Bi-allelic JAM2 Variants Lead to Early-Onset Recessive Primary Familial Brain Calcification.

Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder characterized by a combination of neurological, psychiatric, and cognitive decline associated with calcium deposition on brain imaging. To date, mutations in five genes have been linked to PFBC. However, more than 50% of individuals affected by PFBC have no molecular diagnosis. We report four unrelated families presenting with initial learning difficulties and seizures and later psychiatric symptoms, cerebellar ataxia, extrapyramidal signs, and extensive calcifications on brain imaging. Through a combination of homozygosity mapping and exome sequencing, we mapped this phenotype to chromosome 21q21.3 and identified bi-allelic variants in JAM2. JAM2 encodes for the junctional-adhesion-molecule-2, a key tight-junction protein in blood-brain-barrier permeability. We show that JAM2 variants lead to reduction of JAM2 mRNA expression and absence of JAM2 protein in patient's fibroblasts, consistent with a loss-of-function mechanism. We show that the human phenotype is replicated in the jam2 complete knockout mouse (jam2 KO). Furthermore, neuropathology of jam2 KO mouse showed prominent vacuolation in the cerebral cortex, thalamus, and cerebellum and particularly widespread vacuolation in the midbrain with reactive astrogliosis and neuronal density reduction. The regions of the human brain affected on neuroimaging are similar to the affected brain areas in the myorg PFBC null mouse. Along with JAM3 and OCLN, JAM2 is the third tight-junction gene in which bi-allelic variants are associated with brain calcification, suggesting that defective cell-to-cell adhesion and dysfunction of the movement of solutes through the paracellular spaces in the neurovascular unit is a key mechanism in CNS calcification

Recent increase in the incidence of non-Hodgkin's lymphoma among young men and women in Denmark.

Time-related trends in the incidence of non-Hodgkin's lymphoma (NHL) in Denmark were analysed for the period 1943-89. A total of 13 822 patients (7565 men and 6257 women) were included in the study. In men, world-standardised incidence rates per 100 000 population increased from 2.5 in 1943-47 to 9.3 in 1988-89. In women, a similar increase was seen, i.e. from 1.9 in 1943-47 to 6.5 per 100 000 population in 1988-89. For all birth cohorts, the male-to-female incidence ratio was highest among young subjects and fell significantly after the age of 29 years. Trends in age-specific incidence were analysed separately for two periods, i.e. 1943-77 and 1978-89, reflecting an early, pre-AIDS period and a later period possibly influenced by AIDS. In both periods, the incidence of NHL increased in all age groups. However, in recent years a noticeable increase in incidence averaging 8% annually was observed in men and women aged 40-49 years. A number of factors including changes in the perception of NHL and in the diagnostic methods available are considered insufficient to explain the observed increase. The remarkable and parallel time trends observed in young men and women in recent years indicate that factors other than AIDS must be considered

Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases.

Developmental and/or epileptic encephalopathies (DEEs) are a group of devastating genetic disorders, resulting in early-onset, therapy-resistant seizures and developmental delay. Here we report on 22 individuals from 15 families presenting with a severe form of intractable epilepsy, severe developmental delay, progressive microcephaly, visual disturbance and similar minor dysmorphisms. Whole exome sequencing identified a recurrent, homozygous variant (chr2:64083454A > G) in the essential UDP-glucose pyrophosphorylase (UGP2) gene in all probands. This rare variant results in a tolerable Met12Val missense change of the longer UGP2 protein isoform but causes a disruption of the start codon of the shorter isoform, which is predominant in brain. We show that the absence of the shorter isoform leads to a reduction of functional UGP2 enzyme in neural stem cells, leading to altered glycogen metabolism, upregulated unfolded protein response and premature neuronal differentiation, as modeled during pluripotent stem cell differentiation in vitro. In contrast, the complete lack of all UGP2 isoforms leads to differentiation defects in multiple lineages in human cells. Reduced expression of Ugp2a/Ugp2b in vivo in zebrafish mimics visual disturbance and mutant animals show a behavioral phenotype. Our study identifies a recurrent start codon mutation in UGP2 as a cause of a novel autosomal recessive DEE syndrome. Importantly, it also shows that isoform-specific start-loss mutations causing expression loss of a tissue-relevant isoform of an essential protein can cause a genetic disease, even when an organism-wide protein absence is incompatible with life. We provide additional examples where a similar disease mechanism applies

The incidence of other gastroenterological disease following diagnosis of irritable bowel syndrome in the UK: a cohort study

BACKGROUND: Guidelines recommend Irritable Bowel Syndrome (IBS) diagnosis and management in primary care with minimal investigations; however little evidence exists regarding risk of organic gastrointestinal conditions following diagnosis of IBS and how such risks vary over the long term. This study assesses excess incidence of coeliac disease, inflammatory bowel disease (IBD) and colorectal cancer (CRC) and variation with age and time after IBS diagnosis. METHODS: IBS patients and controls were identified within the UK Clinical Practice Research Dataset. Incidence rates were calculated and stratified by age and time since IBS diagnosis with incident rate ratios generated. RESULTS: Fifteen years after IBS diagnosis there is a significant cumulative excess incidence of coeliac disease, IBD and CRC in IBS of 3.7% compared to 1.7% in controls. For every 10000 patient years, IBS patients experienced an additional 4 diagnoses of coeliac disease, 13 of IBD and 4 CRCs. In each condition peak excess incidence was in the 6 months following diagnosis. After one year, increased incidence of coeliac disease remained consistent without variation by age. IBD incidence fell slowly, with higher rates in those under 30. CRC incidence was increased only in patients aged 30 to 74 during the first 5 years. CONCLUSION: Some IBS patients later receive organic gastrointestinal diagnoses, with the early excess incidence likely detected during diagnostic investigation at the time of IBS diagnosis. More than 5 years after IBS diagnosis there is no increased risk of CRC compared to the general population, but a small excess risk of coeliac disease and IBD persists. Overall, though our findings provide reassurance that non-specialists, especially those in primary care, are unlikely to be missing an organic condition in the majority of their patients. This suggests that current guidelines suggesting avoidance of universal referral for these patients are appropriate

Mutations in TOP3A Cause a Bloom Syndrome-like Disorder

Bloom syndrome, caused by biallelic mutations in BLM, is characterized by prenatal-onset growth deficiency, short stature, an erythematous photosensitive malar rash, and increased cancer predisposition. Diagnostically, a hallmark feature is the presence of increased sister chromatid exchanges (SCEs) on cytogenetic testing. Here, we describe biallelic mutations in TOP3A in ten individuals with prenatal-onset growth restriction and microcephaly. TOP3A encodes topoisomerase III alpha (TopIIIα), which binds to BLM as part of the BTRR complex, and promotes dissolution of double Holliday junctions arising during homologous recombination. We also identify a homozygous truncating variant in RMI1, which encodes another component of the BTRR complex, in two individuals with microcephalic dwarfism. The TOP3A mutations substantially reduce cellular levels of TopIIIα, and consequently subjects’ cells demonstrate elevated rates of SCE. Unresolved DNA recombination and/or replication intermediates persist into mitosis, leading to chromosome segregation defects and genome instability that most likely explain the growth restriction seen in these subjects and in Bloom syndrome. Clinical features of mitochondrial dysfunction are evident in several individuals with biallelic TOP3A mutations, consistent with the recently reported additional function of TopIIIα in mitochondrial DNA decatenation. In summary, our findings establish TOP3A mutations as an additional cause of prenatal-onset short stature with increased cytogenetic SCEs and implicate the decatenation activity of the BTRR complex in their pathogenesis

Near-edge x-ray absorption fine structure investigation of graphene

We report the near-edge x-ray absorption fine structure (NEXAFS) spectrum of a single layer of graphite (graphene) obtained by micromechanical cleavage of Highly Ordered Pyrolytic Graphite (HOPG) on a SiO2 substrate. We utilized a PhotoEmission Electron Microscope (PEEM) to separately study single- double- and few-layers graphene (FLG) samples. In single-layer graphene we observe a splitting of the pi* resonance and a clear signature of the predicted interlayer state. The NEXAFS data illustrate the rapid evolution of the electronic structure with the increased number of layers.Comment: 5 pages, 4 figure

Occupational Physical Activity Among Pregnant Employees in the Danish Workforce: The PRECISE Occupational Cohort Profile

Hannah Nørtoft Frankel,1,2,* Katia Keglberg Hærvig,1,* Esben Meulengracht Flachs,1 Mette Korshøj,3 Charlotte Bertelsen,1,2 Mette Backhausen,4 Camilla Sandal Sejbaek,1 Luise Mølenberg Begtrup1,2 1Department of Occupational and Environmental Medicine, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark; 2Department of Public Health, University of Copenhagen, Copenhagen, Denmark; 3Department of Occupational and Social Medicine, Copenhagen University Hospital Holbæk, Holbæk, Denmark; 4Department of Gynecology and Obstetrics, Zealand University Hospital, Roskilde, Denmark*These authors contributed equally to this workCorrespondence: Hannah Nørtoft Frankel, Department of Occupational and Environmental Medicine, Copenhagen University Hospital -Bispebjerg and Frederiksberg, Bispebjerg Bakke 23, entrance 20F, 1st floor, Copenhagen NV, 2400, Denmark, Tel +45 26598244, Email [email protected]: Occupational physical activity (OPA) has been linked to adverse pregnancy outcomes, although findings are not consistent. This paper describes the PRECISE Occupational Cohort, designed with the purpose to obtain comprehensive information on OPA with objective measurements and prospective information on pregnancy-related discomforts and sick leave among pregnant employees in Denmark.Methods: A total of 1556 pregnant participants were included between January 2023 and June 2024 from six obstetric departments in relation to the first trimester ultrasound scan. Information on OPA, pregnancy-related discomforts and sick leave was collected by repeated weekly questionnaires. Additionally, a subgroup of 327 pregnant participants and 90 non-pregnant co-workers were invited for repeated objective measurements, and/or workplace observations. A total of 603 accelerometer measurements from 412 unique participants, and 138 workplace observations were obtained from 102 unique participants. Time spent standing, walking and forward bending was acquired by accelerometers, and information on lifting and person-handlings was quantified by observations. All participants covered 197 occupational codes.Results: A total of 1008 pregnant participants on average responded to the weekly questionnaires from pregnancy weeks 12– 40. High frequencies of pregnancy discomforts were reported throughout pregnancy, and on average only 11% reported no discomforts. Pregnancy-related sick leave increased throughout pregnancy, peaking in pregnancy week 29, where 26% reported at least one day of pregnancy-related sick leave in the past week.Conclusion: This cohort provides unique repeated measurements with comprehensive information about pregnant employees across many jobs, disclosing high levels of pregnancy discomforts and sick leave throughout pregnancy. The information will enable investigation of the associations of OPA, pregnancy-related discomforts and sick leave on a more detailed level than now. The objective measurements with novel information on OPA will contribute to the development of quantitative Job Exposure Matrices enabling investigation of the association between OPA and adverse pregnancy outcomes in larger populations, with the potential to strengthen preventive guidelines.Keywords: adverse pregnancy outcomes, objective measurements, pregnancy cohort, pregnancy-related sick leav

Heterozygous De Novo UBTF Gain-of-Function Variant Is Associated with Neurodegeneration in Childhood.

Ribosomal RNA (rRNA) is transcribed from rDNA by RNA polymerase I (Pol I) to produce the 45S precursor of the 28S, 5.8S, and 18S rRNA components of the ribosome. Two transcription factors have been defined for Pol I in mammals, the selectivity factor SL1, and the upstream binding transcription factor (UBF), which interacts with the upstream control element to facilitate the assembly of the transcription initiation complex including SL1 and Pol I. In seven unrelated affected individuals, all suffering from developmental regression starting at 2.5-7 years, we identified a heterozygous variant, c.628G\u3eA in UBTF, encoding p.Glu210Lys in UBF, which occurred de novo in all cases. While the levels of UBF, Ser388 phosphorylated UBF, and other Pol I-related components (POLR1E, TAF1A, and TAF1C) remained unchanged in cells of an affected individual, the variant conferred gain of function to UBF, manifesting by markedly increased UBF binding to the rDNA promoter and to the 5\u27- external transcribed spacer. This was associated with significantly increased 18S expression, and enlarged nucleoli which were reduced in number per cell. The data link neurodegeneration in childhood with altered rDNA chromatin status and rRNA metabolism

Novel fibronectin mutations and expansion of the phenotype in spondylometaphyseal dysplasia with “corner fractures”

Heterozygous pathogenic variants in the FN1 gene, encoding fibronectin (FN), have recently been shown to be associated with a skeletal disorder in some individuals affected by spondylometaphyseal dysplasia with “corner fractures” (SMD-CF). The most striking feature characterizing SMD-CF is irregularly shaped metaphyses giving the appearance of “corner fractures”. An array of secondary features, including developmental coxa vara, ovoid vertebral bodies and severe scoliosis, may also be present. FN is an important extra cellular matrix component for bone and cartilage development. Here we report five patients affected by this subtype of SMD-CF caused by five novel FN1 missense mutations: p.Cys123Tyr, p.Cys169Tyr, p.Cys213Tyr, p.Cys231Trp and p.Cys258Tyr. All individuals shared a substitution of a cysteine residue, disrupting disulfide bonds in the FN type-I assembly domains located in the N-terminal assembly region. The abnormal metaphyseal ossification and “corner fracture” appearances were the most remarkable clinical feature in these patients. In addition, generalized skeletal fragility with low-trauma bilateral femoral fractures was identified in one patient. Interestingly, the distal femoral changes in this patient healed with skeletal maturation. Our report expands the phenotypic and genetic spectrum of the FN1-related SMD-CF and emphasizes the importance of FN in bone formation and possibly also in the maintenance of bone strength.Peer reviewe