Pulmonary alveolar proteinosis (PAP) is an ultra-rare disease caused by impaired pulmonary surfactant clearance due to the dysfunction of alveolar macrophages or their signaling pathways. PAP is categorized into autoimmune, congenital, and secondary PAP, with autoimmune PAP being the most prevalent. This article aims to present a comprehensive review of PAP classification, pathogenesis, clinical presentation, diagnostics, and treatment. The PAP diagnosis is usually based on clinical symptoms, radiological imaging, and bronchoalveolar lavage, with additional GM-CSF antibody tests. The gold standard for PAP treatment is whole-lung lavage. This review presents a summary of the most recent findings concerning pulmonary alveolar proteinosis, pointing out specific features that require further investigation. Read the full article here.
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Exploring the Clinical and Genetic Landscape of Angelman Syndrome: Patient-Reported Insights from an Italian Registry
The Angelman Syndrome Registry (Research in Angelman Syndrome in Italy) aimed to assess the clinical history of individuals with Angelman Syndrome in Italy, compare it with existing literature, and explore the link between symptoms and genotypes. Established in 2018, the study enrolled 82 participants, with 62 providing complete data. It collected demographic, clinical, and genetic information using electronic forms, analyzing the data with descriptive statistics and examining genotype-clinical characteristic associations.
Key findings include:
- Median participant age: 8 years
- Males: 48.8%
- Most common genotype: Deletion (58.1%)
- High prevalence of epilepsy (82.2%), with seizures often beginning before age 3
- Majority needed multiple anti-epileptic drugs, with generalized tonic-clonic seizures and atypical absence seizures most common
- Deletion genotype associated with more severe developmental delays and higher seizure severity
- Sleep problems affected 69.4%, mainly involving sleep onset and maintenance difficulties
The study confirms that the clinical history and genetic characteristics of Angelman Syndrome in Italy align with existing research. It also demonstrated that patient registries are effective in collecting comprehensive data on rare diseases, which can enhance research and patient care.Read the full article here.
Hereditary fructose intolerance is a rare genetic disorder that is inherited in an autosomal recessive manner, with mutations sometimes occurring spontaneously. This rare disease it with ICD-10 code: E74.1 and ORPHA code: 469. Consuming fructose triggers biochemical abnormalities, disrupting liver processes like glycogenolysis and gluconeogenesis. Recent studies have revealed elevated intrahepatic fat levels in affected individuals. Symptoms include aversion to fructose-containing foods, hypoglycemia, liver and kidney dysfunction, and growth delays, with severe cases leading to liver enlargement.
In this case study a 20-month-old child with symptoms including difficulty passing stool, abdominal rigidity, abdominal pain with bloating and hypoglycemia is presented. Initial clinical findings reveal elevated liver enzymes, a mildly enlarged hyperechoic liver, hypercholesterolemia, and borderline alpha-fetoprotein values. Diagnostic assessments identify hereditary fructose intolerance with pathogenic variants in the ALDOB gene, along with a diagnosis of celiac disease. Genetic testing of the parents reveals carrier status for pathological aldolase B genes.
This case underscores the importance of comprehensive clinical evaluation and genetic testing in pediatric patients with complex metabolic presentations. Read the full article here.
Advancing fetal diagnosis and prognostication using comprehensive prenatal phenotyping and genetic testing
Prenatal diagnoses of congenital malformations have increased significantly due to high-resolution prenatal imaging. However, discussing these diagnoses with expectant parents remains challenging due to the varied outcomes associated with congenital malformations. Comprehensive prenatal genetic testing, including chromosomal microarray, exome sequencing, and genome sequencing, has become essential for improving prognostic accuracy.
The diagnostic yield of these tests depends on the specific malformations present. Prenatal genetic diagnosis enhances diagnostic clarity, informs pregnancy decisions, aids in neonatal care planning, and assists in reproductive planning. Although the turnaround time for comprehensive genetic testing results has improved, it still poses a challenge, especially for parents making decisions. The uncertainty of many genetic testing results necessitates appropriate genetic counseling to help parents understand the diagnosis and prognosis.
This review details available prenatal genetic testing options, discusses their impact on care using case examples, and consolidates current literature on the yield of genetic testing for diagnosing congenital malformations. Read the full article here.
Rare diseases are an often chronic and progressive group of conditions affecting more than 30 million people in Europe. These diseases are associated with significant direct and indirect costs to a spectrum of stakeholders, ranging from individuals and their families to society overall. Further quantitative research on the economic cost for children and their families living with a rare disease is required as there is little known on this topic.
This article aims to document the extent and type of evidence on the economic impacts of living with a rare disease for children and their families and map the current literature on the economic impact of paediatric rare diseases to understand how these impacts affect children living with rare diseases and their families. This evidence has the potential to influence policy and future research in this area and will support further research on the economic impact of rare diseases on families. Read the full article here.
Computer-Assisted patient identification tool in Inborn errors of metabolism – Potential for rare disease patient registry and big data analysis
Patient registries are crucial for rare disease management. However, manual registry construction is labor-intensive and not user-friendly. The aim of this study is to establish Hong Kong’s first computer-assisted patient identification tool for rare diseases, starting with Inborn errors of metabolism (IEM).
Patient data from 2010 to 2019 is retrieved from electronic databases. Through big data analytics, patients are filtered based on specific IEM-related biochemical and/or genetic tests. The algorithm classifies each extracted paragraph as “IEM-related” or “not IEM-related.”
Out of 46,419 patients with IEM-related tests, the algorithm identifies 100 as “IEM-related.” After pathologists’ validation, 96 cases are confirmed as true IEM, with 1 uncertain case and 3 false positives. A secondary ascertainment yields a sensitivity of 92.3% compared to the previously published IEM cohort.
This artificial intelligence approach provides a novel method to identify IEM patients, facilitating the creation of a centralized, computer-assisted rare disease patient registry at the local and national levels. This data can be accessed by multiple stakeholders for collaborative research and to enhance healthcare management for rare diseases. Read the full article here.
Prader-Willi syndrome (PWS) is a rare disease, which shows a peculiar clinical phenotype, including obesity, which is different from essential obesity (EOB). Metabolomics might represent a valuable tool to reveal the biochemical mechanisms/pathways underlying clinical differences between PWS and EOB. The aim of the present (case-control, retrospective) study is to determine the metabolomic profile that characterizes PWS compared to EOB.
A validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) targeted metabolomic approach is used to measure a total of 188 endogenous metabolites in plasma.
Body composition in PWS is different when compared to EOB, with increased fat mass and decreased fat-free mass. Glycemia and HDL cholesterol are higher in patients with PWS than in those with EOB, while insulinemia is lower, as well as heart rate. Resting energy expenditure is lower in the group with PWS than in the one with EOB.
PWS exhibits a specific metabolomic profile when compared to EOB, suggesting a different regulation of some biochemical pathways, fundamentally related to lipid metabolism. Read the full article here.
The Dyke-Davidoff-Masson syndrome (DDMS) is an uncommon neurological disorder whose prevalence is not yet known. There have only been 21 adult manifestations of this rare brain disorder, out of around 100 cases previously documented. Diagnosis is challenging because of the complexity of radiological findings and clinical symptoms, which include ventricle dilation, hypertrophy of the cranial bones, increased pneumatization of the sinuses, and cerebral hemisphere atrophy. It can be inherited or acquired from infections, brain hemorrhage, and hypoxia during pregnancy. Usually, neuroimaging is used to diagnose it. This case study reports the case of a 17-year-old girl who had complex partial seizures at the age of 17 and right-side paralysis since she was three years old. Read the full article here.
Whole genome sequencing of HER2-positive metastatic extramammary Paget’s disease: a case report
Extramammary Paget’s disease (EMPD) is a rare cancer that occurs within the epithelium of the skin, arising predominantly in areas with high apocrine gland concentration. The aim of this article is to integrate clinicopathological data with genomic analysis of aggressive, rapidly-progressing de novo metastatic EMPD responding to HER2-directed treatment in combination with other agents, to attain a more comprehensive understanding of the disease.
HER2 overexpression is demonstrated through immunohistochemical staining of the scrotal wall tumor and bone marrow metastasis. Whole genome sequencing of the tumor.
Whole genome sequencing reveals the underlying copy number variation landscape in HER2-positive metastatic EMPD. The presence of alternative signalling pathways and genetic variants suggests potential interactions with HER2 signalling, which possibly contributes to the HER2 overexpression and observed response to HER2-directed therapy combined with other agents in a comprehensive treatment regimen. Read the full article here.
Rare diseases have become an increasingly important public health priority due to their collective prevalence. While the approval of orphan drugs requires supportive data from stringent pre-market studies, these data lack the ability to describe the causes of treatment response heterogeneity. Investigation of the pharmacogenomics can potentially lead to the development of new therapeutics, help inform rational use criteria in drug policy, and improve the understanding of underlying disease pathophysiology. In the context of rare diseases where cohort sizes are smaller than ideal, ‘small data’ and ‘big data’ approaches to data collection and analysis should be combined to produce the most robust results. This article presents the importance of studying drug response in parallel to other research initiatives in rare diseases, as well as the need for international collaboration in the area of rare disease pharmacogenomics. Read the full article here.