Background: Loss of function (LoF) variants in GRIN2B lead to neurodevelopmental delay, which is expected to be mediated by alterations in the excitation-inhibition (E/I) balance resulting from reduced activity of the N-Methyl-D-Aspartate receptor. To test this hypothesis, we use quantitative electroencephalogram to provide insights into network-level estimates of the excitation-inhibition ratio. Methods: a single-center, case-control pilot study was conducted. Eyes-open rest EEG recordings were obtained from children with GRIN2B LoF variants (n = 5, aged
Fabry disease (FD) is a rare X-linked lysosomal storage disease resulting from a deficiency of the lysosomal enzyme alpha-galactosidase A, caused by mutations in the GLA gene. This leads to the accumulation of glycosphingolipids, mainly globotriaosylceramide and its deacylated derivate globotriaosylsphingosine. Such non-metabolized substrates accumulate in cells and tissues throughout the body, resulting in significant morbidity, predominately in the kidneys, heart, and nervous system, and impaired quality of life. While FD was initially considered to predominantly affect men, women with this condition may manifest a wide array of clinical symptoms and, in some cases, a significant multi-systemic pathology similar to men. This has been mainly attributed to skewed X-chromosome inactivation, which causes different enzyme activity levels within tissues and organs. The diagnosis of FD in women is often delayed due to the initial non-specificity of presenting symptoms and the heterogeneity of clinical manifestations. The enzyme activities in the leukocytes of a significant number of women with this condition fall within the normal range. Therefore, genetic analysis for mutations in GLA has become the gold standard for the diagnosis of FD in women. Unlike men, the current criteria proposed to start specific treatment for women with this condition can underestimate the appropriate time to do so and impede women from obtaining the benefits of early initiation. In addition, there is some evidence that women with FD are still at risk of being undertreated, unlike male patients.
Highlights
Fabry disease is an X-linked lysosomal storage disease
Similar to men, women may manifest a wide array of clinical symptoms
In some cases, organ damage is as severe as that observed in men
Skewed lyonization of the X-chromosome may cause this clinical heterogeneity
Genetic analysis for GLA mutations is necessary for diagnosis in women
Current guidelines indicate that women may be at risk of undertreatment
Follow-up and treatment criteria for women may require revision
Aim: This study aims to assess the final adult height of patients with juvenile myasthenia gravis (JMG) who received glucocorticoid treatment during childhood.
Methods: A retrospective cohort study was conducted at two neurology centers in Beijing, China, including patients diagnosed with JMG between March 2006 and April 2022. Participants were stratified into two groups: those receiving long-term corticosteroid therapy (≥ 6 months) and those without such treatment. Further subgroup analysis was performed based on treatment timing (prepubertal vs. postpubertal). Mean differences in adult height were calculated, and binary logistic regression was used to evaluate associations between treatment variables and growth outcomes.
Results: Of 120 diagnosed JMG patients, 47 who reached adult height were analyzed. Adult height in the long-term steroid group (168.64 ± 7.58 cm) did not significantly differ from the control group (171.45 ± 9.58 cm)
Conclusion: In JMG patients, steroid treatment after puberty appears to have a relatively smaller impact on adult final height compared to treatment before puberty.
Organellar crosstalk has gained significant interest due to its essential role in maintaining cellular homeostasis and normal function. Conversely, disruptions in organelles and their interactions are increasingly recognized as key contributors to the pathogenesis of numerous diseases. Rare neurodegenerative diseases, such as Gaucher disease (GD) and X-linked adrenoleukodystrophy (ALD), are caused by inherited mutations that disrupt critical metabolic pathways. Genetic variants encoding key proteins involved in these pathways result in the excessive accumulation of corresponding substrates, which subsequently trigger organellar crosstalk dysfunction, often involving mitochondria, lysosomes, endoplasmic reticulum (ER), or peroxisomes. To date, the specific mechanisms underlying organellar interactions and their roles in the pathophysiology of these respective diseases are not fully elucidated, an area that continues to be actively studied. Understanding these mechanisms could reveal novel pathways or targets for future therapeutic development. Furthermore, the severity of these rare neurodegenerative diseases and the lack of effective treatments for patients underscore the urgency for thorough investigations into organellar crosstalk. This review provides an overview of the crosstalk between mitochondria, lysosomes, the ER, and peroxisomes in lysosomal diseases, such as GD, and peroxisomal disorders, including ALD. Additionally, we explore potential therapeutic strategies targeting these interconnected pathways.
Body movement relies on skeletal muscles generating power to move limbs effectively. Power is defined as force multiplied by velocity: a muscle produces force at a specific velocity (the speed of muscle shortening) and this results in power. In diseases like Duchenne Muscular Dystrophy (DMD), the absence of dystrophin weakens muscles and impairs their shortening velocity, leading to decreased power and consequently, impaired movement. Additionally, the diaphragm and heart muscles are also affected in DMD, causing difficulty breathing and impaired cardiac function. Compromised cardiorespiratory function can ultimately lead to death. Given the complex etiology of DMD and the essential role of power in all affected muscles, it is crucial to assess potential treatments for their effectiveness in improving muscle function. This review focuses on fundamental physiological assays used to evaluate muscle function in skeletal and diaphragm muscles. Common assays include force-frequency, force-velocity, power, and eccentric protocols, which are conducted ex vivo, in situ, and in vivo in small rodents (such as mice and rats) and larger intermediate animal models such as the Golden Retriever Muscular Dystrophy dog. Existing data support the use of skeletal muscle contractile assays as objective tools for assessing the efficacy of treatments.
Aim: Fabry disease (FD, OMIM #301500) is a rare, X-linked, lysosomal disorder caused by pathogenic variants in GLA; the consequential lack of alpha-galactosidase A activity results in glycosphingolipid accumulation. Although many systemic manifestations of the disease have been documented, the association between FD and erysipelas has not been previously reported.
Methods: We describe 12 patients with Fabry disease and lymphedema of the lower limbs who experienced one or more episodes of erysipelas (with 67 episodes in total).
Results: All 12 patients (ten males and two females) had classic FD. One of the females had highly skewed X chromosome inactivation, silencing the wild-type GLA allele. Lymphedema of the lower legs (in 10 out of 11 patients with data) was notable in the patients who experienced erysipelas.
Conclusion: The characteristics of this case series suggest that clinicians should be aware of the risk of erysipelas in patients with FD-associated lower limb lymphedema and should seek to prevent or promptly treat skin wounds or infections in this setting.
Aim: Sickle cell disease (SCD) is a debilitating monogenic disorder of red blood cells, characterized by acute pain episodes during vaso-occlusive crises (VOCs). Here, we developed and validated a medical app, SCD-MED-ALERT, for home management of acute pain in patients with SCD.
Methods: The SCD-MED-ALERT app is a multilingual and standalone application for iOS and Android. It was proposed to young adult patients with SCD (n = 47) attending comprehensive sickle cell centers within the Società Italiana Talassemie ed Emoglobinopatie (SITE) network. Patient-Activation-Measure-13 (PAM-13) questionnaire and mHealth App Usability Questionnaire (MAUQ) were used to evaluate patient activation levels in self-management and the app’s usability, respectively.
Results: Among SCD patients using SCD-MED-ALERT, the total PAM score significantly increased from 40 ± 4 (mean ± SD) to 42 ± 4 (P < 0.001). Multivariate analysis revealed that the baseline PAM score was positively associated with patients on crizanlizumab plus hydroxyurea therapy (P = 0.015), suggesting a higher sense of
Conclusion: Our study shows that the SCD-MED-ALERT app enhances patients’ sense of self-efficacy and proactivity in managing pain at home during acute pain crises. We propose that this app might contribute to empowering SCD patients and assist physicians in identifying patients who may benefit from more intensive treatment(s).
Aim: Drug development programs in rare diseases face many challenges, such as the scarcity and geographic dispersion of patients, limited natural history data, the need for novel study designs, and sensitive outcome measures.
Over the past years, tools supporting clinical research have been developed in the context of different projects and for diverse purposes. Therefore, they have not yet been structured to encompass the conduct of rare disease (RD) clinical trials as a whole. To address this issue, the European Joint Program for Rare Diseases (EJP RD) has developed the Rare Diseases Clinical Trial Toolbox. This toolbox collates the accumulated knowledge (collectively termed “tools”) generated by projects/organizations into a structured and guided instrument. By structuring and making resources discoverable, we aim to help RD clinical trialists and trial managers.
Methods: We have designed and developed a toolbox structured around the definition of the clinical trial pathway. It is organized into five domains. Each domain describes one or several activities to be considered throughout the clinical trial pathway. Selection criteria were then defined to include existing resources that are relevant to those activities. Rare disease-specific resources are highlighted as such and include those especially relevant to pediatric clinical research.
Results: The current version of the Toolbox includes 121 resources tagged as relevant to any of the 18 activities within the clinical trial pathway. Overall, 60% of all resources are relevant to any clinical trial while 40% are tagged as “rare disease-specific”.
Conclusion: Access to public resources relevant to the development of clinical trials for rare diseases is sometimes challenged by limited awareness and/or the absence of an adequate framework that enables their findability. This Toolbox aims to build a framework supporting the optimal use of existing tools.