Bloom Syndrome: Features, Inheritance and Biochemistry

Bloom Syndrome: Features, Inheritance and Biochemistry Discuss the inheritance, molecular and biochemical defects underlying the clinical features associated with Bloom syndrome Introduction First described by David Bloom in 1954, Bloom syndrome (BS) is an autosomal recessive genetic condition resulting in widespread genomic instability and a subsequent predisposition to the development of cancer (Cunniff, 2017). BS is an example of a chromosome breakage syndrome, characterised by defective DNA metabolism and genetic repair mechanisms (Duker, 2002). Effecting less than 300 people worldwide, symptoms include abnormally small size and noticeable redness of the cheeks and nose. People with BS also experience impaired immune system function, reduced fertility and decreased intellectual ability in some cases (Cunniff, 2017). Over a third of the patients in the Bloom syndrome registry descend from Ashkenazi Jewish ethnic lineages (Sanz, 2006). The underlying genetic landscape of BS is complex and not yet fully understood. This essay will discuss clinical symptoms, molecular aetiology, functional consequences, methods of diagnosis and current treatment options for BS. Molecular and transmission genetics As BS is inherited in an autosomal recessive fashion, each parent of an affected individual must carry one copy of the recessive gene even if they themselves do not have BS. In cases where both parents are carriers, there is a 25% chance that their offspring will have the condition, a 50% chance that they will be carriers and a 25% chance that they will not have the condition nor be carriers (Sanz, 2006). BS is known to affect both sexes equally and is common among children resulting from parental consanguinity (German, 2007). As there are so few cases, it is difficult to calculate a specific overall incidence rate (Tikoo, 2010). The gene underlying the pathology of BS, BLM, was mapped to the locus 15q26.1 by German et al (1994) and is currently the only gene known to cause BS (Cunniff, 2017). It encodes for the RECQL3 protein (also known as BLM), a DNA helicase important in a number of processes relating to DNA repair and replication. There are other conditions caused by defects in the RECQ family of proteins including Werner Syndrome (WS) and Rothmund-Thomson syndrome (RTS) (Duker, 2002). The specific genes involved play unique and distinct roles in the maintenance of genomic integrity, making these conditions distinct from BS. For instance, premature aging is commonly observed in WS and a hallmark facial rash is observed in RTS (Larizza, 2010). BLM has a huge role in maintaining genomic integrity. Reviewed by Cunniff et al (2017), it participates in several pathways related to the DNA damage response (Figure 1). Described in figure 1 as the hero of the story, BLM is instrumental in processing DNA replication intermediates. Some of its duties include recruiting RAD51 and RPA to sites of stalled replication to prevent premature recombination, helping to dissolve double Holliday junctions to limit DNA crossover formation and separating tangled strands that might otherwise lead to errors in recombination. Consequently, BLM mutation can be catastrophic to the cell. Â   Â   Molecular biology and nature of mutations There have been over 60 mutations of the BLM gene identified that are known to cause BS. The most common, BLMAsh, has a carrier frequency of 1 in 110 in the Ashkenazi Jewish population and is unique to patients with this ethnic background (Cunniff, 2017). Ellis et al (1995) performed a mutation analysis of 13 unrelated patients with BS, identifying ten mutations, seven of which were unique. They suggested that the absence of wild-type BLM in turn affects the activity of other DNA repair enzymes, creating a cascade effect. A 2007 report identified 49 BLM mutations that had not been previously described and represents the most comprehensive study of this kind to date in BS (German, 2007). Nineteen of these mutations were found to recur throughout the population of people with BS. There were also several BLM mutations identified that were unique to just one individual, suggesting that there may still be more as yet unidentified BS-causing BLM mutations. Additionally, in nine of the people studied, no BLM mutation could be detected, highlighting the possibility of BS-causing mutations in genes other than BLM. This study also found that people from similar ethnic backgrounds harbouring the recurrent BLM mutations likely inherited them from a common ancestor or founder. The identified mutations included substitutions, deletions and insertions. The most prominent functional consequence was premature translation termination, resulting in incomplete protein product. Amino acid substitution leading to missense mutation was cited as perhaps the most important identified, given that these generally occurred within the DNA helicase region of the gene that is essential for enzymatic activity. Studies have suggested that heterozygotes with only one pathogenic BLM variant may also be at increased risk of developing cancer while exhibiting no other BS symptoms (Cunniff, 2017). Molecular defects and consequences Cells with mutated BLM are unable to perform double-strand break (DSB) repair and this is a key driver behind the hyper-mutational capability of BS cells (Langland, 2002). Chromosomal mutations also occur at high frequency in BS cells and there is vastly increased chromatid exchange leading to profound genetic instability. These cumulative abnormalities mean BS cells are among the most hyper-mutated known (German, 2007). As a result, people with BS experience a markedly higher incidence of cancer, of any type and often at a young age (Cunniff, 2017). Tikoo et al (2010) suggest that BLM mutation may be central to the common master regulatory step that precedes neoplastic transformation in all cancers. A process known as sister-chromatid exchange (SCE) also occurs at a higher than normal rate in BS cells. During DNA replication, each chromosome becomes two identical sister chromatids that are joined with one another. SCE is when sister chromatids break and recombine with each other, allowing exchange of genetic material between the two. A hallmark characteristic of BS cells is a 10x higher frequency of SCE events than normal cells; this allows BS to be distinguished from other similar conditions during diagnosis (Amor-Gueret, 2006; Sanz, 2006). A higher frequency of SCE is indicative of higher rates of mitosis and is a result of abnormal DNA repair attribute to mutated BLM. In the normal cell, BLM is recruited to DSBs on replication forks these are structures facilitating the synthesis of new DNA prior to cell division. A primary function of BLM is to remove the blockage caused by a DSB to prevent premature recombination (Amor-Gueret, 2006). This is crucial in helping to suppress tumorigenesis and BLM has been shown to be indispensable for this process, even though there are alternative mechanisms available to the cell involving different proteins e.g. GEN1 and MUS81 (Arora, 2014). Such widespread genetic instability would normally trigger affected cells to undergo apoptosis. However, Amor-Gueret et al (2006) suggest that BS cells with BLM mutations are able to evade this mechanism by entering into alternative recombination pathways that allow them to progress through the cell cycle even in a hyper-mutated state. Diagnosisgenetic testing/treatment It has been suggested that analysis of BLM protein by immunoblotting and immunohistochemical analysis may be useful in screening for BS, however mutational analysis is required for a concrete diagnosis (Morimoto, 2002). Mutational analysis and genetic testing are important for at-risk couples who are planning to start a family. BS can be diagnosed by the identification of biallelic mutational variants of the BLM gene. However, should this test prove inconclusive; quantifying the frequency of SCE can be used as a further diagnostic tool. BS is the only condition that exhibits this hyper-recombinability phenotype, and so such a test can provide a definitive answer (Sanz, 2006). Because BS is so rare there, is as yet no effective treatment. People with BS should limit their exposure to UV light and should have any infections treated aggressively with antibiotics. Physicians must be mindful of the increased cancer risk and be scrupulous when any potential signs of cancer arise. Frequent screening has also been advised, particularly for colorectal cancer (Arora, 2014). An important consideration when people with BS do develop cancer is how to treat it. Radiotherapy and chemotherapy can increase the likelihood of secondary tumors such as lymphomas, and should be avoided where possible. Conclusion BS is an extremely rare condition affecting fewer than 300 people worldwide, with a notable prevalence among the Ashkenazi Jewish community. As there is no effective treatment for the condition, patients and physicians alike must be vigilant and take preventative steps to minimise the risk of developing malignancy. Genetic counselling may also be of benefit to affected individuals for educational purposes and to inform their decision-making if they are considering having children (Cunniff, 2017). In addition to BLM mutational analysis, knowledge of BLM posttranslational modifications and how they might affect protein function is likely to be an important area of research going forward (Tikoo, 2010). Furthermore, as German et al (2007) identified patients with BS but no BLM mutations, the possibility of heterogeneity underlying BS must be further explored through the use of genome sequencing. Future treatments ought to focus on restoring the proper functioning of BLM, or on inhibition of excessive recombination. References Amor-Gueret, M., (2006) Bloom syndrome, genomic instability and cancer: the SOS-like hypothesis. Cancer Letters, 236(1), pp.1-12. Arora, H., Chacon, AH., Choudhary, S., McLeod, MP., et al., (2014) Bloom syndrome. International Journal of Dermatology, 53(7), pp.798-802. Cunniff, C., Bassetti, JA., Ellis, NA,. (2017) Blooms Syndrome: Clinical Spectrum, Molecular Pathogenesis, and Cancer Predisposition. Molecular Syndromology, 8(1), pp.4-23. Duker, NJ., (2002) Chromosome breakage syndromes and cancer. American Journal of Medical Genetics, 115(3), 125-9. Ellis, NA., Groden, J., Ye, TZ., Straughen, J., et al., (1995) The Blooms syndrome gene product is homologous to RecQ helicases. Cell, 83(4), pp.655-666. German, J., Roe, AM., Leppert, MF., Ellis, NA., (1994) Bloom syndrome: an analysis of consanguineous families assigns the locus mutated to chromosome band 15q26.1. Proceedings of the National Academy of Sciences, 91(14), pp.6669-6673. German, J., Sanz, MM., Ciocci, S., Ye, TZ., et al., (2007) Syndrome-Causing Mutations of the BLM Gene in Persons in the Blooms Syndrome Registry. Human Mutation, 28(8), pp.743-753. Langland, G., Elliott, J., Li, Y., Creaney, J., et al., (2002) The BLM Helicase Is Necessary for Normal DNA Double-Strand Break Repair. Cancer Research, 62(10), pp.2766-2770. Larizza, L., Roversi, G., Volpi, L., (2010) Rothmund-Thomson syndrome. Orphanet Journal of Rare Diseases, doi: 10.1186/1750-1172-5-2. Morimoto, W., Kaneko, H., Isoqai, K., Kasahara, K., et al., (2002) Expression of BLM (the causative gene for Bloom syndrome) and screening of Bloom syndrome. International Journal of Molecular Medicine, 10(1), pp. 95-9. Sanz, MM., German, J., Cunniff, C., (2006) Blooms syndrome, n.p. Tikoo, S., Senqupta, S., (2010) Time to bloom. Genome Integrity, doi: 10.1186/2041-9414-1-14. Health and Safety Policies in Schools: An Example Health and Safety Policies in Schools: An Example Describe how current health and safety legislation, policies and procedures are implemented in the setting. Describe how health and safety is monitored and maintained in the setting Learn from yesterday, live for today, hope for tomorrow, The important thing is not to stop questioning - Albert Einstein. This famous quote by Albert Einstein is very true and relevant especially when it comes to Health and Safety. The education establishment in the UK has a very strong emphasis and objective on the Health Safety Work Act (HSWA) 1974. Our whole education system revolves around this act efficiently and effectively. This act governs the HS policies and procedures for any working environment. The HWSA outlines basic and generic duties between employers/employees based on common sense principles in the form of a written Health Safety policy This act was amended in 1999 and further emphasised on what employers should do to manage HS and minimise risk. How employees can facilitate the HSWA and incorporate in their own practical working environment. The important points to consider for all employers and employees are as follows:- Have a written Health and Safety Policy in the working environment. Employers should carry a risk assessment as and when required. Employers should set up emergency policies and procedures at all levels. Employers should provide necessary training and procedures to all employees. Employers should implement the recommendations from the risk assessment. Employees should take reasonable care or the HS of themselves and others. Employees should carry assigned tasks and duties safely in accordance with the law Employees should use correct reporting policies and procedures. If in doubt, of their health or someone else reports it to their line manager/supervisor. Like Albert Einstein, we need to think and never stop questioning our safety and consider others safety and promote the wellbeing of all concerned. In my school, the health and safety policies are used effectively in various ways. The school has approximately 43 Health Policy published on their website https://molescroftprimaryschool.wordpress.com/health-and-safety-policies/ These policies have been adopted from the LA. The school promotes a culture of positive, effective working and learning environment for all staff students and visitors in the school. The school takes its Health and Safety policies and procedures very seriously; under the governing body and the local authoritys guidance, Mr Loncaster is responsible for implementing the schools as well as the corporate directorate HS policies and procedures. All Health Safety procedures are conducted termly. In my school, rigorous training of Health Safety Policy is provided to all members of staff who have different roles and responsibilities of; Fire, Child Protection and First Aid The school does an enhanced DBS for all staff and volunteers who come in contact with the school children. The school requires all potential employees/volunteers to have an induction, prior commencing to work. The induction covers all aspect of HS policies. Appropriate Induction booklet, Keeping Children Safe in Education, ERSCB Safe School, Safe Children, Safe Staff code of conduct are handed to all as part of their induction training. After the induction, volunteers are expected to sign that they have understood the HS Schools policy in the presence of the trainer. The induction is done by the head teacher or one of the Assistant Head Teacher. In addition, all visitors to the school must sign and obtain a badge which permits their valid entry in the school. Signing the register also means that they have r ead and understood the safeguarding statements. The school admin is responsible for checking the visitors and maintaining their records. The school also contains various other HS policies such as building, ground, Adventure playground, E-policy. Often school sends letters to parents via email about E-safety for parents and children. The PE policy covers all equipment/apparatus used in the school, should be checked by their respective coordinators or teachers before used by children in the school. Children use this equipment under the supervision of their teachers. Appropriate footwear, clothing is rigorously checked to ensure the safety of children during their PE lessons. The school caretaker also checks specific play area and Adventure playground daily; daily record sheet is maintained in the school. All electricals used in the classroom/school are stored away. Second-hand objects are prohibited to use in the school. All electrical equipment is PAT tested by the caretaker annually or as and when needed. Records of these test are monitored in HS Report. Our school also covers First Aid policies by providing green posters (written procedures) of First Aid provision information and instruction on all main corridors in case of emergency; these consist of, list of first aider and their contact details according to year groups The school has first aid boxes in all the cloak room; these are checked by lunchtime supervisors who are responsible for first aid. The school has also fire alarms, 3 different types of extinguishers, (foam,co2 and water). There is a comprehensive site survey every term, this includes COSHH records, First aid provision, review of Risk Assessments, fire and safety drills. All staff are required to carry out assigned task and duties safely in accordance with instructions, methods and procedures safely coordinating with their supervisors. Another example of health and safety monitored in our school is by providing sanitised hand gels in all classrooms; children should not leave their classroom unnecessarily. Children use the hand gels after their science experiment or any other class activities to stop spreading germs and viruses which may spread infections. All responsible adults working with children monitor the check and use of this policy. The school strongly believes that children must be able to take responsibility and therefore Safeguarding is also incorporated into their curriculum by 2different ways The school teaches Heath Education, Citizenship, Personal, Social. Themes such as Sex Relationship, Drugs Stranger Danger. Secondly, safety concerning; correct equipment and Risk Assessment plan for PE, specific policy for DT, Finally, the school has also water tight safeguarding policies. There are 22 safeguarding policies published in the public domain https://molescroftprimaryschool.wordpress.com/safeguarding-policies/ The school main gates are secured between 9.30am and 3.00pm and entry is only available via main reception area. Once access inside the main school, the doors are automatically sealed internally. On all the doors there are signs indicating that access to the school is by the school reception even if it starts/end of the day. The school is surrounded by a mixture of fencing. Before the start/end of the day, the car park is secured and locked to avoid accidents or use it as a shortcut route to the main reception area. There is a lollipop man patrolling at the start and end of the day outside the school to prevent accidents. Describe how people in the setting are made aware of risks and hazards and encouraged to work safely Parents need to share their childrens medical condition with the school. They need to sign a Health Safety checklist form confirming the information is true. The school stores this information in the schools central office which is maintained by the admin staff. In addition, a brown envelope, containing confidential medical information is available to the class teacher along with the class register and pupil photograph. Medicines are checked, stored away in the designated cabinets in the staff room. They are locked and out of reach of children. All staff are made aware of accessing the keys if needed. Medicines are only administered if prior agreed with the headteacher, Mr Loncaster. Responsible children can administer their own medication. The school holds accountability to any incidents/accidents or unforeseen circumstances to inform parents. The school also is responsible for carrying out extra copies of pupils medical needs for any external educational visit. Collection of pupils: In my school collection of the pupil are ensured for KS1 and Foundation stage by teachers visually identifying parents/carers before letting them go. Occasionally, if a parent is unavailable to collect their child, then they have to ring the school office to notify. The school office passes on this information to the relevant class teacher and simultaneously the teacher writes this information on the board and also lets the child know if there is any change of collection of time/person. vulnerable children are collected by parents/carers on the right day would be subject to, on a confidential basis between the LA, MR Britton, (CPC), and the head teacher Mr Loncaster coordinated by the childrens specific class teacher/TA. The presence of dangerous substances: No one is allowed to bring any substance such as liquid, powder, gels or potions in the school premises without a COSHH Risk Assessment done in advance. A COSHH form must be obtained from the relevant manufacturer/supplier. A detailed COSHH sheet of information and records are maintained in every classroom, where the relevant materials are used and can be accessed easily by any member of staff, A log is kept in the recording sheet which is checked and dated by the caretaker along with the head teacher. All classrooms have Risk Assessment for COSHH checklist sheet posters. These are checked by the class teacher and the TA and ticked off on weekly basis. If a child is found with any kind of medication, then he/she will be taken immediately to the First Aid point and subsequently highlighted to the HS Officer as well as the Head Teacher. Trip/slip: Hazards are notified to all by WET floor signs. Senior members are notified by emails, and the class teacher shares this information with us if it is relevant to us when we are at school. All classrooms have Risk Assessment for trip/hazard checklist sheet posters. These are completed and ticked off on weekly basis. All hazard should be reported to the class teacher or senior management or should be made hazard free if possible in line with the HS policy. If senior members of staff have discovered any hazard or accidental spillage, then its their responsibility to resolve it. This effectively means either informing a caretaker, cleaners. The hazard would be highlighted to the caretaker and assess the risk and if needed act on it. A near miss form would be then completed by the caretaker. Safety or otherwise electrical equipment: Log register is available in all the classroom of electrical safety checks done by the school caretaker every term. The authorities do a formal PAT test, once every 2 years on all electrical equipment; plugs have an up to date PAT test sticker with the date. All classrooms have Risk Assessment electrical safety checklist sheet posters. The checklist also indicates what needs to be done to minimise any accidents happening These checklists are completed by the teachers and the TA and ticked off on weekly basis by the class teacher. Any volunteers/TAs responsibility to let the teacher know if stickers are not on the equipment unless they are a year old. The school follows strict guidelines by The Electricity Work Code of practice/Electricity at Work. Dangers of internet/social networking (staff /pupils): Posters for working safely on the internet is available in all the classrooms. A Clear policy for working safely is also available in the induction pack for staff and volunteers. All classrooms have Risk Assessment checklist sheet posters. These are completed and ticked off on weekly basis by TA and class teacher. Children are supervised when they are learning involving technology. Volunteers are made aware on the Induction of using social networking cautiously especially through emails, social media, or the internet If found compromising confidentiality, disciplinary actions will be taken. The school has published a detailed Acceptable Use Policy; use of Internet/computer specifically for staff and pupils in the school. Some general examples of school monitoring Health Safety: All staff /volunteers get an HS induction/training specific to their job title/role The staff and students hold the corridor and classroom doors to avoid physical injuries All visitors are made aware of fire evacuation process by posters at all main points. There is a fire alarm button indicated at all main exit points, if anyone discovers a fire in any part of the building then they should set the alarm off. A hand gel is available in all classrooms and corridors to avoid infection or virus. All staff toilets have posters and materials to clean bodily fluid and easy quick access to yellow V sign to make aware of slips/hazards. All relevant schools HS policies are easily accessible and are in the public domain. General Safety in school: Fire officer come in school once a year Local Authorities come in school to PAT test once in 2 years. Caretaker PAT test all electrical equipment termly and logs are maintained in relevant areas of the equipment. The site manager/caretaker checks the general safety of the school for eg. site checks, and security, indoor and outdoor of the school, school fencing, playground, Adventure Playground, weekly fire safety system checks, fire log book, including fire drill report, snow and path clearing, yellow line marking, building documentation/records/site maintenance manual. All employees have a responsibility to act immediately upon discovering or receiving a report of a workplace hazard; to rectify or otherwise make the situation safe All employees report all accidents and any unsafe practices or conditions to their Supervisor /line manager as we are all responsible for the safety of ours and other as well as children. Use appropriate tools/equipment in accordance to information/manual/training provided. All staff/volunteers should play a vital role in ensuring the schools cleanliness, tidiness, and maintain the highest hygiene. All staff/volunteers are encouraged to use the Whistleblowing Policy if they believe may compromise School, Local or National Policy and Law. Induction book also contains a phone no 01482394123 of the LA. My role as a Work Experience TA in Molescroft Primary School: As I have written in depth the Health and Safety monitoring policies and procedures in the school, I have a very similar responsibility as any other official staff of the school. Before I commenced to work, the school conducted an enhanced DBS check. Followed by the DBS, I was given an induction. Tour of the school was given by the Head Teacher Mr Loncaster, pointing out posters of emergency procedures such as First Aid, Fire, Fire assembly point. The induction was covered with detailed information on various policy, especially in depth of the Health Safety and the Safeguarding policy because I would be working with children in the classroom. An example from the point of safeguarding policy is I must not work with a lone child in the classroom with doors closed. I must not carry/move awkward objects in the school. I must challenge anyone who is not wearing a badge simultaneously If Im found inside the school premises without a badge, then I would also be challenged. Training was pro vided by using equipment in the school. As mentioned earlier that I have to take responsibility for understanding and implementing the schools HS policies I was made to sign the induction checklist that I have understood the schools policies and will strictly follow in the school. My schools Health and Safety is monitored by