Orphanet Journal of Rare Diseases最新文献

Background: Glutaric Aciduria Type 1 (GA-1) is a rare metabolic disorder characterized by a deficiency in glutaryl-coenzyme A dehydrogenase (GDH), leading to the accumulation of neurotoxic compounds that affect neurodevelopment. This study investigated the neurocognitive profiles and academic challenges faced by pediatric patients with GA-1. To explore the neurocognitive characterization and academic impact in pediatric patients with GA-1 from the National Registry of GA-1.

Methods: This prospective, observational, multicenter study included 42 pediatric patients (25 boys and 17 girls) from a national registry. Neurocognitive evaluations were performed using age-appropriate psychometric tests. Data analysis included analysis of variance (ANOVA) and random forest models to identify the neurocognitive variables that impact learning outcomes.

Results: The patients showed significant variability in neurocognitive outcomes. Children under 4 years of age had average cognitive development and deficits in gross motor skills. Older children had average intelligence scores but moderate to severe impairments in executive functions, attentional processes, and visuocognitive skills. Approximately 60% of the participants required special educational support.

Conclusions: GA-1 patients exhibit neurocognitive impairments that affect learning, necessitating personalized educational interventions. Therefore, early diagnosis and management of this condition are critical. Further research is needed to explore long-term neurocognitive outcomes and the relationship between biochemical subtypes and clinical outcomes.

Background: Rare diseases affect few people, but collectively they affect a substantial proportion of the population. Limited treatment options and the additional challenges of securing public funding make reimbursement decision making particularly complex, mainly due to the inherent evidence uncertainty, lack of understanding of these diseases and the greater impact on non-health outcomes. This study explored societal preferences regarding which factors should be valued when considering public subsidy of drugs to treat rare diseases.

Methods: A discrete choice experiment was developed, and respondents were asked to assume the role of a Government advisor and decide on funding between 2 drugs to treat a rare disease. Attributes were identified from the literature and focus groups, including uncertainty of the evidence, unmet need, magnitude of the clinical benefit, magnitude in quality of life and total cost to government. A representative sample of Australians (n = 1099) completed the online survey. Data were analysed using mixed logit regression and latent class models to examine heterogeneity. Willingness to pay was also estimated.

Results: In general, respondents had a greater preference for drugs that increase survival, where there was greater confidence in the effectiveness of the new drug and which increased patients' capacity to do their usual activities. Preferences were not homogenous, the latent class analysis identified three groups: Class 3 (58%) demonstrated a strong preference for improvements in survival; Class 2 (21%) showed a strong preference for confidence in the evidence; and Class 1 (21%) positively valued increased government expenditure.

Conclusion: These results are consistent with previous studies that used different methodologies in showing a preference for drugs with improved survival and quality of life. However, addressing a societal preference for greater confidence in the evidence - reducing evidential uncertainty - represents a methodological and policy challenge for the evaluation of drugs in rare diseases.

Clinical trial number: Not applicable.

Background: Glycogen storage disease type IXc (GSD IXc) is an ultra-rare disorder impairing liver glycogen degradation, caused by a defect in phosphorylase kinase (PhK) γ subunit in the liver encoded by PHKG2. We aim to investigate the clinical, biochemical, genetic, therapeutic, and follow-up characteristics of 17 GSD IXc patients.

Methods: Medical records were retrieved, focusing on clinical (height, complications etc.), biochemical [blood glucose, liver transaminases, chitotriosidase (Chit), etc.], genetic, treatment, and follow-up data for 17 patients (8 males, 9 females) with GSD IXc including 16 pediatric patients and one adult.

Results: Abdominal distension (16/16), hypoglycemia (16/16), muscular weakness (12/16), and short stature (5/16) were among the most common presenting features in 16 pediatric patients. At first visit, all 16 pediatric patients showed increased alanine aminotransferase and aspartate aminotransferase. Elevated gamma-glutamyl transferase, triglyceride, lactate, uric acid and total cholesterol were found in 15/15, 10/14, 7/13, 7/14 and 2/14 pediatric patients, respectively. Creatine kinase levels were within normal range in 14/14 patients. The adult patient was diagnosed with liver cirrhosis on her first visit at 36 years. Five out of sixteen pediatric patients achieved hepatomegaly remission after 8.6 ± 4.0 years of uncooked cornstarch (UCCS). The standard deviation scores for ΔHeight in 16 pediatric patients increased from - 1.76 ± 1.16 to 0.05 ± 1.02 (p < 0.0001). Significant improvements were observed in preprandial blood glucose levels and liver transaminases (all p < 0.05). Elevated Chit levels at an early stage of therapy decreased with UCCS [44.47 (9.52, 70.03) to 8.22 (6.37, 18.89) nmol/ml/h, p = 0.02]. One girl received liver transplantation and her clinical manifestations were greatly improved. Eighteen PHKG2 variants were identified, including twelve novel variants and one recurrent variant [c.469G > A, p.E157K (allele frequency: 11/34, 32.4%)]. The c.96-11G > A variant was found to cause a 9 bp retention on the right-hand side of intron 1. Patients with biallelic nonnull variants showed better response to UCCS therapy compared to those with null variants.

Conclusion: This study expanded the clinical and variant spectrums of GSD IXc. Chit might be used as a biomarker for monitoring the treatment. Differential response to UCCS therapy based on variant type suggest a genotype-phenotype correlation.

Background: Congenital disorders of glycosylation (CDG) are a complex and heterogeneous family of rare metabolic diseases that affect protein and lipid glycosylation and glycosylphosphatidylinositol synthesis. These disorders can affect multiple organs, leading to a broad spectrum of symptoms that vary among different CDG subtypes and between individuals with same type of CDG. This study aimed to investigate the genetic variants, molecular etiologies, and clinical features of 20 Chinese patients diagnosed with CDG.

Results: Using whole-exome sequencing (WES), functional prediction tools, Sanger sequencing, and segregation analysis, we identified variants in several genes: ALG2 (3 patients), DPM2 (3 patients), PMM2 (3 patients), and ALG13 (2 patients). Additionally, variants in COG5, COG6, MOGS, DPM3, ALG1, ALG3, ALG11, SSR4 and SLC35A2 each were observed in single case. In total, 28 distinct variants were identified, 11 of which were previously unreported. Genotype-phenotype correlations revealed notable findings: variants in the N-terminus of ALG2 before the intramembrane domain were associated with congenital myasthenic syndromes (CMS), whereas those in the C-terminus caused ALG2-CDG; DPM2-CDG patients with variants in transmembrane region 1 exhibited more severe phenotypes; male patients with hemizygous variants in SLC35A2 demonstrated milder phenotypes compared to those with mosaic variants.

Conclusions: This findings expand the spectrum of known clinical presentations and genetic variants in CDG, and establish possible genotype-phenotype correlations of several pathogenic genes, emphasizing the need for functional studies to unravel the underlying mechanisms.

Background: Over the past approximately 40 years, Chinese drug regulations have undergone many major reforms to accelerate the approval of drugs and keep pace with the scientific innovation of drugs in the world, especially developed countries. In 2018 and 2023 China's National Health Commission in collaboration with other departments released China's "First Batch of Rare Diseases Catalogue" and "Second Batch of Rare Disease Catalogue". However, there is currently less relevant research on the overview and speed of the approval of rare disease drugs in China.

Methods: This study used cross-sectional analysis of rare disease drugs approved in China and the USA from 1983 to 2022 through official drug search databases and systematically analyzed and compared rare disease drugs approved in the USA and China, including the number, approval time, related laws and regulations, and expedited programs.

Results: Between 1983 and 2022, the USA Food and Drug Administration (FDA) approved a total of 693 orphan drugs (covering 1228 formulations/specifications). Among these, 201 drugs (425 formulations/specifications) were approved by China's National Medical Products Administration (NMPA), accounting for 29.0% (201/693) of the approved drugs and 34.6%(425/1228) of the approved formulations/specifications. The number of China's rare diseases drugs is increasing year by year, and the approval speed has gradually accelerated. The median approval lag time was 32.3 years (IQR: 22.9-33.6) from 1983 to 1987. In contrast, the shortest median lag time occurred between 2018 and 2022, at approximately 1.4 years (IQR: 0.5-2.6)-a reduction of 94.2% that reflects the success of China's ongoing drug regulatory reforms. The special procedures for drug approval have a great promoting effect on rare diseases drugs' approval.

Conclusion: This research provides evidence of breakthroughs in the review and approval of rare disease drugs in China and demonstrates the tremendous boost to rare disease drugs from China's ongoing restructuring and reform of the drug regulatory ecosystem, as well as a stimulus for future rare disease drugs development in China.

Background: Vascular malformations are congenital disorders characterized by abnormal blood and/or lymphatic vessels, often leading to pain, functional impairment, and severe complications. Recent advances in molecular genetics have identified key mutations and signaling pathway aberrations, particularly in the PI3K/AKT/mTOR axis, as critical contributors to the etiology of vascular malformations.

Main body: The PI3K/AKT/mTOR axis regulates essential endothelial cell processes, including proliferation, migration, and metabolism. Aberrant activation of this pathway is strongly linked to slow-flow vascular malformations and PIK3CA-related overgrowth spectrum, and increasing evidence also implicates it in fast-flow vascular malformations. These findings underscore the pathway as a promising therapeutic target. This review summarizes current mechanistic insights into PI3K/AKT/mTOR signaling in vascular malformations and examines the therapeutic potential of targeted inhibitors. By integrating results from clinical trials with emerging molecular research, it aims to guide clinical practice while providing future directions for translational investigation.

Conclusion: Recognition of PI3K/AKT/mTOR dysregulation provides a rationale for pathway-directed treatment. Development of selective agents and rational combination strategies-guided by molecular profiling and validated in preclinical and clinical studies-will be essential to enhance efficacy while minimizing resistance and toxicity.

Background: Long QT syndrome (LQTS) is a malignant cardiac channelopathy for patients with traditionally normal heart structures. Sporadic cases reported left ventricular hypertrabeculation (LVHT) was a deadly double hit in LQTS patients. Here we summarize the prevalence of LVHT within LQTS subjects and analyse the correlation of LVHT with life-threatening arrhythmic events (LAEs).

Methods: The study cohort consisted of 170 genotype-confirmed LQTS patients, which were classified to two groups, including non-left ventricular hypertrabeculation LQTS patients(LQTS-N-LVHT group) and LQTS-LVHT co-phenotype individuals (LQTS-LVHT group) according to the diagnosis criteria of LVHT. The primary endpoint was LAEs, defined as arrhythmogenic syncope, sustained ventricular tachycardia (VT), appropriate ICD shocks, sudden cardiac death.

Results: Eight LQTS patients (8/170, 4.7%) in the cohort met diagnostic criteria of LVHT. No statistical difference in symptomatology, Schwartz score, QTc interval in electrocardiograms, and proportion of PVCs or torsade de points (Tdp) in ambulatory Holter monitoring was revealed between two groups. By contrast, LQTS-LVHT subjects had a higher ratio of documented VF in ambulatory Holter monitoring compared with LQTS-N-LVHT patients (LQTS-LVHT 2/8, 25.0% vs. LQTS-N-LVHT 3/111, 2.7%, p = 0.036). In total, 59 patients (59/170, 34.7%) developed LAEs during follow-up duration of 52.8 ± 32.3 months. Significant difference was found between two groups by the log-rank test (p < 0.001).A univariate Cox regression analysis was performed demonstrating that LVHT was a significant predictor of LAEs[HR: 4.02 (1.71-9.45), P = 0.001].A multivariate Cox regression analysis indicated that LVHT remained a predictor of LAEs [hazard ratio: 3.02 (1.24-7.36), p = 0.015].

Conclusion: LVHT is a novel predictor of life-threatening arrhythmic events in LQTS patients. Effective prevention treatment should be emphasized to prevent life-threatening cardiac events in LQTS-LVHT patients.

Mitochondrial disorders are a heterogeneous group of inherited metabolic diseases resulting from dysfunctions in oxidative phosphorylation. These conditions predominantly affect high-energy-demand organs such as the brain, heart, liver, and muscles, leading to diverse clinical manifestations and diagnostic challenges. This article presents the first comprehensive Iranian guideline for the diagnosis and management of mitochondrial diseases, developed through an evidence-based and consensus-driven methodology. We conducted a structured literature review across major biomedical databases from 2000 to 2023 and engaged a multidisciplinary panel of Iranian experts to establish context-specific recommendations. The guideline covers clinical presentations, laboratory biomarkers, neuroimaging features, genetic diagnostics, and treatment approaches including "cocktail therapy" and acute management protocols. It also integrates a mitochondrial disease scoring system to standardize diagnosis and provides detailed insights into safe anesthesia practices for affected individuals. Special attention is given to practical implementation in resource-limited settings. These guidelines aim to enhance diagnostic accuracy, optimize management strategies, and improve the quality of life for patients with mitochondrial disorders across Iran and similar healthcare systems.