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Rare disease drug development is wrought with challenges not the least of which is access to the limited data currently available throughout the rare disease ecosystem where sharing of the available data is not guaranteed. Most pharmaceutical sponsors seeking to develop agents to treat rare diseases will initiate data landscaping efforts to identify various data sources that might be informative with respect to disease prevalence, patient selection and identification, disease progression and. Such data are often difficult to come by for highly prevalent, mainstream disease populations let alone for the 8000 rare disease that make up the pooled patient population of rare disease patients. The future of rare disease drug development will hopefully rely on increased data sharing and collaboration among the entire rare disease ecosystem. One path to achieving this outcome has been the development of the rare disease cures accelerator, data analytics platform (RDCA-DAP) funded by the US FDA and operationalized by the Critical Path Institute. Read the full article here.

Autosomal dominant leukodystrophy (ADLD) is an ultra-rare, slowly progressive neurodegenerative disorder associated with the loss of white matter in the central nervous system (CNS). Several years after its first clinical description, ADLD was found to be caused by variants in the LMNB1 gene that cause its overexpression in at least the brain of patients. LMNB1 encodes for Lamin B1, a protein of the nuclear lamina. Lamin B1 regulates many cellular processes such as DNA replication, chromatin organization, and senescence. However, its functions are not fully characterized yet. Nevertheless, Lamin B1 together with the other lamins that constitute the nuclear lamina has firstly the key role of maintaining the nuclear structure. Being the nucleus a dynamic system subject to both biochemical and mechanical regulation, it is conceivable that changes to its structural homeostasis might translate into functional alterations. Under this light, this review aims at describing the pieces of evidence that to date have been obtained regarding the effects of LMNB1 overexpression on cellular morphology and functionality. Moreover, further investigation on ADLD morpho-functional consequences is essential to better understand this complex disease and, possibly, other neurological disorders affecting CNS myelination are suggested. Read the full article here.

Rare disease diagnostics and disease gene discovery have been revolutionized by whole-exome and genome sequencing but identifying the causative variant(s) from the millions in each individual remains challenging. The use of deep phenotyping of patients and reference genotype-phenotype knowledge, alongside variant data such as allele frequency, segregation, and predicted pathogenicity, has proved an effective strategy to tackle this issue. In this article the numerous tools that have been developed to automate this approach and demonstrate the power of such an approach on several thousand diagnosed cases from the 100,000 Genomes Project are reviewed. Finally, the challenges that need to be overcome to improve detection rates and help the majority of patients that still remain without a molecular diagnosis after state-of-the-art genomic interpretation are discussed. Read the full article here.

According to GLOBOCAN 2018, colorectal cancer is the third most common cancer in the world. In 2018, the incidence of colon cancer worldwide is about 2 million, and the number of deaths is close to 1 million. The great morbidity, in combination with the high mortality and its late diagnosis, determine its social importance.

The most common symptoms include iron-deficiency type anemia, change in defecation rhythm, weight reduction, and manifestations of intestinal obstruction. However, the first manifestation of clinical symptoms is not always from the large intestine but also from other organs outside the digestive system. In these cases, colon cancer is usually incurable due to the development of extracolonic dissemination and corresponding organ failure. Genetic factors, sedentary lifestyle, obesity, consumption of red meat, alcohol, smoking, and some metabolic diseases are considered the main risk factors for its occurrence.

We present the case of a 47-year-old woman with histologically verified simultaneous adenocarcinoma and carcinoid of the sigmoid colon, as well as the background of asymptomatic gastroesophageal reflux disease complicated by precancer of the esophagus and stomach – Barrett’s esophagus. Read the full article.

Cancer diseases, as a group of pathological entities, represent a significant social and health problem. However, the consideration of all cancers in a single category in health policymaking has been subject to criticism. Due to their clinical and epidemiological characteristics, patients with rare cancers face obstacles in their access to innovative medicines, combined with a lack of expertise in the diagnostic and treatment processes. The establishment of specific policies for these patients requires a precise definition of the concept.

This article aims to provide a chronological overview of the definition of “rare cancer” in the context of health policy development. A narrative literature review based on the keywords “rare cancers”, “rare tumors”, and “rare neoplasms” was conducted in the PubMed/MEDLINE, ScienceDirect, and Google Scholar databases. The identified articles were organised into three main contextual categories: clinical-based definitions, epidemiological-based definitions, and definitions used in pediatric oncology. Read the full article here.

Hemophilia is a congenital bleeding disorder characterized by a deficiency or functional defects of coagulation factor VIII (FVIII), called hemophilia A, or factor IX (FIX), called hemophilia B. The factor deficiencies are the result of mutations in the FVIII or FIX clotting factor genes. Hemophilia A is much more common than hemophilia B – estimated 80-85% of all hemophilia cases. Estimated prevalence at birth is 24.6/100 000 males for hemophilia A and 5/100 000 males for hemophilia B.

Traditionally, hemophilia A and B have been considered clinically indistinguishable. There is some evidence that severe FIX deficiency may be clinically milder than the corresponding degree of FVIII deficiency. Several possible explanations for differences in disease severity can be hypothesized – genetic defects, associated prothrombotic abnormalities, clotting factor characteristics, etc.

In conclusion, despite the clinical indistinguishability of the two diseases, some phenotypic differences are observed in hemophilia B, which require further investigation of the underlying mechanisms. Read the full article here.