Orphanet Journal of Rare Diseases最新文献

Background: Follow-up assessments form the basis for the continuous optimization of therapy and supportive care on an individual level, for confirming treatment efficacy, and for detecting newly emerging or unexpectedly progressive symptoms early enough to permit timely therapeutic intervention. For Pompe disease, evidence based guidelines on which assessments should constitute the minimum standard and which are required in specific situations only, were missing. Therefore, we started the Austrian Pompe Outcome Consensus (APOC) Study.

Methods: APOC was a Delphi process with two classical online and a modified third round, implemented September 2023-May 2024, following the AWMF S2k guideline. A five-member interdisciplinary steering committee invited 23 clinical experts, achieving response rates of 69.6% and 100%. A questionnaire was developed via literature scoping and an expert workshop. The importance and recommended frequency of follow-up assessments were rated using AGREE II consensus thresholds, and the classification for recommendation strength of the German Association of the Scientific Medical Societies (AWMF;Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e. V.).

Results: 34 statements achieved consensus. Strong recommendations included the 6-minute walk test (6MWT), timed tests, Pompe PEDI and other age-appropriate functional tests in children, muscle tests, handheld dynamometry, Fatigue Severity Scale, patient-reported outcome measures (e.g. R-Pact), forced vital capacity (sitting/supine), morphologic muscle imaging studies, pain and quality of life assessment. Further recommendations included respiratory (MIP/MEP) and sleep studies (polysomnography), creatine kinase, antibody titers, swallowing studies, liver sonography, hearing tests and speech and speech/oromotor function, physical therapy and rehabilitation, bone density assessment, and caregiver psychosocial care.

Conclusions: The APOC Delphi consensus yields AGREE II-compliant, systematically weighted recommendations delineating essential and optional follow-up assessments for Pompe disease in the context of Austrian healthcare. The applied method enabled a structured and efficient consensus-building process and appears well suited for addressing comparable questions in other rare disease contexts.

Clinical trial number: Not applicable.

MECP2 duplication syndrome (MDS) is an ultrarare, X-linked neurodevelopmental disorder that is poorly understood in terms of its natural history and phenotypic variability. There is limited information on how individuals with MDS acquire, retain or lose fundamental functional skills (gross motor, purposeful hand function and communication) - that of which this study aimed to better characterise in the largest case series to date.For 160 individuals with MDS (median age 9.06 y, range: 0.57-51.63 y; 84% male), we report that phenotypic penetrance in females can, in some, result in a similar functional skill deficits to males. However, a higher proportion of females acquired gross motor and fine motor skills compared to males. Use of words was the most common parent-reported skill regression (34/90 [38%]) followed by fine motor/hand function (26/90 [29%]), independent walking (25/90 [28%]) and feeding (25/90 [28%]). Additionally, lower proportions of functional ability were present in those with seizures compared to those without. A general trend was also observed for decreasing functional skills with increasing age. Additionally, those with a larger duplication length (1 + Mb) were less likely to be able to acquire independent walking compared with those with less than a 1 + Mb duplication (p < 0.001).This is the first study to comprehensively map the developmental trajectory of functional skills in MDS and provides a seminal baseline for better characterising the natural history of this disorder. Further investigations are required to understand the importance of interventional therapy on the retainment of functional skills.

Background: Osteogenesis imperfecta (OI) is a rare genetic disorder primarily caused by mutations in genes involved in type I collagen production. We report a 27-year-old female with genetically confirmed OI type XI (OI-XI) who experienced a delayed diagnosis of seropositive rheumatoid arthritis (RA), resulting in irreversible deformities.

Case presentation: The patient had multiple congenital contractures and became wheelchair-dependent in early childhood. She received only one course of bone protection therapy in her lifetime. Two years prior to presentation, she developed bilateral hand pain, stiffness, and progressive deformities. The diagnosis of RA was confirmed based on clinical features, imaging, and high titers of anti-cyclic citrullinated peptide (anti-CCP) antibodies. Genetic analysis revealed a homozygous FKBP10 mutation (c.391 + 4 A > T), confirming OI-XI. Treatment with methotrexate, folic acid, and vitamin D led to symptom improvement and stabilization of deformities.

Conclusions: This is the first reported case of RA in a patient with genetically confirmed OI-XI. The case underscores the importance of early detection and treatment of RA in individuals with OI to prevent irreversible joint damage.

Clinical trial number: Not applicable.

Background: 2-Methylbutyryl-CoA dehydrogenase deficiency (2-MBDD), also known as short/branched-chain acyl-CoA dehydrogenase (SBCAD) deficiency, is a rare inborn error of metabolism classified as an organic acidemia. Early detection through neonatal screening is crucial to prevent irreversible complications. This study reports the first documented case of 2-MBDD in Iran, identified through the national neonatal screening program in 2022.

Materials and methods: Metabolic screening was performed on dried blood spots (DBS) using electrospray ionization tandem mass spectrometry (ESI-MS/MS). Urine organic acid analysis was conducted via gas chromatography-mass spectrometry (GC/MS). Comprehensive clinical assessments, including ophthalmologic and audiologic evaluations, electroencephalography (EEG), echocardiography, and brain magnetic resonance imaging (MRI), were performed. Whole-exome sequencing (WES) was used to confirm the diagnosis.

Results: A male neonate, delivered by cesarean section, was asymptomatic at birth. Initial metabolic screening revealed elevated 2-methylbutyrylcarnitine (C5) levels, confirmed by urine organic acid analysis and genetic testing, which identified a novel likely pathogenic variant in the ACADSB gene (c.907G > C; p.G303R). The infant was managed with a carnitine-supplemented diet and continued breastfeeding. Regular follow-ups demonstrated normal growth, neurodevelopmental milestones, and biochemical parameters, with no abnormalities detected. Post-treatment, C5 levels stabilized at 0.4 µmol/L, within the intermediate range.

Conclusion: This case underscores the pivotal role of neonatal screening in the early diagnosis and management of rare metabolic disorders. Timely intervention can prevent severe complications and improve clinical outcomes, highlighting the need for expanded newborn screening programs and population-specific genetic studies.