Intractable & rare diseases research最新文献

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.

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.

Rare skin diseases in China, recognized through the 2018 National Rare Disease List (121 conditions), pose substantial epidemiological and systemic challenges. The National Rare Diseases Registry System (NRDRS) documented 62,590 cases (2016-2020) of 166 diseases, and yet data remain fragmented: only 53.1% of rare diseases are prevalent and they are found in 94.1% of regions. Eight diseases have an incidence of ≥ 1/1,000. Regional disparities persist, as 60% of cases originate from affluent East/North China, contrasting with lower utilization of genetic testing in Western regions (71.9% vs. 79.2% in the East). Diagnostic delays average 1.4 years, with patients visiting 3.2 hospitals and enduring 1.6 misdiagnoses, exacerbated by limited physician awareness - only 5.3% of clinicians report moderate familiarity with rare diseases. Therapeutic advances, including B cell-targeted therapies (e.g., rituximab), coexist with barriers like orphan drug affordability, exemplified by projected annual budgets exceeding CNY 179 million for 98 patients. Clinical trials increased at a rate of 28.2% annually (2013-2022), yet China lags behind its global counterparts in trial diversity. Policy initiatives, such as the 2019 Drug Administration Law, prioritize orphan drug development but face challenges in regional implementation and insurance coverage. Critical needs include equitable healthcare access, standardized registries, and clinician education. Collaborative networks (e.g., NRDRS-linked biobanks) and media-driven awareness campaigns are vital to alleviating systemic gaps for China's estimated 20 million patients with rare diseases.

This systematic review compares inflammatory bowel disease (IBD) management between China and Japan across epidemiology, clinical strategies, health insurance, and social security policies. Epidemiologically, the incidence of IBD is rapidly increasing in China, contributing to a growing disease burden. In contrast, Japan has a stabilized incidence but a rising prevalence, driven by an aging patient population. Clinically, step-up therapy remains the mainstream approach in China, limited by regional and financial disparities in biologic access. In contrast, Japan, benefiting from the "Designated Intractable Diseases" program, favors early intensive therapy with a focus on mucosal healing. In the area of precision medicine, China is advancing rapidly in therapeutic drug monitoring (TDM) for anti-TNF agents. In contrast, Japan leads in AI-assisted endoscopic assessment, despite slower adoption of TDM. Japan's comprehensive insurance covers most costs of IBD; China has significantly reduced drug prices via national negotiations, and yet reimbursement rates vary regionally. China has made progress in telemedicine and standardized fecal microbiota transplantation (FMT); Japan excels in AI endoscopy and use of an elemental diet. To optimize IBD care in the Asia-Pacific, China should enhance access to advanced therapies, implement hierarchical diagnosis/ treatment, and develop multi-tiered insurance. Japan must address aging-related challenges and insurance sustainability while expanding use of TDM. Sino-Japanese collaboration in genetics, microbiome research, and AI-driven diagnostics, supported by sustained policy dialogue, is key to advancing precision IBD care and shaping a scalable "Asian model" for chronic disease management.

Disorders of sex development (DSDs) encompass a spectrum of congenital conditions characterized by discordance among chromosomal, gonadal, and anatomical sex. Advances in genetic and molecular technologies have elucidated a complex landscape of underlying etiologies, including mutations in genes regulating sex determination and differentiation, copy number variations, and epigenetic alterations. These discoveries have not only enhanced diagnostic accuracy but also deepened our understanding of the molecular mechanisms driving DSDs. This review provides a comprehensive overview of the genetic architecture in DSDs, with a focus on key regulatory genes and their network interactions. We also highlight emerging concepts in the field, such as oligogenic inheritance and regulatory genomic elements, and discuss implications for personalized diagnosis, classification, and therapeutic strategies. By integrating recent advances from both clinical and basic research, this review aims to offer a framework for future investigations and translational applications in the management of DSDs.

To review musculoskeletal disabilities and rehabilitation in adults with thalidomide embryopathy (TE), the authors reviewed the literature related to musculoskeletal disability, quality of life (QOL) and rehabilitation intervention in adults with TE, obtained through a PubMed search, and their experience in clinical practice with Japanese individuals. Through literature search, 25 studies were included for this review. Literature search results and the authors' experiences revealed that, in adults with TE, upper limb disabilities included neuropathy, mainly due to carpal tunnel syndrome; finger pain due to tenosynovitis; and symptoms caused by osteoarthritis, mainly in the shoulders. Disabilities of the trunk and spine included lower back and neck pain. Although disabilities in the lower limbs were uncommon, pain due to hip and knee osteoarthritis were reported. Regarding the health-related QOL in adults with TE, the physical domain of QOL was reduced, which may be related to musculoskeletal disabilities. Reports on rehabilitation approaches for secondary musculoskeletal disabilities in TE, including physical therapy, environmental modification, and alternative medicine, were scarce. This review of musculoskeletal disabilities and QOL in adults with TE revealed that pain is common in the upper limbs and spine, and is associated with reduced physical QOL.

CHOPS (cognitive impairment, coarse facies, heart defects, obesity, pulmonary involvement, short stature, and skeletal dysplasia) syndrome is an extremely rare disorder with multiple congenital anomalies caused by missense variants in the ALF transcription elongation factor 4 gene (AFF4). This study aimed to identify causative variants in a Chinese family with CHOPS syndrome. A Chinese girl with short stature, obesity, and developmental delay underwent comprehensive clinical and genetic evaluations, including karyotyping analysis, multiple ligation-dependent probe amplification, detection of aberrant methylation, whole exome sequencing, Sanger sequencing, and copy number variation analysis, followed by in silico analyses. Reverse transcription, polymerase chain reaction, and Sanger sequencing were performed to evaluate the gene expression levels. The patient exhibited cognitive impairment, coarse facial appearance, obesity, short stature, skeletal involvement, and ophthalmic abnormalities. Genetic analyses identified a de novo heterozygous c.778A>G (p.Met260Val) variant in AFF4 in the proband, absent in parents and little sister, with no other remarkable results. This novel variant was classified as pathogenic, without apparent effect on relative gene expression. The identification of this de novo missense variant as the genetic cause of CHOPS syndrome in this Chinese family broadens the genetic and phenotypic spectrum of the disorder.

X-linked nephrogenic diabetes insipidus (X-NDI) is a rare congenital disease caused by inactivating mutations of the vasopressin type-2 receptor (AVPR2), characterized by impaired renal concentrating ability, dramatic polyuria, polydipsia and risk of dehydration. This study aims to elucidate the pathogenic mechanisms associated with a novel variant in the AVPR2 gene, which has been implicated in X-NDI. Whole exome sequencing (WES) was employed to identify genetic variants, complemented by bioinformatic analyses to predict the functional impact of these mutations. A male patient, aged 11.5 years, presented with polydipsia, polyuria, rapid weight gain, and associated physical anomalies, alongside hormonal imbalances and elevated serum sodium and chloride levels. Notably, WES revealed a hemi variant in the AVPR2 gene (NM_000054.6:exon3:c.245G>A(p. Cys82Tyr)), classified as a variant of uncertain significance. The findings indicate that a combined pharmacological approach can effectively manage X-NDI symptoms without significant side effects, suggesting a favorable prognosis for the patient. After hydrochlorothiazide for one month, both serum sodium and chloride recovered a normal level. This study highlights the importance of early diagnosis and personalized treatment strategies in enhancing patient outcomes. Future research should focus on expanding genetic testing within the population to further elucidate the genetic underpinnings of X-NDI and explore the potential for targeted therapies, ultimately improving the management of this challenging condition. This newly identified mutation expands the spectrum of mutations in X-NDI.

Juvenile idiopathic arthritis (JIA) is the most common rheumatological disease in children. Besides the more severe systemic form, non-systemic JIA is divided into 5 different subgroups. Polyarticular JIA (polyJIA), particularly rheumatoid factor (RF)-positive, which is defined as the disease involving five or more joints in the first 6 months of disease, has the worst prognosis. Biologic disease-modifying antirheumatic drugs (bDMARDs), particularly tumor necrosis factor inhibitors (TNFi), are the backbone of JIA treatment regimens. This research analyzed the published articles for: i) optimal sequence, timing and outcomes; ii) comparative effectiveness of various bDMARDs; and iii) safety concerns for use of bDMARDs. For patients with polyJIA, early effective treatment with bDMARDs is associated with drug-free remission, lower disease activity, better disease control and outcomes. Adalimumab, etanercept and tocilizumab have comparable effectiveness for treating polyJIA, and these drugs are also well-tolerated. JIA patients had a higher rate of hospitalized/serious infection and malignancy compared to the general population. The use of TNFi did not seem to significantly increase this risk further when compared to using methotrexate. Patients treated with IL-1 inhibitors or IL-6 inhibitors reported significantly more serious infections, compared with patients treated with TNFi. Clinicians and patients should consider potential risk in light of benefits of bDMARDs. The reimbursement policy and pricing issue of bDMARDs are out of the scope of the present literature analysis. The current review may help inform shared decision-making discussions between families and physicians as they weigh the risks and benefits of various treatment approaches for children with JIA.

Renal oncocytomas are benign renal tumours characterized by a central stellate scar that are indistinguishable on CT/MR imaging from malignant chromophobe renal cell carcinomas (ChrRCCs). Renal oncocytomas and ChrRCCs can be separate entities but can also co-exist on a spectrum in hybrid oncocytic/ chromophobe tumours. In the past, invasive biopsy and pathologic diagnosis has been relied on to differentiate these lesion and direct management. Early research demonstrates the effectiveness of technetium 99m sestamibi (99mTc-sestamibi) single-photon emission computed tomography (SPECT)/CT in differentiating benign versus malignant renal tumours. A new diagnostic algorithm has previously been proposed to reduce unnecessary biopsy and/or targeted therapy in managing enhancing 1-4 cm renal masses by incorporating 99mTc-sestamibi SPECT/CT in management. We present a case of suspected renal oncocytoma found incidentally on surveillance imaging post-treatment of uveal melanoma. We illustrate the incorporation of the proposed diagnostic algorithm using 99mTc-sestamibi SPECT/CT for enhancing 1-4 cm renal masses into the existing diagnostic algorithm for incidental renal masses and demonstrate its use in our case of suspected renal oncocytoma.