Orphanet Journal of Rare Diseases最新文献

Background: Spinocerebellar ataxia type 3 (SCA3) is a hereditary disease caused by abnormally expanded CAG repeats in the ATXN3 gene. The study aimed to identify potential biomarkers for assessing therapeutic efficacy by investigating the associations between expanded CAG repeat size, brain and spinal cord volume loss, and motor functions in patients with SCA3.

Methods: In this prospective, cross-observational study, we analyzed 3D T1-weighted MRIs from 92 patients with SCA3 and 42 healthy controls using voxel-based morphometry and region of interest approaches. Associations between expanded CAG repeat size, brain and spinal cord volume loss, and International Cooperative Ataxia Rating Scale (ICARS) scores were investigated using partial correlation and mediation analyses. Sample sizes of potential biomarkers were calculated.

Results: Compared with healthy controls, SCA3 patients had lower cerebellar volume and cervical spinal cord area. SCA3 patients evolved along a stage-independent decline that began in the cerebellum, progressed to spinal cord, brainstem, thalami, and basal ganglia, and extensive subcortex. Expanded CAG repeat size was associated with right cerebellar lobule IV volume (r = - 0.423, P < 0.001) and cervical spinal cord area (r = - 0.405, P < 0.001), and higher ICARS (r = 0.416, P < 0.001). Mediation analysis revealed an indirect effect of expanded CAG repeat size on ICARS through spinal cord. Sample sizes estimation revealed that a minimum sample size was achieved with spinal cord measures.

Conclusions: Our results indicate the potential of cervical spinal cord area as a biomarker for disease progression and a minimum sample size estimation in future clinical studies of SCA3.

Background & aim: Twenty-four-hour urinary copper excretion (24 h-UCE) is the standard diagnostic tool for dose adjustments in maintenance therapy in Wilson disease (WD) patients. Guidelines lack data if both variants of 24 h-UCE measurement (with or without 48 h of treatment interruption) are equally interpretable.

Methods: Eighty-four patients with a confirmed diagnosis of WD treated with chelators (50% of patients with D-Penicillamine and 50% with trientine) and with pairwise 24-h-UCE values on-therapy and off-therapy were included in the analysis. Pairwise urinary sampling between October 2022 (T0) and a 12-month FU (T2) was compared, and exchangeable copper (CuEXC) was additionally measured at T0.

Results: Among the 84 patients, 65% had predominant hepatic symptoms, the median age was 42 years, and 58% were female. At T0, patients were in the stable maintenance phase, with a median treatment duration of 21.9 years. The levels of the biochemical markers liver and copper metabolism remained stable over the 12-month observation period for all patients. 24 h-UCE off-therapy significantly decreased from T0 to T2 (p = 0.03), whereas no statistically significant differences were detected for 24 h-UCE after therapy. Both sampling methods did not correlate. CuEXC was significantly correlated with 24 h-UCE after 48 h of dose interruption (p = 0.018) but not with 24 h-UCE after therapy. A total of 46% of the 24 h-UCE value pairs were discordant, laying out the aimed therapeutic ranges given in current international guidelines.

Conclusion: Off-therapy 24 h-UCE reflects the "free" copper pool more accurately than does urinary sampling. The study shows discordant results for both sampling methods in approximately half of the patients, revealing that interpretation of 24 h-UCE with respect to chelator-dosing decisions should be performed with caution.

Background: Compound inheritance of TBX6 accounts for approximately 10% of sporadic congenital scoliosis (CS) cases. Such cases are called TBX6-associated congenital scoliosis (TACS). TACS has been reported to have certain common clinical phenotypes. However, whether the surgical outcomes of TACS patients differ from those of other CS patients remains unclear.

Methods: We retrospectively searched for patients who were diagnosed with scoliosis. TACS was identified in genetic testing for CS. After propensity score matching, patients with TACS were matched with patients with NTACS according to sex, age, main curvature, classification, deformity location, surgical methods, fusion segment and number of fusions. We evaluated and compared the coronal and sagittal radiographic parameters before surgery, immediately after surgery, and at the final follow-up. Surgical information, including surgical method, fusion segment, blood loss and complications, was also compared and analyzed.

Results: Twenty-eight TACS patients were propensity score matched with 28 NTACS patients among 473 CS patients. The preoperative matching parameters mentioned in the Methods section were similar between the TACS group and the NTACS group. In the TACS group, the correction rate of the cranial compensatory curve (64.9 ± 18.6% vs. 51.2 ± 24.0%, P = 0.014) and the correction rate of the caudal compensatory curve (77.4 ± 12.5% vs. 65.4 ± 22.7%, P = 0.011) were significantly greater than those in the NTACS group, and the loss rate of correction of the cranial compensatory curve in the TACS group (0.6 ± 19.2% vs. 26.7 ± 50.8, P = 0.002) was significantly lower than that in the NTACS group. The total complication rate (7.2% vs. 14.3%) and incidence of adding-on (0 vs. 7.1%) were lower in the TACS group than in the NTACS group. There were no significant differences between the two groups in terms of blood loss, revision rate, other correction parameters, balance parameters or incidence of complications.

Conclusions: TACS patients had better surgical outcomes than NTACS patients, which means that genetic diagnosis of the TBX6 gene mutation in CS before surgery can help predict better surgical outcomes. The specific genetic mechanism is not yet clear and may be related to the relatively normal development of paravertebral tissues in TACS patients. Further research is needed.

Level of evidence: Leve: III.

Background: Compliance to highly restrictive diets is critical for children with Methylmalonic Acidemia (MMA), and their caregivers play a prominent role in children's dietary treatment from early childhood through to adulthood. Despite lots of efforts by the multidisciplinary medical team to ensure the smooth implementation of dietary treatment, restricting dietary protein remains particularly challenging for children with MMA. This study aimed to assess dietary treatment compliance in children with MMA and evaluate the impact of WeChat-based parent education on compliance.

Methods: A sample of 151 caregiver-child dyads was obtained through online recruitment using convenience sampling from February to March 2023. At least one month following the enrollment of MMA caregivers in the WeChat public account "Methylmalonic Acidemia Diet Manager", structured questionnaires were distributed to them through the electronic platform "Questionnaire Star" in collaboration with the Chinese National Alliance of Rare Diseases. Subsequently, the collected data was analyzed using quantitative methods.

Results: Children with MMA aged over 5 years were more likely to present a lower level of dietary treatment compliance compared to those under 1 year old. Besides, the levels of children's dietary treatment compliance were higher when their caregivers had higher levels of satisfaction and benefit from using the public account.

Conclusion: Our findings highlighted the significance of age-related challenges in dietary treatment compliance among children with MMA and the promising impact of utilizing WeChat public accounts as a supportive education tool.

Background: Lynch syndrome (LS)-associated colorectal cancer (CRC) always ascribes to pathogenic germline mutations in mismatch repair (MMR) genes. However, the penetrance of CRC varies among those with the same MMR gene mutation. Thus, we hypothesized that the gut microbiota is also involved in CRC development in LS families.

Methods: This prospective, observational study was performed from December 2020 to March 2023. We enrolled 72 individuals from 9 LS families across six provinces in China and employed 16S rRNA gene amplicon sequencing to analyze the fecal microbiota components among LS-related CRC patients (AS group), their spouses (BS group), mutation carriers without CRC (CS group), and non-mutation carriers (DS group) using alpha and beta diversity indices.

Results: There were no apparent differences in age or gender among the four groups. Alpha and beta diversity indices exhibited no significant differences between the AS and BS groups, verifying the role of germline mutations in the occurrence of CRC in LS families. Beta diversity analysis exhibited significant differences between the AS and CS groups, revealing the importance of the gut microbiota for the occurrence of CRC in LS families. A greater difference (both alpha and beta diversity indices) was shown between the AS and DS groups, demonstrating the combined impact of the gut microbiota and genetic germline mutations on the occurrence of CRC in LS families. Compared with those in the CS and DS groups, we identified ten microbial genera enriched in the AS group, and one genus (Bacteroides) decreased in the AS group. Among the elevated genera in the AS group, Agathobacter, Coprococcus and Prevotellaceae_NK3B31_group were butyrate-producing genera.

Conclusion: This study found the development of CRC in the LS families can be attributed to the combined effects of gene germline mutations as well as the gut microbiota and provided novel insights into the prevention and treatment of CRC in the LS families.

Background: Sturge-Weber Syndrome (SWS) is a rare, sporadic neurocutaneous disorder affecting the skin, brain, and eyes, due to somatic activating mutations in GNAQ or, less commonly, GNA11 gene. It is characterized by at least two of the following features: a facial capillary malformation, leptomeningeal vascular malformation, and ocular involvement. The spectrum of clinical manifestations includes headache, seizures, stroke-like events, intellectual disability, glaucoma, facial asymmetry, gingival hyperplasia, etc. An early diagnosis is crucial to guarantee an appropriate care, which is best performed in reference centres by multidisciplinary teams. The aim of this study was to develop a multidisciplinary expert consensus for diagnosis, treatment, and follow-up of all disease manifestations, according to the recommendations of the Italian Law on Rare Disease Care.

Results: Through a Delphi consensus methodology, 28 recommendations have been developed concerning (i) dermatological SWS manifestations and related treatment timing and modalities, (ii) neurological referral, diagnosis, pharmacological treatment of neurological signs and symptoms, neurosurgical indications, neurocognitive evaluation and related treatment, psychosocial support and patient follow-up, (iii) diagnosis of ophthalmological manifestations, medical and surgical treatment, and follow-up, (iv) maxillofacial surgical treatment, (v) oral cavity assessment, care and follow-up, and (vi) primary care paediatrician/general practitioner involvement.

Conclusions: The present consensus developed by a multidisciplinary group of experts from Italian reference centres comprises practical recommendations for SWS global management, including currently controversial issues. Specific statements for all disease aspects, from skin manifestations and neurological and ocular signs and symptoms to oral and maxillofacial care, are provided. They can be exploited to uniform clinical practice in reference centres, but also in other hospitals and outpatient settings. Though this consensus has been developed taking primarily into account the Italian National Health System organization and rules on rare disorders, it could be translated also to other countries.

Introduction: Significant advances in the treatment of transthyretin (ATTR) amyloidosis has led to an evolving understanding of the epidemiology of this condition. This systematic literature review (SLR) aims to synthesize current evidence on epidemiology and mortality outcomes in ATTR amyloidosis, addressing the need for a comprehensive understanding of its current global impact.

Methods: An SLR of the literature from January 2018 to April 2023 was conducted using the Medline and Embase databases. The review followed the PRISMA guidelines. Studies evaluating populations with genotypes and phenotypes of ATTR amyloidosis (variant and wild-type cardiomyopathy, polyneuropathy, and mixed) were included. Observational studies, systematic reviews, and meta-analyses were eligible, while reports, commentaries, clinical trials, and non-ATTR amyloidosis studies were excluded. Extracted data included prevalence, incidence, and mortality rates.

Results: Of the 1,458 studies identified, 113 met the inclusion criteria. Forty-nine studies reported on epidemiology, while 64 focused on mortality rates in cohorts of patients with ATTR amyloidosis from Europe (n = 16), North America (n = 26), Asia (n = 5), and Australia (n = 2). No studies were found that exclusively focused on ATTR amyloidosis in Africa or South America. ATTR prevalence ranged from 6.1/million in the US to 232/million in Portugal with very limited data on ATTR-PN. The 2-year mortality risk ranged from 10 to 30% among wild-type ATTR-CM and from 10 to 50% for variant type of ATTR-CM.

Conclusions: This SLR demonstrated heterogeneity in ATTR epidemiology and mortality rates across global regions. Further investigation is needed to address knowledge gaps of the epidemiology and burden of ATTR, which may improve early diagnosis and management.

Background: Inclusion Body Myositis is an acquired muscle disease. Its pathogenesis is unclear due to the co-existence of inflammation, muscle degeneration and mitochondrial dysfunction. We aimed to provide a more advanced understanding of the disease by combining multi-omics analysis with prior knowledge. We applied molecular subnetwork identification to find highly interconnected subnetworks with a high degree of change in Inclusion Body Myositis. These could be used as hypotheses for potential pathomechanisms and biomarkers that are implicated in this disease.

Results: Our multi-omics analysis resulted in five subnetworks that exhibit changes in multiple omics layers. These subnetworks are related to antigen processing and presentation, chemokine-mediated signaling, immune response-signal transduction, rRNA processing, and mRNA splicing. An interesting finding is that the antigen processing and presentation subnetwork links the underexpressed miR-16-5p to overexpressed HLA genes by negative expression correlation. In addition, the rRNA processing subnetwork contains the RPS18 gene, which is not differentially expressed, but has significant variant association. The RPS18 gene could potentially play a role in the underexpression of the genes involved in 18 S ribosomal RNA processing, which it is highly connected to.

Conclusions: Our analysis highlights the importance of interrogating multiple omics to enhance knowledge discovery in rare diseases. We report five subnetworks that can provide additional insights into the molecular pathogenesis of Inclusion Body Myositis. Our analytical workflow can be reused as a method to study disease mechanisms involved in other diseases when multiple omics datasets are available.

Background: Bulbar function is frequently impaired in patients with spinal muscular atrophy (SMA). Although extremely important for the patient's quality of life, it is difficult to address therapeutically. Due to bulbar dysfunction, maximum mouth opening (MMO) is suspected to be reduced in children with SMA. However, no published MMO values exist for SMA children younger than 24 months. This study presents a novel approach to measuring MMO in infants and toddlers with SMA and compares it with healthy controls.

Methods: Children with SMA (0-24 months) who received disease-modifying therapy at a single neuropediatric center and similarly aged healthy children were prospectively recruited. MMO was measured using a cardboard scale and a custom-designed instrument.

Results: A total of 115 children were included (SMA = 24, healthy controls = 91). Inter-rater reliability between two examiners was excellent (ICC = 0.987, 95% CI 0.959 to 0.995), as was the reliability between the cardboard scale and the custom-designed instrument (ICC = 0.986, 95% CI 0.968 to 0.994). A mixed linear model showed a significant increase of MMO with age, and a significantly wider mouth opening in healthy controls (p < .001).

Conclusion: For future research, MMO can provide valuable information about the involvement of cranial nerves, particularly in the context of disease-modifying therapies, even at a very early age.

Background: Homozygous familial hypercholesterolaemia (HoFH) increases risk of premature cardiovascular events and cardiac death. In severe cases of HoFH, clinical signs and symptoms cannot be controlled well by non-surgical treatments, liver transplantation (LT) currently represents the viable option.

Method: To assess the clinical efficacy, prognosis, and optimal timing of LT for HoFH, a retrospective analysis was conducted on the preoperative, surgical conditions, and postoperative follow-up of children who received an LT for HoFH at the Beijing Friendship Hospital over the period from December 2014 to August 2022.

Results: Xanthoma and decreased activity tolerance were the primary clinical manifestations in the 7 HoFH children initially assessed (one child died suddenly prior to surgery due to cardiac arrest). Accompanying these symptoms were increased blood total cholesterol (TC) and low density lipoprotein (LDL) levels, along with severe cardiovascular diseases. HoFH was confirmed in all cases by genetic and biochemical assays. Initial treatments administered to these patients consisted of low-fat diets and lipid-lowering drugs with poor outcomes. Accordingly, all 6 patients received orthotopic liver transplantations (OLT), with the result that significant postoperative reductions were observed in levels of TC and LDL. The median follow-up of these six cases was 37.41 months (range: 19.40-94.10 months). Regular postoperative follow-ups revealed that all survived and showed significant improvements in their clinical symptoms.

Conclusion: So far, LT is the only way to heal HoFH. LT before the appearance of obvious cardiovascular atherosclerotic lesions can significantly improve the quality of life and prognosis of patients. At the same time, the blood cholesterol level of patients should be continuously monitored after LT to further control the progression of vascular complications.