Japan has developed two separate frameworks to support patients with chronic and rare diseases: the Specified Pediatric Chronic Diseases (SPCD) Program and the Designated Intractable Diseases (DID) System. Although both aim to provide medical and social assistance, they differ in age of eligibility, diseases covered, and administrative procedures. The SPCD Program provides support to individuals under 18 years of age (extendable to 20) with 858 eligible conditions, whereas the DID System, with 348 designated diseases, applies to all ages. These structural discrepancies create a critical policy gap when pediatric patients transition into adulthood. Those whose conditions are not listed under the DID System lose their eligibility for public subsidies, resulting in sudden financial strain and reduced social participation. Additional issues include inconsistencies in diagnostic criteria, limited access to transitional care facilities — currently established in only 12 prefectures — and insufficient family-centered support, especially for siblings acting as young carers. To achieve continuity of care and equity, Japan must harmonize disease definitions and transition criteria, introduce temporary relief measures for non-designated patients, increase the number of Transitional Care Support Centers in regions, and institutionalize family-inclusive assistance. Establishing a seamless policy framework over a patient's life will not only encourage patients' independence but also strengthen the sustainability of Japan's healthcare system in the face of an aging population.

Prader-Willi syndrome (PWS) is a genetic disorder resulting from the absence of paternal 15q11-q13 alleles and is clinically characterised by pathological obesity, delayed satiety, hyperphagia, decreased muscle mass, and increased fat mass. Dietary management constitutes a key component in the prevention and treatment of obesity in individuals with PWS. This scoping study aimed to identify dietary interventions available for treating obesity among PWS individuals. A systematic search using the six stages of the scoping review methodology proposed by Arksey and O'Malley was conducted across four databases: PubMed, Scopus, EBSCOhost, and Cochrane Library. The inclusion criteria were full-text research articles published in English between 2017 and 2023, involving human participants with PWS, and reporting on dietary interventions for obesity management. Out of 100 articles retrieved, five studies were identified. Two studies described multidisciplinary programs integrating dietary and physical activity components, while three focused exclusively on dietary interventions. The outcomes varied by intervention and study design. Ketogenic diets and multidisciplinary programs with exercise often resulted in favourable weight and body fat reduction. However, strict diets like the modified Atkins faced adherence challenges and frequent weight regain. Multidisciplinary, supervised programs result in higher adherence and more effective weight management, with body mass index near normal. In conclusion, although research in this area remains limited, current evidence suggests that both dietary and multidisciplinary interventions have the potential to support obesity management in individuals with PWS.

The mitochondrial DNA A3243G variant, located in the MT-TL1 gene encoding tRNA^Leu(UUR), represents one of the most clinically significant pathogenic mitochondrial mutations. This point mutation accounts for approximately 80% of Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes (MELAS) syndrome cases and is the primary cause of Maternally Inherited Diabetes and Deafness (MIDD) syndrome. The clinical spectrum associated with this mutation ranges from asymptomatic carriers to severe multisystem disease with early mortality. The pathophysiology involves impaired mitochondrial protein synthesis leading to respiratory chain dysfunction, with phenotypic expression determined by heteroplasmy levels and tissue-specific energy demands. Understanding the complex inheritance patterns, genetic bottleneck effects during oogenesis, and heteroplasmy variations is crucial for comprehending the variable clinical presentations observed in affected families. Histological examination reveals characteristic features including ragged-red fibers, cytochrome c oxidase-deficient fibers, and abnormal mitochondrial proliferation. Current therapeutic approaches focus on metabolic support, antioxidant therapy, and management of specific complications, with L-arginine showing promise for stroke-like episodes. However, careful attention to drug safety profiles and potential mitochondrial toxicity is essential in treatment planning. Understanding the diverse clinical manifestations and implementing appropriate screening strategies are crucial for early diagnosis and optimal patient management. This review synthesizes current knowledge regarding the A3243G variant's pathophysiology, clinical features, diagnostic approaches, and therapeutic interventions.

Congenital and hereditary intestinal diseases are a group of major disorders caused by gene mutations or embryonic developmental anomalies and are characterized by diverse clinical manifestations and complex management. This review systematically explores the molecular genetic basis and pathogenic mechanisms of common intestinal diseases, including familial adenomatous polyposis (FAP), Peutz-Jeghers syndrome (PJS), Lynch syndrome (LS), Hirschsprung disease (HSCR), congenital short bowel syndrome (SBS), and cystic fibrosis (CF). It focuses on cross-disease commonalities in translational research frontiers such as gene-environment interactions, organoid-based precision medicine, the immune microenvironment, and metabolic and microbiome remodeling. The review also forecasts future directions, including gene therapy, targeted drugs, and other cutting-edge research advances.

Rare diseases, characterized by low prevalence and high heterogeneity, impose a significant burden on patients and healthcare systems globally. Utilizing clinical data from the Hospital Information System's Patient Discharge Summaries (2015–2023), we analyzed all rare disease inpatient admissions at a major tertiary hospital in Western China. We examined demographic characteristics, classification of disease systems, medical costs, and readmission rate. Among 1086 inpatient admissions identified with rare diseases (mean age: 46.89 ± 18.99 years), diseases of the nervous system (39.69%), the blood and blood-forming organs and certain disorders involving the immune mechanism (18.32%), the musculoskeletal system and connective tissue (10.50%) constituted the top three disease system categories. The number of the top15 diseases accounted for 73.66% of the total number of patients. The top 3 diseases were POEMS syndrome (11.23%), optical neuromyelitis (10.22%), and Castleman disease (7.46%). Hospitalization costs were predominantly composed of diagnostic (ranged from 6.41% to 49.75%) and medication costs (ranged from 12.97% to 46.22%). The 10 highest readmission rates ranged from 42.86% to 95.90%. The rare diseases in this hospital had a large age span, diverse disease types, high hospitalization costs and large individual differences, which was representative to a certain extent, and can provide scientific basis for the diagnosis, treatment, and prevention of rare diseases in Gansu Province and even the northwest region of China.

Late-onset cobalamin C (cblC) deficiency, an inherited metabolic disorder, is often misdiagnosed due to its heterogeneous clinical presentation. This study aims to characterize the clinical and genetic spectrum of late-onset cblC deficiency in a large northern Chinese cohort and proposes a novel clinical classification based on initial symptoms. A retrospective, multicenter study of 156 patients diagnosed between October 2012 and December 2023 was conducted. Clinical, biochemical, neuroimaging, and genetic data were analyzed. Patients were classified into six subtypes based on predominant initial symptoms, and genotype-phenotype correlations were explored. The cohort (95 males, 61 females) had a median onset age of 16 years (range: 2–65). Common symptoms included spastic paralysis (41.0%), mental and behavioral abnormalities (36.5%), and renal damage (28.8%). Genetic analysis identified 52 MMACHC variants, with c.482G>A (34.3%) and c.609G>A (17.6%) being most frequent. Elevated total homocysteine (tHcy) levels correlated with mental and behavioral abnormalities, renal damage, and anemia (p < 0.05). The proposed clinical classification identified six subtypes, with encephalopathy-dominant and encephalomyelopathy-dominant types being most prevalent. This study highlights the clinical heterogeneity of late-onset cblC deficiency and introduces a novel symptom-based classification system to aid diagnosis and management. Elevated tHcy levels and specific MMACHC variants are key biomarkers for disease severity. These findings underscore the importance of early intervention to improve outcomes.

Rare diseases affect fewer than 1 in 2,000 individuals. Patients often encounter barriers to specialist care and prompt diagnosis, hindering effective disease management and access to appropriate treatments. This study aimed to identify determinants of diagnostic delay among patients with rare diseases affiliated with Peruvian associations in 2024. A descriptive cross-sectional design was employed in 2024, enrolling patients with rare diseases or their caregivers from Peruvian associations. Data collection utilized an expert-validated survey encompassing sociodemographic characteristics, medical history, and diagnostic challenges. The primary outcome was diagnostic delay, defined as the interval from symptom onset to confirmed diagnosis. Data analysis included descriptive and inferential statistical methods. A total of 236 participants responded, with the majority being women (61.4%). A diagnosis was received within a year of symptom onset for 54.7% of participants, and 46.2% reported difficulties accessing healthcare. Major barriers identified included prolonged wait times for appointments or treatment (52.3%) and geographic limitations impeding access (37.6%). The median diagnostic delay was longer for women (63.1 months) compared to men (26.9 months). Limited access to healthcare was associated with an average delay of 21.8 months, whereas consulting more than ten general practitioners was associated with a 42.6-month delay. In summary, over half of the patients with rare diseases in Peru included in this study received a diagnosis within one year. However, the most significant delays were observed in non-genetic rare diseases. Key contributors to prolonged diagnostic timelines included limited access to healthcare and consultations with multiple general practitioners.

This study investigated the association between the novel KRT5 gene mutation c.987C>G (p.Asn329Lys) and the clinical phenotype of epidermolysis bullosa simplex (EBS), to provide a basis for the molecular diagnosis and genetic counseling of EBS. Clinical data were collected from a 20-year-old female patient. Whole-exome sequencing was performed on the proband, 5 affected family members, and 2 healthy family members, with mutations verified by Sanger sequencing. Functional prediction was conducted using SIFT, PolyPhen-2, and MutationTaster, while conservation analysis was performed using ConSurf and NCBI CDD databases. The pathogenicity of the mutation was evaluated according to the 2015 ACMG guidelines. Results showed that the proband and all affected family members carried the heterozygous KRT5 gene mutation c.987C>G (p.Asn329Lys), while healthy members did not, consistent with autosomal dominant co-segregation. This mutation was not recorded in databases such as gnomAD, indicating it is a novel mutation. Functional prediction showed SIFT score 0.00 (damaging), PolyPhen-2 score 1.000 (PROBABLY DAMAGING), and MutationTaster classification as "Deleterious". Conservation analysis confirmed that the 329th amino acid is located in the highly conserved Filament domain (ConSurf score 0.92, CDD E-value = 1.04e-158). The ACMG classification determined it as "Pathogenic". Affected family members exhibited a mild phenotype characterized by "friction-induced blisters, seasonal dependence, and scarless healing". The KRT5 gene mutation c.987C>G (p.Asn329Lys) is a novel pathogenic mutation for EBS. Its unique phenotype enriches the genotype-phenotype spectrum of EBS and has important reference value for clinical practice.

Mucopolysaccharidosis type IVA (MPS IVA) is a rare genetic disorder characterized by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase, leading to significant growth and developmental challenges, increased morbidity, and reduced life expectancy. We report the clinical characteristics and genetic basis of MPS IVA in an 11-year-old male patient, emphasizing the critical role of early diagnosis and intervention. The combination of enzyme activity testing and genetic testing screening for suspected clinical cases may shorten the diagnosis time and reduce the difficulty of diagnosis. Early screening for respiratory and cardiac complications in confirmed cases is beneficial for reducing patient mortality.

Rare diseases are characterized by an extremely low prevalence, high phenotypic heterogeneity, and complex pathogenesis. This combination of factors presents significant challenges, including prolonged diagnostic delays, lack of standardized care, and difficulties in pathological interpretation. The integration of artificial intelligence (AI) offers a transformative approach to overcoming these barriers. In recent years, researchers worldwide have been actively exploring the use of AI to diagnose and manage rare diseases. Key advances include few-shot learning algorithms designed to tackle data scarcity, clinically validated foundation models that enhance diagnostic consistency across institutions, and multimodal AI frameworks that integrate imaging, genomic, and phenotypic data to improve diagnostic accuracy. In addition, there is growing recognition that AI can enhance diagnostic efficiency and thereby optimize support systems for rare diseases. As challenges such as AI model interpretability and data equity are addressed, AI is expected to make significant strides in the diagnosis and treatment of rare diseases.