Orphanet Journal of Rare Diseases最新文献

Background: Children and adolescents with rare diseases represent a population that may be at risk for an avoidant/restrictive food intake disorder (ARFID). This study aimed to quantitatively examine the symptoms of ARFID in a sample of children and adolescents with rare diseases and their association with sociodemographic characteristics, eating disorder psychopathology, health-related quality of life (HRQoL), and mental health.

Methods: In this observational study, data from 309 families of children with rare diseases drawn from a multicenter clinical study were used to estimate the prevalence of ARFID symptoms in children and adolescents aged 8-21 years in Germany was estimated via self-report (n = 169) and parent report (n = 502). Differences between the sample of individuals with rare diseases and normative population data, between those with and without ARFID symptoms, and between subgroups of rare diseases were investigated. Additionally, correlations between eating disorder psychopathology, sociodemographic, and psychosocial variables were investigated.

Results: The prevalence of symptoms of ARFID was relatively high, with a relevant difference between self-report (3.6%) and parent report (10.2%). A vast proportion of self-reported ARFID symptoms were relevantly higher in children and adolescents with rare diseases than in normative population data. Moreover, the presence of ARFID symptoms in both self-report and parent report versions suggests that these symptoms may be consistent across varying severity levels of coexisting rare diseases. Both self-reported and parent reported ARFID symptoms in children and adolescents with rare diseases were associated with impaired HRQoL and mental health.

Conclusion: The study underscores the importance of considering ARFID in children and adolescents with rare diseases. The comorbidity of rare diseases and ARFID may impact clinical care; however, healthcare professionals often lack sufficient knowledge of these patient populations. Therefore, further research and consideration in clinical practice are necessary.

Trial registration: German Clinical Trials Register: DRKS00015859 (registered 18 December 2018) and ClinicalTrials.gov: NCT04339465 (registered 8 April 2020).

Background: Cerebrotendinous xanthomatosis (CTX) is an inherited metabolic disorder caused by variants in CYP27A1 leading to loss of sterol-27-hydroxylase activity. Sterol-27-hydroxylase generates two classes of bioactive signaling molecules: bile acids and oxysterols. The broader metabolic consequences resulting from perturbations in bile acid and oxysterol signaling and their reversibility with FDA-approved treatment chenodeoxycholic acid (CDCA), are not fully described.

Methods: To establish a comprehensive map of metabolic consequences of CTX, we performed large-scale, untargeted plasma metabolomics in a single subject with CTX, both before and after 6 months of CDCA therapy, and compared results with a reference cohort of over 1100 individuals. Data were analyzed for significant metabolite changes and pathway alterations.

Results: Untreated CTX exhibited marked depletion of bile acid intermediates and elevations in sterol precursors, consistent with the known enzymatic block in this pathway. Metabolomics highlighted additional pathways affected by bile acid and oxysterol signaling such as fatty acid metabolism, NAD⁺ de novo synthesis, phosphatidylethanolamines, sphingolipids and ferroptosis. Following six months of CDCA therapy, sterol precursors normalized, bile acid intermediates partially recovered, and phosphatidylethanolamines were restored toward reference ranges, while steroid and phosphatidylcholine metabolites remained largely unchanged.

Conclusions: This study exposes the comprehensive nature of metabolic disturbance in CTX beyond the bile acids pathway, revealing perturbations in bile acids, steroids, fatty acids, phospholipids and NAD+ synthesis and highlights the dynamic early response to CDCA therapy. The metabolomic profile of untreated CTX can be leveraged for diagnostic screening. These findings report new candidate biomarkers for diagnosis and monitoring and underscore the potential of metabolomics to uncover broader metabolic consequences in rare disease.

Background: Tenosynovial giant cell tumor (TGCT) is a rare, locally aggressive tumor originating in the synovial lining of the joint, bursa, and tendon sheath. TGCT typically affects individuals between 20 and 50 years of age and pediatric cases are considered ultra-rare. Research and clinical trials thus far have been largely focused on the adult TGCT population. Therefore, data are needed to understand the impact of TGCT on pediatric patients' quality of life and any differences between adults. Here we report the result of the pediatric TGCT population enrolled in an observational patient registry.

Patients and methods: A total of 122 pediatric patients (9.5%) were included in this exploratory, cross-sectional analysis of a longitudinal 1,278-patient registry from October 06, 2022 to November 26, 2024. Among pediatric patients, 73.0% had diffuse TGCT (D-TGCT; n = 89), 16.4% had localized TGCT (L-TGCT; n = 20), and 10.6% had unspecified TGCT (n = 13). Pediatric patients had a median age at diagnosis of 14.5 years.

Results: More than half of pediatric patients were initially misdiagnosed and were more likely to be misdiagnosed than adults (62.3% vs. 49.9%, p < 0.01) and received joint aspirations significantly more frequently than adult patients (47.5% [n = 58] vs. 22.5% [n = 112], p < 0.05). Most pediatric patients were diagnosed by orthopedic surgeons (n = 79, 64.8%), and 52.5% of pediatric patients were diagnosed ≥ 1 years after symptom onset. Pediatric patients with D-TGCT underwent an average of 3.4 surgeries, compared to 1.8 surgeries for those with L-TGCT. Recurrence rates were similar among adults and pediatric patients with 66.3% of pediatric patients with D-TGCT having ≥ 1 post-operative recurrence compared to 15.0% of L-TGCT pediatric patients, respectively. Despite no approved systemic therapies for pediatric use, pediatric and adult patients consulted medical oncologists in similar rates and systemic therapies were prescribed similarly but infrequently overall (n = 21, 17.2% in pediatric patients and n = 95, 19.1% in adults).

Conclusions: Pediatric patients had significant disease burden, as compared to adults with TGCT, which severely affected their quality of life. The reliance on surgical treatment and underuse of multidisciplinary care emphasizes the unmet need for provider education and treatment advancements tailored to this population.

Trial registration: This study was an analysis of an observational patient registry and therefore was not registered as a clinical trial; no trial registration number is available. The study protocol was approved by Advarra (protocol reference number: Pro00077310). Patient enrollment for this analysis occurred from October 6, 2022, to November 26, 2024.

Background: Isobutyryl-coenzyme A dehydrogenase deficiency (IBDD) is a rare inborn error of valine metabolism caused by variants in the ACAD8 gene. Since its initial description in 1998, a wide range of clinical features has been reported, but the disease status and clinical significance of IBDD remain under debate. We systematically studied all published cases of IBDD to provide an overview of the reported phenotype and molecular spectrum.

Results: A comprehensive literature review identified 172 individuals with IBDD reported up to December 2024. Seven children were diagnosed following selective screening due to family history or clinical suspicion, while 165 were identified through expanded newborn screening programs. Elevated blood or plasma C4-acylcarnitine was observed universally, and isobutyrylglycinuria was a common but not invariable urinary marker. Of these 172 individuals, 146 were asymptomatic at follow-up, whereas 26 presented with diverse, non-specific manifestations, including motor delay, failure to thrive, muscular hypotonia, speech delay, developmental delay, and anemia-the latter being the most frequently reported abnormality. Biallelic pathogenic variants in ACAD8 were identified in most cases with available genetic information, with c.286G > A p.(Gly96Ser) emerging as the most prevalent variant, predominantly among individuals of Chinese origin. Notably, altered biochemical markers of liver function were reported in 19 individuals, including 18 with isolated elevations of serum transaminases and γ-glutamyl transferase. One 11-year-old boy exhibited hepatomegaly and ultrasound findings suggestive of hepatic steatosis, along with markedly elevated transaminase levels. Hepatic steatosis has also been observed in an IBDD mouse model, suggesting a potential link between IBDD and liver involvement.

Conclusions: Most individuals with IBDD remain asymptomatic following detection through newborn screening, yet a minority develop heterogeneous clinical features. Our overview highlights that some liver enzyme abnormalities and hepatic steatosis may occur in some individuals with IBDD. These findings suggest that further research is warranted to clarify possible hepatic implications of IBDD and to determine whether long-term monitoring of affected individuals should be considered, particularly in light of ongoing discussions about the appropriateness of IBDD as a target condition in newborn screening programs.