F1000Res. 2023 Apr 11;11:175. doi: 10.12688/f1000research.76218.2. eCollection 2022.

ABSTRACT

Polygenic Risk Score (PRS) analysis is a method that predicts the genetic risk of an individual towards targeted traits. Even when there are no significant markers, it gives evidence of a genetic effect beyond the results of Genome-Wide Association Studies (GWAS). Moreover, it selects single nucleotide polymorphisms (SNPs) that contribute to the disease with low effect size making it more precise at individual level risk prediction. PRS analysis addresses the shortfall of GWAS by taking into account the SNPs/alleles with low effect size but play an indispensable role to the observed phenotypic/trait variance. PRS analysis has applications that investigate the genetic basis of several traits, which includes rare diseases. However, the accuracy of PRS analysis depends on the genomic data of the underlying population. For instance, several studies show that obtaining higher prediction power of PRS analysis is challenging for non-Europeans. In this manuscript, we review the conventional PRS methods and their application to sub-Saharan African communities. We conclude that lack of sufficient GWAS data and tools is the limiting factor of applying PRS analysis to sub-Saharan populations. We recommend developing Africa-specific PRS methods and tools for estimating and analyzing African population data for clinical evaluation of PRSs of interest and predicting rare diseases.

PMID:37273966 | PMC:PMC10233318 | DOI:10.12688/f1000research.76218.2

Ugeskr Laeger. 2023 May 15;185(20):V12220788.

ABSTRACT

Unilateral acute maculopathy is a rare inflammatory macular disorder believed to be caused by viral infection, especially Coxsackievirus. It most commonly affects young healthy adults. This is a case report of unilateral acute maculopathy in a 28-year-old man with concurrent hand, foot and mouth disease. Although the typical acute manifestation of the disease is sudden, severe, unilateral central vision loss, most patients achieve full visual recovery over the course of several weeks without therapy.

PMID:37264868

Clin Lymphoma Myeloma Leuk. 2023 May 12:S2152-2650(23)00157-X. doi: 10.1016/j.clml.2023.05.007. Online ahead of print.

NO ABSTRACT

PMID:37263876 | DOI:10.1016/j.clml.2023.05.007

Proc Natl Acad Sci U S A. 2023 Jun 6;120(23):e2300052120. doi: 10.1073/pnas.2300052120. Epub 2023 May 30.

ABSTRACT

Short trinucleotide expansions at the FMR1 locus are associated with the late-onset condition fragile X-associated tremor/ataxia syndrome (FXTAS), which shows very different clinical and pathological features from fragile X syndrome (associated with longer expansions), with no clear molecular explanation for these marked differences. One prevailing theory posits that the shorter, premutation expansion uniquely causes extreme neurotoxic increases in FMR1 mRNA (i.e., four to eightfold increases), but evidence to support this hypothesis is largely derived from analysis of peripheral blood. We applied single-nucleus RNA sequencing to postmortem frontal cortex and cerebellum from 7 individuals with premutation and matched controls (n = 6) to assess cell type-specific molecular neuropathology. We found only modest upregulation (~1.3-fold) of FMR1 in some glial populations associated with premutation expansions. In premutation cases, we also identified decreased astrocyte proportions in the cortex. Differential expression and gene ontology analysis demonstrated altered neuroregulatory roles of glia. Using network analyses, we identified cell type-specific and region-specific patterns of FMR1 protein target gene dysregulation unique to premutation cases, with notable network dysregulation in the cortical oligodendrocyte lineage. We used pseudotime trajectory analysis to determine how oligodendrocyte development was altered and identified differences in early gene expression in oligodendrocyte trajectories in premutation cases specifically, implicating early cortical glial developmental perturbations. These findings challenge dogma regarding extremely elevated FMR1 increases in FXTAS and implicate glial dysregulation as a critical facet of premutation pathophysiology, representing potential unique therapeutic targets directly derived from the human condition.

PMID:37252957 | DOI:10.1073/pnas.2300052120

Nat Methods. 2023 Jun;20(6):803-814. doi: 10.1038/s41592-023-01886-z. Epub 2023 May 29.

ABSTRACT

High-throughput profiling methods (such as genomics or imaging) have accelerated basic research and made deep molecular characterization of patient samples routine. These approaches provide a rich portrait of genes, molecular pathways and cell types involved in disease phenotypes. Machine learning (ML) can be a useful tool for extracting disease-relevant patterns from high-dimensional datasets. However, depending upon the complexity of the biological question, machine learning often requires many samples to identify recurrent and biologically meaningful patterns. Rare diseases are inherently limited in clinical cases, leading to few samples to study. In this Perspective, we outline the challenges and emerging solutions for using ML for small sample sets, specifically in rare diseases. Advances in ML methods for rare diseases are likely to be informative for applications beyond rare diseases for which few samples exist with high-dimensional data. We propose that the method community prioritize the development of ML techniques for rare disease research.

PMID:37248386 | DOI:10.1038/s41592-023-01886-z

Nat Commun. 2023 May 29;14(1):3090. doi: 10.1038/s41467-023-38782-1.

ABSTRACT

Long-read HiFi genome sequencing allows for accurate detection and direct phasing of single nucleotide variants, indels, and structural variants. Recent algorithmic development enables simultaneous detection of CpG methylation for analysis of regulatory element activity directly in HiFi reads. We present a comprehensive haplotype resolved 5-base HiFi genome sequencing dataset from a rare disease cohort of 276 samples in 152 families to identify rare (~0.5%) hypermethylation events. We find that 80% of these events are allele-specific and predicted to cause loss of regulatory element activity. We demonstrate heritability of extreme hypermethylation including rare cis variants associated with short (~200 bp) and large hypermethylation events (>1 kb), respectively. We identify repeat expansions in proximal promoters predicting allelic gene silencing via hypermethylation and demonstrate allelic transcriptional events downstream. On average 30-40 rare hypermethylation tiles overlap rare disease genes per patient, providing indications for variation prioritization including a previously undiagnosed pathogenic allele in DIP2B causing global developmental delay. We propose that use of HiFi genome sequencing in unsolved rare disease cases will allow detection of unconventional diseases alleles due to loss of regulatory element activity.

PMID:37248219 | PMC:PMC10226990 | DOI:10.1038/s41467-023-38782-1

Rev Infirm. 2023 May;72(291):1. doi: 10.1016/j.revinf.2023.04.001. Epub 2023 May 11.

NO ABSTRACT

PMID:37247978 | DOI:10.1016/j.revinf.2023.04.001

Isr Med Assoc J. 2023 May;25(5):369-371.

NO ABSTRACT

PMID:37245110

Mol Genet Metab. 2023 May 21;139(3):107612. doi: 10.1016/j.ymgme.2023.107612. Online ahead of print.

ABSTRACT

Clinical trial development in rare diseases poses significant study design and methodology challenges, such as disease heterogeneity and appropriate patient selection, identification and selection of key endpoints, decisions on study duration, choice of control groups, selection of appropriate statistical analyses, and patient recruitment. Therapeutic development in organic acidemias (OAs) shares many challenges with other inborn errors of metabolism, such as incomplete understanding of natural history, heterogenous disease presentations, requirement for sensitive outcome measures and difficulties recruiting a small sample of participants. Here, we review strategies for the successful development of a clinical trial to evaluate treatment response in propionic and methylmalonic acidemias. Specifically, we discuss crucial decisions that may significantly impact success of the study, including patient selection, identification and selection of endpoints, determination of the study duration, consideration of control groups including natural history controls, and selection of appropriate statistical analyses. The significant challenges associated with designing a clinical trial in rare disease can sometimes be successfully met through strategic engagement with experts in the rare disease, seeking regulatory and biostatistical guidance, and early involvement of patients and families.

PMID:37245378 | DOI:10.1016/j.ymgme.2023.107612

Int J Mol Sci. 2023 May 22;24(10):9064. doi: 10.3390/ijms24109064.

ABSTRACT

Rare Diseases (RD) do not have an exact definition since local authorities define the criteria in different ways, from fewer than 5 people in 10,000, according to the European Union, to the standard world average of 40 cases per 100,000 people [...].

PMID:37240412 | PMC:PMC10219232 | DOI:10.3390/ijms24109064

Orphanet J Rare Dis. 2023 May 24;18(1):123. doi: 10.1186/s13023-023-02728-z.

ABSTRACT

BACKGROUND: Osteogenesis imperfecta (OI) is a group of rare inheritable disorders of connective tissue. The cardinal manifestations of OI are low bone mass and reduced bone mineral strength, leading to increased bone fragility and deformity that may lead to significant impairment in daily life. The phenotypic manifestations show a broad range of severity, ranging from mild or moderate to severe and lethal. The here presented meta-analysis aimed to analyze existing findings on quality of life (QoL) in children and adults with OI.

METHODS: Nine databases were searched with predefined key words. The selection process was executed by two independent reviewers and was based on predetermined exclusion and inclusion criteria. The quality of each study was assessed using a risk of bias tool. Effect sizes were calculated as standardized mean differences. Between-study heterogeneity was calculated with the I2 statistic.

RESULTS: Among the studies included two featured children and adolescents (N = 189), and four adults (N = 760). Children with OI had significantly lower QoL on the Pediatric quality of life inventory (PedsQL) with regards to the total score, emotional, school, and social functioning compared to controls and norms. The data was not sufficient to calculate differences regarding OI-subtypes. In the adult sample assessed with Short Form Health Survey Questionnaire, 12 (SF-12) and 36 items (SF-36), all OI types showed significantly lower QoL levels across all physical component subscales compared to norms. The same pattern was found for the mental component subscales namely vitality, social functioning, and emotional role functioning. The mental health subscale was significantly lower for OI type I, but not for type III and IV. All of the included studies exhibited a low risk of bias.

CONCLUSIONS: QoL was significantly lower in children and adults with OI compared to norms and controls. Studies in adults comparing OI subtypes showed that the clinical severity of the phenotype is not related to worse mental health QoL. Future research is needed to examine QoL in children and adolescents in more sophisticated ways and to better understand the association between clinical severity of an OI-phenotype/severity and mental health in adults.

PMID:37226194 | DOI:10.1186/s13023-023-02728-z

Orphanet J Rare Dis. 2023 May 24;18(1):122. doi: 10.1186/s13023-023-02731-4.

ABSTRACT

BACKGROUND: Wilson disease (WD) is a rare, hereditary disorder of copper metabolism. Due to its variable symptoms and manifestations, diagnosis remains challenging. Affected patients must obtain lifelong medical treatment, as the disease is fatal if untreated. Patients require continuous monitoring, but little is known about the care of these patients in Germany. Therefore, we analyzed the medical care of WD patients at German university centers. We sent a questionnaire containing 20 questions to a total of 108 departments of pediatrics, neurology and gastroenterology in 36 university hospitals. Our questions referred to the characteristics of WD patients at the different sites and internal procedures regarding diagnosis, therapy and follow-up. A descriptive statistical analysis was performed.

RESULTS: Sixty-three departments (58%) returned our questionnaire. In total, approximately one-third of the estimated WD patients in Germany are seen annually in the outpatient clinics of these departments (approx. 950 patients). There are only a few departments which treat patients in a multidisciplinary setting (12%). Our survey revealed that for diagnosis, 51% of all departments used an algorithm based on the Leipzig score as recommended by international guidelines. Most departments apply essential parameters recommended by WD guidelines. Routine monitoring is performed at least biannually by 84% of the departments, and standard investigations for monitoring are regularly applied. A routine family screening is performed by 84% of all departments. A reduction in medical therapy during pregnancy is recommended by 46% of the departments. Only 14% suggested that WD patients should not breastfeed. Liver transplantation (LT) due to WD is a rare but repeatedly occurring event. Most departments of gastroenterology (72%) reported at least one patient with LT within the last decade.

CONCLUSIONS: Medical care of WD patients at German university centers follows the recommendations set forth by international guidelines, but only a few centers treat significant numbers of patients. The surveillance of patients does not follow specified standards, but most departments adhere to the accepted guidelines. The formation of central units and networks in a multidisciplinary setting should be evaluated to improve the care of WD patients.

PMID:37226184 | DOI:10.1186/s13023-023-02731-4

BMC Pediatr. 2023 May 24;23(1):259. doi: 10.1186/s12887-023-04077-z.

ABSTRACT

BACKGROUND: Neurofibromatosis Type 1 (NF1) is a rare genetic disorder characterized with the development of multiple benign tumors on the nerves and skin.

CASE PRESENTATION: This report described a neonatal case with a large mass observed on the left side of the maxillofacial and cervical region at birth. Meantime, multiple cafe-au-lait macules (CALMs) were seen on the trunk and both lower extremities.

CONCLUSIONS: In this case, the clinical features of the rare NF1 neonate are discussed along with its ultrasound findings.

PMID:37226143 | DOI:10.1186/s12887-023-04077-z

Rev Gastroenterol Peru. 2023 Jan-Mar;43(1):65-68.

ABSTRACT

Colonic malacoplakia is an unusual cause of chronic diarrhea, and it may present as a consumptive disease. At the colon, it can induce ulcerative and erosive nodular lesions, that mimic other common granulomatous or infectious diseases. Diagnosis is support in biopsies showing groups of histiocytes, with typical Michaelis-Gutmann inclusions, which are positive with the Von Kossa stain. We present the case of a 55-year-old male, without associated diseases, who presented with diarrhea, weight loss and anemia, showing a very good clinical response to antibiotics.

PMID:37226073

BMC Cardiovasc Disord. 2023 May 23;23(1):267. doi: 10.1186/s12872-023-03289-6.

ABSTRACT

BACKGROUND: Kounis syndrome is a rare clinical condition characterized by the occurrence of an acute coronary event induced by an acute allergic episode. The ongoing pandemic of coronavirus disease 2019 (COVID-19) has contributed to an increase in the incidence of allergic reactions to a certain extent, thereby increasing the incidence of Kounis syndrome. Timely diagnosis and effective management of this disease are important in clinical practice.

CASE PRESENTATION: We report a 43-year-old woman who developed generalized pruritus, breathlessness, paroxysmal precordial crushing pain, and dyspnea after receiving the third dose of the COVID-19 vaccine. After anti-allergic treatment and therapy for acute myocardial ischemia, her symptoms resolved with improvement in cardiac function and resolution of ST-segment changes. The prognosis was satisfactory, and the final diagnosis was type I Kounis syndrome.

CONCLUSION: This patient with type I Kounis syndrome rapidly developed acute coronary syndrome (ACS) after an acute allergic reaction to the COVID-19 vaccine. ​Timely diagnosis of acute allergic reaction and ACS, and targeted treatment based on the relevant guidelines are the key to successful treatment of the syndrome.​.

PMID:37221464 | DOI:10.1186/s12872-023-03289-6

BMJ Case Rep. 2023 May 23;16(5):e254113. doi: 10.1136/bcr-2022-254113.

ABSTRACT

Infectious scleritis is a rare disease entity with potentially devastating visual sequelae. Here we present the clinical history, work-up and aetiology of an unusual case of infectious scleritis.

PMID:37221000 | DOI:10.1136/bcr-2022-254113

Dermatol Online J. 2023 Apr 15;29(2). doi: 10.5070/D329260772.

ABSTRACT

A 75-year-old man with a three-year history of metastatic lung adenocarcinoma was diagnosed with cutaneous lymphangitic carcinomatosa of unique morphology. He was admitted to our hospital for right neck swelling, erythema, and failure to thrive. Skin examination demonstrated an indurated, thickened, firm, hyperpigmented plaque extending from the right neck and chest to the right ear, cheek, and eyelids. Skin biopsy demonstrated poorly differentiated adenocarcinoma, morphologically consistent with metastasis from the patient's known pulmonary adenocarcinoma and showed dermal invasion, perineural invasion, and involvement of dermal lymphatics. The diagnosis was an atypical presentation of cutaneous lymphangitis carcinomatosa from metastatic lung adenocarcinoma. This case presentation affirms that cutaneous lymphangitis carcinomatosa has a variety of atypical presentations, so physicians must maintain a high index of suspicion when evaluating cutaneous lesions in patients with known or suspected internal malignancy.

PMID:37220288 | DOI:10.5070/D329260772

BMC Med Res Methodol. 2023 May 20;23(1):121. doi: 10.1186/s12874-023-01947-z.

ABSTRACT

BACKGROUND: There is a pressing need to improve the accuracy of rare disease clinical study endpoints. Neutral theory, first described here, can be used to assess the accuracy of endpoints and improve their selection in rare disease clinical studies, reducing the risk of patient misclassification.

METHODS: Neutral theory was used to assess the accuracy of rare disease clinical study endpoints and the resulting probability of false positive and false negative classifications at different disease prevalence rates. Search strings were extracted from the Orphanet Register of Rare Diseases using a proprietary algorithm to conduct a systematic review of studies published until January 2021. Overall, 11 rare diseases with one disease-specific disease severity scale (133 studies) and 12 rare diseases with more than one disease-specific disease severity scale (483 studies) were included. All indicators from clinical studies were extracted, and Neutral theory was used to calculate their match to disease-specific disease severity scales, which were used as surrogates for the disease phenotype. For those with more than one disease-severity scale, endpoints were compared with the first disease-specific disease severity scale and a composite of all later scales. A Neutrality score of > 1.50 was considered acceptable.

RESULTS: Around half the clinical studies for half the rare diseases with one disease-specific disease severity score (palmoplantar psoriasis, achalasia, systemic lupus erythematosus, systemic sclerosis and Fournier's gangrene) met the threshold for an acceptable match to the disease phenotype, one rare disease (Guillain-Barré syndrome) had one study with an acceptable match, and four diseases (Behcet's syndrome, Creutzfeldt-Jakob disease, atypical hemolytic uremic syndrome and Prader-Willi syndrome) had no studies. Clinical study endpoints in almost half the rare diseases with more than one disease-specific DSS (acromegaly, amyotrophic lateral sclerosis, cystic fibrosis, Fabry disease and juvenile rheumatoid arthritis) were a better match to the composite, while endpoints in the remaining rare diseases (Charcot Marie Tooth disease, Gaucher disease Type I, Huntington's disease, Sjogren's syndrome and Tourette syndrome) were a worse match. Misclassifications varied with increasing disease prevalence.

CONCLUSIONS: Neutral theory confirmed that disease-severity measurement needs improvement in rare disease clinical studies, especially for some diseases, and suggested that the potential for accuracy increases as the body of knowledge on a disease increases. Using Neutral theory to benchmark disease-severity measurement in rare disease clinical studies may reduce the risk of misclassification, ensuring that recruitment and treatment effect assessment optimise medicine adoption and benefit patients.

PMID:37210484 | DOI:10.1186/s12874-023-01947-z

JNMA J Nepal Med Assoc. 2023 Apr 1;61(260):379-382. doi: 10.31729/jnma.8116.

ABSTRACT

Toxic epidermal necrolysis in pregnancy is a rare disease that can have an adverse effect on Toxic epidermal necrolysis in pregnancy is a rare disease that can have an adverse effect on pregnancy outcomes. Common etiology of the condition includes medication triggered followed by mycoplasma infection. Almost one-third of cases are idiopathic. Despite the rarity of data, terbinafine causing toxic epidermal necrolysis has been reported. Toxic epidermal necrolysis manifests as a macule, erythema followed by a blister in the chest and spreading to other parts of the body. Removal of the offending agent and supportive management is the cornerstone of management. Here we report 22-year-old primipara pregnant women presenting with toxic epidermal necrolysis after 3 weeks of oral terbinafine use with good pregnancy outcomes.

KEYWORDS: case reports; pregnancy; Stevens-Johnson syndrome; toxic epidermal necrolysis.

PMID:37208883 | PMC:PMC10089020 | DOI:10.31729/jnma.8116

Hum Genomics. 2023 May 19;17(1):44. doi: 10.1186/s40246-023-00491-7.

ABSTRACT

BACKGROUND: Ubiquitin-related rare diseases are generally characterized by developmental delays and mental retardation, but the exact incidence or prevalence is not yet fully understood. The clinical application of next-generation sequencing for pediatric seizures and developmental delay of unknown causes has become common in studies aimed at identification of a causal gene in patients with ubiquitin-related rare diseases that cannot be diagnosed using conventional fluorescence in situ hybridization or chromosome microarray tests. Our study aimed to investigate the effects of ubiquitin-proteasome system on ultra-rare neurodevelopmental diseases, through functional identification of candidate genes and variants.

METHODS: In our present work, we carried out genome analysis of a patient with clinical phenotypes of developmental delay and intractable convulsion, to identify causal mutations. Further characterization of the candidate gene was performed using zebrafish, through gene knockdown approaches. Transcriptomic analysis using whole embryos of zebrafish knockdown morphants and additional functional studies identified downstream pathways of the candidate gene affecting neurogenesis.

RESULTS: Through trio-based whole-genome sequencing analysis, we identified a de novo missense variant of the ubiquitin system-related gene UBE2H (c.449C>T; p.Thr150Met) in the proband. Using zebrafish, we found that Ube2h is required for normal brain development. Differential gene expression analysis revealed activation of the ATM-p53 signaling pathway in the absence of Ube2h. Moreover, depletion of ube2h led to induction of apoptosis, specifically in the differentiated neural cells. Finally, we found that a missense mutation in zebrafish, ube2h (c.449C>T; p.Thr150Met), which mimics a variant identified in a patient with neurodevelopmental defects, causes aberrant Ube2h function in zebrafish embryos.

CONCLUSION: A de novo heterozygous variant in the UBE2H c.449C>T (p.Thr150Met) has been identified in a pediatric patient with global developmental delay and UBE2H is essential for normal neurogenesis in the brain.

PMID:37208785 | PMC:PMC10199504 | DOI:10.1186/s40246-023-00491-7