The recent description of a cohort with both adults and children harboring biallelic pathogenic variants of cubilin (CUBN) changed the paradigm for the management of isolated proteinuria. Indeed, the detection of proteinuria in a patient, regardless of age, often leads to an exhaustive check-up, including a kidney biopsy, but also to the prescription of renin-angiotensin system (RAS) blockers to slow the progression of kidney disease. Patients with CUBN variants have nondetrimental proteinuria and are non-responsive to RAS blockers. We herein describe two siblings treated for isolated proteinuria for several years, who were eventually diagnosed with CUBN biallelic pathogenic variants (c.703 C > T and c.10363-3A > G). We review the pathophysiological mechanisms of this newly discovered disease and discuss its implications for clinical management.

Rare diseases occur in their large majority from a genetic cause, which makes them good candidates for genetic RNA drugs. The basic concepts, principles, mechanisms of action and chemical optimizations of synthetic antisense oligonucleotides (ASO) and small interfering RNA (siRNA) are illustrated. These drugs act either by leading to RNA degradation, or as steric blockers of RNA translation, microRNA antagonists, splicing modulators or inducers of exon skipping. Chemical modifications and delivery techniques differ and are adapted to their distinct functions. The successes, potential, and challenges of synthetic RNA drugs are illustrated for several muscular and neuromuscular diseases: Duchenne muscular dystrophy, spinal muscular atrophy, transthyretin amyloidosis, Type 1 myotonic dystrophy, centronuclear myopathy, oculopharyngeal muscular dystrophy.

Aim: Defective mitochondrial function and increased oxidative stress have been documented in Autism Spectrum Disorder (ASD) and Phelan-McDermid syndrome (PMS), one of the best-known monogenic forms of ASD. The purpose of this exploratory, double-blind, randomized cross-over trial (RCT) is to verify the efficacy and safety of a “metabolic support therapy” (MST) in PMS, while defining the experimental methodology most apt at maximizing sensitivity and reliability.

Methods: A total of 31 PMS patients completed 4 months of Coenzyme Q10 (50/100 mg b.i.d.) + vitamin E (30/60 mg/d) + polyvitamin B ("active compound") vs. 4 months of only Vitamins E and B ("active comparator"). To explore their sensitivity and reliability, four primary outcome measures were used: VABS, CARS, CGI-I, and VAS. Secondary outcome measures span adaptive behaviors, social cognition, autism, problem behaviors, quality of life (QoL), communication, and comorbidities.

Results: CoQ10+vit. E and B yielded significantly greater improvement in several measures of cognition and adaptive functioning, motor skills, and stereotypic behaviors compared to vit. E and B only. Maternal QoL was especially improved in the presence of CoQ10 (P < 0.004). Time x Treatment interactions in CGI-I and VAS "restricted interests" scores support positive contributions also by vitamins E and B. Side effects, including hyperactivity, insomnia, and irritability, were mild, rare, and did not differ between treatment periods.

Conclusion: MST may produce small-to-moderate improvement, especially in motor skills, social motivation, adaptive behaviors, responsiveness to environmental stimulation, and stereotypic behaviors in up to approximately 70% of PMS patients. A targeted confirmatory RCT contrasting Q10+vit E and B vs. inactive placebo is now warranted.

Cathepsin C is a papain-like cysteine peptidase known primarily for its involvement in the activation of serine peptidases in neutrophils and other immune cells. Its critical role in this process qualifies cathepsin C as a target for the treatment of inflammatory diseases, and its most advanced inhibitor, brensocatib (Insmed), is currently in phase 3 clinical trials for the treatment of non-cystic fibrosis bronchiectasis. Beyond neutrophils, its importance is highlighted by loss-of-function mutations that cause the recessively inherited Papillon-Lefèvre syndrome. At the molecular level, cathepsin C has several structural and functional features that set it apart from other members of the family and enable its selective targeting. It possesses dipeptidyl-peptidase activity (its other common name is dipeptidyl-peptidase I) due to the presence of an additional exclusion domain that also controls its stepwise tetramerization during maturation. In this review article, we summarize the current state of the art regarding the biochemical properties of cathepsin C, its physiological and pathological roles in neutrophils and beyond, and recent advances in the development and evaluation of cathepsin C inhibitors.

Aim: With the costs of genomic sequencing falling quickly and an ever-increasing number of clinical laboratories equipped with new-generation sequencing machines, healthcare systems around the world are getting ready to enter the era of genomic newborn screening (NBS). However, the adoption of Genomic Sequencing (GS), encompassing whole-exome sequencing (WES) and whole-genome sequencing (WGS), in NBS programs raises a number of clinical, ethical, and legal questions as well as organizational and economic challenges. This systematic review is part of a feasibility study to assess the introduction of WGS for NBS in Lombardy region with the specific aim of gathering evidence from existing pilots in the field whose results have been published.

Methods: Three different sources were identified for the selection of articles in order to obtain a various and unbiased set of publications. 33 articles were retained for analysis to answer the following questions:

1. Clinical: Does genomic sequencing demonstrate clinical utility in the context of NBS? What are the limitations of these kind of programs?

2. Societal: What are the social, ethical and psychological implications of using GS for NBS?

3. Governance: What are the legal, economic, and organizational challenges for GS-based NBS programs?

Results: There is a general consensus in the literature on the key principles that should guide the adoption of GS in NBS, such as the inclusion of actionable genes only, the need for informed consent from the parents, the right of the newborn to an open future, which means the exclusion of late-onset diseases even when those are considered treatable. However, there are still several differences in how these principles are detailed and applied.

Conclusion: Real-world evidence from a handful of pilot projects (namely BabySeq and NC-Nexus, both carried out in the USA) have been published recently; however, this evidence is not yet sufficient to put an end to the broad and animated debate on the use of GS for NBS. Ethical, legal, and social issues still constitute great challenges and major barriers to wide and uniform adoption of GS in NBS. On the clinical side, a number of issues remain unaddressed, such as the benefits and limitations of the different approaches (targeted sequencing, GS only versus GS+standard NBS), the genes/diseases to include and the frequency of incidental findings, identification of carrier status, and variants of uncertain significance (VUS). Further pilots and consultations with involved stakeholders will be necessary before GS-based NBS can be accepted and systematically implemented in national healthcare programs.

Data federation intermediated through trusted research environments can help accelerate the adoption and utilization of newborn genome screening worldwide. Data federation will protect individual datasets from unauthorized security breaches, allow analysis in situ, and bypass the need for cumbersome data sharing agreements between parties. Finally, data federation could accelerate the adoption of new therapies for rare genetic diseases with the use of synthetic clinical trials.

A range of pulmonary arterial pressures was observed in three related patients with Cantú syndrome. The incident patient developed a moderately high pulmonary vascular resistance. Several factors influenced the severity of his pulmonary vascular disease and the events, which ultimately resulted in his death. However, he had an acute improvement in blood pressure and respiratory support after a single dose of glyburide when he was critically ill. The father and sister of the incident patient have evidence of mildly increased pulmonary arterial pressure with normal pulmonary vascular resistance. They are being treated with glyburide to potentially decrease the high cardiac output associated with a gain in K_ATP channel function. Additional experience with glyburide or other K_ATP channel inhibitors is needed to determine the most appropriate agent, dose, time, and duration of treatment for patients with Cantú syndrome.