Orphanet Journal of Rare Diseases最新文献

Background: Phenylketonuria (PKU) is an inherited metabolic disorder where the body cannot break down phenylalanine (Phe), leading to its harmful accumulation if left untreated. Concerns have been raised about growth and risk of overweight in PKU patients, with conflicting research findings. This retrospective study aims to assess growth patterns and the prevalence of overweight and obesity in Danish children and adults with PKU by comparing them with Danish growth charts and prevalence rates.

Results: Data were collected from medical records of 291 Danish patients from the National PKU Clinic at Rigshospitalet in Copenhagen, including data on age, sex, PKU phenotype, Phe levels, and anthropometric measurements from their last clinic visit. Weight status for children was classified according to Danish guidelines, while World Health Organization criteria were used for adults. All data analyses were carried out separately for children and adults. A total of 291 PKU patients were included, 116 children and 175 adults. Children had normal growth patterns compared to Danish growth charts. The rates of overweight and obesity among children were 15% and 1%, respectively, while 32% of adults were overweight, and 28% were obese. Adults with classic PKU were significantly more obese and had higher BMI levels compared to other phenotypes. Additionally, a slight positive correlation was noted between high Phe levels and the risk of being overweight.

Conclusions: Children with phenylketonuria following a restricted diet achieve normal growth. However, overweight and obesity rates rise with age, particularly in adults with the most severe phenotype, suggesting disease severity may influence weight gain. The potential link between high phenylalanine levels and overweight requires further investigation. These findings highlight the need for ongoing weight and metabolic monitoring, as well as strategies to support weight management in adults with phenylketonuria.

Background: transthyretin-mediated familial amyloid polyneuropathy (ATTR-PN), caused by TTR gene mutations, leads to systemic amyloid deposition and multisystem dysfunction. The c.165G > C (p.Lys55Asn) mutation is a rare variant with limited clinical data. This study investigates a family with this mutation, focusing on genotype-phenotype correlations and clinical challenges.

Methods: We conducted a detailed clinical analysis of a family with ATTR-PN, using whole exome sequencing to identify the transthyretin (TTR) mutation. Clinical data from 17 affected individuals were collected, including symptom onset, disease progression, and outcomes. Electromyography and gastric emptying studies were performed to assess peripheral nerve and gastrointestinal function.

Results: The c.165G > C mutation was confirmed in all affected family members, presenting with early-onset gastrointestinal dysfunction and sensorimotor polyneuropathy. The mean age at onset was 39.76 ± 2.77 years, with rapid progression to death (mean age 46.13 ± 2.97 years) due to cachexia from gastrointestinal complications. Genetic anticipation was observed, with earlier onset in successive generations.

Conclusion: The p.Lys55Asn mutation in the TTR gene leads to a severe, rapidly progressive ATTR-PN phenotype, characterized by prominent gastrointestinal dysfunction. This study enhances understanding of the clinical spectrum associated with this rare mutation, emphasizing the need for early diagnosis and targeted management strategies.

Background: The mTOR inhibitor Sirolimus was shown to improve symptoms in patients with slow-flow vascular malformations, but long-term continuous use is limited by cumulative toxicity. A personalized approach with intermittent regimens may offer similar efficacy with fewer adverse effects (AE). This retrospective analysis evaluated the effectiveness and safety of individualized sirolimus strategies in patients who experienced symptom recurrence after completing the 2-year course in the VASE phase III trial. All patients initially resumed continuous sirolimus for 3 months, then transitioned to one personalized regimen based on their pain profiles: intermittent sirolimus 5 days-ON/2 days-OFF (Group A), hybrid intermittent plus on-demand (Group B), or fully on-demand administration triggered by pain or known stressors (Group C).

Results: Thirty adults were included (Group A: n = 13; Group B: n = 6; Group C: n = 11). Across all groups, intermittent, hybrid or on-demand sirolimus maintained pain control comparable to continuous administration, significantly reducing pain intensity, crisis frequency, and crisis duration from baseline. AEs decreased from 73-85% during continuous therapy to 9-33% with intermittent/on-demand regimens, with no reported grade ≥3 event.

Conclusion: Personalized intermittent sirolimus regimens may effectively control symptoms and substantially reduce toxicity in patients with vascular malformations. This strategy supports individualized, long-term therapy and merits prospective validation.

Trial registration: NCT02638389 and EudraCT 2015-001703-32.

Background: Neuromuscular diseases (NMDs) are rare, progressive conditions that require lifelong, multidisciplinary care. Advances in diagnosis and treatment have increased survival into adulthood, making the transition from paediatric to adult care a critical stage of its management. However, evidence suggests that transition practices remain inconsistent across Europe. This study aimed to map and evaluate the current transition practices for patients with NMDs across Europe.

Methods: A cross-sectional survey was conducted by the European Reference Network for Rare Neuromuscular Diseases (ERN EURO-NMD) to assess current transition practices across European healthcare providers (HCPs). Sixty-seven healthcare professionals from 20 countries participated. The survey explored training provision, transition structures, professional involvement, timing, psychosocial support, and perceived barriers. Both descriptive and thematic analyses were performed.

Results: Only 29.9% of respondents reported structured transition protocols, and fewer than one in five (17,9%) had received formal training in transition care. The age to initiate transition was reported for most centres at 17-18 years, even though most clinicians identified 15-16 years as the ideal starting point. Multidisciplinary collaboration was present in some centres but was inconsistently implemented. Barriers included insufficient staff, lack of funding, inadequate adult care services, and poor inter-team communication. Post-transfer feedback to paediatric teams was limited. Despite these challenges, 59.7% of respondents believed that ERN EURO-NMD could facilitate improvement in transition care.

Conclusions: Transition care for patients with NMDs in Europe remains fragmented and under-resourced. To ensure continuity and improve outcomes, structured, multidisciplinary transition models are needed. A European roadmap, coordinated by ERN EURO-NMD, could harmonise practices, support professional training, and guide policy development across member states.

Background: This article aims to elucidate the potential role of a comprehensive tooth extraction procedure in preventing mdication-related osteonecrosis of the jaw (MRONJ) through a prospective cohort study. By systematically assessing clinical outcomes following this procedure, the study seeks to provide evidence regarding its effectiveness in MRONJ prevention, thereby contributing to improved clinical guidelines and patient care related to dental extractions in at-risk populations.

Methods: Patients using anti-resorptive agents (ARAs) who required extraction of at least one tooth were included in the study. Patients' medical history, medication history, and intraoral dental conditions were documented, and CBCT scans were performed. Following a standardized treatment protocol, patients received professional oral cleaning and antibiotics preoperatively. During surgery, minimally invasive extraction and concentrated growth factor (CGF) filling were performed with meticulous suturing whenever possible. Postoperatively, mouthwash was used within one month. Follow-up visits were scheduled at 10, 30, and 90 days to monitor and analyze MRONJ incidence and surgical outcomes.

Results: A total of 101 patients were included in the study, with 20 receiving oral ARAs for osteoporosis, 57 receiving intravenous ARAs for osteoporosis, 13 undergoing combination therapy for osteoporosis, and 11 using ARAs for malignancy. Zoledronic acid and denosumab were the most commonly used drugs. Increased bone density was observed on preoperative CBCT in 26 patients, and on postoperative CBCT at 90 days in 31 patients. In total, 248 teeth were extracted, mostly due to severe defects; periapical periodontitis and periodontitis were also major reasons for extraction. Most patients could not achieve complete and tight suturing. All patients remained free of MRONJ during the 90‑day postoperative period, with complete mucosal healing in every case.

Conclusion: This prospective cohort study provides evidence that implementing an effective and rational treatment protocol during tooth extractions significantly benefits high-risk MRONJ patients. Adherence to such protocols minimizes the risk of postoperative infection, fosters improved healing of extraction sites, and maximizes the prevention of MRONJ.

Clinical trial number: Not applicable.

Background: Mucopolysaccharidosis type I (MPS I), is an autosomal recessive disorder caused by a deficiency in the enzyme α-L-iduronidase (IDUA), leading to the accumulation of glycosaminoglycans (GAGs) in tissues. Early diagnosis and treatment [i.e., bone marrow transplantation and/or enzyme replacement therapy (ERT) with laronidase] are essential to prevent irreversible damage. The long-term effectiveness of exclusive ERT has been primarily described in attenuated phenotypes, while only a few cases have been reported in severe phenotypes.

Methods: This study is a retrospective analysis summarising the collective experience of disease progression in 48 patients with severe and attenuated MPS I who were treated exclusively with laronidase over a median of 10 years at the Lyon Reference Centre for Hereditary Metabolic Diseases in France. Patients were categorised by genotype and further stratified by age at treatment initiation. The study assessed the evolution of urinary excretion of GAGs, pulmonary function, cardiac involvement and evolution, height, cognitive impairment, functional status, orthopaedic and ear-nose-throat (ENT) procedures, sleep apnoea, and carpal tunnel syndrome. Descriptive statistical analysis methods were used.

Results: ERT reduced the GAGus levels by 88% in severe MPS I and by 71% in attenuated MPS I, of which 47% and 65% patients, respectively achieved normal age-related GAG levels at the last follow-up. ERT provided stable or consistent improvement in forced vital capacity, slowed progression of adverse cardiac course and improved auditory transmission in majority of the severe and attenuated patients. At the last follow-up, 84% attenuated patients had normal cognitive development. In alive Hurler patients, cognitive development was very heterogenous; however, 73% patients had a developmental quotient (DQ) ≥ 70. Laronidase was effective in improving statural growth of attenuated patients treated before 9 years of age.

Conclusion: Early ERT and regular multidisciplinary management are effective in slowing disease progression in severe and attenuated patients with MPS I and helping to maintain autonomy in patients with attenuated MPS I, ensuring a better quality of life.

Background: Lysosomal acid lipase deficiency (LAL-D) is an autosomal recessive ultrarare lysosomal storage disease caused by pathogenic/likely pathogenic variants in the LIPA gene. The age of onset and progression rate can significantly vary, possibly due to the nature of the underlying variants. The disorder is often misdiagnosed or undiagnosed in the Gulf Cooperation Council (GCC) countries owing to its nonspecific clinical presentation; this necessitates establishing campaigns to increase awareness among healthcare professionals and strategies for identifying and screening high-risk populations. This narrative review is based on an analysis of the available literature, complemented by key discussions among a group of recognized healthcare professionals from the GCC region with expertise in clinical genetics, hepatology, gastroenterology, and lipidology. The outcome of their discussions is a set of practical recommendations and insights aimed at assisting physicians across multiple specialties in the identification and management of individuals affected by this ultrarare genetic disorder.

Conclusion: LAL-D presents significant diagnostic and management challenges, particularly within the GCC region, owing to its rarity, limited awareness, and insufficient utilization of genetic testing. The prevalence and distribution of genetic variations associated with LAL-D remain inadequately explored in this population. The development of standardized regional guidelines is essential to harmonize diagnostic and management practices. Continued research efforts focusing on the genetic landscape of LAL-D in the GCC are imperative to bridge knowledge gaps and enhance clinical outcomes for affected patients.

Background: Spinal muscular atrophy (SMA) is a rare, life-limiting neuromuscular disorder characterised by progressive motor neuron degeneration. The recent emergence of disease-modifying therapies (DMTs), nusinersen, onasemnogene abeparvovec, and risdiplam, has revolutionised SMA care but presents economic challenges due to high treatment costs and limited long-term evidence.

Objective: To review and critically appraise economic evaluations that assessed the cost-effectiveness of DMTs in people living with SMA.

Methods: A systematic literature review was conducted following Cochrane and PRISMA guidelines. Initial searches were conducted in January 2024 and updated in February 2025. Searches were carried out in key biomedical and economic databases, as well as grey literature. Two reviewers independently screened the titles and abstracts of all identified records, as well as the full texts of potentially relevant studies. Data extraction and quality appraisal employed established tools, including the CHEERS and Philips checklists. The conduct and findings of included studies were summarised and discussed narratively.

Results: Of 1,984 records, 21 studies met the inclusion criteria. All studies used Markov modelling approaches, varying by SMA type, time horizon (often lifetime), and assumptions around sustained treatment benefits. Key drivers of cost-effectiveness included treatment costs, health-state utility values (frequently based on expert opinion), and survival modelling. Heterogeneity was noted in health technology definitions, utility measurement, and data sources. Limitations across studies included reliance on short-term clinical data, inconsistent assumptions, and limited of transparency in modelling practices. Sensitivity analyses were inconsistently applied, limiting robustness of the findings reported in each study.

Conclusions: The economic evaluation landscape for SMA treatments is evolving. However, challenges remain due to data gaps and methodological variability across studies. Future research should prioritise the integration of long-term real-world data into economic evaluations, consider the development of patient- and caregiver-derived utility values, and the use of transparent, standardised modelling approaches. These improvements will enhance the robustness, comparability, and policy relevance of economic evaluations in rare disease treatment funding.