Orphanet Journal of Rare Diseases最新文献

Background: Lymphangioleiomyomatosis (LAM) is a rare, multisystemic metastatic disease. Chemokines are implicated in promoting LAM cell migration and tumor progression. Our prior plasma proteomics identified elevated C-C motif chemokine ligand 14 (CCL14) in LAM, yet its role remains unexplored.

Methods: Proteomic analysis identified CCL14 as differentially expressed in LAM patients versus healthy controls. Single-cell RNA sequencing (scRNA-seq) of lung tissues (six LAM patients, five healthy donors) identified the cellular source of CCL14 and explored its functional pathways bioinformatically. ELISA-quantified plasma CCL14 levels were analyzed for correlations with clinical phenotypes and longitudinal disease progression in 53 LAM patients and 25 controls.

Results: Proteomics and scRNA-seq revealed upregulation of CCL14 in LAM patients, primarily localized to lymphatic and vascular endothelial cells. Functional enrichment linked CCL14 to proliferative (mTORC1, MYC), inflammatory (TNF-α/NF-κB), and chemotactic pathways. CellPhoneDB indicated CCL14 mediates interactions between endothelial cells and innate immune/alveolar epithelial cells, and between endothelial cells themselves, via ACKR2, CCR3 and CCR1. Clinically, plasma CCL14 levels were significantly elevated in LAM patients versus controls (p = 0.003). Subgroup analyses demonstrated higher CCL14 levels in patients with angiomyolipomas (AMLs) versus those without, and in CT grade III versus grade I/II. Critically, CCL14 predicted disease progression: baseline CCL14 levels were higher in progressive versus stable patients (p = 0.0266) and positively correlated with annual increase in the percentage of cystic lung volume (r = 0.4051, p = 0.0446).

Conclusions: CCL14 is a critical regulatory molecule within the LAM microenvironment and a promising biomarker for disease severity and progression.

Background: Fabry disease (FD) is a multisystemic, progressive, X-linked genetic disorder caused by dysfunction of the enzyme α-galactosidase A. Symptoms commonly present in childhood in classic patients. Prior studies in classic patients suggest primary presenting features include gastrointestinal (GI) symptoms such as abdominal pain, bloating, and diarrhea. In this longitudinal study, we collected annual questionnaires and medical records from families of 29 children between 3 months and 9.5 years old, including the Rome III questionnaire. We compared symptom detection of abdominal pain, constipation, diarrhea, and bloating via three methods: the Rome III, a simple review of symptoms questionnaire, and pediatrician notes including a review of systems.

Results: Both questionnaires elicited all GI symptoms more frequently than pediatrician notes (log rank test, p < 0.001). The two questionnaires had weaker agreement for constipation than other symptoms (per kappa statistic) and more similar detection at a younger age. After 24 months, the Rome III outperformed the simple review of symptoms questionnaire (Fisher's exact test, p < 0.001). Pediatrician notes never recorded bloating or severe episodes of abdominal pain.

Conclusions: Targeted questionnaires elicit early gastrointestinal symptoms in pediatric Fabry disease patients that would otherwise go unnoticed at a standard doctor's appointment. Based on manual analysis of questionnaire data, a list of questions is suggested to support pediatricians of young patients with FD in recognizing GI symptoms. Use of more targeted and specific questions regarding GI symptoms is warranted in pediatric appointments of patients with FD, with age-appropriate expansion of the questions at 24 months of age. Early detection of symptoms in this population is critical as individual treatment plans are based on symptom onset and as newborn screening is expanding.

Achondroplasia is the most common form of short-limbed short stature of genetic origin. Most people with achondroplasia live fully independent, productive, and socially engaged lives. However, the condition is associated with several potential medical complications. Individuals with achondroplasia may experience medical, functional, and psychosocial challenges at different times in their life. The goal for lifelong care of individuals with achondroplasia is to optimize their physical and mental health through provision of individualized care and to promote participation and inclusion in society. In this article, as a tool for individuals with achondroplasia, their families, and their healthcare team, we provide a guided overview of the 2022 International Consensus Statement for management and care of individuals with achondroplasia. The International Consensus Statement recommendations are based on current, best available knowledge. We provide commentary on the recommendations from the perspective of both patients and physicians through addressing medical/developmental considerations, the healthcare system, and psychosocial considerations.

Background: Follow-up assessments form the basis for the continuous optimization of therapy and supportive care on an individual level, for confirming treatment efficacy, and for detecting newly emerging or unexpectedly progressive symptoms early enough to permit timely therapeutic intervention. For Pompe disease, evidence based guidelines on which assessments should constitute the minimum standard and which are required in specific situations only, were missing. Therefore, we started the Austrian Pompe Outcome Consensus (APOC) Study.

Methods: APOC was a Delphi process with two classical online and a modified third round, implemented September 2023-May 2024, following the AWMF S2k guideline. A five-member interdisciplinary steering committee invited 23 clinical experts, achieving response rates of 69.6% and 100%. A questionnaire was developed via literature scoping and an expert workshop. The importance and recommended frequency of follow-up assessments were rated using AGREE II consensus thresholds, and the classification for recommendation strength of the German Association of the Scientific Medical Societies (AWMF;Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e. V.).

Results: 34 statements achieved consensus. Strong recommendations included the 6-minute walk test (6MWT), timed tests, Pompe PEDI and other age-appropriate functional tests in children, muscle tests, handheld dynamometry, Fatigue Severity Scale, patient-reported outcome measures (e.g. R-Pact), forced vital capacity (sitting/supine), morphologic muscle imaging studies, pain and quality of life assessment. Further recommendations included respiratory (MIP/MEP) and sleep studies (polysomnography), creatine kinase, antibody titers, swallowing studies, liver sonography, hearing tests and speech and speech/oromotor function, physical therapy and rehabilitation, bone density assessment, and caregiver psychosocial care.

Conclusions: The APOC Delphi consensus yields AGREE II-compliant, systematically weighted recommendations delineating essential and optional follow-up assessments for Pompe disease in the context of Austrian healthcare. The applied method enabled a structured and efficient consensus-building process and appears well suited for addressing comparable questions in other rare disease contexts.

Clinical trial number: Not applicable.

MECP2 duplication syndrome (MDS) is an ultrarare, X-linked neurodevelopmental disorder that is poorly understood in terms of its natural history and phenotypic variability. There is limited information on how individuals with MDS acquire, retain or lose fundamental functional skills (gross motor, purposeful hand function and communication) - that of which this study aimed to better characterise in the largest case series to date.For 160 individuals with MDS (median age 9.06 y, range: 0.57-51.63 y; 84% male), we report that phenotypic penetrance in females can, in some, result in a similar functional skill deficits to males. However, a higher proportion of females acquired gross motor and fine motor skills compared to males. Use of words was the most common parent-reported skill regression (34/90 [38%]) followed by fine motor/hand function (26/90 [29%]), independent walking (25/90 [28%]) and feeding (25/90 [28%]). Additionally, lower proportions of functional ability were present in those with seizures compared to those without. A general trend was also observed for decreasing functional skills with increasing age. Additionally, those with a larger duplication length (1 + Mb) were less likely to be able to acquire independent walking compared with those with less than a 1 + Mb duplication (p < 0.001).This is the first study to comprehensively map the developmental trajectory of functional skills in MDS and provides a seminal baseline for better characterising the natural history of this disorder. Further investigations are required to understand the importance of interventional therapy on the retainment of functional skills.