Fabry disease (FD) is an X-linked lysosomal storage disorder caused by pathogenic variants in the GLA gene encoding for alpha-galactosidase A. Renal, cardiac, and cerebrovascular involvement are the leading complications in early adulthood and are associated with severe morbidity and mortality. Cerebrovascular manifestations in FD manifest as ischemic stroke and transient ischemic attack and less frequently as hemorrhagic strokes. Many patients may develop their stroke not only before other major complications but also before the diagnosis of FD is made. This review will describe the frequency and characteristics of cerebrovascular disease in FD, the complex pathophysiological mechanisms, the neuroimaging findings, the value of screening studies in young patients with stroke, and the controversies regarding the beneficial effect of ERT for the prevention of cerebrovascular disease in FD.

Fabry disease is an X-linked lysosomal storage disorder due to alpha-galactosidase A deficiency. This deficiency results in a progressive accumulation of globotriaosylceramide and related glycosphingolipids, particularly in vascular endothelial cells, renal cells, nerve cells, and cardiomyocytes. Gastrointestinal symptoms are frequent and can be extremely debilitating. It is known that most of the well-characterized gastrointestinal manifestations of Fabry disease are the result of the accumulation of glycosphingolipids, which causes vascular occlusion and malfunction of the peripheral and autonomic nervous system. Although improvement is noted in treating patients with enzyme replacement therapy and migalastat, some continue to experience symptoms after treatment; thus, it remains a significant cause of morbidity, necessitating concurrent adjuvant treatment. Current research is focused on clarifying the underlying dysmotility and further analyzing the correlation between the gut-brain axis, the histologic disease progression, and the clinical symptom presentation.

The high variability in clinical features and outcomes observed in monogenic diseases such as Fabry disease suggests the presence of additional pathogenetic pathways beyond the lysosomal deposition of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3). Research indicates that the deposition of Gb3 and lyso-Gb3 can stimulate inflammatory processes. Immune-competent mononuclear cells exposed to Gb3 deposition exhibit surface adhesion molecules and release pro-inflammatory and fibrotic cytokines such as interleukin-1β, tumor necrosis factor-α, and transforming growth factor-β. This culminates in the activation of inflammatory cascades associated with oxidative stress and apoptotic mechanisms maintained by renal resident and infiltrating cells, leading to chronic inflammation and tissue fibrosis. Furthermore, from another angle (termed Agalopathy), the mutated galactosidase alpha gene can result in the production of an altered alpha-galactosidase A enzyme, inducing endoplasmic reticulum stress and triggering the unfolded protein response (UPR) in an effort to prevent the production of altered proteins. The UPR, in turn, instigates the release of pro-inflammatory cytokines, thereby contributing to the inflammatory milieu. Experimental findings have demonstrated that the pathogenetic mechanisms activated by the deposition of Gb3 and lyso-Gb3 can become independent of the initial stimulus and may exhibit limited responsiveness to therapy. Cellular pathway alterations can persist post-therapy or after gene correction. Moreover, biochemical and histological lesions characteristic of Fabry disease manifest in the absence of Gb3 in the zebrafish experimental model. This review endeavors to describe the role of these processes in Fabry nephropathy and aims to summarize the available evidence on the pathogenesis of renal damage.

Since its inception in 1963, newborn screening (NBS) has played a pivotal role in early detection and the establishment of appropriate care for infants and children afflicted with inherited metabolic disorders (IMDs). Despite significant advancements in biomarker identification and metabolomics, current NBS protocols only cover a fraction of known IMDs. The integration of genomics holds promise for expanding the scope of standard NBS, albeit presenting additional challenges. Drawing from the experiences of the authors across three European countries, this article reviews the current landscape of conventional NBS for IMDs and explores the potential integration of genomic tools as a primary screening tier. Recommendations are provided for the seamless transition to genomic NBS, considering factors such as regional birth prevalence differentials, treatability of conditions, and technological capabilities.

Major organ involvement in Anderson-Fabry disease (FD) is clinically silent for a long period and clinically heterogeneous; thus, it is difficult to identify the patients at increasing risk of a progressive disorder. Moreover, accumulating evidence suggests that early disease-specific treatment (DST) is safe and effective in preventing the progression of heart and kidney damage, with poorer results in patients with extensive myocardial fibrosis, advanced glomerulosclerosis, and/or heavy proteinuria. Therefore, biomarkers defining preclinical involvement, with a prognostic value and a correlation with response to treatment, are an urgent need in FD. Several types of biomarkers are recognized in FD, pertaining to total disease burden and specific organ involvement (central nervous system, heart, and kidney). Currently, plasma globotriaosylsphingosine (lyso-Gb3), cardiac and brain imaging, and albuminuria are recognized as the “gold standard” biomarkers of total disease burden or specific organ involvement in FD. However, severe globotriaosylceramide (Gb3) storage and organ damage may occur within the affected organs with minimal changes in these standard tests. Given the heterogeneity and rarity of the disease, the identification of new biomarkers is challenging. Several ways may be used to identify new biomarkers in FD, namely “omic” medicine, biomarkers identified in other pathological models similar to FD, and biomarkers linked to the pathophysiological pathways involved in FD. This article aims to review the clinical value of the available biomarkers in FD and give an overview of the research on new biomarkers.

Phelan-McDermid syndrome (PMS) is a chromosomal microdeletion syndrome generally caused by loss-of-function variants or deletions affecting the SHANK3 gene. We report on a case of a 19-year-old woman with a diagnosis of PMS, autism, and developmental disability. She has been under clinical care since the age of 9 and received treatment with subcutaneous IGF-1 from 11 to 15 years of age. The treatment spanned 2 periods, totaling 35 months, interspersed with a 16-month off-treatment interval. Clinically significant improvement was evident during the treatment periods, particularly in the Social Responsiveness Scale, the Aberrant Behavior Checklist, and clinical assessments, contrasted with a clear deterioration during the off-treatment period. Sleep difficulties worsened during the first period, and EKG repolarization abnormalities emerged during the second period, ultimately leading to definitive treatment discontinuation. In conclusion, an experimental long-term on-off-on treatment with IGF-1 in an adolescent with PMS resulted in mixed results, showcasing positive clinical improvements alongside potentially severe adverse events in the long run.

The mission of the NCATS Division of Rare Diseases Research Innovation (DRDRI), formerly known as the Office of Rare Diseases Research, is to advance rare diseases research to benefit patients. DRDRI is part of the National Center for Advancing Translational Sciences, one of the 27 components of the US National Institutes of Health. DRDRI facilitates and coordinates NIH-wide activities involving rare diseases research, as well as directly supporting rare diseases research activities. These activities include the development and maintenance of a centralized database on rare diseases; collaboration and coordination with organizations focused on orphan products development and rare diseases research across the globe, advising the Office of the NIH Director on matters related to NIH-sponsored research involving rare diseases; and responding to information and policy requests about rare diseases within the NIH. DRDRI also supports various rare diseases research activities, including the Rare Diseases Clinical Research Network, rare disease-related conference grants, and assessment of the costs of untreated rare diseases. In addition, several of the projects DRDRI is supporting are “many diseases at a time” translational approaches for rare diseases, which emphasize leveraging commonalities across multiple rare diseases. These include the support of “basket trials” based on shared molecular etiologies across multiple rare diseases, as well as therapeutic platforms for the treatment of monogenic diseases, such as gene therapy and genome editing. This Perspective will provide an overview and summary of these various activities, noting where relevant our collaborative partnerships within the U.S. and internationally.