Orphanet Journal of Rare Diseases最新文献

Background: Spinocerebellar ataxias (SCAs) encompass a wide spectrum of inherited neurodegenerative diseases, primarily characterized by pathological changes in the cerebellum, spinal cord, and brainstem degeneration. Autosomal dominant spinocerebellar ataxia type 48 (SCA48) is a newly identified subtype of SCA, marked by early-onset ataxia and cognitive impairment, and is associated with mutations in the STIP1 homology and U-box-containing protein 1 (STUB1) gene. The STUB1 gene encodes the protein CHIP (C-terminus of HSC70-interacting protein) which functions as E3 ubiquitin ligase and is crucial to the development of neural systems.

Results: Here, we reported a Chinese SCA48 family exhibited typical features and defined a novel missense mutation STUB1 c.755A>C (CHIP p. Y252S) through whole-exome sequencing. The variant was interpreted as a variant of uncertain significance, so we conducted a series of experiments using minigene plasmids to evaluate the pathogenicity of the variant. We found that the variant STUB1 c.755A>C caused a significant reduction of CHIP level and the loss function of ubiquitin ligase activity as the pathogenic STUB1 mutations reported before. Besides, we also found that the CHIP p. Y252S could cause tau aggregation, which is considered to contribute to the progression of neurodegenerative disorders.

Conclusions: We diagnose the SCA48 pedigree in China and highlight the role of decreased ubiquitination and increased tau aggregation in the pathogenesis of the novel STUB1 c.755C>A mutation.

Background: the protein phosphatase 3 catalytic subunit alpha (PPP3CA) gene encodes for the alpha isoform of the calcineurin catalytic subunit, which controls the phosphorylation status of many targets. Currently, 23 pathogenic variants of PPP3CA are known, with clinical manifestations varying by mutation type and domain.

Results: through whole exome sequencing, we found two de novo variants in PPP3CA: a frameshift variant predicted leading to a truncated protein in Pt.1 and a splicing variant in Pt.2 associated with mild phenotype. PPP3CA is ubiquitously expressed with tissue-specificity of; namely, splicing isoform 1 prevailing over isoform 2 in the central nervous system. By analyzing isoform distribution in patient-derived cell lines, we highlight a skewed expression of both isoforms in Pt.1, whereas only isoform 2 shows a moderate reduction in Pt.2. In contrast, we did not observe significant abundance changes at the protein level. Cell lines derived from Pt.1 showed a reduced proliferation, associated with an increase in cell death and the upregulation of the unfolded protein response (UPR) pathway.

Conclusion: data suggest that an aberrant PPP3CA protein in Pt.1 could lead to UPR activation resulting in increased cell death. In Pt.2 an imbalance between the two main isoforms possibly explains the peculiar pathological manifestations, such as a moderate developmental delay.

Introduction: Osteogenesis Imperfecta (OI) is characterised by brittle bones, severe skeletal deformities, low sleep quality, and restricted breathing. We aimed to distinguish how disease and obesity affect these results.

Methods: According to BMI, we considered four groups of peer adults (median age: 35.0 years): 13 subjects affected by moderate or severe OI without obesity (OIno), 14 affected by moderate or severe OI with obesity (OIob), 10 without obesity not affected by OI (OB) and 10 without obesity not affected by OI.

Results: Obstructive Sleep Apnoea Syndrome was diagnosed in 4 OIno (30%) and 9 OIob (64%). Restricted lung pattern (z-score of total lung capacity < - 1.64) was diagnosed in 10 OIno (77%); 9 OIob (65%), and 1 OB (10%) subjects. In the seated position, OIob breathed with reduced tidal volume and higher respiratory rate, resulting in hypoventilation. Both OIno and OIob were characterised by rapid and shallow breathing and lower ribcage expansion (negative in 3 (23%) OIno and 3 (21%) OIob). In the supine position, the ventilatory pattern was similar among the four groups, while both OIno and OIob were characterised by reduced ribcage contribution, which was negative in 6 (46%) OIno, 11 (78%) OIob and 1 (10%) OB.

Conclusions: This is a pilot study on a small sample, the findings and conclusions apply only to this study population. The preliminary results suggest that in subjects with moderate or severe OI per se implies (1) a 30% prevalence of obstructive sleep apnoea syndrome, (2) a restricted lung pattern, (3) a lower ribcage expansion, and (4) rapid and shallow breathing in the seated position. The additional impacts of obesity on OI seem to determine (1) a higher incidence of obstructive sleep apnoea syndrome, (2) hypoventilation in the seated position, and (3) a higher incidence of paradoxical breathing lying supine. Reversing obesity in OI is even more challenging as knowledge of the diet and the physical activity suited for these patients is still scarce.

Background: Bile acid synthesis defects (BASDs) can be severely disabling involving the liver and nervous system, potentially due to elevated levels of toxic C₂₇-bile acid intermediates. Cholic acid (CA) supplementation is hypothesized to decrease bile acid production, stimulate bile secretion and -flow, and slowing down disease progression. This systematic review assesses the clinical and biochemical effectiveness, and safety of CA in BASDs patients.

Methods: A systematic review of MEDLINE, Embase and clinical trial registries (ClinicalTrials.gov, ICTRP registry) using controlled MeSH- and Emtree terms.

Results: From 526 articles 70 publications were deemed eligible for inclusion based on title and abstract. 14 publications were included after full-text assessment comprising case reports and -series with 1-35 patients (162 patients in total) receiving 1 week to 16,5 years of CA treatment. All presented data on effectiveness, 8 studies also presented data on safety. The included population concerned patients with Zellweger spectrum disorders (n = 73), 3β-Hydroxy-Δ5-C₂₇-steroid oxidoreductase deficiency (n = 62), cerebrotendinous xanthomatosis (n = 22), Δ4-3-oxosteroid 5β-reductase deficiency (n = 13), and α-methylacyl-CoA racemase deficiency (n = 3). Main outcomes concerned liver disease (12 studies), general physical examinations, biochemical outcomes, and safety (9 studies), and fat-soluble vitamin absorption (7 studies). The overall risk of bias score was considered to be critical (1 study), serious (4 studies), and moderate (9 studies). Major issues were missing data (10 studies), generalized data (8 studies), and no wash-out between treatments (4 studies).

Conclusion: More controlled studies are required as the available data is insufficient to draw definite conclusions on the effectiveness and safety of CA treatment in BASD patients. Establishing an independent international disease registry could better utilize existing real-world data.

Diamond-Blackfan anemia (DBA) is a rare constitutional inherited bone marrow failure syndrome (iBMF) characterized by progressive severe non-regenerative anemia and congenital abnormalities. Diagnosis is made by identification of a DBA-causing variant, typically in a ribosomal protein gene. More than 99% of patients are diagnosed in the pediatric age, but clinical manifestation may be mild and severe anemia can occur later in the patient's life. Moreover, the expanding availability of molecular testing is increasing the ability to identify DBA variants also in adults with a non-canonical DBA phenotype. Therefore, adult hematologists must maintain a high clinical suspicion and awareness towards possible DBA diagnosis in adulthood. In this context, the most common differential diagnoses are acquired BMFs such as pure red cell aplasia (PRCA) or hypoplastic myelodysplastic syndrome (MDS). Here, we present three adult patients diagnosed with DBA, where the identification of the causative mutation occurred several years from PRCA misdiagnosis or was made after screening for an affected relative. We also provide a review of 16 cases available in the literature and give hints on possible treatment strategies.

The majority of multicentric Castleman disease (MCD) patients in China are of the idiopathic subtype (iMCD) with systemic manifestations. However, the impact of iMCD on life quality, mental and psychological status, social function, and caregiving burden is poorly understood. To address this gap, a cross-sectional web-based survey was conducted with 178 iMCD patients and 82 caregivers, including 42 patient-caregiver dyads. Patient-reported outcome measurements were performed using four self-administered questionnaires (MCD-SS, SF-36, PHQ-9, and WPAI:GH). Caregiver-reported outcome measurements were performed using three questionnaires (SF-36, Zarit-22, CRA) to assess the caregiving burden. Correlation analysis was performed in patient-caregiver dyads. Patients reported a median of nine symptoms by MCD-SS, with a high mean score of 4.34 for the Fatigue domain. Their SF-36 scores indicated significant declines in physical and mental health compared to the Chinese general population (p < 0.001). Based on PHQ-9, around 65% of patients exhibited depressive symptoms, with 28.6% of them experiencing mild to severe major depression. Only 47.2% (84/178) of the patients were employed, and 28.5% experienced impaired work time. Caregivers also reported lower SF-36 scores than the general population (p < 0.05) and expressed feeling of self-criticism, lack of family support and financial problems. Correlations were observed between patients' symptom burden, mental health impairment and caregiving burden (correlation coefficient: 0.31 ~ 0.55). Our study concluded that fatigue and depressive symptoms significantly impact the life quality and social well-being of iMCD patients. The disease also affect the physical and mental health of caregivers, leading to feelings of guilt and a lack of family support.

Background: The European Joint Programme on Rare Diseases aims to enhance the rare diseases research ecosystem by bringing together stakeholders such as research funders, institutions and patient organizations. Work Package 20 focuses on the validation, use and development of innovative methodologies for rare disease clinical trials. This paper reports on the outcomes of a retreat held in April 2023, where areas for innovation and educational needs in rare disease clinical trials were discussed in multi-stakeholder sessions.

Methods: Multi-stakeholder sessions covered the topics: Future Educational System, Randomization in Rare Disease Clinical Trials, Endpoints in Rare Disease Clinical Trials and Using History Course Data. The sessions began with expert presentations to set the scene, followed by guided discussions facilitated by questions on a collaborative digital whiteboard. Participants wrote responses, which were then discussed live with the experts.

Results: Training is needed for diverse stakeholders in rare disease clinical trials to enhance understanding and drive innovation. Challenges include a lack of standardized terminology for multiple endpoints, inadequate understanding of randomization in small sample studies and various obstacles in effectively using natural history data.

Conclusion: Creating a comprehensive and sustainable educational program for rare diseases clinical trial methodology requires strategic collaboration and adherence to FAIR principles. The workshop highlighted the need for innovations for topics in areas such as handling missing data, optimizing the extraction of information from small samples, remote endpoint measurement and new randomized inference techniques. Additionally, integrating innovations into tailored training programs is crucial for advancing the field.

Background: This study evaluated the clinical characteristics of neuronal ceroid lipofuscinosis type 7 or CLN7 disease spectrum to characterize the clinical, electrophysiologic and neuroimaging phenotypes.

Methods: We performed a single-center cross sectional data collection along with retrospective medical chart review in patients with a genetic diagnosis of CLN7. This study received ethical approval by the University of Texas Southwestern Medical Center Institutional Review Board. A total of 8 patients were included between the ages of 4 to 6 years. All patients had a genetic diagnosis of CLN7 with homozygous or compound heterozygous mutations in the MFSD8 gene. The information collected includes patient demographics, developmental history, neurological events including seizures and neurodevelopmental regression along with further evaluation of brain magnetic resonance imaging and electrophysiological findings. The clinical phenotype is described through cross sectional and retrospective data collection and standardized tools assessing quality of life and functional skills.

Results: Our findings in this cohort of CLN7 patients indicated that development is initially normal with onset of clinical symptoms as early as two years of age. Language problems were noted prior to or at the onset of seizures in all cases. Gait problems were noted prior to seizure onset in 3 of 8 patients, and at or within 6 months after the onset of seizures in 5 of 8 patients. All patients followed a progressive course of language, motor, and neurocognitive deterioration. Congruent with the medical history, our patients had significantly low scores on adaptive abilities. Natural history data such as this can be used to support future clinical trial designs.

Conclusions: This study provides a comprehensive description of CLN7 disease, highlighting clinical data alongside standardized neuropsychological assessments, neuroimaging, and electrophysiologic data. It emphasizes the value of importance of standardized tools for understanding disease phenotype and their potential use as endpoints in future clinical trials. The findings established can provide a baseline for developing future prospective natural history studies and potential therapeutic clinical trials.

Background: Meier-Gorlin syndrome (MGORS) is a rare autosomal inherited form of primordial dwarfism. Pathogenic variants in 13 genes involved in DNA replication initiation have been identified in this disease, but homozygous intronic variants have never been reported. Additionally, whether growth hormone (GH) treatment can increase the height of children with MGORS is unclear.

Methods: The medical history data of a young girl were collected and reviewed. Whole-exome sequencing (WES) and bioinformatic analysis were performed to identify any variants and predict their pathogenicity. Minigene constructs were generated and transfected into HEK-293T cells for in vitro splicing assays. The literature was reviewed to explore the mutational spectrum and efficacy of GH treatment for this disease.

Results: A girl with microtia, hypoplastic patellae, and severe growth retardation carried a novel homozygous intronic variant (NM_030928.4: exon 3: c.352-30 A > C) in CDT1. The variant was predicted to break a branch point and alter splicing, and the minigene assay confirmed abnormal splicing with exon 3 skipping. The patient was treated with GH for 5 years, with an increase in growth velocity from 4.0 cm/year to an average of 6.2 cm/year. A literature review revealed that the most common variant type and inheritance state were missense and compound heterozygous, respectively. Additionally, the vast majority of children with MGORS treated with GH had normal insulin-like growth factor 1 (IGF-1) levels, and half of them responded positively to GH therapy.

Conclusions: We reported a novel pathogenic homozygous intronic variant (c.352-30 A > C) of CDT1 in a girl with MGORS, and this mutation extended the genetic spectrum of the disease. GH therapy may be beneficial for height outcomes in children with MGORS with normal IGF-1 levels.

Propionic aciduria (PA) and methylmalonic aciduria (MMA) are rare inherited disorders caused by defects in the propionate metabolic pathway. PA due to propionyl coenzyme A carboxylase deficiency results in accumulation of propionic acid, while in MMA, deficiency in methylmalonyl coenzyme A mutase leads to accumulation of methylmalonic acid. Hyperammonemia is related to a secondary deficiency of N-acetylglutamate (NAG), the activator of carbamoyl phosphate synthetase 1, which is an irreversible rate-limiting enzyme in the urea cycle. Carglumic acid (CGA) is a synthetic structural analog of human NAG and is approved for the treatment of patients with hyperammonemia due to PA or MMA. CGA is well tolerated and its use in normalizing ammonia levels during acute hyperammonemic episodes in patients with PA and MMA is well established. This expert opinion analyzed clinical evidence for CGA and discussed its place, along with other management strategies, in the long-term management of PA or MMA. A literature search of PubMed was undertaken to identify publications related to the chronic use of CGA, transplantation, dietary management, ammonia scavengers, and gene therapy for treatment of patients with PA or MMA. The authors selected the most relevant studies for inclusion. Four clinical studies, one single center case series, and three case reports show that CGA is safe and effective in the chronic treatment of PA and MMA. In particular, the addition of CGA is associated with a reduction in hyperammonemic decompensation episodes and admission to hospital, compared with conventional dietary treatment alone. Current treatment guidelines and recommendations include the use of CGA mainly in acute decompensation, however, lag in considering the benefits of long-term CGA treatment on clinical and biochemical outcomes in patients with PA or MMA. CGA is safe and effective in the chronic treatment of PA and MMA and may help to resolve some of the issues associated with other strategies used to treat these disorders. Thus, CGA appears to have potential for the chronic management of patients with PA and MMA and should be recommended for inclusion in the chronic treatment of these disorders.