Orphanet Journal of Rare Diseases最新文献

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.

Objective: Spinal muscular atrophy (SMA) is a motor neuron disorder encompassing 5q and non-5q forms, causing muscle weakness and atrophy due to spinal cord cell degeneration. Understanding its genetic basis is crucial for genetic counseling and personalized treatment options.

Methods: This study retrospectively analyzed families of patients suspected of SMA at our institution from February 2006 to March 2024. Various molecular techniques, including multiplex ligation-dependent probe amplification analysis, long-range polymerase chain reaction (PCR) combined with nested PCR, Sanger sequencing, and whole-exome sequencing were employed to establish a thorough genetic variant profile in 680 Chinese pedigrees with clinically suspected SMA.

Results: Out of 680 families suspected of having SMA, 675 exhibited mutations in the SMN1 gene, while three families were linked to mutations in the IGHMBP2 gene. One family exhibited a genetic variation in the NEB gene, and another family exhibited a variation in the SCO2 gene. Among the families with mutations in the SMN1 gene, 645 families exhibited either E7‒E8 or E7 homozygous deletion. Some families displayed E7‒8 heterozygous deletions along with other mutations, such as E1 or E1‒6 heterozygote deletion and point mutations. Furthermore, one family demonstrated a compound-heterozygous double mutation, while another carried a type "2 + 0" mutation alongside a point mutation.

Conclusions: This study comprehensively analyzed the genetics of suspected familial SMA cases in the Chinese population, providing insights into the molecular genetic mechanisms of SMA and the utility of various detection techniques. The findings revealed important implications for genetic counseling, prenatal diagnosis, and targeted therapies in clinical practice.

Background: Syndromic genetic disorders affecting vision can also cause hearing loss, and Usher syndrome is by far the most common etiology. However, many other conditions can present dual sensory impairment. Accurate diagnosis is essential for providing patients with genetic counseling, prognostic information, and appropriate resources. This study aimed to describe the genetic profile of combined inherited deaf-blindness in Portugal.

Methods: This was a cross-sectional study conducted at a tertiary hospital in Portugal. Patients were identified through the national, web-based inherited retinal dystrophies registry (IRD-PT, retina.com.pt). Demographics, clinical, and genetic data were retrieved from individual patient records. Genetic variants were classified according to the American College of Medical Genetics and Genomics; only likely pathogenic or pathogenic variants were considered relevant for solved cases.

Results: Eighty-four patients (58.3% males; mean age 40.0 ± 17.9 years) from 71 families were included. Usher syndrome was the most frequent etiology (71.4%) followed by Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract syndrome (6.0%), Autosomal dominant optic atrophy plus (4.8%) and cone-rod dystrophy and hearing loss (4.8%). Other less frequent etiologies included Alport syndrome (2.4%), Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (2.4%), Heimler syndrome (2.4%), Senior-Loken syndrome (1.2%), Waardenburg syndrome (1.2%), Maternally inherited diabetes and deafness (1.2%), and Stickler syndrome (1.2%). The overall diagnostic yield of deleterious variants in our deaf-blind cohort was 73.2%. A total of 55 genetic variants were identified across 16 different genes; 11 of these variants are novel and herein reported for the first time.

Conclusions: This is the first study to describe the genetic profile of patients with dual sensory impairment in Portugal, highlighting the genetic heterogeneity associated with inherited deaf-blindness. Usher syndrome was the most prevalent cause in this cohort. Nevertheless, several other less frequent causes must also be considered. This study showed a high diagnostic yield and reported 11 novel genetic variants, thereby contributing to expand the mutational spectrum of these conditions.

Background: Late-onset Pompe disease (LOPD) is an autosomal recessive lysosomal storage disorder that results in severe progressive proximal muscle weakness. Over time, reductions in muscle strength result in respiratory failure and a loss of ambulation. Delayed diagnosis of LOPD deprives patients of treatments that can enhance quality of life and potentially slow disease progression. The objective of this study is to determine if patients with a nonspecific diagnosis, such as muscle weakness, may be at risk for LOPD using retrospective chart review of patients seen at two centers: an academic center and a community health system.

Results: Initial data pulls identified 80,070 patients with one of the ICD-10 codes of interest. Chart review found 551 of these patients also had at least one lab value commonly abnormal in individuals with LOPD and of these 110 scored as "at-risk". After removing phenocopies/other confirmed unrelated diagnoses, 46 individuals were contacted either directly or through their healthcare provider for genetic counseling. Three patients had pretest genetic counseling and were tested for decreased levels of acid-α-glucosidase. One patient was found to have deficient acid-α-glucosidase. Additionally, a physician educated through the program ordered LOPD testing for their patient and diagnosed them with LOPD.

Conclusion: This study confirms that a symptom-based scoring tool and chart review combined with provider education can identify patients who are at increased likelihood to have a missed LOPD diagnosis.

Background: There is no unified prognostic scoring system for light chain cardiac amyloidosis (AL-CA), particularly stage IIIb AL-CA. This study aimed to use invasive haemodynamic information to investigate markers that can more accurately evaluate the prognosis of patients with stage IIIb AL-CA.

Methods: In this retrospective cohort study, we conducted invasive haemodynamic measurements concurrently with myocardial biopsies to diagnose AL-CA. We used Cox regression analysis and time-dependent receiver operating characteristic curve analysis to study the associations between these measurements and overall mortality. Echocardiographic parameters were also recorded and analysed via logistic regression to explore their relationships with haemodynamic changes.

Results: Although traditional haemodynamic parameters, such as the cardiac index (CI), pulmonary artery wedge pressure (PAWP), pulmonary artery pressure, and vascular resistance, did not correlate with mortality, the PAWP/CI ratio emerged as a vital prognostic marker. Patients with a PAWP/CI ratio above 11 mmHg/L/min/m² had markedly poorer survival. Kaplan‒Meier analysis highlighted the prognostic significance of the ratio, revealing distinct survival differences. Furthermore, logistic regression confirmed that echocardiographically measured pulmonary artery systolic pressure independently correlated with increases in the PAWP/CI ratio.

Conclusions: In stage IIIb AL-CA patients, the PAWP/CI ratio, which surpasses traditional haemodynamic indicators, significantly predicts all-cause mortality, emphasizing its prognostic value. Our findings suggest that echocardiography-derived PASP could alternatively reflect the PAWP/CI ratio.

Purpose: X-linked adrenoleukodystrophy (XALD) can affect the eyes. Existing therapies are hampered by early quantitative examination methods. This study used an optical coherence tomography angiography system (OCTA) to investigate retinal microvascular density and perfusion in XALD patients.

Methods: Fifty-two patients and 47 age-matched controls were included in this cross-sectional study. The patients were divided into three groups (symptomatic, less symptomatic, and controls). We compared the foveal avascular zone area, vascular density and perfusion area at the superficial vascular complex (SVC) and deep vascular complex (DVC) of the peripapillary and macular between the groups. We correlated these measurements with scale scores.

Results: Compared with the controls, the symptomatic group had significantly lower vascular density in the superior nasal sector of the peripapillary SVC (MD - 4.940884; 95% CI - 9.655061 to - 0.226707; p = 0.036), lower vascular density (MD - 4.259225; 95% CI - 8.248627  to  - 0.269823; p = 0.032) and lower perfusion area (MD - 0.180304; 95% CI - 0.337135  to  - 0.023472; p = 0.018) in the peripheral ring superior quadrant of the macular SVC. Compared with the less symptomatic group, the symptomatic group exhibited a significantly lower vascular density (MD - 5.635483; 95% CI - 10.450009  to  - 0.820957; p = 0.015) and perfusion area (MD - 0.063351; 95% CI - 0.116611  to  - 0.010091; p = 0.013) in the superior nasal sector of the peripapillary SVC; lower vascular density (MD - 4.817846; 95% CI - 8.924294  to  - 0.711399; p = 0.015) and perfusion area (MD - 0.202707; 95% CI - 0.369499  to  - 0.035915; p = 0.011) in the peripheral ring superior quadrant of the macular SVC; and greater vascular density (MD 7.209401; 95% CI 0.818716-13.600086; p = 0.021) and perfusion area (MD 0.047320; 95% CI 0.001685-0.092956; p = 0.039) in the inferior nasal sector of the peripapillary DVC. Among the 52 patients, the expanded disability status score (EDSS) was moderately negatively correlated with the vascular density (p = 0.001) and perfusion area (p = 0.002) in the peripheral ring superior quadrant of the macular SVC.

Conclusion: Changes in retinal vascular density and perfusion exist in XALD patients and are correlated with disease severity. OCTA has the potential to monitor the progression of XALD.

Background: Intestinal Behçet's syndrome (IBS) has high morbidity and mortality rates with serious complications. However, there are few specific biomarkers for IBS. The purposes of this study were to investigate the distinctive metabolic changes in plasma samples between IBS patients and healthy people, active IBS and inactive IBS patients, and to identify candidate metabolic biomarkers which would be useful for diagnosing and predicting IBS.

Methods: In this study, we performed a global untargeted metabolomics approach in plasma samples from 30 IBS patients and 20 healthy subjects. P value < 0.05 and variable importance projection (VIP) values > 1 were considered to be statistically significant metabolites. Univariate receiver operating characteristic (ROC) curve analysis was plotted as a measure for assessing the clinical performance of metabolites, and area under curve (AUC) were assessed.

Results: A total of 147 differentially abundant metabolites (DAMs) were identified between IBS patients and normal control (NC) group. The potential pathways involved in the pathogenesis of IBS include linoleic acid metabolism; GABAergic synapse; biosynthesis of unsaturated fatty acids; valine, leucine and isoleucine biosynthesis; ovarian steroidogenesis; and others. In addition, a total of 103 significant metabolites were selected to distinguish active IBS from inactive IBS patients. Tyrosine metabolism, dopaminergic synapse and neuroactive ligand-receptor interaction were found to be closely related to the disease activity of IBS. Furthermore, three potential metabolites including quinate, stearidonic acid (SDA) and capric acid (CA) could significantly differ IBS patients from NC group. On the other hand, 1-methyladenosine (m1A), genipin, methylmalonic acid (MMA) and ascorbate could significantly differentiated active IBS from inactive IBS patients.

Conclusion: In conclusion, this study demonstrated the characteristic plasma metabolic profiles between IBS group and NC group, as well as between active and inactive IBS patients by using an untargeted LC/MS metabolomics profiling approach. In this study, quinate, SDA and CA were identified as potential diagnostic biomarkers for IBS. Additionally, m1A, genipin, MMA and ascorbate could serve as potential biomarkers for evaluating IBS activity. These findings might provide potential valuable insights for developing therapeutic strategies to manage IBS in the future.