Journal of rare diseases (Berlin, Germany)最新文献

Purpose: Treating obesity in complex disorders requires individualized health management plans. Effective obesity management in the Smith-Magenis syndrome (SMS) population has multiple inherent barriers related to their cognitive impairments, anxiety, behavioral disturbances, and sleep disorders. However, to date, no research exists related to strategies caregivers successfully employ to help individuals with SMS manage their food intake and mitigate associated behaviors.

Methods: We performed a qualitative thematic analysis of group interviews from 23 caregivers representing 21 individuals with SMS. Hybrid thematic analysis revealed that successful strategies employed by caregivers in this unique population revolved around a global theme of Empowering Through Structured Boundaries.

Results: Four themes emerged: Fostering Balanced Eating, Structuring Environments, Setting the Stage for Success, and Managing Challenges and Resistance. Together, our analysis shows that successful strategies utilized by caregivers often involve setting up explicit boundaries, both literal and figurative, that provide choice empowerment to the individual with SMS. Additionally, anticipatory guidance, deflection, and positive language were utilized throughout different contexts.

Conclusions: These data are the first to define and disseminate a variety of successful strategies utilized by caregivers of individuals with SMS to decrease food-related disruptive behaviors.

Supplementary information: The online version contains supplementary material available at 10.1007/s44162-025-00145-3.

According to the Food and Drug Administration's definition, natural history studies (NHS) are observational studies that collect data on the course of a disease from onset to resolution or death, in the absence of an intervention. NHS plays a critical role in rare disease research to support clinical development objectives, including estimating disease prevalence, identifying diagnostic biomarkers. In this study, we present a machine learning based approach for systematically identifying NHS from PubMed as a foundational step toward large-scale NHS analysis for drug development in rare diseases. We explored a manually curated NHS corpus to develop machine learning and deep learning predictive models for NHS classification. We evaluated both binary and multiclass classifications and found that models trained specifically for binary classification (distinguishing NHS-relevant from NHS-irrelevant studies) achieved substantially higher performance than those trained to distinguish among four NHS-related categories, namely, Unrelated, Irrelevant, Secondary and Primary. Among all models tested, the pretrained PubMedBERT-base-uncased-abstract model achieved the best performance (precision = 0.8171, recall = 0.8079, F1 score = 0.8125, AUCPR = 0.8768). These results highlight the feasibility of automated NHS identification using deep learning and underscore the effectiveness of binary classification as an initial approach. This work demonstrates potential to accelerate NHS data collection and lays the foundation for NHS analysis to enhance our understanding of disease progression in rare diseases, and may extend to common diseases as well.

Alport syndrome (AS) is a progressive monogenic glomerular kidney disease characterised by kidney function decline, hearing loss, and ocular abnormalities, often leading to early-onset kidney failure (KF). While current therapies, such as renin-angiotensin system inhibitors (RASi), offer some benefits, many patients still experience KF at a young age, highlighting the need for additional treatment options. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as promising agents with demonstrated cardiovascular and nephroprotective effects in type 2 diabetes (T2D) and chronic kidney disease (CKD) patients. Evidence from several major clinical trials has shown that GLP-1 RAs can reduce cardiovascular events and slow CKD progression by reducing albuminuria. Their potential mechanisms of action include anti-inflammatory, anti-fibrotic, and antioxidative effects, making them particularly relevant for the treatment of AS, where inflammation and fibrosis play crucial roles in disease progression. This review explores the therapeutic potential of GLP-1 RAs in AS, summarising pre-clinical and clinical data and elucidating the pathways through which GLP-1 RAs might offer renoprotective benefits. We advocate for further research into their application in AS and recommend the inclusion of AS patients in future clinical trials to better understand their impact on disease progression and patient outcomes.

CYP24A1 is gene that encodes one of the cytochrome P450 superfamily enzymes involved in the breakdown of 1,25-dihydroxyvitamin D3. Genetic variants in CYP24A1 lead to a range of phenotypical and biochemical presentations, including idiopathic infantile hypercalcemia, elevated concentrations of 1,25 dihydroxy vitamin D, adult onset nephrocalcinosis, hypercalciuria, hypercalcemia and nephrolithiasis. Here we present an adult female, aged 68 years of age who presented with intermittent abdominal pain, with a past medical history of hypertension. There was a history of oral vitamin D supplementation, however patient denied tanning bed use. There was a family history of kidney stones, with her mother having recurrent kidney stones. Investigations revealed normal serum calcium and total vitamin D levels but evidence of hypercalciuria. Abdominal imaging revealed bilateral nephrocalcinosis. A genetic screen revealed a heterozygous pathogenic variant in CYP24A1. She was managed with stopping vitamin D supplements and encouraging a high fluid intake and initiation of a thiazide diuretic which led to a normalisation of urinary calcium levels. The case exemplifies late onset genetic disease secondary to CYP24A1 loss of function, likely triggered by excessive vitamin D supplementation.

Purpose: Leigh Syndrome French Canadian (LSFC) is a rare autosomal recessive metabolic disorder characterized by severe lactic acidosis crises and early mortality. LSFC patients carry variants in the Leucine Rich Pentatricopeptide Repeat Containing (LRPPRC) nuclear gene, which lead to defects in the respiratory chain complexes and mitochondrial dysfunction. Mitochondrial respiration modulates cellular metabolic activity, which impacts many cell processes, including the differentiation and function of immune cells. The purpose of this study is to define the role of Lrpprc on immune cell function.

Methods: As genetic deletion of Lrpprc is not viable, we generated two conditional mouse models: a model for systemic deletion of Lrpprc and a knock-in (KI) model carrying the most common LSFC pathogenic variant in Quebec, NM_133259.4(LRPPRC):c.1061C > T (p.Ala354Val).

Results: We demonstrate that Lrpprc is an essential gene even in adult mice, as systemic deletion of Lrpprc leads to prominent weight loss and mortality. We also find an increase in lactate levels, a symptom of metabolic crises in LSFC. Lrpprc deletion and pathogenic variant affect various immune cell subsets, with a strong impact on B cell development and proliferation.

Conclusions: We generated a viable disease-relevant mouse model to study the role of Lrpprc in vivo and find that disruption of Lrpprc strongly impairs B cell development and proliferation.

Supplementary information: The online version contains supplementary material available at 10.1007/s44162-025-00094-x.

The spectrum of disease associated with pathogenic mitochondrial DNA (mtDNA) variants is wide. Most often, heteroplasmic mitochondrial DNA disease is the result of an adenine to guanine transition at position 3243 of mtDNA (m.3243A > G) in the MT-TL1 gene encoding tRNA^Leu(UUR). Here, we present a case of a patient with a rarer m.3243A > T variant whose phenotype was severe and included delayed growth, developmental delay, myoclonic jerks and tonic-clonic seizures, progressive myopathy, cerebellar ataxia, severe malnutrition due to intestinal dysmotility despite naso-jejunal feeding requiring total parenteral nutrition, bilateral sensorineural hearing loss, and visual impairment, including bilateral cataracts requiring treatment and pigmentary retinopathy. At age 18 years, he developed severe nephrotic syndrome secondary to a membranoproliferative pattern of glomerular injury, which was resistant to treatment and led to premature death.

Purpose: This study investigates receptive and expressive language abilities in individuals with Smith-Lemli-Opitz syndrome (SLOS) and examines how these are associated with intellectual functioning, sex, autism spectrum disorder (ASD) diagnosis, and biochemical markers of cholesterol metabolism.

Methods: Participants (ages 4-18) with mild to classic SLOS were enrolled from a double-blind, placebo-controlled simvastatin trial. Receptive and expressive language scores were assessed using the Peabody Picture Vocabulary Test, Third Edition (PPVT-3), the Expressive One-Word Picture Vocabulary Test, 2000 Edition (EOWPVT-2000), and the MacArthur Communicative Developmental Inventories (MCDI). Intellectual ability and adaptive functioning were measured using the Stanford-Binet Intelligence Scales, Fifth Edition (SB-5) and Vineland Adaptive Behavior Scales, Third Edition (VABS-3). The SLOS Severity Scale (SSS) quantified disease severity. Associations with plasma and CSF sterol biomarkers (cholesterol, 7-dehydrocholesterol [7-DHC], 8-dehydrocholesterol [8-DHC]) were examined using nonparametric statistics with correction for multiple comparisons.

Results: Twenty-one participants (mean age 7.85 years) had complete data; 71.4% had a diagnosis of ASD. Receptive and expressive language scores correlated with IQ and adaptive functioning. Receptive vocabulary scores were significantly negatively associated with disease severity, plasma 7-DHC and 8-DHC, and CSF 7-DHC. Expressive vocabulary scores also declined with increasing disease severity, but associations with sterol biomarkers were not significant. ASD was linked to higher rates of non-scorable assessments, though did not fully explain floor effects. No sex differences were found.

Conclusions: Language impairment in SLOS reflects contributions from disease severity, disrupted cholesterol metabolism, and ASD. Receptive language showed stronger biomarker associations, while expressive impairments were more pervasive. Integrating clinical, biochemical, and caregiver-report tools is critical for comprehensive assessment of individuals with SLOS.

Background: Tuberous sclerosis complex (TSC) is a rare approximate 1:6000 birth incidence, a genetic disease with a wide variability of physical and neuropsychiatric symptoms. Patients require lifelong care from multiple healthcare specialities, for which International and United Kingdom (UK) TSC consensus recommendations exist. Personalised care delivered by a centralised coordinated team of TSC experts is recommended. There is no such service for the estimated 600 TSC patients in the Republic of Ireland (ROI) and there is a paucity of information regarding the healthcare of this group.

Purpose: Evaluate the baseline care of patients with TSC attending epilepsy services in the Republic of Ireland (ROI) against UK TSC consensus recommendations.

Methods: Patients with a diagnosis of TSC attending 12 adult and paediatric epilepsy centres in the ROI were identified. Clinical audits measured the baseline care of a subset of these patients against UK, TSC clinical recommendations. Data was anonymised and analysed at Trinity College Dublin.

Results: One hundred thirty-five TSC patients attending twelve epilepsy centres were identified. Adults (n = 67) paediatric (n = 68). The care of 83 patients was audited (n = 63 ≥ 18 years) and (n = 20 < 18 years). Many baseline tests were completed, however, they required intra or interhospital referral. Care appears fragmented and there was no evidence of formal disease surveillance plans.

Conclusions: The number of TSC patients attending epilepsy services is lower than expected (n = 135). Specialist services and treatments for TSC are available through informal referral pathways. Although UK, TSC consensus baseline recommendations are roughly adhered to, care is fragmented. Increased coordination of care could benefit disease management.

Supplementary information: The online version contains supplementary material available at 10.1007/s44162-024-00049-8.

A precise diagnosis in medicine allows appropriate disease-specific management. Kidney failure of unknown aetiology remains a frequent diagnostic label within the haemodialysis unit and kidney transplant clinic, accounting for 15-20% of these patients. Approximately 10% of such cases may have an underlying monogenic cause of kidney failure. Modern genetic approaches can provide a precise diagnosis for patients and their families. A search for extra-renal disease manifestations is also important as this may point to a specific genetic diagnosis. Here, we present two patients where molecular genetic testing was performed because of kidney failure of unknown aetiology and associated retinal phenotypes. The first patient reached kidney failure at 16 years of age but only presented with a retinal phenotype at 59 years of age and was found to have evidence of rod-cone dystrophy. The second patient presented with childhood kidney failure at the age of 15 years and developed visual difficulties and photophobia at the age of 32 years and was diagnosed with cone dystrophy. In both cases, genetic tests were performed which revealed a homozygous whole-gene deletion of NPHP1-encoding nephrocystin-1, providing the unifying diagnosis of Senior-Løken syndrome type 1. We conclude that reviewing kidney and extra-renal phenotypes together with targeted genetic testing was informative in these cases of kidney failure of unknown aetiology and associated retinal phenotypes. The involvement of an interdisciplinary team is advisable when managing such patients and allows referral to other relevant specialities. The long time lag and lack of diagnostic clarity and clinical evaluation in our cases should encourage genetic investigations for every young patient with unexplained kidney failure. For these and similar patients, a more timely genetic diagnosis would allow for improved management, a risk assessment of kidney disease in relatives, and the earlier identification of extra-renal disease manifestations.

Supplementary information: The online version contains supplementary material available at 10.1007/s44162-024-00031-4.

Alport syndrome is a genetic kidney disease that causes worsening of kidney function over time, often progressing to kidney failure. Some types of Alport syndrome cause other symptoms and signs, including hearing loss and eye abnormalities. Research now indicates that Alport syndrome (autosomal dominant inheritance) is the most common form. Alport syndrome can have X-linked or a rare form of autosomal recessive inheritance. Traditionally, a kidney biopsy was used to diagnose Alport syndrome, but genetic testing provides a more precise and less invasive means of diagnosis and reveals the underlying pattern of inheritance. At present, there are no specific curative treatments for Alport syndrome however there is a strong international effort in pursuit of future therapies. Currently, angiotensin-converting enzyme inhibitors (ACEi), or an angiotensin receptor blocker (ARB) if a patient cannot tolerate an ACEi, slow down the progression of kidney disease and can delay the onset of kidney failure by years. There are other potential treatments in research that potentially can help delay the onset of kidney issues. Early treatment of patients and identification of their at-risk relatives is a priority. People living with Alport syndrome and their doctors now benefit from an active international research community working on translating further treatments into clinical practice and providing up-to-date clinical guidelines.