The current case report presents a male baby, second born to nonconsanguineous parents at 38 weeks of gestation by lower segment cesarean section, with engorged blood vessels and distinctive patterns of discoloration and dilation of blood vessels on the left leg. A Doppler of the femoral artery and vein showed normal triphasic flow and waveforms without any evidence of significant luminal stenosis. There was also a lower limb length discrepancy of 1.5 cm. Genetic testing using fluorometric enzyme immunoassay screening revealed a negative screening report. Otologic screening using distortion product otoacoustic emissions revealed normal functioning of outer hair cells in both ears. The case was diagnosed as cutis marmorata telangiectatica congenita (CMTC), after ruling out genetic diseases. It was not associated with any other significant health problems. The diagnosis of CMTC was based on the appearance of the skin at birth, which became more noticeable shortly after two days. In this case, no specific treatment was warranted and the condition improved with time.

Neuromuscular disorders are a group of rare heterogenous diseases with profound impact on quality of life, for which overall pediatric prevalence has rarely been reported. The purpose of this study was to determine the point prevalence of pediatric neuromuscular disorders and its subcategories in the central region of Portugal. Retrospective case identification was carried out in children with neuromuscular disorders seen between 1998 and 2020 from multiple data sources. Demographics, clinical and molecular diagnoses were registered. On January 1, 2020, the point overall prevalence in the population <18 years of age was 41.20/100 000 (95% confidence interval 34.51-49.19) for all neuromuscular disorders. The main case proportion were genetic disorders (95.7%). We found a relatively higher occurrence of limb-girdle muscular dystrophies, congenital myopathies, and spinal muscular atrophy and a slightly lower occurrence of Duchenne muscular dystrophy, hereditary spastic paraparesis, and acquired neuropathies compared to previous studies in other countries. Molecular confirmation was available in 69.5% of pediatric neuromuscular patients in our cohort.Total prevalence is high in comparison with the data reported in the only previous study on the prevalence of pediatric neuromuscular disorders in our country. Our high definitive diagnostic rate underscores the importance of advances in investigative genetic techniques, particularly new sequencing technologies, in the diagnostic workup of neuromuscular patients.

There are many different genetic diseases called inborn errors of metabolism (IEM) which result from defective enzymes in the metabolic pathway. As a result, these defects either cause a harmful accumulation of substances or lead to a lack of certain types of molecule. The present review traces the origin and development of IEMs from Sir Archibald Garrod\'s theory in the early 20th century to current diagnostic and therapeutic approaches. It also involves a systematic literature review complying with PRISMA which included studies sourced from PubMed, Scopus, Web of Science and Google Scholar. It points out that high rates of consanguinity are associated with high prevalence rates for IEMs especially in the Eastern Mediterranean area. IEMS are classified as energy deficiency disorders, intoxication disorders, and storage disorders. Each category has a variety of clinical manifestations. This study incorporates different diagnostic methods ranging from simple biochemical tests to tandem mass spectrometry and next generation sequencing; while management approaches such as dietary modifications, enzyme replacement therapy and gene therapy were assessed for their efficacy. Specific attention is paid to Pakistan where there exists considerable consanguinity among people coupled with inadequate health care services which have seriously affected delivery of health care services thereby leading to numerous challenges for the country healthcare system during service provision.

Proteus syndrome (PS) is an exceptionally uncommon genetic disorder that has been documented in only approximately 250 cases in the literature spanning the past four decades. It is characterized by a disproportionate, asymmetric overgrowth of all types of tissues, provoked by a somatic activating mutation in serine/threonine protein kinase 1. We report a case of PS in a two-year-old female patient with the following clinical features: unilateral overgrowth of connective tissue in the right buttock and right foot, where multiple surgeries were performed to achieve a desirable aesthetic outcome and ensure psychological comfort of the young patient. The insights provided by this case underscore the pivotal role of obtaining pleasing aesthetic outcomes in the surgical management of untreatable genetic disorders, with the aim of nurturing psychological contentment in affected children.

In their paper, using zebrafish models, Gioacchino et al. have demonstrated the GATA2 haploinsufficiency, the genetic hallmark of GATA2 deficiency syndrome, promotes erythroid and myeloid cytopenia, and have discovered a self-regulatory mechanism to compensate GATA2 levels and protein function. Commentary on: Gioacchino et al. GATA2 heterozygosity causes an epigenetic feedback mechanism resulting in myeloid and erythroid dysplasia. Br J Haematol 2024;205:580-593.

OBJECTIVE: To showcase the successful use of ICSI with PGT-M to overcome Beckwith-Wiedemann syndrome (BWS)-related reproductive challenges, resulting in the birth of a healthy baby boy. By targeting the maternally inherited CDKN1C pathogenic gene variant, this report highlights the genetic interventions in BWS reproductive risk management.
METHODS: This case report describes a 41-year-old woman seeking fertility assistance after a previous pregnancy revealed a fetal anomaly related to BWS. Families with BWS recurrence face challenges, as maternally inherited CDKN1C pathogenic variants contribute to approximately 40% of genetic alterations, with a potential recurrence risk as high as 50%. Genetic analysis identified a pathogenic variant in the CDKN1C gene of the fetus that was maternally inherited. The pregnancy was terminated due to the fetal anomalies. The couple underwent intra-cytoplasmic sperm injection (ICSI) combined with preimplantation genetic testing for monogenic diseases (PGT-M) and preimplantation genetic testing for aneuploidy (PGT-A).
RESULTS: Two embryos from IVF with low-risk PGT-M and euploid status. One transferred via frozen embryo transfer (FET) in February 2023 resulted in the successful birth of a healthy baby boy. This study reports the first successful delivery of a healthy boy after PGT-M for the CDKN1C gene variant c.79_100delinsGTGACC, contributing to the limited literature on successful outcomes for BWS.
CONCLUSIONS: Utilizing PGT-M in combination with IVF can lead to favorable outcomes in managing BWS-associated reproductive challenges, offering insights into potential genetic interventions and successful birth.

BACKGROUND: Congenital myasthenic syndromes (CMS) are among the most challenging differential diagnoses in the neuromuscular domain, consisting of diverse genotypes and phenotypes. A mutation in the Docking Protein 7 (Dok-7) is a common cause of CMS. DOK7 CMS requires different treatment than other CMS types. Regarding DOK7\'s special considerations and challenges ahead of neurologists, we describe seven DOK7 patients and evaluate their response to treatment.
METHODS: The authors visited these patients in the neuromuscular clinics of Tehran and Kerman Universities of Medical Sciences Hospitals. They diagnosed these patients based on clinical findings and neurophysiological studies, which Whole Exome Sequencing confirmed. For each patient, we tried unique medications and recorded the clinical response.
RESULTS: The symptoms started from birth to as late as the age of 33, with the mean age of onset being 12.5. Common symptoms were: Limb-girdle weakness in 6, fluctuating symptoms in 5, ptosis in 4, bifacial weakness in 3, reduced extraocular movement in 3, bulbar symptoms in 2 and dyspnea in 2 3-Hz RNS was decremental in 5 out of 6 patients. Salbutamol was the most effective. c.1124_1127dupTGCC is the most common variant; three patients had this variant.
CONCLUSIONS: We strongly recommend that neurologists consider CMS in patients with these symptoms and a similar familial history. We recommend prescribing salbutamol as the first-choice treatment option for DOK7 patients.

Capitalizing on breakthroughs in reproductive genetics, the utilization of in vitro embryo culture and stem cell technologies heralds a transformative era in addressing global challenges posed by rare genetic diseases. These cutting-edge practices illuminate the intricacies of early human development, elucidate the mechanisms behind rare diseases, and guide the development of potential therapies. Balancing this remarkable innovation with necessary ethical considerations, these technologies have the potential to revolutionize the trajectory of rare genetic disorders, transforming the landscape of diagnosis, treatment, and genetic counseling while offering renewed hope for affected individuals and families worldwide.

Williams syndrome (WS) and Down syndrome (DS) are two neurodevelopmental disorders with distinct genetic origins characterized by mild to moderate intellectual disability. Individuals with WS or DS exhibit impaired hippocampus-dependent place learning and enhanced striatum-dependent spatial response learning. Here, we used the Weather Prediction Task (WPT), which can be solved using hippocampus- or striatum-dependent learning strategies, to determine whether individuals with WS or DS exhibit similar profiles outside the spatial domain. Only 10% of individuals with WS or DS solved the WPT. We further assessed whether a concurrent memory task could promote reliance on procedural learning to solve the WPT in individuals with WS but found that the concurrent task did not improve performance. To understand how the probabilistic cue-outcome associations influences WPT performance, and whether individuals with WS or DS can ignore distractors, we assessed performance using a visual learning task with differing reward contingencies, and a modified WPT with unpredictive cues. Both probabilistic feedback and distractors negatively impacted the performance of individuals with WS or DS. These findings are consistent with deficits in hippocampus-dependent learning and executive functions, and reveal the importance of congruent feedback and the minimization of distractors to optimize learning in these two populations.

Recent years have witnessed unprecedented progress in therapeutic gene editing, revolutionizing the approach to treating genetic disorders. In this comprehensive review, we discuss the progression of milestones leading to the emergence of the clustered regularly interspaced short palindromic repeats (CRISPR)-based technology as a powerful tool for precise and targeted modifications of the human genome. CRISPR-Cas9 nuclease, base editing, and prime editing have taken center stage, demonstrating remarkable precision and efficacy in targeted ex vivo and in vivo genomic modifications. Enhanced delivery systems, including viral vectors and nanoparticles, have further improved the efficiency and safety of therapeutic gene editing, advancing their clinical translatability. The exploration of CRISPR-Cas systems beyond the commonly used Cas9, such as the development of Cas12 and Cas13 variants, has expanded the repertoire of gene editing tools, enabling more intricate modifications and therapeutic interventions. Outstandingly, prime editing represents a significant leap forward, given its unparalleled versatility and minimization of off-target effects. These innovations have paved the way for therapeutic gene editing in a multitude of previously incurable genetic disorders, ranging from monogenic diseases to complex polygenic conditions. This review highlights the latest innovative studies in the field, emphasizing breakthrough technologies in preclinical and clinical trials, and their applications in the realm of precision medicine. However, challenges such as off-target effects and ethical considerations remain, necessitating continued research to refine safety profiles and ethical frameworks.