Lysosomal storage disorders (LSDs) constitute a large group of rare, multisystemic, progressive, inherited disorders of metabolism. The aberrant metabolic processes often lead to the cellular accumulation of incompletely metabolized macromolecules or their metabolic byproducts. Most of the patients affected by LSD can experience a variety of neurological presentations including, but not limited to, psychiatric complications, seizures, and/or developmental delays. The onset of symptoms can range from birth to adulthood, and disease severity can vary. Since there is significant overlap in the symptomatology of LSDs, diagnosis is typically confirmed through biochemical and molecular assays. There are currently no approved cures for any LSDs; however, in most cases, treatment of symptoms can lead to better outcomes and improvements in quality of life. The use of hematopoietic stem cell transplantation, enzyme replacement or substrate reduction therapy, and viral vector gene transfer is the subject of many ongoing and completed clinical trials. In this mini review, we provide an overview of LSDs with neurological manifestations, describe the current endeavors in alleviating peripheral symptoms and discuss effective therapeutics strategies.
Rare diseases are complex and difficult to diagnose, with parents and caregivers often reporting significant delays in receiving a definitive diagnosis. Following diagnosis, parents and caregivers often feel overwhelmed with emotions, including relief, guilt, and shock. The culmination of this emotional burden may lead to a deterioration of psychological health, ultimately reaching a stage where the parents struggle to cope. A systematic literature review was conducted of the articles on this topic by searching the electronic database, PubMed. Further studies were retrieved from a reference listing of relevant articles and consultation with experts in the field. The review was based on the guidance in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol. The initial search identified 1276 articles, of which 37 met the inclusion criteria and were included in this review. The literature revealed key factors that appeared to contribute to psychological stress, including prolonged diagnostic odyssey, poor diagnostic delivery, lack of information and specialist knowledge, and convoluted healthcare systems. This review reinforces the need for psychological support amongst parents and caregivers of children with a rare disease at the time of diagnosis. The results of this literature review will be used to develop a statement of good practice for the support of parents and caregivers when a rare disease diagnosis is given.
ZEB2 and TCF4 are transcription factors (TFs) whose locations in embryos overlap in many sites and developmental phases, including in the forebrain and its cortical neurons. De novo mutations cause the phenotypically overlapping, haploinsufficient Mowat-Wilson (MOWS, in the ZEB2 gene) and Pitt-Hopkins (PTHS, in TCF4) syndromes, which currently cannot be cured. Mutant alleles have been mapped and defects documented (also in brain function) in MOWS and PTHS patients. Appropriately designed mouse models and cells derived from these, as well as cellular models including cultured pluripotent cells, enable investigating the genetic and molecular mechanisms underlying the developmental deficiencies that manifest after birth in the nervous systems and their multiple cell types, as well as those of organs other than the brain, in MOWS and PTHS. Biochemical analyses of cell type-specific transcriptomic changes in these perturbation models as compared to control cells, the identification of the intact-factor dependent and direct target genes, and of partner proteins including chromatin modulators, are revealing complex and multiple modes of action that eventually will explain target gene selectivity for these TFs. Both TFs have also been found to operate in acute and chronic diseases and cell-based repair processes after tissue or organ injury. In addition, the defective function also arises from their aberrant gene expression, which will require a deeper investigation of how the transcription of these TF genes is regulated. Furthermore, these two factors genetically and biochemically interact. This review combines the essentials and recent progress for both TFs for the first time, with a focus on MOWS and PTHS.
Healthcare networks for rare diseases are developing worldwide, concentrating expertise and knowledge from China and Japan to the United States and across Europe. Networked care is scaling up as an effective model of care for rare diseases, with prevention, diagnosis, care, and treatment administered locally, informed by the body of knowledge and expertise from the whole network. Now, as the United Nations encourages the development of rare disease networks in all countries, it is timely to reflect on the key characteristics of an effective network. This article aims to identify the core themes needed for a clinical network to be healthy. Drawing on experience from existing networks through a series of semi-structured interviews, insights from leaders of existing networks are then triangulated with the published evidence. The review seeks to identify themes that allow a clinical network to be effective and flourish. Healthcare networks are best understood as learning systems to generate collaborative knowledge used to inform the best possible care. Six themes are consistently reported in the literature and leaders’ experience: Trust, Communication, Leadership, Learning, Diversity, and Resources. Learning together is a key element of the success of effective networks and is most effective when networks are professionally multicultural and diverse, including the voices of people living with a rare disease. The involvement of patient representatives is fundamental to network collaboration and is recognized as a key aspect of early successes. Clinical leadership is critical to providing legitimacy and trust, creating a common identity, and promoting collaboration. Networks take time, resources, and coordination to develop. Although in-kind support and voluntary contributions of network members are important, inadequate resourcing is a critical barrier to the long-term sustainability and effectiveness of networks. This review explores the core themes of effective networks. By harnessing digital solutions that enable experts to coordinate care virtually across a clinical network, healthcare for people living with a rare disease is evolving to meet their complex needs. However, payment models to finance these models of care still lag behind innovative healthcare delivery models.
Around 4% of the global population suffers from a rare disease. Apart from the medical aspect, economic, organizational, and political approaches remain key aspects concerning the evolution of the world of rare diseases. Here we review the principal specific national initiatives and organizations dedicated to rare diseases in Europe, North America, and East Asia. We then present the outline of a possible optimal approach inspired by the successes of individual national organizations. This work should be taken into account in the definition of