Inborn errors of metabolism

nonherit equal to(p) errors of metamorphosis1.0 Abstract subjective errors of metabolism occurs 1 in 5000 births collectively. They croupeister be treated if the ind swell uping error is diagnosed properly and early. They atomic number 18 manly pay backd by a component defect that fudges vital metabolic pathways. The pile be server, which is primarily collectible to amount of enzymes that is causing the block or inadequacy of the answer product. This can affect the organs and as well bind local effect such as lysosomal depot disease. The symptoms can vary, from mild to severe. They affect any organs and occur at any season. To recognise the Inborn Errors of Metabolism, the doctor essential be suspicious for employment a baby that pose signs of antecedent pargonntal fever should under(a)(a)go a blood grow and alike tolerate simple adjudicates such as Amino stingings, Organic doses, Glucose, Electrolytes, Lactate, and Ammonia which is d unmatchable in the laboratory.2.0 AbstractInborn errors of metabolism (IEM) be a pigeonholing of hereditary disorders that be r ar. These disorders are brokertic diseases that are involved in metabolism disorders. A large atom of these disorders arise from single genes that encodes for enzymes that absorb been defective. These enzymes are important that they catalyses chemical reactions converting substrates to products essential for daily living. Inborn errors of metabolism disorders can arise from a number of conditions such as prolong motion picture and accumulation of substances which are toxic, and the interference of normal functions and the inability to sustain and synthesize essential compounds. Inborn errors of metabolism has related to defects in or dam get on with to a captureing foetus that may extradite been ca utilise to genetic changes, that is why Inborn errors of metabolism is fewtimes referred as congenital metabolic diseases. Inborn errors of metabolism energize also been linked to heritable disorders within biochemistry, for example phenylketonuria (PKU). That is why some times it is referred as inherited metabolic diseases as well. In the perspective of changes of normal mechanical, physical, and biochemical functions, IEM can divided into 3 effectual separates that can be analysed diagnostically. classify 1 Disorders which instances intoxication. Group 2 Disorders involving zilch metabolism. And Group 3 Disorders involving complex molecules.1.0 Introduction1.1 Inborn Errors of MetabolismIn the early 1900s, a researcher called Sir Archibald Garrods base his studies on genetic metabolic disorders and discovered IEM 1, 2. He was known for his work on the one gene, one enzyme hypothesis, based on his studies on the nature and inheritance of alkaptonuria. And gave the name and wrote a book on IEM (The Incidence of alkaptonuria a Study in Chemical Individuality.) 1, 2.IEM can arise from a number of causes, simply the battleground cause is alteration of a unique(predicate) metabolic reaction 1, 2. IEM has been shown to develop at a really young age, where epidemiology findings indicated that hundreds of IEM affects about 1 in every 5000 born babies 2. But as technology advances and improve proficiencys such as metabolomics, has been easy to develop newborn screen that improves early diagnosis and interposition in a number of IEM disorders 2. But as these new techniques cost a administer to run and time increases, proving to be unreliable 2.The study and the knowledge about inwrought errors of metabolism (IEM) develop improved collect to the latest advancement in technology and techniques 2, 3. These improvement have led us to the conclusion, for example carbamide cycle disorders and positive acidemias may and pull up stakes come about to the accumulation of ammonia, which is a toxic product of amino group acid metabolism 2, 3. Also the latest findings are that inborn errors of metabolism (IEM) may impai r fountainhead function collect to defects in the mitochondrial respiratory chain and disorders in gluconeogenesis 4. on that point are 10 facts that learn to take in parcel outation when people with IEM undergo clinical diagnosis 5.Common condition such as, intoxication, encephalitis and brain tumours in one-time(a)er diligent ofs and also sepsis have to be analysed properly and always consider IEM in the corresponding field 5.Symptom that persists and that are unexplained even before, during and subsequently initial manipulation and normal investigations has been performed, have to be interpreted to consideration that it could be IEM 5.Newborn babies that have organ dysfunction, hypo-perfusion, or hypotension can develop sepsis, which can be caused by IEM. So any babies in neonatal intensive misgiving unit that die, the starting signal cause that has to be taken to account is IEM 5.Have to take extra mission in re billeting all autopsy findings 5.The examiner must no t confuse a symptom for example circumferential neuropathy or syndrome such as sudden infant death with etiology 5.IEM can develop and present at any age, for example from foetal life to old age 5.The examiner must take to account that not all genetic metabolic errors causes are due to hereditary and familial recessionary disorders, unless a large section of individual cases are sporadic 5.Always consider inborn errors of metabolism are open to treatment for example with patients that have inborn errors of metabolism due to intoxication 5.In server situations, the examiner will need to take a few patients with IEM that are able to diagnose and treat the patient with IEM 5.The examiner must be open to obtain attention from specialised centres that specialise with IEM 5.The metabolic disorders can be set into lead useful groups that can advantageously be distinguished from each other 5, 6, 7. These three groups are sorted from a pathophysiological point of view 5, 6, 7. The grou ps are Group 1 Disorders which is caused by intoxication 5, 6, 7. Group 2 Disorders involving energy metabolism 5, 6, 7. And Group 3 Disorders involving complex molecules 5, 6, 7.1.2 Group 1- Disorders which is caused by intoxicationIn this group, it describes inborn errors of intermediary metabolism. These inborn errors cause acute of progressive intoxication from long exposure and increase of toxic compounds, forming a metabolic block 5, 6, 7. In group 1 the inborn errors are manly amino acid catabolism 5, 6, 7. These take on phenylketonuria, where there is a inadequacy in the enzyme phenylalanine hydroxylase (PAH) which is needed to metabolise the amino acid phenylalanine to the amino acid tyrosine 5, 6, 7. Homocystinuria is an inherited disorder of the metabolism of methionine 5, 6, 7. Tyrosinemia is where remains cannot break down the amino acid tyrosine 5, 6, 7. Also organic acidurias such as methylmalonic acidemia, and propionic acidemia 5, 6, 7.Sugar intolerances are also classified in group 1 5, 6, 7. These embroil hereditary fructose intolerance caused by a deficiency of liver enzymes that metabolise fructose. Metal toxication also falls under group 1 such as hemochromatosis, where the patient has accumulated a lot of iron 5, 6, 7.All these metabolic disorders have something in common, in that they do not affect the fertilized egg victimization, and also show similar symptoms of clinical intoxication 5, 6, 7. A patient with group 1 disorders may show an acute signs of vomiting, asphyxia and liver failure or continuing signs which are cardiomyopathy, developmental s lowly and failure to thrive. Acute symptoms that can worsen are catabolism, fever, and food intake 5, 6, 7.The analysis in group 1 is easy, and without any complications 5, 6, 7. It needs the use of chromatography in which the plasma and urine amino acid. Most of group 1 disorders are treatable. Treatment is usually involves special diets and cleansing drugs such as sodium benzoate and penicillamine, to take away the toxins 5, 6, 7.The inborn error of amino acid synthesis is also included to this group, as they have the same or similar features 7, 8. They are inborn errors of intermediary metabolism the analysis requires the plasma and urine where disorders are able to be treated even when the disorder starts with in the uterus, for example 3-phosphoglycerate dehydrogenase deficiency 5, 6, 7, 8.1.3 Group 2- Disorders involving energy metabolismIn this group inborn errors are errors of intermediary metabolism as well. The symptoms are mainly caused by a lack of energy production or utilization. This will involve the liver, myocardium, musclebuilder, and brain 5, 6, 7.There are two types of disorders involving energy metabolism. 1. involves mitochondrial energy defects. 2. involves cytoplasmic energy defects 5, 6, 7.Mitochondrial energy defects are more offensive and are not fully treatable 5, 6, 7. Mitochondrial energy defects cause lactic acidemias where t here is dextrorotatory lactic acid in the circulating blood, resulting to defects of the pyruvate transporter resulting to PKU, pyruvate carboxylase this causes lactic acid to accumulate in the blood, pyruvate dehydrogenase where the patient can show symptoms of severe lethargy, and defects in the Krebs cycle 5, 6, 7. But some defects such as fatty acid oxidization and ketone personify defects are partly treatable 5, 6, 7.Cytoplasmic energy defects are not as much in-your-face then mitochondrial energy defects. A cytoplasmic energy defect causes disorders of glycolysis, glycogen metabolism and gluconeogenesis 5, 6, 7. And recent study showed it causes disorders of creatine metabolism which it is partly treatable by oral creatine supplementation 5, 6, 7. Cytoplasmic energy defects can cause disorders that are untreatable, such as errors of the pentose phosphate pathway which will be draw in further details 5, 6, 7.In group 2, the common symptoms are heart muscle disease, hypogly caemia, myopathy which is a sizable disease, cardiac failure, specific failure of the circulation, sudden death especially in infancy 5, 6, 7.Mitochondrial disorders and as well as the pentose phosphate pathway defects can obstruct embryo-foetal development and give rise to dysmorphism, dysplasia causing an abnormality in maturation of cells within a tissue and congenital disorder 5, 6, 7, 9. The analysis and the diagnosis are hard to put through as it requires 4 different tests 5, 6, 7. 1. Function tests 5, 6, 7. 2. Enzymatic analyses needing biopsies 5, 6, 7. 3. Cell culture 5, 6, 7. 4. Molecular analyses 5, 6, 7.1.4 Group 3- Disorders involving complex molecules.Group 3 involves cellular organelles 5, 6, 7. The diseases that fall under group 3 modify the synthesis or the catabolism of complex molecules 5, 6, 7. There are symptoms that are permanent and progressive, and some symptoms free from intercurrent events 5, 6, 7.In this group there are disorders such as lysosomal storag e disorders, peroxisomal disorders and inborn errors of cholesterin synthesis etcetera In this group treatment is difficult would need enzyme replacement therapy, especially for lysosomal disorders 5, 6, 7, 10.2.0 command Symptoms and SignsThere is a way for testing newborn babies for inborn errors 11. This process is called Newborn wake. This tests babies at a very early age for foursome types of diseases that are treatable genetic, endocrinologic, metabolic and hematologic diseases 11. Dr Robert Guthrie was a microbiologist who designed a dried blood spot testing, and used it to screen for phenylketonuria 12. To this present day that spotting test is still be used. As techniques have improved so have the screening 12. A atomic number 101 who is screening a newborn baby for a metabolic disorder has follow four groups of clinical circumstancesThe physician must find early symptoms, especially in the antenatal and neonatal level of development.In the later stages the physician must find symptoms that are server and recurring. Symptoms such as coma and vomiting.If the physician finds any symptoms that are chronic and aggressive, they could be due to three things 1) Gastro enteral. 2) Muscular. 3) Neurological. These will be depict in more detail belowThe physician must find any signs of cardiomyopathy, hepatomegaly etc. This could lead to organ failures.The three groups have symptoms that are chronic and aggressive that can be easily ignored or misinterpreted.2.1 Gastrointestinal Symptoms.If a patient has inborn errors of metabolism (IEM), the person might have symptoms that fall under the Gastrointestinal Symptoms (GI) group 13. These symptoms include Anorexia, which is an eating disorder 5, 13. Osteoporosis which untreated could lead to finger cymbals fracturing. Chronic vomiting, feeding difficulties, and failure to thrive are also symptoms of (GI). But they are also associated with chronic diarrhoea 5, 13. This could lead to false and the wrong diagn osis 5, 13.There are two groups that have been describe to have caused chronic diarrhoea and failure to thrive within inborn errors of metabolismThese disorders include errors of the intestinal mucosa or the exocrine function of the pancreas, for example congenital chloride diarrhoea, glucose- galactose malabsorption a condition in which the cells lining the intestine cannot take in the sugars. Lactase and sucrose-isomaltase deficiencies where the person is unable to metabolise lactose or sucrose. Abetalipoproteinemia type II disorder that interferes with the normal absorption of fat and fat-soluble vitamins from food 5, 13. Enterokinase deficiency Enterokinase is an enzyme involved in human digestion. Acrodermatitis enteropathica, a condition that affects that absorption of Zinc. Etc 5, 13.Systemic disorders such as diabetes mellitus, diabetes, sickle cell disease, sarcoidosis, etc can also give rise to GI abnormalities. A problem has risen in distinguishing systemic abnormalities and inborn error of metabolism and vice versa 5, 13.2.2 Muscle Symptoms.There are a number of symptoms that fall under this group. For example Hypotonia, where there is a disorder that causes low muscle tone and strength 5, 14. Muscular impuissance and poor muscle book 5, 14. These symptoms are common with many inborn errors of metabolism. These symptoms can be caused by urea cycle defects and many amino acid metabolism disorders 5, 14. Recent studies have shown that the cause of muscle symptoms can be due to mutations in the monocarboxylate transporter 8 gene, which can develop Allan-Herndon-Dudley syndrome 14. Allan-Herndon-Dudley syndrome falls under the muscle symptoms group as it causes hypotonia, general weakness of the muscle, reduced muscle mass and delayed development 14. Further studies showed that this X-linked mental retardation syndrome is involved in the transport of triiodothyronine into neurones and disrupts the blood levels of thyroid ductless gland 14.2.3 Neurolo gical Symptoms.Patients with inborn errors often have neurologic symptoms. These include of neurological abnormalities, in the central and peripheral system. Studies have shown that these neurological symptoms are very frequent with inborn errors 5, 15. These symptoms include poor feeding, hypotonia, ataxia, and even sick features 5, 15. The analysis of inborn errors, due to the screening of neurological symptoms is very difficult due to symptoms that are non specific signs sings that include for example developmental delay, and hypotonia 15.3.0 Screening Newborns for Inborn Error of Metabolism3.1 Newborn screeningNewborn screening is a technique, used to detect inborn errors 17, 12. It was first used to detect phenylketonuria (PKU) by a bacterial inhibition assay, developed in the 1961 by Dr Robert Guthrie as already stated. His technique in using dried blood attempt was further developed in the mid 1975, where a scientist called Dussault used a method to screening for congenita l hypothyroidism 16. A lot of time and money has been invested into the screening programme, and now they have uncovered new disorders that are related to inborn errors 17, 12. Disorders such as cystic fibrosis, congenital suprarenal gland hyperplasia, which is a form mutation of genes that produces enzymes that mediating production of cortisol from cholesterol by the adrenal glands. Glucose-6-phosphate dehydrogenase deficiency and many more 5.To this present day, for screening newborns, tandem mass spectrometry is used 18. It is a lot easier for screening and diagnosis. The application of tandem mass spectrometry to newborn screening was first described in 1990 18.The primary aim of newborn screening is to key patients, manly infants with serious disorders that are treatable 18. This will make it easy to prevent or improve clinical symptoms of the disease 18. Tandem mass-spectrometry is very useful in detecting more than one disorder at one time 18. This can be used to detect ear ly untreatable disorders and also can be beneficial if the screening was not check to just individual babies, but the whole family as well 18.The screening process uses MSMS 18. MSMS is the method used to measure analytes by two mass and structure 18. First the compounds are ionised, where the first mass spectrometer selects the ion of interest, where it is sorted by weight 18. Then the compounds travel through a collision cell, are dissociated to tinge fragments, and then pass into a second mass spectrometer where ions are selected for detection. 18.3.2 Method for screening look into have been done where most newborn screening programmes use simplifying sample preparation, instead derivatisation of the sample which is the old method 18. When investigating, the sample might show more than one disorder. But the use of ratio of analytes improves sensibility and specificity 19. Specialised biochemical genetic testing is always done to verify which type of disorder the patient has 1 8. Theses genetic tests include amino acid analysis, organic acid analysis by gas chromatography/mass spectrometry, and plasma acylcarnitine profile by MSMS 18.4.0 Screening for Individual Inborn Errors of MetabolismWell over 40 inborn errors of metabolism can now be detected by newborn screening 20. This section will look at three inborn errors.4.1 Pentose Phosphate PathwayThe pentose phosphate pathway (PPP) is an anabolic pathway where is uses a 6 carbon glucose to generate a 5 carbon sugars and reducing equivalents, as shown in Fig. 1. There are three primary functions of this pathway 21To generate reducing equivalents, such as NADP forming NADPH. NADPH allows reduction biosynthesis reactions to occur within cells 21.To produce ribose-5-phosphate (R5P) for the cell, for the synthesis of the nucleotides and nucleic acids 21.Can metabolise dietetical pentose sugars that are derived from digestion of nucleic acids 21. These also rearrange the carbon skeletons of dietary carbohydrat es into glycolytic/gluconeogenic intermediates 21.4.1.1 Disorders of the Pentose Phosphate PathwayThere are three inborn error in the pentose phosphate pathway that have been identified 21.4.1.2 Glucose-6-phosphate dehydrogenase deficiencyThe enzyme glucose-6-phosphate dehydrogenase (G6PDH), catalyses the reaction that converts glucose-6-phosphate to 6-phosphogluconate. This creates one mole of NADPH each for every mole of glucose-6-phosphate (G6P) that enters the PPP 21. A deficiency would lead to an error to the first irreversible step of the pathway 21. This would lead further to a lower production in NADPH, do the cell more acceptable to oxidative stress 21.G6PDH is very important for Erythrocytes metabolism 21. A deficiency could lead Individuals to nonimmune hemolytic anaemia which can be caused by, infection or exposure to veritable medications or chemicals 21. G6PDH deficiency is also linked to favism 21. It is thought to be an X-linked recessive hereditary disease 21.4.1. 3 Ribose-5-Phosphate Isomerase inadequacyA recent study have shown that a patient with of ribose-5-phosphate isomerise deficiency, had developed progressive leucoencephalopathy and, developmental and speech delay 21. They did further studies using NMR and prove that polyols ribitol and D-arabitol concentration was abnormal in body fluids 21, 22. They did their studies on fibroblasts and form that the enzyme gene-sequence analysis showed a frame-shift and a missense mutation 22.4.1.31 Metabolic upsetRibose-5-phosphate isomerase deficiency would believe that the reversible reaction converting ribose-5-phosphate to ribulose-5-phosphate and vice versa will halt 22. If there was no deficiency ribulose-5-phosphate would be born-again to xylulose 5-phosphate, which will provide the substrates for transketolase and further conversion into glycolytic intermediates 22.Studies have found that there are two genetic mutation allele one from each parents that results in ribose-5-phosphate isomerise gene that causes the deficiency 22. So it could be an autosomal recessive inheritance disorder 22. The best way to do a diagnostic test for Ribose-5-phosphate isomerase deficiency would be to take a urine sample 22. Polyols ribitol and D-arabitol would be analysed 22. Also enzyme assay can be used to sequence the ribose-5-phosphate isomerise gene 22.4.1.4 Transaldolase DeficiencySome studies have been done where three misrelated families had Transaldolase deficiency 23. One patient had aortic coarctation where the aorta narrows 23. During the patients life they found that ammonia was rising. But neurological and intellectual development has been normal. Another patient had HELLP syndrome (hemolysis, elevated liver enzymes and low platelet count) 23, 24.Children with transaldolase deficiency have been diagnosed have found that the development of intellectual and neurological showed no abnormalities 23, 24. But there is a satisfying link to liver cirrhosis which results fr om increased cell death of hepatocytes and biliary epithelial cells 23, 24.4.1.41 Metabolic DerangementTransaldolase catalyses the reaction Sedoheptulose 7-phosphate + glyceraldehyde 3-phosphate erythrose 4-phosphate + fructose 6-phosphate 59.It is a reversible reaction in the pentose phosphate pathway. The deficiency lead to the accumulation of polyols derived from the pathway intermediates erythritol, arabitol and ribitol 59.Studies have shown that all patients were homozygous for these specific mutations, suggesting autosomal recessive inheritance 23, 24. A simple urine test can be done to diagnose of transaldolase deficiency, mainly because there is a high concentration of arabitol and ribitol in urine. Also enzyme assay can be used to sequence the gene 23, 24. Liver transplant would be the only option with patients that have severe liver cirrhosis 23, 24.4.2.0 Insulin secernment by the pancreatic -cellIn the production of insulin glucose enters the -cell through a GLUT2 transp orter where it is phosphorylated to glucose-6-phosphate by the enzyme glucokinase 58. The enzyme is used as a control, where it monitors the level of glucose 58. As blood glucose raises the rate of glucose metabolism also increases, where the cell will undergo glycolysis generating ATP 58. This increase of ATP concentration causes K+ channels to close, making the membrane depolarised 58. This depolarisation causes the emf sensitive Ca2+ channels to open and Ca ions flood in, stimulating insulin secretion by exocytosis from storage granules this is shown in Fig. 2.4.2.1Persistent Hyperinsulinemic HypoglycaemiaHyperinsulinism has been diagnoses in all ages but it is very common in childhood 25. Persistent hyperinsulinemic hypoglycaemia (PHHI) is the one of the main cause of hypoglycaemia especially in young children. Patients who are older, that develop PHHI are due to pancreatic adenoma 25. Hypoglycaemia when there is an overproduction of insulin by the -cells in the pancreas 25. Hy poglycaemia can produce a variety of symptoms the most dangerous is brain defile which can lead to death, and that is why treatment is vital 25. PHHI has two histopathological lesions that can be easily distinguished, making PHHI a heterogeneous disorder 25. central hyperinsulinemic hypoglycaemia (FoPHHI) is caused by loss of heterozygosity which is a somatic event 25. This causes central adenomatous hyperplasia, which is a pancreatic lesion 25. They are treated with pancreatectomy, where they surgically remove part of the pancreas.Diffuse hyperinsulinemic hypoglycaemia (DiPHHI) is also a heterogeneous disorder, in that fact that it is unable to encode for proteins needed for insulin secretion 25. This can also be caused autosomal recessive and dominant genes which are rare 25. Positron emission tomography (PET) is used to distinguish between focal and diffuse PHHI 25. This gives a 3D image or picture of functional processes in the body 25. at a time a patient is diagnosed with P HHI, they are on treatment straight away with glucose and glucagon 25.4.2.12Metabolic DerangementHyperinsulinemic hypoglycaemia is due to insulin hypersecretion by the pancreas 25. The Action insulin causes a decrease in plasma glucose by inhibiting hepatic glucose release from glycogen and gluconeogenesis, and by increasing glucose uptake in muscle and fat 25.PHHI is a disorder that is caused by a variety of defects, either in regulation of insulin secretion, unable to transcribe the enzymes needed of even a limited receptor 26. For example diseases that can affect the ion channels like seizures 27, 28, 29. Also lack of enzyme production of glucokinase (GK), and glutamate dehydrogenase (GDH) 30, 31.Epidemiology has found that 1/50,000 patients are born with PHHI 32, 33. Focal hyperinsulinemic hypoglycaemia is strongly linked to mutation of the sulfonylurea-receptor and the K+ channels, both used to depolarise the cell 32, 33. Both are found to be located on the chromosome 11p15 32, 33. To identify these mutations they would need to be tested in a foetus or embryo before it is born. Sulfonylurea-receptor gene (SUR1) will not respond to diazoxide, which is used as a K+ channels activator 34.Studies have found that a high activity of the enzyme glutamate dehydrogenase (GDH) has resulted to hyperinsulism/hyperammonemia syndrome. This would make sense as GDH is needed to produce insulin and this would impair detoxification of ammonia in the liver 31. The enzyme glucokinase (GK) is also expressed highly, where the affinity is increased for glucose, causing high levels of insulin secretion 30.4.2.13 diagnostic TestsDiagnostic of HI is easy, in the fact that, it can be indicated by the levels of glucose in the blood. Treatment varies from age 35. Hyperammonemia should be treated as another disease, when a patient has PHHI, when treating hyperinsulism/hyperammonemia syndrome. This can be done by analysis of urine organic acids and plasma acylcarnitines 36.Patients wh o show the FoPHHI can have lesion ranging from 2.5 to 7.5 mm in diam 37, 38. People who have DiPHHI found that there was -cells that were abnormal 39. Pancreatic venous catheterization (PVS) and pancreatic arteriography have prove very useful in locating the site of insulin secretion 40, 41. PVS procedure will have to able to maintain blood glucose level, which is between 2 and 3 mmol/l. Blood sample would then be taken from the pancreas to measure 3 things 1.plasma glucose, 2.insulin and 3.C-peptide levels 40, 41.Studies have shown that people with FoPHHI tend to have high concentration of plasma insulin and C-peptide levels in some samples and low concentration in others 40, 41. People who have DiPHHI tend to find that all their sample have high concentration of plasma insulin and C-peptide 40, 41.The use of 18F-labelled fluoro-L-DOPA whole-body positron emission tomography (PET), has proved to be very useful in detecting hyperfunctional islet pancreatic tissue, where this can b e used on patients with focal lesion 42.Recent studies have shown that a new technique have been use to locate focal lesion and separate focal from diffuse forms of HI this is the tolbutamide test 44, 45.4.2.14 Treatment and PrognosisBrain damage can occur if you are hypoglycaemic, so treatment needs to be quick. Glucagon would be given, where the patient would have to take 1 to 2 mg per day if blood glucose levels are unstable 35. To treat PHHI, diazoxide would be given, usually at a dose of 15-10 mg/kg/day depending on your age 35. Normal blood glucose levels should be between 4 and 7 mmol/l, before and after a meal 56. This could need to be check every time once taking diazoxide 35, 56.Octreotide treatment, can also be used as it is a hormone inhibitor 46. But a high could lead to a more severe hypoglycaemia, as it can inhibit glucagon and growth hormone 46. Patients will find that after treatment with octreotide, they might vomit or have diarrhoea 46.Calcium-channel blockers co uld be used, such as Lercanidipine and Pranidipine 46. These treatments that have been mentioned are very effective in controlling blood sugar 46.If a patient is diagnosed with FoPHHI, the treatment tends to be surgical as drugs are ineffective 46. They would undergo pancreatectomy. This procedure has its risk as the patient might develop diabetes mellitus 46. DiPHHI patients have been found to have large nuclei in the -cells 35, 47. And patients with FoPHHI showed no abnormal s-cell nuclei but did show shrunken cytoplasm 49, 50.4.3 Glucose Transporter DeficiencyMonosaccharides such as glucose and fructose have the properties of being hydrophilic 59. The lipid bilayer has hydrophilic heads and hydrophobic tails, prevent polar molecule such as glucose from distribute across the membrane 59, 60. So transport mechanisms are needed. These are hydrophilic pores allowing polar molecules to diffuse in and out of the cell 59, 60.There are two types of glucose transporters. 1. Sodium-depend ent glucose transporters (SGLT), which have been found to be located in the small intestine and the proximal tubule 59, 60. SGLT uses the difference in concentration of sodium to transport glucose 59, 60. From high to low concentration of sodium causes the transport of glucose against its own concentration gradient 59, 60. 2. Facilitative glucose transporters (GLUT), which has been found throughout the body, but manly in muscle and pancreas cells 59, 60. These transporters transport glucose from high to low concentration 59, 60.Studies have shown that there are four defects in the transport of monosaccharides 59, 60. These defects can depend on where the transporters are located within the body and what they transport in and out of the cell 59, 60.As already stated there are four defects. 1. SGLT2, which is found in renal tubulus cells that can cause renal glucosuria 59, 60. 2. SGLT1, which is found in the intestine, which can cause glucose-galactose malabsorption 59, 60. 3. GLUT2, a transporter that carries glucose to the liver kidneys and pancreas 59, 60. 4. GLUT1 is important, in the fact that it carries glucose to the brain cell (neuron and glia cells)