J Clin Densitom. 2025 Jan-Mar;28(1):101559. doi: 10.1016/j.jocd.2024.101559. Epub 2024 Dec 28.

ABSTRACT

The 24th Annual Santa Fe Bone Symposium (SFBS) was held in Santa Fe, New Mexico, USA, on August 2-3, 2024. This was a "hybrid" meeting, with in-person and real-time remote participants representing a broad range of geographical locations and medical disciplines. The focus was on new developments in the care of patients with osteoporosis, other metabolic bone diseases, and inherited skeletal disorders. The most current medical evidence was presented and discussed with consideration of implications for patient management. Topics included an update on clinical uses of osteoanabolic agents, management of patients discontinuing denosumab, bone health optimization for orthopedic surgery, estrogen and testosterone in the management of osteoporosis, osteoporosis treatment in the very old, overview of rare bone diseases, treat-to-target for osteoporosis, and a progress report on global activities of Bone Health ECHO. There were two highly interactive faculty panel discussions - one with case presentations by attendees and another with open microphone for all topics of interest. Endocrinology fellows, selected from attendees of the Santa Fe Fellows Workshop on Metabolic Bone Diseases, held the two days preceding the SFBS, participated with presentations of oral abstracts. Ancillary events addressed modern approaches to menopause and bone health, case studies of management of patients at very high fracture risk, and management of patients with rare bone diseases, such as hypophosphatasia, fibrodysplasia ossificans progressiva, X-linked hypophosphatemia, and hypoparathyroidism. These proceedings of the SFBS present the clinical highlights of the plenary sessions and the discussions that followed.

PMID:39826229 | DOI:10.1016/j.jocd.2024.101559

Nat Med. 2025 Feb;31(2):478-489. doi: 10.1038/s41591-024-03420-w. Epub 2025 Jan 17.

ABSTRACT

Genetic diagnosis of rare diseases requires accurate identification and interpretation of genomic variants. Clinical and molecular scientists from 37 expert centers across Europe created the Solve-Rare Diseases Consortium (Solve-RD) resource, encompassing clinical, pedigree and genomic rare-disease data (94.5% exomes, 5.5% genomes), and performed systematic reanalysis for 6,447 individuals (3,592 male, 2,855 female) with previously undiagnosed rare diseases from 6,004 families. We established a collaborative, two-level expert review infrastructure that allowed a genetic diagnosis in 506 (8.4%) families. Of 552 disease-causing variants identified, 464 (84.1%) were single-nucleotide variants or short insertions/deletions. These variants were either located in recently published novel disease genes (n = 67), recently reclassified in ClinVar (n = 187) or reclassified by consensus expert decision within Solve-RD (n = 210). Bespoke bioinformatics analyses identified the remaining 15.9% of causative variants (n = 88). Ad hoc expert review, parallel to the systematic reanalysis, diagnosed 249 (4.1%) additional families for an overall diagnostic yield of 12.6%. The infrastructure and collaborative networks set up by Solve-RD can serve as a blueprint for future further scalable international efforts. The resource is open to the global rare-disease community, allowing phenotype, variant and gene queries, as well as genome-wide discoveries.

PMID:39825153 | DOI:10.1038/s41591-024-03420-w

Prog Mol Biol Transl Sci. 2025;210:163-203. doi: 10.1016/bs.pmbts.2024.07.019. Epub 2024 Aug 31.

ABSTRACT

The groundbreaking CRISPR-Cas gene editing method permits exact genetic code alteration. The "CRISPR" DNA protects bacteria from viruses. CRISPR-Cas utilizes a guide RNA to steer the Cas enzyme to the genome's gene editing target. After attaching to a sequence, Cas enzymes cleave DNA to insert, delete, or modify genes. The influence of CRISPR-Cas technology on molecular biology and genetics is profound. It allows for gene function research, animal disease models, and patient genetic therapy. Gene editing has transformed biotechnology, agriculture, and customized medicine. CRISPR-Cas could revolutionize genetics and medicine. CRISPR-Cas may accurately correct genetic flaws that underlie rare diseases, improving their therapy. Gene mutations make CRISPR-Cas gene editing a viable cure for uncommon diseases. We can use CRISPR-Cas to correct genetic abnormalities at the molecular level. This strategy offers hope for remedies and disease understanding. CRISPR-Cas genome editing may enable more targeted and effective treatments for rare medical illnesses with few therapy options. By developing base- and prime-editing CRISPR technology, CRISPR-Cas allows for accurate and efficient genome editing and advanced DNA modification. This advanced method provides precise DNA alterations without double-strand breakage. These advances have improved gene editing safety and precision, reducing unfavorable effects. Lipid nanoparticles, which use viral vectors, improve therapeutic cell and tissue targeting. In rare disorders, gene therapy may be possible with CRISPR-Cas clinical trials. CRISPR-Cas research is improving gene editing, delivery, and rare disease treatment.

PMID:39824580 | DOI:10.1016/bs.pmbts.2024.07.019

JCO Glob Oncol. 2025 Jan;11:e2400239. doi: 10.1200/GO.24.00239. Epub 2025 Jan 16.

ABSTRACT

PURPOSE: The availability of drugs and national public policies for patients with rare cancers, including sarcomas, varies in different parts of the world.

METHODS: In this manuscript, we have conducted a comprehensive analysis to evaluate rare cancer policies in Latin American countries' national policy documents. Additionally, we have reviewed the approvals for sarcoma drugs in selected Latin American countries and compared them with US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approvals.

RESULTS: The documents reviewed showed a lack of explicit focus on rare cancers, with no mention in 70% of the countries analyzed. Drug approval data reveal that in the last 15 years, the FDA and EMA have approved 19 and 13 drugs for sarcoma, whereas their Latin American counterparts, namely ANVISA, ANMAT, and COFEPRIS, approved six, eight, and seven drugs, respectively.

CONCLUSION: Our data suggest that improving rare cancer and sarcoma care in Latin America requires enhanced collaboration for better rare cancer policies.

PMID:39819122 | DOI:10.1200/GO.24.00239

Gen Physiol Biophys. 2025 Jan;44(1):1-11. doi: 10.4149/gpb_2024038.

ABSTRACT

Pulmonary alveolar proteinosis (PAP) is a rare disease characterised by excessive accumulation of surfactant components in alveolar macrophages, alveoli, and peripheral airways. The accumulation of surfactant is associated with only a minimal inflammatory response but can lead to the development of pulmonary fibrosis. Three clinical forms of PAP are distinguished - primary, secondary and congenital. In recent years, significant findings have helped to clarify the ethiology and pathogenesis of the disease. Apart from impaired surfactant protein function, a key role in the development of PAP is played by signal pathway of granulocyte and macrophage colonies stimulating growth factor (GM-CSF) which is necessary for the functioning of alveolar macrophages and for surfactant homeostasis. Surfactant is partially degraded by alveolar macrophages that are stimulated by GM-CSF. The role of GM-CSF has been shown especially in primary PAP, which is currently considered an autoimmune disease involving the development of GM-CSF neutralising autoantibodies. Clinically, the disease may be silent or manifest with dyspnoeic symptoms triggered by exertion and cough. However, there is a 10 to 15% rate of patients who develop respiratory failure. Total pulmonary lavage is regarded as the standard method of treatment. In addition, recombinant human GM-CSF has been studied as a prospective therapy for the treatment of PAP.

PMID:39815895 | DOI:10.4149/gpb_2024038

JAMA Pediatr. 2025 Feb 1;179(2):197-202. doi: 10.1001/jamapediatrics.2024.5100.

ABSTRACT

IMPORTANCE: Cell and gene therapies are revolutionizing the treatment landscape for children and adults with rare diseases and can be life-changing for patients and their families. Successful implementation of these new therapies into clinical practice depends on their accessibility and affordability, particularly through publicly funded Medicaid agencies, which cover many children and adults with rare diseases.

OBJECTIVE: To provide a framework to broadly assess cell and gene therapies, evaluate payment options, and ensure equitable access through the lens of publicly funded Medicaid programs.

EVIDENCE REVIEW: This review draws on peer-reviewed articles, federal reports, and other relevant publications as well as the expertise of chief medical officers and medical directors of state Medicaid agencies across 5 diverse states.

FINDINGS: Twenty-nine articles and other references provide the foundation for this review. The recommendations presented focus on thoughtful implementation of cell and gene therapies, including policy recommendations in the domains of safety, effectiveness, population health, access, and budget.

CONCLUSIONS AND RELEVANCE: Proposed health care policy changes are intended to balance innovation, affordability, and equitable access for children and adults with rare diseases.

PMID:39804636 | DOI:10.1001/jamapediatrics.2024.5100

medRxiv [Preprint]. 2024 Oct 4:2024.10.04.24313542. doi: 10.1101/2024.10.04.24313542.

ABSTRACT

INTRODUCTION: Structural variants (SVs) of the nebulin gene (NEB), including intragenic duplications, deletions, and copy number variation of the triplicate region, are an established cause of recessively inherited nemaline myopathies and related neuromuscular disorders. Large deletions have been shown to cause dominantly inherited distal myopathies. Here we provide an overview of 35 families with muscle disorders caused by such SVs in NEB.

METHODS: Using custom Comparative Genomic Hybridization arrays, exome sequencing, short-read genome sequencing, custom Droplet Digital PCR, or Sanger sequencing, we identified pathogenic SVs in 35 families with NEB-related myopathies.

RESULTS: In 23 families, recessive intragenic deletions and duplications or pathogenic gains of the triplicate region segregating with the disease in compound heterozygous form, together with a small variant in trans, were identified. In two families the SV was, however, homozygous. Eight families have not been described previously. In 12 families with a distal myopathy phenotype, eight unique, large deletions encompassing 52 to 97 exons in either heterozygous (n = 10) or mosaic (n = 2) state were identified.In the families where inheritance was recessive, no correlation could be made between the types of variants and the severity of the disease. In contrast, all patients with large dominant deletions in NEB had milder, predominantly distal muscle weakness.

DISCUSSION: For the first time, we establish a clear and statistically significant association between large NEB deletions and a form of distal myopathy. In addition, we provide the hitherto largest overview of the spectrum of SVs in NEB.

PMID:39802796 | PMC:PMC11722492 | DOI:10.1101/2024.10.04.24313542

Int J Mol Sci. 2025 Jan 3;26(1):353. doi: 10.3390/ijms26010353.

ABSTRACT

Fucosidosis is a rare lysosomal storage disease caused by α-L-fucosidase deficiency following a mutation in the FUCA1 gene. This enzyme is responsible for breaking down fucose-containing glycoproteins, glycolipids, and oligosaccharides within the lysosome. Mutations in FUCA1 result in either reduced enzyme activity or complete loss of function, leading to the accumulation of fucose-rich substrates in lysosomes. Lysosomes become engorged with undigested substrates, which leads to secondary storage defects affecting other metabolic pathways. The central nervous system is particularly vulnerable, with lysosomal dysfunction causing microglial activation, inflammation, and neuronal loss, leading to the neurodegenerative symptoms of fucosidosis. Neuroinflammation contributes to secondary damage, including neuronal apoptosis, axonal degeneration, and synaptic dysfunction, exacerbating the disease process. Chronic neuroinflammation impairs synaptic plasticity and neuronal survival, leading to progressive intellectual disability, learning difficulties, and loss of previously acquired skills. Inflammatory cytokines and lysosomal burden in motor neurons and associated pathways contribute to ataxia, spasticity, and hypotonia, which are common motor symptoms in fucosidosis. Elevated neuroinflammatory markers can increase neuronal excitability, leading to the frequent occurrence of epilepsy in affected individuals. So, fucosidosis is characterized by rapid mental and motor loss, along with growth retardation, coarse facial features, hepatosplenomegaly, telangiectasis or angiokeratomas, epilepsy, inguinal hernia, and dysostosis multiplex. Patients usually die at an early age. Treatment of fucosidosis is a great challenge, and there is currently no definitive effective treatment. Hematopoietic cell transplantation studies are ongoing in the treatment of fucosidosis. However, early diagnosis of this disease and treatment can be effective. In addition, the body's immune system decreases due to chemotherapy applied after transplantation, leaving the body vulnerable to microbes and infections, and the risk of death is high with this treatment. In another treatment method, gene therapy, the use of retroviral vectors, is promising due to their easy integration, high cell efficiency, and safety. In another treatment approach, enzyme replacement therapy, preclinical studies are ongoing for fucosidosis, but the blood-brain barrier is a major obstacle in lysosomal storage diseases affecting the central nervous system. Early diagnosis is important in fucosidosis, a rare disease, due to the delay in the diagnosis of patients identified so far and the rapid progression of the disease. In addition, enzyme replacement therapy, which carries fewer risks, is promising.

PMID:39796208 | DOI:10.3390/ijms26010353

Int J Mol Sci. 2024 Dec 27;26(1):135. doi: 10.3390/ijms26010135.

ABSTRACT

DNA methylation is an essential epigenetic modification that plays a crucial role in regulating gene expression and maintaining genomic stability. With the advancement in sequencing technology, methylation studies have provided valuable insights into the diagnosis of rare diseases through the various identification of episignatures, epivariation, epioutliers, and allele-specific methylation. However, current methylation studies are not without limitations. This mini-review explores the current understanding of DNA methylation in rare diseases, highlighting the key mechanisms and diagnostic potential, and emphasizing the need for advanced methodologies and integrative approaches to enhance the understanding of disease progression and design more personable treatment for patients, given the nature of rare diseases.

PMID:39795993 | DOI:10.3390/ijms26010135

Medicine (Baltimore). 2025 Jan 10;104(2):e41259. doi: 10.1097/MD.0000000000041259.

ABSTRACT

RATIONALE: Malignant melanoma is a rare cancer that accounts for approximately 1% of all cancers. Primary malignant melanoma of the female genital tract accounts for approximately 3% to 7% of all malignant melanomas, and 0.3% to 0.8% of all melanomas in women. It affects postmenopausal women ages 60 to 80 years. Various hormonal factors, including puberty, pregnancy, menopause, oral contraceptive use, and human papillomavirus infection are associated with primary malignant melanoma of the vagina.

PATIENT CONCERNS: Symptoms often include vaginal bleeding, discharge, and pain; however, it can also present as pigmented or nonpigmented lesions, making diagnosis challenging.

DIAGNOSES: Diagnosis involves detailed history, physical examination, and imaging (CT, MRI, and positron emission tomography). Immunohistochemical staining for markers, such as human melanoma black-45 and Melan-A, is crucial for confirmation. The diagnosis was made through careful physical examination, imaging studies, and immunohistochemistry.

INTERVENTIONS: The treatment includes wide local excision, radical surgery, radiotherapy, chemotherapy, and immunotherapy. The prognosis of primary malignant melanoma of the vagina is usually poor owing to late diagnosis, and the 5-year survival rate is 5% to 25%.

OUTCOMES AND LESSONS: To consider the possibility of primary malignant melanoma of vagina, postmenopausal women, particularly those who with human papillomavirus infection, should be performed thorough examination regardless of symptoms of vaginal bleeding or discharge.

PMID:39792728 | DOI:10.1097/MD.0000000000041259

J Neuropsychiatry Clin Neurosci. 2025 Jan 10:appineuropsych20240072. doi: 10.1176/appi.neuropsych.20240072. Online ahead of print.

ABSTRACT

OBJECTIVE: Catatonia is a neuropsychiatric disorder that is associated with a range of medical and psychiatric illnesses. Although many single-center studies have been conducted, uncertainty over the population-based incidence and prevalence of the disorder remains. This study reports on the incidence and prevalence rates of catatonia extrapolated from two large epidemiologic studies in the United Kingdom and United States.

METHODS: Incidence rates (defined as the number of catatonic episodes per 100,000 person-years) and prevalence rates (defined as the proportion of individuals with catatonia in a given year) were calculated from the two studies.

RESULTS: U.K. data showed an incidence of 4.34 (95% CI=3.98-4.72) catatonic episodes per 100,000 person-years with an average 1-year prevalence of 4.39 (95% CI=4.03-4.77) catatonic episodes per 100,000 persons. U.S. data revealed a 1-year prevalence of 5.15 (95% CI=5.08-5.23) catatonia-related hospitalizations per 100,000 persons.

CONCLUSIONS: Catatonia is a rare disorder, qualifying as an orphan disease under both European Medicines Agency and U.S. Food and Drug Administration criteria. Further research is needed to rigorously define the epidemiology of catatonia in other populations.

PMID:39789943 | DOI:10.1176/appi.neuropsych.20240072

Int J Technol Assess Health Care. 2025 Jan 9;41(1):e6. doi: 10.1017/S0266462324004835.

ABSTRACT

OBJECTIVE: The aim of this study is to propose and validate a value assessment framework for Health Technology Assessment (HTA) for rare diseases drugs in Brazil.

METHODS: A scoping review was performed to identify criteria used by HTA agencies in countries with public healthcare systems when evaluating orphan drugs. Based on the findings, a criteria framework for rare disease drugs was proposed for Brazil. Content validity was conducted over three rounds using Delphi technique and content validity ratio (CVR) approach was employed to evaluate the ratings from the eighteen stakeholders (experts and patients).

RESULTS: Twenty-nine HTA criteria for rare disease drugs were identified to compose the Brazilian framework. After three Delphi rounds, the final value framework comprised fifteen criteria categorized into four domains: disease-related factors, treatment-related factors, social and political factors, and economic factors. Among the most well-rated criteria by the CVR, considering the relevance attribute, were "relevance of outcomes for a rare disease," "impact on patient's quality of life," "price negotiation," and "adjusted cost-effectiveness threshold." On the other hand, "budget impact threshold," "innovative nature of treatment," and "willingness to accept greater uncertainty in clinical evidence" received negative evaluations and were excluded from the final framework.

CONCLUSIONS: A value assessment framework validated by key stakeholders of rare diseases in Brazil could contribute to improve HTA transparency, decision making, and efficiency of the healthcare system, and inspire the development of a local guidance for rare-disease HTA.

PMID:39783027 | DOI:10.1017/S0266462324004835

Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2025 Oct 10;42(10):34-40. doi: 10.3760/cma.j.cn511374-20240809-00433.

ABSTRACT

OBJECTIVE: To explore the clinical and genetic characteristics of two children diagnosed with two rare genetic diseases simultaneously.

METHODS: Two children with comorbidity of two genetic diseases due to dual genetic mutations diagnosed at the Third Affiliated Hospital of Zhengzhou University respectively in May 2022 and March 2023 were selected as the study subjects. Clinical and genetic data of the two children were retrospectively analyzed. This study has been approved by the Ethics Committee of the Third Affiliated Hospital of Zhengzhou University (Ethic No. 2021-062-01).

RESULTS: Child 1 was a 2-year-and-4-month-old boy whose clinical manifestations included facial dysmorphism, developmental delay, short stature, microcephaly, cleft palate, cryptorchidism, hypospadias, recurrent infections and immunological abnormalities. Whole exome sequencing revealed that he had harbored a heterozygous c.6595delT (p.Y2199Ifs*65) variant of the KMT2D gene and a heterozygous c.1892G>A (p.R631Q) variant of the PIK3R1 gene. This has led to a dual genetic diagnosis of Kabuki syndrome and PI3Kδ-related immunodeficiency type 36. Child 2 was a 15-year-old girl whose clinical manifestations included epilepsy, Albright's hereditary osteodystrophy, long body trunk, short limbs, hypocalcemia, hyperphosphatemia and hyperparathyroidism. The child also had a family history of short stature. Whole exome sequencing revealed that she had harbored a heterozygous c.2T>C (p.Met1?) variant of the GNAS gene and deletion of exons 2 to 6 of the SHOX gene. The two variants have led to dual diagnose of pseudohypoparathyroidism and X-linked idiopathic short stature.

CONCLUSION: When the clinical phenotype of a genetic disease is complex and cannot be fully explained with a single genetic variant, multiple pathogenic variants should be considered, and this may lead to the diagnosis of co-morbid genetic diseases. To adopt or supplement corresponding genetic testing in time and re-analyze the genetic data may facilitate accurate diagnosis of co-morbid genetic diseases.

PMID:39779334 | DOI:10.3760/cma.j.cn511374-20240809-00433

Epidemiol Serv Saude. 2024 Dec 20;33:e20240204. doi: 10.1590/S2237-96222024v33e20240204.en. eCollection 2024.

ABSTRACT

OBJECTIVE: To analyze the first referral service for rare diseases accredited by the Brazilian Ministry of Health, focusing on referral from the primary healthcare network through to diagnosis.

METHODS: This is a descriptive study with patients treated between 2016 and 2021 at a referral hospital service located in Curitiba, Paraná, Brazil. Clinical and epidemiological data were obtained from medical records, as were the results of genetic tests at the hospital's clinical analysis laboratory. Qualitative data were expressed as absolute and relative frequencies, while quantitative data were expressed as medians and interquartile ranges and compared using the Kruskal-Wallis test.

RESULTS: The study included 1,751 cases, 34.1% were diagnosed with rare diseases, with average time until diagnosis being 3.0 years, whereby mucopolysaccharidosis type II (4.0%) and tuberous sclerosis (3.9%) were the most common. Greater length of time for obtaining diagnosis (p-value 0.004) and receiving specialized care (p-value<0.001) was found in patients from the interior region of Paraná state, compared to those residing in Curitiba city and its metropolitan region.

CONCLUSION: Diagnosis of rare diseases occurred in approximately one third of cases. The average time until diagnosis suggests a possible positive impact of implementing the referral service. The longer time until diagnosis and specialized care found among patients from the interior region of Paraná represent challenges regarding adequate referral to specialized services.

PMID:39776132 | DOI:10.1590/S2237-96222024v33e20240204.en

BMC Cancer. 2025 Jan 7;25(1):22. doi: 10.1186/s12885-024-13369-1.

ABSTRACT

BACKGROUND: Small Bowel Adenocarcinoma (SBA) is a rare gastrointestinal cancer with a limited understanding of the molecular pathology. This study aims to bridge the knowledge gap, providing a robust molecular foundation for SBA and addressing the clinical challenges inherent in treating this orphan disease. The study proposes to redefine the clinical management for SBA patients through advanced molecular profiling techniques to improve potential precision medicine.

METHODS/DESIGN: This National multicenter, observational cohort study combines retrospective and prospective analyses across Danish University Hospitals. The study enrolls patients diagnosed with SBA, retrospectively from 2009 and prospectively from 2022 onwards. Molecular profiling, including DNA, RNA, and T-cell receptor sequencing, will be conducted on SBA tissue samples. The primary outcome is to categorize SBA into consensus molecular-guided subgroups. Secondary outcomes include correlating these subgroups with clinical features, treatment responses, and patient outcomes. Machine learning algorithms will be employed for bioinformatic analyses to interpret molecular data. Ethical approval has been obtained, and patient consent will be secured for the retrospective study component.

DISCUSSION: The molecular and clinical characterization of SBA is expected to add novel insights into the heterogeneity of this rare disease. By identifying molecular subgroups, the research could enable the development of personalized treatment strategies, a paradigm shift within SBA. The study acknowledges the challenges of working with orphan diseases, including limited patient numbers and diverse clinical presentations. However, its findings will have the potential to substantially impact future clinical practices and guide targeted therapies for SBA patients.

TRIAL REGISTRATION: ClinicalTrials.gov NCT06234306.

PMID:39773121 | DOI:10.1186/s12885-024-13369-1

J Prim Care Community Health. 2025 Jan-Dec;16:21501319241311567. doi: 10.1177/21501319241311567.

ABSTRACT

INTRODUCTION/OBJECTIVES: Individually rare, rare diseases are collectively common resulting in frequent health system use. Navigating the health system persists as a challenge. Primary care provides longitudinal contact with the health system and is placed to provide integrated rare-disease-care.

METHODS: This scoping review used Joanna Briggs Institute and PRISMA methods with a Consolidated Framework for Implementation Research based data extraction tool to find how integrated rare-disease-care is delivered, enablers and barriers to the same, in primary care settings in contemporary literature in OECD countries.

RESULTS: The Primary Care Provider (PCP) role varies from routine primary care to shared-rare-disease-care models. In the 26 papers, the most frequently cited PCP roles included involvement in diagnosis (n = 14), care coordination (n = 16), primary and preventative care (n = 18), management of components of rare-disease-care (n = 13), and treatment monitoring (n = 10). Individuals whose PCP was actively involved in their care were reported to have shortened diagnostic delay, improved transitions of care across the lifespan, reduced unplanned utilization of emergency and hospital services, comprehensive psychosocial care, improved quality of life across environments including home, school and work and improved palliative care experiences.

CONCLUSIONS: Sufficient communication from specialists, information, resources, time and reimbursement for complex care are still needed. Future integrated-rare-disease-care models should be developed by, or with, PCPs.

PMID:39772949 | DOI:10.1177/21501319241311567

J Inherit Metab Dis. 2025 Jan;48(1):e12830. doi: 10.1002/jimd.12830.

ABSTRACT

Mucopolysaccharidosis type I (MPS I) is an inherited lysosomal storage disorder leading to deleterious brain effects. While animal models suggested that MPS I severely affects white matter (WM), whole-brain diffusion tensor imaging (DTI) analysis was not performed due to MPS-related morphological abnormalities. 3T DTI data from 28 severe (MPS IH, treated with hematopoietic stem cell transplantation-HSCT), 16 attenuated MPS I patients (MPS IA) enrolled under the study protocol NCT01870375, and 27 healthy controls (HC) were analyzed using the free-water correction (FWC) method to resolve macrostructural partial volume effects and unravel differences in DTI metrics accounting for microstructural abnormalities. FWC analysis in MPS IH compared to HC revealed higher free-water fraction (FWF) in all WM regions with increased radial (RD) and mean diffusivity (MD). Higher RD, MD, and FWF in cingulate and FWF in temporal WM were observed in MPS IA relative to HC. FWF and RD in the corpus callosum (CC) were higher in MPS IH than in MPS IA. Reaction time was correlated with fractional anisotropy (FA) in frontal and parietal WM in MPS IH. FA in temporal and central WM correlated with d-prime in MPS IA. The HSCT age was related to FA in parietal WM and FWF in frontal WM in MPS IH. FWC delineated subtype-specific WM microstructural abnormalities linked to myelination that were more extensive in MPS IH than IA, with CC findings being a key differentiator between subtypes. Earlier age at HSCT was related to preserved WM microstructure in the brain of MPS IH patients. Free water-corrected DTI distinguishes severe and attenuated MPS I patients and reveals a relationship between attention, age at HSCT, and white matter microstructure.

PMID:39761695 | DOI:10.1002/jimd.12830

Ital J Pediatr. 2025 Jan 5;51(1):3. doi: 10.1186/s13052-024-01806-7.

ABSTRACT

BACKGROUND: Rare bleeding disorders (RBDs) include fibrinogen (Factor I), prothrombin (Factor II), Factor V(FV), combined Factor V and Factor VIII, Factor VII, Factor X, Factor XI, Factor XII, and Factor XIII deficiencies. This group accounts for 3-5% of all factor deficiencies. Different symptoms may occur, ranging from mild or moderate bleeding to serious and life-threatening bleeding, which may not be related to the factor level. This study aimed to evaluate the diagnosis, genetics, treatment, prophylaxis features and surgical experiences of patients those are followed up in our clinic and the review of the literature of rare factor deficiency.

METHODS: Demographic data, number of follow-up visits throughout the study period, clinical symptoms, number and locations of bleeding symptoms of 19 patients diagnosed with RBD (fibrinogen, prothrombin, FV, FVII, FX, FXI or FXIII) who were followed up in our pediatric hematology clinic between year 2023-2024 and complications, inhibitor levels, previous operations, treatment and prophylaxis approaches are recorded in the patient chart and all data had been evaluated retrospectively. In our article, all patients included in this study are mentioned according to the consecutive numbering system as Patient 1(P1) to P19 in Table 2. A comprehensive literature search was performed in PubMed and after primary elections 4 studies are selected from total 23 studies those are most relevant to RBDs in pediatric age as there is only plenty of articles about RBDs. Most of the other studies are reviews without clinical patient trails just including recommadations for diagnosis and laboratuary screenings. In contrast, our study includes a clinical trail on diagnosis, treatment and prophylaxis information of 19 patients with RBDs.

RESULTS: The average age of total 19 patients was 11.2 years (range 2,5-17 years). 14 patients were boys (74%) and 5 patients were girls (26%). 10 of the patients (52%) had FVII deficiency (mean FVII: 8,3%, range 2,5-17%), 4 of patients (21%) had FX deficiency (mean FX:16,2%, range 15-17%) and 4 of patients (21%) had FV deficiency (mean FV:14%, range 10-17%) and 1 had FXIII deficiency (1%) respectively. The normal range laboratory reference values for rare blood factor levels in our institute (factor V, VII and X deficencies) is 70-120%. In our study group, 63% (12/19) of our patients were diagnosed over one year of age. Considering all of our cases, skin and soft tissue bleedings are listed as 52% (10/19), intraoral bleedings as 42% (8/19), nose bleedings as 63% (12/19), joint bleedings as 42%(8/19) and santral nerveous system(CNS) bleedings as 15%(3/19). Among the serious bleedings of our cases, joint bleeding 42% (8/19) takes the first place with followed by CNS bleeding 15% (3/19) and gastro-intestinal system(GIS) bleeding (15%) (3/19) respectively. Among totally 19 patients, FX deficiency-P17 had a null mutation of FX gene and FV deficiency-P3 had a missense mutation of FV gene has been detected those both were severe deficencies. The medical genetics of the sibling patients with combined FVII deficency and hypofibrinogenemia have been evaluated, but the genetic results have not been completed yet.

CONCLUSIONS: We believe that data-based service is required in every clinic and healthcare system for early diagnosis and follow-up of RBDs. Additionially family screenings and more effective genetic counseling may heal the overall survival and prevent further severe complications. Moreover; the missing factor, severity of deficiency, personal and family history of bleeding or thrombosis, availability of treatment options, plasma half-life of infused exogenous clotting factors and infusion frequency, advantages and disadvantages should all be considered before a prophylaxis program or treatment of RBDs.

PMID:39757163 | DOI:10.1186/s13052-024-01806-7

Nihon Yakurigaku Zasshi. 2025;160(1):48-52. doi: 10.1254/fpj.24090.

ABSTRACT

Distal myopathy with rimmed vacuoles (GNE myopathy) is an incurable disease that develops after the late teens, progresses slowly, and has no effective treatment. It is inherited in an autosomal recessive manner, and the number of patients in Japan is estimated to be around 400. The causative gene was revealed to be GNE, the rate-limiting enzyme in the sialic acid biosynthesis pathway, and non-clinical studies demonstrated the effectiveness of sialic acid. Tohoku University Hospital conducted an investigator-initiated phase I trial with aceneuraminic acid in 2010. After that, trials were conducted overseas, and a phase II trial using acenoiraminic acid sustained-release tablets confirmed that muscle strength in the upper limbs had recovered, and the drug progressed to a phase III trial. In Japan, a Phase II/III study was conducted at five domestic facilities using the same protocol as the overseas Phase III study, and efficacy and safety were confirmed. However, Phase III trials overseas failed to show efficacy and development was discontinued. An additional confirmation study was conducted in Japan, and as a result of confirming reproducibility, the product was approved for manufacturing and sales in March 2024, ahead of the rest of the world. This is a successful example of the development of a therapeutic drug for an ultra-orphan disease, which is said to be difficult to develop, and is expected to lead to early treatment for patients.

PMID:39756906 | DOI:10.1254/fpj.24090

Pediatr Neurol. 2024 Dec 18;164:1-3. doi: 10.1016/j.pediatrneurol.2024.12.005. Online ahead of print.

NO ABSTRACT

PMID:39756185 | DOI:10.1016/j.pediatrneurol.2024.12.005