26th is where some alleles are dominant whereas

26th October 2017 – Learning Topic 2: Pedigree Drawing
It was useful to revise the topic on Pedigree Drawing although I have knowledge on Pedigree Drawing from my previous studies, it was a useful refresher.
Pedigree Drawing is a drawing of a family tree which is used to identify and assess indications and patterns of families which would help in both diagnosing and managing the health of individuals as the pedigree drawing gives a depth insight of past health history.
I had found the lecture topic of Mendelian Inheritance interesting as this was an area where my knowledge was limited. As a biomedical scientist, it is important to keep updated with new techniques and knowledge because as biomedical scientist you are continuously developing knowledge and new skills throughout your career. This topic was beneficial as this is something that would be encountered daily by a biomedical scientist as certain disease are inherited.
Briefly describe Mendelins Inheritance Laws.
There are three main “Laws” of inheritance, which are, the law of dominance, the law of segregation and the law of independent assortment. Below are the three laws which are listed and briefly described.
The law of dominance is where some alleles are dominant whereas the other are recessive; the effect of the dominant allele will display an organism with at least one dominant allele.
The law of segregation the second inheritance law occurs during gamete formation, this is where the alleles for each gene segregate from each other so that each gamete carries only one allele for each gene.
Law of independent assortment is where the genes for various traits segregate independently during the formation of gametes.

High-throughput pedigree drawing
Ville-Petteri Mäkinen, Maija Parkkonen, Maija Wessman, Per-Henrik Groop, Timo Kanninen & Kimmo KaskiEuropean Journal of Human Genetics (2005) 13, 987–989. doi: 10.1038/sj.ejhg.5201430;
published online 4 May 2005. Available at https://www.nature.com/articles/5201430. Accessed on 26th October 2017.

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With reference to the above article, it states how family trees have been used as a valuable visual tool for geneticists in identifying clusters of inherited traits and genotypes. Within this article it looks at the importance of family tress and how they help in inherited traits and genotypes, in addition to this the article looks at how pedigree drawings should be drawn. After reading this article I found it was interesting but when coming to an overall judgement on whether this subject has made a huge impact, I believe the article was not in much depth for me to reach a decision.

Multipoint Quantitative-Trait Linkage Analysis in General Pedigrees. Laura Almasy and John Blangero Volume 62, Issue 5, May 1998, Pages 1198-1211. Available at https://ac.els-cdn.com/S0002929707615420/1-s2.0-S0002929707615420-main.pdf?_tid=96fb6f44-ef31-11e7-8d7c-00000aab0f6c&acdnat=1514838372_9a544c524c7ca24c195b65f869947a9f. Accessed on 26th October 2017.
The above article discusses the multipoint linkage analysis of quantitative-trait loci. The article stated how variance-component linkage methods are used in pedigrees of arbitrary size and the complexity but also it looks at how they have developed general framework for multipoint identity-by-descent probability calculations. When reading further into the article different methods are investigated, methods like Variance-Component Linkage Analysis in General Pedigree, Estimation of the IBD Probability Matrix for a Genetic Marker, Derivation of IBD Correlation Formulas for Multipoint Analysis, each of the methods are discussed in depth within the article where a description is provided. I personally believe that after reading this article that this subject has made an impact as this article goes in depth as each method is discussed separately.
Eichler EE, Nickerson DA, Altshuler D, Bowcock AM, Brooks LD, Carter NP, Church DM, Felsenfeld A, Guyer M, Lee C, et al. Completing the map of human genetic variation, Nature, 2007, vol. 447 (pg. 161-165). Available at https:// https://www.scopus.com/record/display.uri?eid=2-s2.0-0025172940&origin=inward&txGid=661088e35c2e782eda7de11696e6586f. Accessed on 26th October 2017.
With the article above, I had found that this article discussed how long-scale studies of human genetic variation have focused largely on the pattern and nature of single-nucleotide difference within the human genome. I personally believe that after reading this article that this subject has made an impact as this article goes in depth.

Modeling genetic inheritance of copy number variations. Kai Wang, MahletG. Tadesse, Joseph Glessner, Struan F. A. Grant, Hakon Hakonarson, Maja Bucan, Mingyao Li. Nucleic Acids Research, Volume 36, Issue 21, 1st December 2008, pages e138. Available at: https://academic.oup.com/nar/article/36/21/e138/2409932 Accessed on 26th October 2017.

The art of pedigree drawing: algorithmic aspects. Frédéric Tores, Emmanuel Barillot Bioinformatics, Volume 17, Issue 2, 1 February 2001, Pages 174–179. Available at https://doi.org/10.1093/bioinformatics/17.2.174 26th October 2017.

27th October 2017 – Learning Topic 3: Risk Assessment
Revising the topic on Risk Assessment was useful to revise as although I already possessed knowledge on Risk Assessment it was helpful to use as a refresher as this was a topic which was studied in my previous studying.
It was beneficial to study the topic on Angelman Syndrome, imprinting and risk assessment but however I preferred studying Angelman Syndrome as this is where I lacked knowledge. CPD is an essential element for a Biomedical Scientist to understand and after studying this learning topic I have gained knowledge on an area where my knowledge was limited.
I had read the provided research paper upon Principles of Genetic Risk Assessment which was intriguing to read as the paper provided me with knowledge. It is important for me as a Biomedical Scientist to understand CPD as this is a major part in involving within my career, after reading this I had developed a broader understanding, as well as at the same time developing as a biomedical scientist.
Define Angelman Syndrome?
Angelman Syndrome is known to be a rare neuro-genetic disorder which primarily affects the nervous system which is characterized by severe mental retardation. The causation of Angelman Syndrome is the deletion of the maternally inherited UBE3A gene which is located within chromosome 15q11-q13. The UBE3A gene is encoded at 100kDA protein which functions as Ubiquitin Ligase and Transcriptional Coactivator. There are a range of symptoms of Angelman Syndrome, symptoms include;
• Development Delay
• Speech Impairment
• Balance or Movement Disorder
• Behavioral Uniqueness
• Delayed and Disproportionate Growth in head circumference
• Seizures
• Hypopigmented skin and eyes
• Tongue suck and swallowing
• Strabismus
• Hyperactive Tendon Reflexes
• Feeding problems in infancy
• Prominent Mandible
• Increased sensitivity to heat
• Wide-spaced teeth
• Sleeping Disorder
• Frequent Drooling
• Smooth Palms
• Excessive chewing and mouthing behaviors
Heshka JT, Palleschi C, Howley H, Wilson B, Wells PS. A systematic review of perceived risks, psychological and behavioral impacts of genetic testing. Genet Med 2008; volume 10, pages19-32. Available at http://cel.webofknowledge.com/InboundService.do?customersID=atyponcel&smartRedirect=yes&mode=FullRecord&IsProductCode=Yes&product=CEL&Init=Yes&Func=Frame&action=retrieve&SrcApp=literatum&SrcAuth=atyponcel&SID=F3yWfx69M9DvwnJAlIc&UT=WOS%3A000252542700004. Accessed on 27th October 2017
After reading the above article referenced, it describes genetic testing and how it helps in the early detection of disease as well as looking at how effective the strategies of prevention are. The article begins to develop on how genetic risk helps look at behavioural change but however the impact of the carrier status from the viewpoints of psychological, behaviour and perceived risk perspectives are not fully understood. The paper further looks at literature review which is performed to identify studies which measured the perceived risk, psychological, behavioural impacts of genetic testing on individuals. The studies which were investigated were not limited to certain disease, but they excluded the impacts of testing for single gene disorders, further studies looked at hereditary nonpolyposis colorectal carcinoma, hereditary breast and ovarian cancer and Alzheimer disease. When coming to an overall judgement, I had found that this paper was rather intriguing as it was written in depth which helped not only gain knowledge but made it interesting.

Principles in genetic risk assessment
Pedro Viana Baptista
Author information ? Copyright and License information ? Disclaimer https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1661604/

The above article states how a risk assessment constitutes an essential component of genetic counselling and testing, it has been said in the article that the genetic risk should be estimated as accurately as one can for an individual and family decision making. The article also described how all relevant information which was gathered from the population studies, pedigrees and genetic testing enhances the accuracy of the assessment of a person’s genetic risk but also it emphasised how this review would focus on the general aspects implicated within the risk assessment; the increasing genetic information regarding disease; complex traits versus Mendelian disorders; and the influence of the environment and disease susceptibility are factors which would be provided. The influence of the factors were provided and discussed within the article.

Down Syndrome: Prenatal Risk Assessment and Diagnosis
DAVID S. NEWBERGER, M.D., State University of New York at Buffalo, Buffalo, New York
Am Fam Physician. 2000 Aug 15;62(4):825-832 https://www.aafp.org/afp/2000/0815/p825.html

With reference to the above article I had found that Down Syndrome (Trisomy 21) was the most commonly recognized causation of mental retardations. Trisomy 21 is the risk which is directly related to maternal age, however all the forms of prenatal testing for Down Syndrome must be done voluntary. The article described how a nondirective approach should be used when patients are presented with various options for diagnostic testing and prenatal screening. The patients which are 35 years of age or older are offered chorionic villus sampling or a second-trimester amniocentesis on their due date, females who however or younger than 35 years of ages would be offered a maternal serum screening at 16 to 18 weeks of gestation. Alpha-fetoprotein, unconjugated estriol and human chorionic gonadotropin are maternal serum markers which are used to screen for Trisomy 21. The article stated how the use of an ultrasound to estimate gestational age helped improve the sensitivity and specificity of the maternal serum screening.
In reference to the article, after reading the article referenced I had found that Down Syndrome is a variable combination of congenital malformations which were caused by trisomy 21. This is known to be the most commonly recognized genetic causes of mental retardation and is approximated prevalence of 9.2 cases per 10,000 live births in the US, the article looks at the cases of Down Syndrome within the US.

Genetic Risks to the Mother and the Infant: Assessment, Counselling, and Management
Stuart K. Shapira1 and Siobhan Dolan https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1592163/

Genetic Risk Assessment for Adult Children of People With Alzheimer’s Disease: The Risk Evaluation and Education for Alzheimer’s Disease (REVEAL) Study
J. Scott Roberts, PhD
, L. Adrienne Cupples, PhD
, Norman R. Relkin, MD, PhD http://journals.sagepub.com/doi/abs/10.1177/0891988705281883 First Published December 1, 2005


28th October 2017 – Learning Topic 4: Dysmorphology
Dysmorphology was the other learning topic which I had studied, again due to my previous studying I had a vague idea of Dysmorphology, but it was useful to study this again.
The lecture topic on this area (Dysmorphology) was interesting as this topic led to discussions which had opened this lecture topic further. Dysmorphology was a lecture topic regarding the developmental structural defects, this was a refresher for me as this was studied previously. I had found this learning topic fascinating as it had covered a variety of elements which opened discussions but also in-depth theory which was provided had made it interesting as I was able to absorb more knowledge. The paper on Dysmorphology and Jouberts Syndrome was rather interesting to read as it has provided information on key areas which would help later.
There are two key factors which a Biomedical Scientist like one must consider throughout their career, development on knowledge and skills are the two major factors which would help me develop and prosper within my working field.
It is equally important for me as a Biomedical Scientist to keep updated with the new techniques and knowledge as development of techniques and knowledge is a cyclical cycle as a Biomedical Scientist is continuously developing knowledge and various new skills.
Portray a portion of the terms which are routinely used in birth defects.
• Malformation or Anomaly are a primary defect which is caused by the basic alterations in the structure, this occurs before ten weeks of gestation. Cleft Palate, Anencephaly, Agenesis of limb or part limb are examples of Malformation or Anomaly birth defects.

• Malformation Sequence is the defect pattern of numerous defects which result from a single malformation. Talipes is a key example of malformation sequence also referred to as Clubfoot and Hydrocephalus can result from a Lumbar Neural Tube Defect.

• Malformation Syndrome defect is a pattern of features that often have an underlying cause, these commonly arise from several different causes in Morphogenesis. This consists of Chromosomal Disorders such as Down Syndrome, Microdeletion Syndromes like Prader-Willi Syndrome, Polygenic Disorders as well as Club Foot, Environmental Causes (Teratogenesis) such as Rubella, Congenital Viral Infection.


Chapter 7 – Next Generation Sequencing in Dysmorphology Robert Smigiel1, Urszula Demkow2 2016, Pages 137–151 available at https://www.sciencedirect.com/science/article/pii/B9780128017395000076. Accessed on 28th October 2017

In regard to the article referenced above, it highlights the dynamic progress in molecular techniques which have created new diagnostic tools in dysmorphology. The article begins to examine how some dysmorphic conditions can be recognized by detailed clinical examination which are accompanied by convectional karyotyping, multiplex ligation-dependent probe amplification tests and array comparative genomic hybridization (aCGH) analysis. The article begins to develop on Sanger Sequencing which is of single gene which exclude genomic imbalance and point mutations as well as next generation sequencing which have helped in the rapid identification of known heterogenous entities and novel genetic syndromes. Again, when judging the above article, I had found it interesting to read as the level of depth which was provided showed that this subject had an impact as this article looked at the various molecular techniques in Dysmorphology.

Down syndrome—recent progress and future prospects
Frances K. Wiseman, Kate A. Alford, Victor L.J. Tybulewicz, Elizabeth M.C. Fisher
Human Molecular Genetics, Volume 18, Issue R1, 15 April 2009, Pages R75–R83, available at https://doi.org/10.1093/hmg/ddp010. Accessed on 28th October 2017

The above article looks at Down Syndrome and the causation of this disease. Down syndrome is known to be caused by trisomy of chromosome 21 which is associated with various deleterious phenotypes which cause learning difficulties, heart defects, early-onset Alzheimer’s disease and childhood leukemia. The article examines recent research undertaken on Down Syndrome which looks how patients and relevant animal models, the article refers to the advances in therapy used to improve cognitive function in individuals with Down Syndrome as well as the significant developments in understanding the trisomy of chromosome 21 gene. In addition to this the article it investigates future research directions considering new technologies, the use of chromosome engineering to generate new trismic mouse models. The paper overall regarding Down Syndrome was written in depth but however I still personally believe that this has not particularly made an impact on this certain topic yet more research needs to be done.

The prevalence of Down syndrome in County Galway. O’Nualláin S , Flanagan O ,
Raffat I , Avalos G , Dineen B. Irish Medical Journal 01 Jan 2007, 100(1):329-331 available at http://europepmc.org/abstract/med/17380922 Accessed on 28th October 2017
The referenced article above looks at the retrospective survey of all cases of Down Syndrome which were recorded between 1981 and 2000 mothers who were resident in Co. Galway. The article looks at studies and makes a comparison of the incidence of Down Syndrome in both decades which then examines the effects of changing demographics on incidence rates. The paper further looks at the overall prevalence rate in the previous decade. It was founded that Down Syndrome was significantly increased in women whom are over the age of 30. I had found the paper was interesting to read as it showed how over the decades the number increased but also the paper looked at how Down Syndrome linked but I believe that this article has made an impact.

Dysmorphology demystified William Reardon and Dian Donnai Arch Dis Child Fetal Neonatal Ed. 2007 May; 92(3): F225–F229. Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2675338/ Accessed on 28th October 2017

Is Down syndrome a disappearing birth defect? Collins VR, Muggli EE, Riley M, Palma S, Halliday JL
The Journal of pediatrics 2008 Jan;152(1):20-4, 24.e1 Available at http://europepmc.org/abstract/MED/18154892 / Accessed on 28th October 2017

29th October 2017 – Learning Topic 5: Chromosome Analysis
It was useful to revise the topic Chromosome Analysis. Even though I have knowledge on Chromosome Analysis it was a useful refresher. I have studied this area in my previous studying.
I found the lecture topic Chromosome Analysis quite interesting as this was an area which is discussed a lot. Chromosome Analysis is the process which evaluates the number and structure of an individual’s chromosomes to detect abnormalities, this was studied during my previous studies which meant that I had knowledge on this area already but by studying it again it enabled me to refresh my mind and develop a better understanding of chromosome analysis. Cytogenetics was a topic which was discussed in depth making it interesting.
Having the role of a biomedical scientist, understanding new techniques is important as this would help me tackle everyday situations in a new way, but as well as this as it is important for myself to ensure I have new knowledge which can be brought forward into my work to help me develop better and accurate results.
As a biomedical scientist it’s important to keep update with new techniques and knowledge, because as a biomedical scientist you are continuously developing knowledge and new skills throughout your career.
Provide an explanation of your understanding of the term “Karyotype Analysis” providing examples of diseases which can be detected by a Karyotype.
Karyotype analysis is the process which is used for the identification of abnormalities within chromosomes, this includes missing chromosomes, extra chromosomes, deletions, duplications and translocations. These specific abnormalities can cause genetic disorders like Down Syndrome Turner Syndrome, Klinefelter Syndrome and Fragile X-syndrome, below are examples of abnormalities identified by Karyotype analysis;
? Down Syndrome (Trisomy 21): This is where one has an extra copy or third chromosome 21 which then causes learning disabilities as well as the physical characteristics of an individual.
? Edwards Syndrome (Trisomy 18): This is where a person has an extra 18th chromosome.
? Patau Syndrome (Trisomy 13): This is where an individual has extra 13th chromosome but however one would not survive more than a year as they would usually have cardiac problems and severe mental impairment.
? Klinefelter Syndrome: Klinefelter Syndrome is when a male has an extra X chromosome (XXY).

Complex patterns of copy number variation at sites of segmental duplications: an important category of structural variation in the human genome.
Goidts V1, Cooper DN, Armengol L, Schempp W, Conroy J, Estivill X, Nowak N, Hameister H, Kehrer-Sawatzki H. https://www.ncbi.nlm.nih.gov/pubmed/16838144?dopt=Abstract

With regards to the above article, it was founded that structural diversity of the human genome was much higher than previously assumed although the full extent remains unknown. The article had stated that to investigate the connection between segmental duplications which display constitutive copy number difference between humans and the great apes and those which exhibit polymorphic copy number variations between humans, it was analysed a BAC array enriched with segmental duplications which displayed such CNDS. The study documents for the first time in addition to human-specific gains common to all humans, these duplications clusters (DCs) also exhibit polymorphic CNV ; 40kb.

Science. 2002 Aug 9;297(5583):1003-7.
Recent segmental duplications in the human genome.
Bailey JA1, Gu Z, Clark RA, Reinert K, Samonte RV, Schwartz S, Adams MD, Myers EW, Li PW, Eichler EE. https://www.ncbi.nlm.nih.gov/pubmed/12169732?dopt=Abstract

With reference to the article it had looked at how primate-specific segmental duplications were considered significant in human disease and evolution. The inability to differentiate between allelic and duplication sequence overlap had hampered the characterisation as well as assembly and annotation of our genome. The article further explained how a developed method whereby each public sequence was analysed at clone level for overrepresentation within a whole-genome shotgun sequence. The test had the capability of detecting duplications which were larger than 15 kilobases irrespective of copy number, location or high sequence similarity. The article described how the researchers mapped 169 large regions flanked by highly similar duplications, 24 of the hot spots of genomic instability had been associated with genetic disease. The analysis had indicated a highly non-random chromosomal and genic distribution of recent segmental duplications with likely roles in expanding protein diversity.

Nat Genet. 2006 Jan;38(1):82-5. Epub 2005 Dec 4.
Common deletions and SNPs are in linkage disequilibrium in the human genome.
Hinds DA1, Kloek AP, Jen M, Chen X, Frazer KA. https://www.ncbi.nlm.nih.gov/pubmed/16327809?dopt=Abstract

Regarding the article referenced, after thoroughly reading this article it was founded that humans show a great variation in phenotypic traits such as age, height, susceptibility to disease and eye colour. The genomic DNA sequence differentiates between individuals which are responsible for the inherited components of these complex traits. The article had showed that reports suggested that intermediate and large-scale DNA copy number and structural variations were prevalent enough to be a vital important source of genetic variation between people. Due to the association studies to identify genomic loci associated with particular phenotypic traits had focused primarily on genotyping SNPs, it is important to determine whether a common structural polymorphism are in linkage disequilibrium with common SNPs and which can be assessed indirectly in SNP-based studies. The article had presented a test which examined 100 deletion polymorphisms ranging from 70 bp to 7kb. It was showed that common deletions and SNPs ascertained with similar criteria have essentially the same distribution of linkage disequilibrium with surrounding SNPs which indicated that polymorphisms may share evolutionary history and that most deletion polymorphisms were effectively assayed by proxy in SNP-based association studies.
PLoS Genet. 2006 Feb;2(2):e20. Epub 2006 Feb 17.
Bias of selection on human copy-number variants.
Nguyen DQ1, Webber C, Ponting CP. https://www.ncbi.nlm.nih.gov/pubmed/16482228?dopt=Abstract

Sharp AJ, Locke DP, McGrath SD, Cheng Z, Bailey JA, Vallente RU, Pertz LM, Clark RA, Schwartz S, Segraves R, Oseroff VV, Albertson DG, Pinkel D, Eichler EE (2005) Segmental duplications and copy number variation in the human genome. Am J Hum Genet 77:78-88 https://www.ncbi.nlm.nih.gov/pubmed/15918152?dopt=Abstract

30th October 2017 – Learning Topic 6: Biochemical Diagnosis
The topic Biochemical Diagnosis for me was the second most difficulty one to understand at the start, however after studying all the lectures a couple of times I started to grasp the understanding of Biochemical Diagnosis.
After studying the lectures, I have gained a broader knowledge on what the principles of Biochemical Diagnosis are and how it plays a role in the diagnosis of disease.
Biochemical Diagnosis was a topic which I had found beneficial as after learning this topic I now have the capability to apply the knowledge learnt to my day to day practice but also by understanding the importance of Biochemistry Analysis I can understand what test results mean ad what the importance is in diagnosis.

Provide examples of Metabolic Disorders and briefly discuss this below.
Disease Defective Enzyme or System Symptoms Treatment

Phenylketonuria (PKU) Phenylalanine Hydroxylase severe mental retardation screening; dietary adjustment
Malignant PKU Biopterin Cofactor neurological disorder —
Type 1 tyrosinemia Fumarylacetoacetate Hydrolase nerve damage, pain, liver failure liver transplantation; preceding enzyme inhibitor plus dietary adjustment
Type 2 tyrosinemia Tyrosine Aminotransferase irritation to the corneas of the eyes diet with reduced phenylalanine and tyrosine content
Alkaptonuria Disorder of Tyrosine breakdown progressive arthritis and bone disease; dark urine —
Homocystinuria and Hyperhomocysteinemia cystathionine-?-synthase or methylenetetrahydrofolate reductase or various deficiencies in formation of the Methylcobalamin form of vitamin B12 hypercoagulability of the blood; vascular episodes; dislocation of the lens of the eye, elongation and thinning of the vitamin B12, folic acid, betaine, a diet restricted in cysteine and methionine

Glycogen Storage Disease Type III
Synonyms: Cori Disease, Debrancher Deficiency, Forbes Disease, GSD III
Aditi Dagli, MD, Christiaan P Sentner, MD, and David A Weinstein, MD, MMSc.
Initial Posting: March 9, 2010; Last Update: December 29, 2016. https://www.ncbi.nlm.nih.gov/books/NBK26372/
With reference to the article, it had stated how Glycogen Storage Disease type III (GSD III) is characterized by variable liver, cardiac muscle and skeletal muscle involvement.
GSD III was seen as the most common subtype which was present in approcximately 85% of the affected individuals; it was told that it manifests with liver and muscle involvement, GSD IIIb with liver involvement only comprised about 15% of all GSD III.
The article further explained that in infancy and early childhood, the liver involvement presents as ketotic hypoglycaemia, hepatomegaly, hyperlipidaemia and elevated hepatic transaminases. Liver disease becomes less prominent in adolescence and adulthood. It was told that hypertrophic cardiomyopathy develops in a majority of those with GSD IIIa usually during childhood. The clinical significance however ranges from asymptomatic in a majority to severe cardiac dysfunction, congestive heart failure and (rarely) sudden death. It was told that skeletal myopathy manifesting as weakness was not usually evident in childhood but slowly it progresses which typically becomes prominent in the third to fourth decade.
In regards to diagnosis and testing, hepatomegaly, ketotic hypoglycaemia with fasting and elevated serum concentrations of transaminases and CK are hallmarks of GSD III. The serum CK however may not be elevated at the time of the diagnostic work up but the absence of lactic acidosis and markedly elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations may give clues to the diagnosis. The measurement of fasting serum concentration of the glucose after glucagon administration can be used to help the diagnosis; however the glucagon administration should not cause the glucose concentration to rise following the prolonged fast but it should be done so after a fast of two hours or less. The article stated that the diagnosis is established by the identification of Biallelic pathogenic variants in AGL.
In reference to this article, it was told that a high-protein diet and frequent feeds (every 3-4 hours) to maintain euglycemia which is the mainstay of the management in infancy. The article further explains how fructose and galactose can be used but however special formulas are not required, it is told that towards the end of the first year of life, one to three daily doses of 1g/kg of corn-starch can be used to avoid hypoglycaemia the protein intake of 3g/kg is recommended. Glycosade extended-release corn-starch can be used however for those who cannot make it through the night on protein and corn-starch. The article further explained how individuals who have severe hepatic cirrhosis, liver dysfunction and/or hepatocellular carcinoma have liver transplantation reserved. Liver transplantation was described to exacerbate myopathy and cardiomyopathy.

Curr Mol Med. 2002 Mar;2(2):167-75.
Molecular characterization of glycogen storage disease type III.
Shen JJ1, Chen YT. nlm.nih.gov/pubmed/11949933
In reference to the article, it has been told that the deficiency of the glycogen debranching senzyme (gene, AGL) is the causation of glycogen storage disease type III (GSD- III) which is an automosal recessive disease affecting glycogen metabolism. It shown that most GSD- III patients have AGL defiency within the liver and muscle (type llla), however some have this within their liver and not muscle (type lllb). The cloning of human AGL cDNAs and determination of the genomic structure and mRNA isoforms of AGL have allowed studies of GSD-lll at the molecular level. However the resulting information had greatly facilitated the understanding of the storage disease with remarkable clinical and enzymatic variability. With this review it was summarized by researchers that all 31 GSD-lll mutations in the literature and discuss the clinical and laboratory implications. The article described how most of the mutations were nonsense mutations which were caused by a nucleotide substitution or small insertion or deletion; it was written in the article that only one is caused by missense amino acid change, as I read further it was told that some vital genotype-phenotype correlation have emerged in particulate that exon 3 mutations (17delAG and Q6X) which were specifically associated with GSD-lllb. The test had shown that three other mutations appeared to have had some phenotype correlation, the spilice mutation IVS32-12A;G was specifically founded in GSD-lll patients who had mild clinical symptoms whilst mutations 3965delIT and 4529insA were connected with severe phenotype and early onset of clinical manifestations. It was shown that a molecular diagnostic scheme has been proposed to diagnose GSD-lll noninvasively, the characterisation of AGL mutations in GSD-lll patients had helped the structure function analysis of the bifunctional enzyme for glycogen metabolism.

Curr Mol Med. 2002 Mar;2(2):121-43.
Type I glycogen storage diseases: disorders of the glucose-6-phosphatase complex.
Chou JY1, Matern D, Mansfield BC, Chen YT https://www.ncbi.nlm.nih.gov/pubmed/11949931

With reference to this article it showed that Glycogen storage disease type I (GSD-I) is a group of autosomal recessive disorders with an incidence of 1 in 100,000. I had found that there were two major subtypes are GSD-Ia (MIM232200), caused by a deficiency of glucose-6-phosphatase (G6Pase), and GSD-Ib (MIM232220), which were caused by a deficiency in the glucose-6-phosphate transporter (G6PT). However both G6Pase and G6PT are linked with the endoplasmic reticulum (ER) membrane. G6PT translocates glucose-6-phosphate (G6P) from the cytoplasm into the lumen of the ER, where G6Pase hydrolyses the G6P into glucose and phosphate. Further on the article read developed on how together G6Pase and G6PT maintain glucose homeostasis. G6Pase is expressed in gluconeogenic tissues, the liver, kidney and intestine. However G6PT, which transports G6P efficiently only in the presence of G6Pase, which is expressed ubiquitously. I had found that this suggested that G6PT could play other roles in tissues lacking G6Pas, both GSD-Ia and GSD-Ib patients manifest phenotypic G6Pase deficiency, characterized by growth retardation, hypoglycemia, hepatomegaly, nephromegaly, hyperlipidemia, hyperuricemia, and lactic academia and the current treatment is a dietary therapy. GSD-Ib patients who also suffer from chronic neutropenia and functional deficiencies of neutrophils and monocytes, which is treated with granulocyte colony stimulating factor to restore myeloid function. The GSD-Ia and GSD-Ib genes are then cloned. It has been written in the article to date that 76 G6Pase and 69 G6PT mutations have been identified in GSD-I patients. A database of the residual enzymatic activity retained by the G6Pase missense mutants is facilitating the correlation of the disease phenotype with the patients’ genotype whilst the molecular basis for the GSD-I disorders are known and symptomatic therapies which are available in various aspects of the diseases which are poorly understood, and have no cures. Recently developed animal models of the disorders are now thought to be exploited to delineate the disease more precisely and develop new, more causative therapies.

Lucchiari S, Santoro D, Pagliarani S, Comi GP. Clinical, biochemical and genetic features of glycogen debranching enzyme deficiency. Acta Myol. 2007;26:72–4. https://www.ncbi.nlm.nih.gov/pubmed/17915576

J Inherit Metab Dis. 2015 May;38(3):511-9. doi: 10.1007/s10545-014-9772-x. Epub 2014 Oct 7.
Type I glycogen storage diseases: disorders of the glucose-6-phosphatase/glucose-6-phosphate transporter complexes.
Chou JY1, Jun HS, Mansfield BC. https://www.ncbi.nlm.nih.gov/pubmed/25288127


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