compared to CTRL. We utilized single CpG sites to develop a ML pipeline able to discriminate FSHD subjects. The model identified four CpGs sites as the most relevant for the discrimination of FSHD subjects and showed high metrics values (accuracy: 0.94, sensitivity: 0.93, specificity: 0.96). Two additional models were developed to differentiate patients with lower D4Z4 size and patients who might carry pathogenic variants in FSHD genes, respectively. Overall, the present model enables an accurate classification of FSHD patients, providing additional evidence for DNA methylation as a powerful disease biomarker that could be employed for prioritizing subjects to be tested for FSHD. Full article

Over the recent years, the SMCHD1 (Structural Maintenance of Chromosome flexible Hinge Domain Containing 1) chromatin-associated factor has triggered increasing interest after the identification of variants in three rare and unrelated diseases, type 2 Facio Scapulo Humeral Dystrophy (FSHD2), Bosma Arhinia and Microphthalmia Syndrome (BAMS), and the more recently isolated hypogonadotrophic hypogonadism (IHH) combined pituitary hormone deficiency (CPHD) and septo-optic dysplasia (SOD). However, it remains unclear why certain mutations lead to a specific muscle defect in FSHD while other are associated with severe congenital anomalies. To gain further insights into the specificity of SMCHD1 variants and identify pathways associated with the BAMS phenotype and related neural crest defects, we derived induced pluripotent stem cells from patients carrying a mutation in this gene. We differentiated these cells in neural crest stem cells and analyzed their transcriptome by RNA-Seq. Besides classical differential expression analyses, we analyzed our data using MOGAMUN, an algorithm allowing the extraction of active modules by integrating differential expression data with biological networks. We found that in BAMS neural crest cells, all subnetworks that are associated with differentially expressed genes converge toward a predominant role for AKT signaling in the control of the cell proliferation–migration balance. Our findings provide further insights into the distinct mechanism by which defects in neural crest migration might contribute to the craniofacial anomalies in BAMS. Full article

Induced pluripotent stem cells (iPSCs) obtained by reprogramming primary somatic cells have revolutionized the fields of cell biology and disease modeling. However, the number protocols for generating mature muscle fibers with sarcolemmal organization using iPSCs remain limited, and partly mimic the complexity of mature skeletal muscle. Methods: We used a novel combination of small molecules added in a precise sequence for the simultaneous codifferentiation of human iPSCs into skeletal muscle cells and motor neurons. Results: We show that the presence of both cell types reduces the production time for millimeter-long multinucleated muscle fibers with sarcolemmal organization. Muscle fiber contractions are visible in 19–21 days, and can be maintained over long period thanks to the production of innervated multinucleated mature skeletal muscle fibers with autonomous cell regeneration of PAX7-positive cells and extracellular matrix synthesis. The sequential addition of specific molecules recapitulates key steps of human peripheral neurogenesis and myogenesis. Furthermore, this organoid-like culture can be used for functional evaluation and drug screening. Conclusion: Our protocol, which is applicable to hiPSCs from healthy individuals, was validated in Duchenne Muscular Dystrophy, Myotonic Dystrophy, Facio-Scapulo-Humeral Dystrophy and type 2A Limb-Girdle Muscular Dystrophy, opening new paths for the exploration of muscle differentiation, disease modeling and drug discovery. Full article

FacioScapuloHumeral muscular Dystrophy (FSHD) is one of the most prevalent hereditary myopathies and is generally characterized by progressive muscle atrophy affecting the face, scapular fixators; upper arms and distal lower legs. The FSHD locus maps to a macrosatellite D4Z4 repeat array on chromosome 4q35. Each D4Z4 unit contains a DUX4 gene; the most distal of which is flanked by a polyadenylation site on FSHD-permissive alleles, which allows for production of stable DUX4 mRNAs. In addition, an open chromatin structure is required for DUX4 gene transcription. FSHD thus results from a gain of function of the toxic DUX4 protein that normally is only expressed in germ line and stem cells. Therapeutic strategies are emerging that aim to decrease DUX4 expression or toxicity in FSHD muscle cells. We review here the heterogeneity of DUX4 mRNAs observed in muscle and stem cells; and the use of antisense oligonucleotides (AOs) targeting the DUX4 mRNA to interfere either with transcript cleavage/polyadenylation or intron splicing. We show in primary cultures that DUX4-targeted AOs suppress the atrophic FSHD myotube phenotype; but do not improve the disorganized FSHD myotube phenotype which could be caused by DUX4c over-expression. Thus; DUX4c might constitute another therapeutic target in FSHD. Full article