Hereditary Forms Research Articles

Incidental Germline Findings During Comprehensive Genomic Profiling of Pancreatic and Colorectal Cancer: Single-center, Molecular Tumor Board Experience.

Abstract Multidisciplinary molecular tumor boards (MTB) are already well established in many comprehensive cancer centers and play an important role in the individual treatment planning for cancer patients. Comprehensive genomic profiling of tumor tissue based on next-generation sequencing is currently performed for diagnostic and mainly predictive testing. If somatic genomic variants are identified, which are suspected to be pathogenic germline variants (PGVs), MTB propose genetic counseling and germline DNA testing. Commonly used comprehensive genomic profiling approaches of tumor tissue do not include a matched germline DNA control. Therefore, the detection of PGVs could be only predicted based on the content of tumor cells (CTC) in selected tumor area (%) and variant allele frequency score (%). For conclusion, the role of a medical geneticist is essential in these cases. The overall prevalence of PGVs in patients with pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) is approximately 10%. In this single-center study, we present 37 patients with PDAC and 48 patients with CRC who were presented at MTB and tested using the large combined DNA/RNA sequencing panel. Content of tumor cells and variant allele frequency scores were evaluated in all tested patients. In case of suspicion of PGV and no previous genetic testing based on the standard guidelines, genetic counseling was recommended regardless of age, sex, and family history. In the PDAC subgroup, five patients were recommended by MTB for genetic counseling based on suspicious genetic findings. Based on a medical geneticist’s decision, germline DNA sequencing was performed in four of these cases, and all of them tested positive for PGV in the following genes: ATM, ATM, BRCA1, and BRCA2. In the CRC subgroup, no PGV was confirmed in the two patients genetically tested based on the MTB recommendations. Furthermore, we present data from our center’s registry of patients with PDAC and CRC who underwent genetic counseling and germline DNA testing based on the standard screening criteria. Our data confirm that comprehensive genomic profiling of tumor tissue can identify patients with hereditary forms of PDAC, who could remain unidentified by standard screening for hereditary forms of cancer.

TRANSTYRETIN CARDIAC AMYLOIDOSIS IN ELDERLY PATIENTS: ALWAYS A WILD TYPE?

Abstract Background Transthyretin amyloidosis (ATTR) exists in two forms: a genetic form transmitted by autosomal dominant inheritance (ATTRv) and a wild type form (ATTRwt). Clinically, the hereditary form tends to have an early onset in adulthood and it is characterized by a particular tropism for nervous as well as cardiac tissue. In contrast, the "wild type" form has a later onset with major cardiac involvement and neurological manifestations usually limited to carpal tunnel syndrome. Methods and Results In our centre, from September 2021 to June 2023, 52 patients older than 70 years received a diagnosis of cardiac ATTR (87% male, 13% female, mean age 81±5y). In all patients, blood tests showed a significant and stable increase in the values of troponin Ths (0.079 microg/L±0.074) and NT–proBNP (2000±1800 pg/ml), with the absence of a monoclonal component in the blood and urine, and miocardial bisphosphonate scintigraphy positive grade 2/3. All patients underwent genetic testing by amplification of exons 2,3 and 4 of the TTR gene with subsequent sequencing. Unexpectedly, in 10 elderly (70%male, 30% female, mean age 77±4 y) patients (19%) the genetic test resulted positive with 4 different mutations of pathogenetic significance (Val30Met; Ile68Leu; Val142Ile;, Phe84Leu). Three patients showed peripheral neuropathy with the presence of carpal tunnel syndrome, while isolated carpal tunnel syndrome was present in the remaining 7 cases. The three patients with neurologic involvement started Patisiran therapy, and 7 patients were treated with Tafamidis. First–degree relatives (16 consanguineous, average age 49±12 years) agreed to be subjected to genetic screening; of these 9 (3 male and 6 females, age 47±8 years) were positive for the corresponding mutation and underwent echocardiogram, MRI and myocardial scintigraphy. These tests were normal in 8 probands, included in an annual follow–up protocol to identify an early manifestation of the disease, and was diagnostic for amyloidosis in 1 patient who started specific therapy. Conclusions Our experience shows that 19% of patients older than 70 years with a diagnosis of cardiac ATTR may be affected by a genetic form. Making genetic diagnosis in this context is particularly important for screening family members: current therapies are in fact much more effective if started early before organ damage occurs.

A comparative analysis of surgically excised hereditary and sporadic pheochromocytomas: Insights from a single-center experience.

Pheochromocytoma is a tumor that usually originating from adrenal medullary chromaffin cells and producing one or more catecholamines, can manifest as hereditary or sporadic. While the majority pheochromocytomas are sporadic, hereditary forms are often associated with genetic syndromes such as von Hippel-Lindau, multiple endocrine neoplasia type 2, and neurofibromatosis type 1. This study aims to analyze data from our series of surgically excited pheochromocytoma patients and compare the characteristics between hereditary and sporadic cases. We retrospectively evaluated 33 diagnosed pheochromocytoma patients, documenting clinical features, surgical complications, and tumor characteristics in both hereditary and sporadic cases. Among the patients, 21% (7 individuals) had hereditary pheochromocytoma, while 79% (26 individuals) had sporadic cases. During diagnosis, hereditary pheochromocytoma patients exhibited a significantly lower mean age compared to the sporadic group (26.4 ± 9.9 years vs. 50.4 ± 14.0 years; p < 0.001). The maximum tumor size was also lower in hereditary cases compared to sporadic cases (p = 0.004). Adrenal tumor localization analysis showed that 63.6% were right-sided, 24.2% were left-sided, and 12.1% were bilateral. Laboratory analysis revealed significantly higher urinary norepinephrine levels in hereditary pheochromocytoma patients (p = 0.021). Our findings suggest that hereditary pheochromocytoma cases are characterized by a younger age at diagnosis, smaller tumor size, and a higher prevalence of multiple bilateral adrenal adenomas. We recommend genetic testing for all pheochromocytoma patients, particularly those with early-onset disease and bilateral adrenal tumors.

Medullary Thyroid Cancer: Epidemiology and Characteristics According to Data From the Marne-Ardennes Register 1975-2018.

Medullary thyroid cancer (MTC) is a rare disease. The main objective of our study was to analyze the incidence evolution of MTC with a follow-up of more than 40 years. Further, a descriptive and survival analysis was performed according to the Kaplan-Meier analysis. This is a retrospective epidemiological study using data from the Marne-Ardennes registry from 1975 to 2018. Two hundred sixty patients with MTC were included. The incidence was calculated in the territory of the register (Marne and Ardennes departments of France) and standardized on the demographic structure of France. Patient and tumor characteristics were described. An analysis in a subgroup comparing hereditary and sporadic forms was performed. An analysis of survival was performed. The standardized incidence shows an increasing trend over time. The incidence increased significantly from 0.41 to 0.57/100 000 person-years between 1986 and 1996 and 2008 and 2018. The MTC was hereditary in 21.2% of cases. The sex ratio (males:females) was 0.73. The average age at diagnosis was 53 years. Ninety-seven patients (37.3%) were N1, 26 (10%) were M1, and 56 (21.5%) developed metastases during the follow-up. Complete remission was obtained in 58.5% of patients. The disease was refractory for 18.1% of patients. The 5-year survival rate was 88.4%. Sporadic cases had a poorer prognosis than hereditary MTC. Our study demonstrates a moderate increase in the incidence of MTC between 1975 and 2018. The prognosis remains worse for sporadic MTC than for hereditary MTC.

“Unravelling Colorectal Cancer: From Origin to Treatment”

The colon and rectum are the primary organs affected by colorectal cancer (CRC), which is the primary cause of cancer-related morbidity and mortality. Inflammation, particularly in disorders like inflammatory bowel diseases, increases the risk of colorectal cancer, with environmental factors playing a crucial role. The majority of adenocarcinomas typically develop from the epithelial cells that line the colon and rectum as a result of a complex series of genetic and epigenetic modifications. Benign precursor lesions such as adenomatous polyps trigger the slow progression of CRC over a period of ten years or longer. Its etiology is influenced by sporadic, familial, and hereditary forms; prominent hereditary syndromes include Lynch syndrome and familial adenomatous polyposis. Chromosome instability and microsatellite instability are the two main tumorigenic pathways that underpin the pathophysiology of CRC, exhibiting regional differences in the global epidemiology. Approaches: TNM classification is the basis for diagnosis, and various treatment modalities, such as surgery, radiotherapy, chemotherapy, targeted therapy, immunotherapy, and gene therapy, are employed during treatment. Surgical treatments, from minimally invasive procedures to colectomy, are essential and highlight the importance of total excision of the mesocolic region. The standard therapeutic approach consists of chemotherapy and targeted agents; however, newer like gene therapy and immunotherapy show promise. In order to improve outcomes and lessen the burden of the disease, combating CRC requires comprehensive strategies that include early detection, prevention, and innovative therapeutic interventions.

Prognostic Value of Standard Heart Failure Medication in Patients with Cardiac Transthyretin Amyloidosis.

Introduction: Cardiac transthyretin amyloidosis (ATTR) is a progressive, fatal disease leading to heart failure due to accumulation of amyloid fibrils in the interstitial space and may occur as a hereditary (ATTRv) or wild-type (ATTRwt) form. Guidelines recommend the use of ACE inhibitors (ACEis) and beta-blockers (BBs) as heart failure therapy (HFT) in all patients with symptomatic heart failure and reduced ejection fraction, independent of the underlying etiology. However, the prognostic benefit of ACEis and BBs in ATTR has not been elucidated in detail yet. We thus sought to retrospectively investigate the outcome of patients with ATTRwt or ATTRv under HFT. Methods: Medical records of 403 patients with cardiac ATTR (ATTRwt: n = 268, ATTRv: n = 135) were screened for long-term medication as well as clinical, laboratory, electrocardiographic and echocardiographic data. Patients were assessed between 2005 and 2020 at the University Hospital Heidelberg. Kaplan-Meier analysis was used to analyze potential differences in survival among different subgroups. Results: The mean follow-up was 28 months. In total, 43 patients (32%) with ATTRv and 140 patients (52%) with ATTRwt received HFT. Survival was significantly shorter in patients receiving HFT in ATTRv (46 vs. 83 months, p = 0.0007) vs. non-HFT. A significantly better survival was observed in patients with comorbidities (coronary artery disease, arterial hypertension) and HFT among ATTRwt patients (p = 0.004). No significant differences in survival were observed in the other subgroups. Conclusions: Survival analysis revealed a potential benefit of HFT in patients with ATTRwt and cardiac comorbidities such as coronary artery disease and/or arterial hypertension. In contrast, HFT should be used with caution in patients with ATTRv.

Timing, incidence and management of delayed bleeding after partial nephrectomy in patients at risk for recurrent, bilateral, multifocal renal tumors

IntroductionDelayed bleeding is a potentially serious complication after partial nephrectomy (PN), with reported rates of 1%–2%. Patients with multiple renal tumors, including those with hereditary forms of kidney cancer, are often managed with resection of multiple tumors in a single kidney which may increase the risk of delayed bleeding, though outcomes have not previously been reported specifically in this population. The objective of this study was to evaluate the incidence and timing of delayed bleeding as well as the impact of intervention on renal functional outcomes in a cohort primarily made up of patients at risk for bilateral, multifocal renal tumors. MethodsA retrospective review of a prospectively maintained database of patients with known or suspected predisposition to bilateral, multifocal renal tumors who underwent PN from 2003 to 2023 was conducted. Patients who presented with delayed bleeding were identified. Patients with delayed bleeding were compared to those without. Comparative statistics and univariate logistic regression were used to determine potential risk factors for delayed bleeding. ResultsA total of 1256 PN were performed during the study period. Angiographic evidence of pseudoaneurysm, AV fistula and/or extravasation occurred in 24 cases (1.9%). Of these, 21 were symptomatic presenting with gross hematuria in 13 (54.2%), decreasing hemoglobin in 4(16.7%), flank pain in 2(8.3%), and mental status change in 2 (8.3%), while 3 patients were asymptomatic. Median number of resected tumors was 5 (IQR 2–8). All patients underwent angiogram with super-selective embolization. Median time to bleed event was 13.5 days (IQR 7–22). Factors associated with delayed bleeding included open approach (OR 2.2, IQR(1.06–5.46), P = 0.04 and left-sided surgery (OR 4.93, IQR(1.67–14.5), P = 0.004. Selective embolization had little impact on ultimate renal functional outcomes, with a median change of 11% from the baseline eGFR after partial nephrectomy and embolization. One patient required total nephrectomy for refractory bleeding after embolization. ConclusionsDelayed bleeding after PN in a cohort of patients with multifocal tumors is an infrequent event, with similar rates to single tumor series. Patients should be counseled regarding timing and symptoms of delayed bleeding and multidisciplinary management with interventional radiology is critical for timely diagnosis and treatment.

Two Novel Genetic Variants Involved in the Oxygen Sensing Pathway in JAK2-unmutated Erythrocytosis.

JAK2-unmutated erythrocytosis or non-polycythemia vera erythrocytosis is a rare condition comprising both acquired and hereditary forms. Although acquired erythrocytosis has been well-studied, hereditary erythrocytosis remains poorly studied. Genetic alterations associated with hereditary erythrocytosis include mutations in erythropoietin receptor and erythropoietin (EPO), altered oxygen affinity mutations, and variants associated with the oxygen-sensing pathway. We established a molecular diagnostic approach based on these genes and retrospectively evaluated. Peripheral blood from 56 erythrocytosis patients, lacking JAK2 mutation, were screened for oxygen-sensing pathway abnormalities. Two novel mutations were identified in the EGLN1 gene: NM_022051.2:c.712G > C (p.Gly238Arg) and NM_022051.2:c.122A > C (p.Tyr41Ser) in two patients separately. Notably, both reported heterozygous mutations were absent in the population database. Predictions using multiple computer software indicated that these two missense mutations were harmful and induced a highly conserved amino acid change in EGLN1. Patients with the two mutations exhibited normal serum EPO levels and high hemoglobin and hematocrit levels. Additionally, three other variants of genes were identified in the oxygen-sensing pathway, including endothelial PAS domain protein 1 (EPAS1) rs184760160(2/56), and EGLN1 rs186996510(2/56), rs555121182(2/56). These variants were categorized as benign or likely benign. Our findings provide a framework for etiological research and highlight the importance of screening for genetic mutations associated with erythrocytosis in clinical practice.

Abstract 979: Cell-free DNA fragmentomics and second malignant neoplasm risk in patients with PTEN hamartoma tumor syndrome

Abstract Individuals with PTEN hamartoma tumor syndrome (PHTS) harbor germline PTEN variants that confer a significantly increased lifetime risk of various organ-specific cancers, and a 7-fold increased risk of second primary malignant neoplasms (SMNs). Currently, there is no reliable biomarker that can accurately predict which individuals with PHTS will develop malignancies, let alone SMN. Currently, there is no reliable biomarker that can accurately predict which individuals with PHTS will develop malignancies, let alone SMN. Despite the highly promising value of cell-free DNA (cfDNA) as a biomarker for underlying sporadic cancers, the utility of cfDNA in individuals with hereditary forms of cancer remains poorly understood. Thus, we performed a retrospective study in prospectively accrued patients with PHTS investigating whether plasma cfDNA profiles can be leveraged as a predictive marker of cancer risk. We performed ultra-low pass whole genome sequencing of cfDNA of archived plasma samples from patients with PHTS without cancer (N = 50), and those with cancer (N = 49). Those with cancer included patients with only a single primary malignant neoplasm (PMN, N = 23) and patients with second malignant neoplasms (SMN, N = 26). To investigate cfDNA profiles in patients with PHTS and subclinical cancer, we included nine patients with plasma archived before their cancer diagnosis. We observed that patients with PHTS and SMNs have significantly decreased proportion of di- and tri-nucleosome-associated cfDNA fragments compared to patients with PMNs and those without cancer. Furthermore, SMN status was associated with increased genome-wide fragmentation (ratio of short to long fragments) of mono- (OR 2.37, 95% CI [1.09, 7.27]; P = 0.025) and di-nucleosome-associated (OR 3.03, 95% CI [1.07, 15.7]; P = 0.029) cfDNA fragments, even after controlling for age at plasma draw and phenotypic burden. Fragment end profiling was performed by calculating the frequencies of the first 4-nucleotide sequence (4-mer end motif) at each 5’ end of cfDNA fragments. We identified 35 differentially abundant 4-mer end motifs when comparing patients with SMN to those without cancer. Patients with PHTS and SMNs were characterized by a decrease in A-end motifs with concurrent increases in G- and T-end motifs. Increased frequency of C-motifs—namely CC- and CA-end motifs—appeared to be unique to patients who had plasma drawn before their SMN diagnosis, a potential marker for active cancer. Our findings provide evidence that cfDNA fragmentomic features can be leveraged as a potential marker of individual SMN risk in PHTS. These results may facilitate earlier cancer detection and intervention as well as prevent unnecessary high-risk cancer surveillance and prophylactic surgeries in this vulnerable population. Citation Format: Darren Liu, Lamis Yehia, Andrew Dhawan, Ying Ni, Charis Eng. Cell-free DNA fragmentomics and second malignant neoplasm risk in patients with PTEN hamartoma tumor syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 979.

Hereditary forms of breast malignant neoplasms: prognosis, screening and prevention. A review

Hereditary forms of breast malignant neoplasms: prognosis, screening and prevention. A review

Metabolic alterations in hereditary and sporadic renal cell carcinoma.

Kidney cancer is the seventh leading cause of cancer in the world, and its incidence is on the rise. Renal cell carcinoma (RCC) is the most common form and is a heterogeneous disease comprising three major subtypes that vary in their histology, clinical course and driver mutations. These subtypes include clear cell RCC, papillary RCC and chromophobe RCC. Molecular analyses of hereditary and sporadic forms of RCC have revealed that this complex and deadly disease is characterized by metabolic pathway alterations in cancer cells that lead to deregulated oxygen and nutrient sensing, as well as impaired tricarboxylic acid cycle activity. These metabolic changes facilitate tumour growth and survival. Specifically, studies of the metabolic features of RCC have led to the discovery of oncometabolites - fumarate and succinate - that can promote tumorigenesis, moonlighting functions of enzymes, and substrate auxotrophy owing to the disruption of pathways that enable the production of arginine and cholesterol. These metabolic alterations within RCC can be exploited to identify new therapeutic targets and interventions, in combination with novel approaches that minimize the systemic toxicity of metabolic inhibitors and reduce the risk of drug resistance owing to metabolic plasticity.

Precision medicine in endocrinology exemplified by medullary thyroid cancer

Medullary thyroid cancer (MTC) is a prime example for precision medicine in endocrinology and underlines the immediate benefits of basic, translational and healthcare research for patients with a rare disease in clinical . A mutation in the rearranged during transfection (RET) proto-oncogene that codes for a transmembrane receptor protein tyrosine kinase, leads to constitutive activation of the kinase, which is the decisive pathomechanism for the disease. The MTC occurs in a sporadic (somatic RET mutation) or hereditary form (RET germline mutation, multiple endocrine neoplasia types 2 and 3). For germline mutation carriers the timing of preventive thyroidectomy depends on the RET genotype. For advanced metastasized RET-mutant MTC, selective RET kinase inhibitors are available, which are currently considered to be game changers in the treatment. Based on the specific tumor marker calcitonin, MTC can be identified at an early stage during the differential diagnosis of thyroid nodules. The preoperative calcitonin level even enables statements on the degree of dissemination of the disease and on the probability of a cure through surgery. A new development is the consideration of desmoplasia as a histopathological biomarker for the metastatic potential of a MTC, which could possibly modify the operative approach as well as the future MTC nomenclature. Furthermore, the postoperative calcitonin level and the calcitonin doubling time are highly valid prognostic markers for tumor burden and biological aggressiveness of MTC and therefore decisive for patient follow-up. Biochemical, molecular and histological markers enable a risk-adapted surgical treatment and together with new targeted systemic treatments have contributed to a paradigm shift in the diagnostics, prognosis and treatment of MTC in recent years. Endocrine precision medicine for MTC therefore enabled a change from the previous purely symptom-oriented to a modern preventive and individualized treatment.

Bilateral osteochondroma in a child: A rare case report

Abstract Osteochondroma has an incidence of 1 in 50,000 and is the most common benign bone tumor, which accounts for 30% (range 20%–50%) of all benign bone tumors. The incidence of osteochondroma is higher in males than females in both its solitary and hereditary forms. Osteochondroma can arise from any bone that develops from enchondral ossification. It commonly involves the long bones, and it rarely involves the ribs. Lesion is common in childhood, with 75%–80% occurring before the age of 20. Here, we report a case of bilateral rib osteochondroma that was presented during infancy.

Hereditary Pulmonary Alveolar Proteinosis in a Pediatric Patient – A Diagnostic and Therapeutic Challenge

Abstract The abstract will be: “Pulmonary Alveolar Proteinosis (PAP) is a rare but potentially fatal respiratory disorder. The hereditary form is due to mutations affecting the GM-CSF receptor subunits. We are presenting this case report of a 3-year-old girl -who was the child of a fourth-degree consanguineous marriage- who developed Hereditary Alveolar Proteinosis. Her diagnosis was confirmed by surgical biopsy as well as whole exome sequencing (WES) genetic testing that revealed homozygous gene deletion of the CSF2RA gene (Colony Stimulating Factor 2RA). She had a favorable outcome and spontaneous resolution of her disease on follow-up.”

Diagnosis, treatment, and management of rickets: a position statement from the Bone and Mineral Metabolism Group of the Italian Society of Pediatric Endocrinology and Diabetology.

Rickets results from impaired mineralization of growing bone due to alterations in calcium and phosphate homeostasis. Clinical signs of rickets are related to the age of the patient, the duration of the disease, and the underlying disorder. The most common signs of rickets are swelling of the wrists, knees or ankles, bowing of the legs (knock-knees, outward bowing, or both) and inability to walk. However, clinical features alone cannot differentiate between the various forms of rickets. Rickets includes a heterogeneous group of acquired and inherited diseases. Nutritional rickets is due to a deficiency of vitamin D, dietary calcium or phosphate. Mutations in genes responsible for vitamin D metabolism or function, the production or breakdown of fibroblast growth factor 23, renal phosphate regulation, or bone mineralization can lead to the hereditary form of rickets. This position paper reviews the relevant literature and presents the expertise of the Bone and Mineral Metabolism Group of the Italian Society of Pediatric Endocrinology and Diabetology (SIEDP). The aim of this document is to provide practical guidance to specialists and healthcare professionals on the main criteria for diagnosis, treatment, and management of patients with rickets. The various forms of rickets are discussed, and detailed references for the discussion of each form are provided. Algorithms to guide the diagnostic approach and recommendations to manage patients with rare forms of hereditary rickets are proposed.

Функции монархической власти в политическом процессе европейских государств

The article examines functional component of monarch institution within the frame-work of its influence on the political process of European countries with hereditary form of rule. The multifaceted nature of crown power and its ability to have a significant impact on management decisions made in corresponding states are emphasized. The author comes to the conclusion that a wide range of monarchical authority is a natural result of the devel-opment of hereditary form of rule as part of its adaptation to the realities of the 21st century.

НАСЛЕДСТВЕННЫЕ ФОРМЫ ПРИОННОЙ БОЛЕЗНИ В ПЕДИАТРИЧЕСКОЙ ПРАКТИКЕ: ОБЗОР ЛИТЕРАТУРЫ И ОПИСАНИЕ СОБСТВЕННЫХ КЛИНИЧЕСКИХ НАБЛЮДЕНИЙ

As for now, there is very limited and surely insufficient scientific data published Worldwide on the manifestation of hereditary forms of prion disease in childhood. Authors provide brief overview of PRNP-associated prion diseases and the description of their own two clinical cases of this disease with manifestation in childhood. Both of the observed patients had many similar clinical manifestations at the onset of the disease at the age of 15 to 16 y/o, such as: predominance of neuropsychiatric symptoms at the onset, rapid progression of the disease, early development of dementia and the lethal outcome within 1 to 1.5 years. Genotype that had been identified by the results of a molecular genetic study was also similar in both patients: the repeatedly described mutation D178N in combination with the M129M polymorphism in the PRNP gene. Prion disease in all cases initially occurred under the guise of mental disorders, making it difficult to suspect a diagnosis at an early stage. Considering the extreme rarity of the manifestation of hereditary forms of prion disease in childhood, the Article is drawing attention to the current problematics connected with low alertness and delayed diagnosis of this pathology in pediatric practice.

Targeting ER Acetylation to Rescue Proteotoxicity

Transient acetylation within the endoplasmic reticulum (ER) lumen has emerged as a novel mechanism that regulates proteostasis and dynamics of the secretory pathway. The ER acetylation machinery includes AT-1, a membrane transporter that imports acetyl-CoA from the cytosol into the ER lumen, and two acetyltrasferases, ATase1 and ATase2, which acetylate ER cargo and resident proteins. Loss-of-function mutations or gene duplication events that affect ER acetylation are linked to developmental delay and premature death (homozygous mutation), hereditary forms of peripheral neuropathy (homozygous mutation), and autism spectrum disorder with intellectual disability and progeria (gene duplication). Mouse models of dysfunctional ER acetylation mimic associated human phenotypes.

Genetic Variations and Risk Factors on Medulloblastoma

Medulloblastoma, a highly aggressive brain tumor, presents a complex clinical landscape driven by intricate genetic variations and diverse risk factors. This review delves into the tumor's genetic origins, emphasizing molecular subgroups and their prognostic implications. Examining risk factors such as age, gender, genetics, and ethnicity provides a holistic perspective. Unraveling hereditary forms sheds light on familial predispositions. Racial disparities underscore the importance of tailored approaches. Decoding the complexities surrounding medulloblastoma informs refined diagnostics and personalized treatments, offering hope for enhanced patient outcomes.

The past, present and future of Alzheimer's disease - part 1: the past.

Alzheimer's disease (AD) was described in 1907, and since then it changed from a relatively rare condition to one of the most prevalent diseases. To describe the evolution of the notions of dementias and AD, and to investigate the reasons for the increase in scientific interest in AD. A historical analysis was carried out on knowledge about dementia, the site of mental activity, the relationships between brain diseases and mental activity, and on the advances in research about AD, since its discovery until the publication of the amyloid cascade hypothesis in 1992. A search was carried out in the National Library of Medicine (PubMed) for scientific articles that included the terms dementia or AD over 50 years, from 1972 to 2021. The scientific research on AD increased from 615 papers with the term AD in the first decade (1972-1981), to 100,028 papers in the last decade (2012-2021): an increase of 162.6 times whereas publications with the term dementia increased 28.6 times in the same period. In the 1960s and 1970s, a consensus was reached that AD is responsible for the majority of cases of dementia previously known as senile dementia. In the 1980s, beta-amyloid peptide was identified in the core of the senile plaque, hyperphosphorylated tau protein was found in neurofibrillary tangles, and a mutation was discovered in a hereditary form of AD. The expansion of the concept of AD to include senile dementia, and the discoveries that occurred in the 1980s greatly expanded research in AD.