Metabolic Disorders UCD PDF

Metabolic Disorders Dr Suja Somanadhan Associate Professor in Children's Nursing 10-09-24 Dr Suja Somanadhan 2024 Learning outcomes After studying this subject you will be able to: Define Inborn Errors of Metabolic Disorders (IEMs) Demonstrate an understanding of the abnorm...

Metabolic Disorders Dr Suja Somanadhan Associate Professor in Children's Nursing 10-09-24 Dr Suja Somanadhan 2024 Learning outcomes After studying this subject you will be able to: Define Inborn Errors of Metabolic Disorders (IEMs) Demonstrate an understanding of the abnormality contributing to metabolic disorders. Discuss the classification of Metabolic disorders. Discuss the management of a child with Metabolic disorders. Dr Suja Somanadhan 2024  What Is Metabolism? Metabolism refers to the countless chemical processes going on continuously inside the body to convert or use energy that allow life and normal functioning. Dr Suja Somanadhan 2024 Example of metabolism include: 1 2 3 Breaking down the Transforming excess Breaking down or carbohydrates, nitrogen into waste converting chemicals proteins, and fats in products excreted in into other substances food to release urine. and transporting energy. them inside cells. Dr Suja Somanadhan 2024  TWO PROCESSES OF METABOLISM  Metabolic rate Basal metabolic rate (BMR) Thermic effect of food (also known as thermogenesis) Energy used during physical activity Dr Suja Somanadhan 2024  Body Age Size FACTORS THAT Dietary AFFECT OUR Drugs deficincies BMR Gender Growth Hormones Genetics  > 500 known disorders Genetic conditions that result in metabolism problems. Metabolic Most people with inherited metabolic disorders have a defective gene that results in an enzyme deficiency. Disorders Individually rare diseases Collectively common - account for a significant proportion of illness, especially in children. Dr Suja Somanadhan 2024 Inborn errors of metabolism (IEMs) Inborn errors of metabolism (IEMs) are rare genetic or inherited disorders resulting from an enzyme defect in biochemical and IEMs can be categorized based on their metabolic pathways affecting proteins, fats, onset, predominant signs and symptoms, carbohydrates metabolism or impaired main organs or systems affected, or acuity organelle function presenting as or chronicity of presentation (Saudubray complicated medical conditions involving JM, Garcia-Cazorla À. 2018) several human organ systems (Agana, M. et al.2018 ) Dr Suja Somanadhan 2024  Inherited biochemical abnormalities of urea cycle, amino acid, and organic acid metabolism. Genetics rare diseases Inborn errors of Metabolism Multi systems (IEMs) ( BINDLER ET AL.(2019) Life-limiting condition Palliative care Dr Suja Somanadhan 2024 Inborn errors of Metabolism (IEMs) ▪ Inborn Errors of Metabolism (IEM) comprise a group of disorders in which a single gene defect causes a clinically significant block in a metabolic pathway resulting either in accumulation of substrate behind the block or deficiency of the product (NCIMD, 2015) ▪ All IEMs are all genetically transmitted typically in an autosomal recessive or X-linked recessive fashion. ▪ Present at birth, persisted through life, relatively benign and transmitted recessively in families Dr Suja Somanadhan 2024 Metabolic Pathway Dr Suja Somanadhan 2024 Metabolic Disorders Think of metabolic pathways as a river Dr Suja Somanadhan 2024 What happens downstream? Think of metabolic disease as a block in that river Dr Suja Somanadhan 2024 Normal Metabolic Pathway Dietary Intake Substrate Normal gene Enzyme Reactions Enzyme Product Dr Suja Somanadhan 2024  Abnormal Metabolic Pathway Dietary Intake Mutant gene eg: Accumulation of substrate Galctose (Galactosemia) Phenylalanine ( PKU) Substrate Defective gene product Accumulation Blocked Product Dr Suja Somanadhan 2024 Metabolic Disorders ▪ > 500 known disorders ▪ Individually rare diseases ▪ 1:2,500 to 5,000 (Burton 2005) ▪ Collectively common - account for a significant proportion of illness, especially in children ▪ Disease burden of adult onset IMDs less well documented – Some are milder versions of childhood disease Dr Suja Somanadhan 2024  Disorders of protein metabolism (PKU, MSUD,HCU) Inherited Disorders of carbohydrate metabolism (Galactosemia, Glycogen storage disease) Metabolic Disorders: Disorders of fat metabolism Classification I (Fatty acid oxidation disorders e.g. MCAD) Disorders of organelles (LSDs,Mitochondrial) Dr Suja Somanadhan 2024 What conditions are included in newborn Bloodspot screening? (HSE, 2023) Phenylketonuria (PKU) Classical Galactosaemia, Homocystinuria (HCU) Maple Syrup Urine Disease (MSUD) Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCADD) Glutaric Aciduria Type 1 (GA1) Cystic Fibrosis Congenital Hypothyroidism Adenosine Deaminase Deficiency – Severe Combined Immunodeficiency (ADA-SCID) Dr Suja Somanadhan 2024 New-born Bloodspot Screening ▪ Heel prick screening ▪ All newborn babies are screened for 8 conditions that are rare but treatable, if detected early in life. This is known as the ‘heel prick’ because a small blood sample is taken from the baby's heel. ▪ The 'Heel Prick Test' screens all newborn babies for six rare conditions. ▪ The screening ensures that any babies with these rare conditions are identified and treated as early as possible (HSE, 2023) ▪ More information, please visit: https://www2.hse.ie/heel-prick-screening/ ▪ A Practical Guide to Newborn Bloodspot Screening In Ireland is available via: https://www.hse.ie/eng/health/child/newbornscreening/newbornbloodspotscreening/ information-for-professionals/a-practical-guide-to-newborn-bloodspot-screening-in- ireland.pdf Dr Suja Somanadhan 2024 Mode of Inheritance An affected child must have two parents who carry the recessive gene. Unaffected siblings can be carriers for the recessive gene. Each pregnancy 25% possibility of having a child with the condition Dr Suja Somanadhan 2024 Autosomal recessive genetic disorders To learn more about autosomal recessive genetic disorders. Please click this short video https://www.youtube.com/watch?v=_oVvTkjDm6g To learn more about Autosomal Dominant Conditions: How do they arise and what does it mean for the affected person's children?: Please click this short video https://www.youtube.com/watch?v=yANF0bxHpzU Acknowledgement: National Centre for Medical Genetics & UCD. Funded by a Knowledge Exchange & Dissemination grant from the Health Research Board, Medical Research Charities Group and the National Children's Research Centre, Ireland. Dr Suja Somanadhan 2024 Macronutrients Protein (meat, chicken, fish, eggs, legumes, cheese) Building blocks Carbohydrate (rice, potatoes, pasta, cereals) Energy Fat (oils, butter, cream, lard) Energy Dr Suja Somanadhan 2024 Amino acids Amino acids are organic compounds that combine to form proteins. Amino acids and proteins are the building blocks of life. When proteins are digested or broken down, amino acids are left. The human body uses amino acids to make proteins to help the body: Break down food Grow Repair body tissue Perform many other body functions Amino acids can also be used as a source of energy by the body. Dr Suja Somanadhan 2024  Essential amino acids Amino Essential amino acids cannot be made by the body. As a result, they must come from food. There are 9 essential amino acids. acids are Nonessential amino acids classified Nonessential means that our bodies produce an amino acid, even if we do not get it from the food we eat. into three Conditional amino acids: groups Conditional amino acids are usually not essential, except in times of illness and stress Dr Suja Somanadhan 2024  Protein is made up of smaller building blocks called amino acids. A number of different enzymes are needed to process these amino acids for use by the body. Because of missing or non-working enzymes, people with amino acid disorders cannot process certain amino acids. Aminoacid These amino acids, along with other toxic substances, then build up in the body and cause problems. Disorders The symptoms and treatment vary between different amino acid disorders. They can also vary from person to person with the same amino acid disorder Eg: HOMOCYSTINURIA, Maple Syrup Urine Disease, PKU Dr Suja Somanadhan 2024 Patient Stories (NCIMD, 2021) Here are some of the stories from parents and children who attend National Centre of Inherited Metabolic Disorders: https://metabolic.ie/patient- family-information/patient- stories-2/ Dr Suja Somanadhan 2024  Amino Acids Amino acids are organic compounds that contain amine (–NH2) and carboxyl (–COOH) functional groups, along with a side chain (R group) specific to each amino acid. The key elements of an amino acid are carbon (C), hydrogen (H), oxygen (O), and nitrogen (N), although other elements are found in the side chains of certain amino acids. The essential amino acids are arginine (required for the young, but not for adults), histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine. These amino acids are required in the diet. Plants, of course, must be able to make all the amino acids. Dr Suja Somanadhan 2024 Metabolic screening tests SPECIMEN TEST BLOOD Amino acids Homocysteine Acylcarnitine profile Glycosylation URINE Organic acids GAA/creatine metabolites Purines and pyrimidines Mucopolysaccharide screen Oligosaccharide screen Phenylketonuria Phenylketonuria (fen-ul-key-toe-NU-ree-uh), also called PKU is caused by a defect in the gene that helps create PKU, is a rare inherited disorder that causes an amino the enzyme needed to break down phenylalanine. acid called phenylalanine to build up in the body. Dr Suja Somanadhan 2024  Phenylketonuria (PKU) is an inherited condition. It means that a baby's body cannot break down the amino acid phenylalanine, which is found in protein. This is caused by a problem with a gene, which limits production of the enzyme needed to break down phenylalanine. High levels of phenylalanine in a baby's body are harmful. Phenylketonuria If untreated, they can lead to intellectual or physical (PKU) disability. It is caused a mutation in the Phenylalanine hydroxylase (PAH) gene, often leading to an elevation in blood phenylalanine levels and decreased levels of tyrosine, a dopamine precursor (Lou, 1994; Ball et al.2018). Incidence (HSE, 2018) Around 1 in every 4,500 babies born in Ireland will have PKU or a milder form called hyperphenylalaninaemia. Dr Suja Somanadhan 2024 METABOLIC PATHWAY OF PKU www.newbornscreening.info/Parents/aminoaciddi Dr Suja Somanadhan 2024  Classification of PKU (Scriver et al.2000) Physiological levels of Phenylalanine in 0 - 182 micromoles / L non – PKU person Classical PKU > 1200 micromoles / L Mild PKU 600 – 1200 micromoles / L Non- PKU Hyperphenylalaninaemia (HPA) 182 - 599 micromoles / L Therapeutic range in PKU Child 120-360 micromoles Dr Suja /l (allows for adequate growth) Somanadhan 2024  New Born Screening (GUTHRIE CARD) Confirmation by Bio Chemical Analysis Diagnosis Test for quantitative Phe and Tyrosine levels Blood to out rule Dihyhdropteridine Reductase Activity (DHPR) and Pertins disorder Dr Suja Somanadhan 2024  Monitoring of serum levels of phenylalanine identifies degree of control and needs for normal growth. Normal levels of phenylalanine < 200 micromoles/ l. (78-188) Optimum levels in PKU are 120-360 Monitoring micromoles /l (allows adequate growth) phenylalanine (Vockley et al. 2014) HPA >200 micromoles/ l levels Levels checked 0-2 yrs - once a week 2-6 yrs - twice a month For life - monthly.  Symptoms A musty odor in the breath, skin or urine, caused by too much phenylalanine in the body Neurological problems that may include seizures Skin rashes (eczema) Fair skin and blue eyes, because phenylalanine can't transform into melanin — the pigment responsible for hair and skin tone Abnormally small head (microcephaly) Hyperactivity Intellectual disability Delayed development Behavioral, emotional and social problems Psychiatric disorders (Ball et al. 2018) Developmental Delay in late diagnosis Phenylalanine levels of greater than 360 micromoles / litre in a newborn infant necessitates commencement of a low protein diet (CHI, 2018 ) Dr Suja Somanadhan 2024  If women don't follow the special PKU diet before and during pregnancy, blood phenylalanine levels can become high and harm the developing fetus or cause a miscarriage. Even women with less severe forms of PKU may place their unborn children at risk by not following the PKU diet. Babies born to mothers with high phenylalanine levels don't often inherit PKU. Pregnancy and But they can have serious consequences if the level of phenylalanine is high in the mother's blood during pregnancy. PKU Complications at birth may include: Low birth weight Delayed development Facial abnormalities Abnormally small head Heart defects and other heart problems Intellectual disability Behavioral problems  If you have PKU and are considering getting pregnant: Follow a low-phenylalanine diet. PKU and Women with PKU can prevent birth defects by sticking to or returning to a low-phenylalanine diet before becoming pregnant. Pregnancy If you have PKU, talk to your doctor before you start trying to conceive. Ford S, O'Driscoll M, MacDonald A. Reproductive experience of women Consider genetic counseling. living with phenylketonuria. Mol Genet Metab Rep. 2018 Nov 2;17:64-68. doi: 10.1016/j.ymgmr.2018.09.008. PMID: If you have PKU, a close relative with PKU or a child with PKU, you may 30416967; PMCID: PMC6218656. also benefit from genetic counseling before becoming pregnant. A doctor who specializes in medical genetics (geneticist) can help you better understand how PKU is passed through your family tree. He or she can also help determine your risk of having a child with PKU and assist with family planning. Dr Suja Somanadhan 2024 The aims of dietary treatment are to; Reduce phenylalanine levels to 120-360 µmol/l 12years Provide adequate protein, energy, vitamins and minerals for growth and development. Replace tyrosine and prevent deficiencies Provide variety, palatability and flexibility to suit individual lifestyles. Dr Suja Somanadhan 2024  Dietary Management Dietary management for PKU consists of 3 components: 1. Natural Protein (Measured amounts of phenylalanine ) This is restricted in order to maintain optimum levels 2. Synthetic Amino Acid mixture (phenylalanine-free infant formula / drink) This is a manufactured protein source, usually in the form of a drink and balances the child’s protein requirements 3. “Free Foods” & Vitamins and minerals This refers to foods that are “free” from protein. Avoid medications which have been sweetened using the substance Aspartame eg. Some antibiotics, regular & diet drinks etc. Dr Suja Somanadhan 2024  istockphoto_3102433-slice-of-white-bread “Diet is for life” ❑ Synthetic Amino acid mixture Phenyalalanine-free drink will provide all amino acids except Phenylalanine. ❑ Natural Protein (Measured amount of Phenylalanine, 1Ex=50mg of Phenylalanine. Exchanges will vary in number from child to child, depends on serum Phe-Levels. 1slice of bread=3 gms of protein =3 exchange ❑ Free Foods: Rich in CHO AND FAT, Vitamins and Minerals may need to be added to diet. THERAPEUTIC MANAGEMENT (NCIMD, 2018) ▪ Dietary treatment should commence as soon as the diagnosis is confirmed (Acosta, 2010). ▪ To reduce phenylalaine level to therapeutic range ▪ (120 – 360 umol/L 12yrs) ▪ Support family following diagnosis ▪ Provide initial education to parents/guardians ▪ Instruct parents/guardians on blood sample collection ▪ Introduction to the Multi-disciplinary team Dr Suja Somanadhan 2024  Abnormal blood levels of phenylalanine - check more often. Parents -skin pricks samples sent to Unit. PKU Dietician and CNS liase with families to advise on diet and overall management. (NCIMD, Condition covered by Long term Illness Scheme – special foods are ordered through pharmacies. 2018) Incidence of condition Ireland: 1: 4,600 USA and worldwide: 1:12,000  Nursing Problems? Goals? Nursing Care Nursing Management? Long-Term Problems? Dr Suja Somanadhan 2024  Assessment (Skin Integrity) General observations (T.P.R) GCS Weight and Height Dietary Management Other advice: Avoid alcohol (except cider, wine and spirits), Avoid fruit juices, food and medications which have been sweetened using the substance Aspartame e.g. all diet drinks. Education. (Diet, blood letting) High levels of maternal phenylalanine is toxic to the foetal brain and other organs (Smith &Forbes (2004), Clarke (2005)). Multidisciplinary support http://metabolic.ie/wp-content/uploads/2015/04/CP-Phenylketonuria_New_Diagnosis_2011.pdf Dr Suja Somanadhan 2024 Homocystinuria (HCU) In HCU, the body is unable to break down an amino acid called methionine. This causes a build up of methionine and another amino acid called homocysteine in the eyes, brain, bones and blood vessels and can cause problems when untreated (NCIMD, 2015). HCU caused by cystathionine beta-synthase deficiency (CβS) Untreated methinine accumulates in the circulatory, skeletal, central nervous systems and eyes resulting in thrombosis, stroke, mild intellectual disability and FTT. Incidence Ireland 1: 65,000 (HSE, 2018) (worldwide 1:200,000 (HSE, 2018) Dr Suja Somanadhan 2024 Dr Suja Somanadhan 2024 Elevated Homocysteine Linked to Atherosclerosis Pregnancy complicated by neural tube defects Early pregnancy loss Venous thrombosis (Mazaheri A, et al. 2017) Clinical Signs: (HSE, 2022) ▪ vision problems, such as severe short-sightedness ▪ weak bones (osteoporosis) ▪ bone and joint problems ▪ a risk of developing blood clots and strokes Dr Suja Somanadhan 2024 Management of HCU Principles of treatment same as PKU. Adherence to diet essential to avoid complications. Synthetic amino acid formula supplies essential amino acids. Variance of condition known as pyridoxine responsive. Vitamin B6 helpful in approx 50% of cases. Pyroxine is essential co-factor of the (CβS) enzyme. http://metabolic.ie/wp-content/uploads/2015/04/CP-Homocystinuria_2011.pdf Dr Suja Somanadhan 2024 Maple Syrup Urine Disease (MSUD) In MUSD three essential aminoaciads (Leucine, isoleucine and valine) cannot be metabolized due to absent or defective enzyme called branched-chain-alpha –ketoacid dehyrogenase (Ball et al. 2018). one in every 125,000 babies born in Ireland may have this condition or about one baby every two years (HSE, 2023) The disorder is characterised by a specific odour (maple syrup, burnt sugar) in urine, perspiration and earwax. Symptoms develop in the first few days of life Neurological problems Feeding difficulties, vomiting, convulsions, hypoglycaemia Untreated - brain damage followed by death Dr Suja Somanadhan 2024 Dr Suja Somanadhan 2024  Treatment is life-long and involves the controlled intake of BCAAs ACUTE Remove or limit intake of lethal substrate Provide calories to promote anabolism & Treatment prevent catabolism Continue Synthetic protein (if known patient) Dialysis Classical Galactosaemia (HSE, 2018) Classical Galactosaemia is also an autosomal recessive condition caused by a deficiency of an enzyme galactose-1-phosphate uridyl transferase. This enzyme is important for the breakdown of galactose, one of the two sugars that make up lactose in human and cow’s milk. Approximately one in every 19,000 infants born in Ireland may have this condition. However, it is particularly common among infants born to Traveller parents in whom the incidence is approximately 1 in 450 births. Consequently in the non-traveller Irish community the incidence occurs in about one in every 36,000 births. Dr Suja Somanadhan 2024 Galactosaemia Disorder of carbohydrate metabolism. Deficiency of enzyme that metabolises the sugar galactose present in lactose. Signs and symptoms (NCIMD, 2023) Poor sucking reflex, Poor feeding and poor weight gain Vomiting and diarrhoea Jaundice Cataracts Lethargy and hypotonia Hepatomegaly Coagulopathy with impaired liver function (Vitamin K and Plasma substitute may be needed to correct abnormal clotting times). Tendency to bleed spontaneously – can result in cerebral haemorrhage. Susceptibility to infection, especially E. coli. Dr Suja Somanadhan 2024 Management Untreated galactose accumulates in the brain, liver, kidneys, eyes and ovaries resulting in intellectual disability, cirrhosis, cataracts, renal problems. Female infertility present in 95% of affected women. (O’Connor, 2004). A galactose free diet for life is only form of treatment. No dairy or milk derivatives including breast feeding. Dietary teaching is on-going. Dr Suja Somanadhan 2024 History of Galactosaemia and infants of traveller parents Beutler Test - immediately after birth and before a blood transfusion. New-born screening sample taken 72-120 hrs after to detect other abnormalities. All ‘at risk’ infants are fed lactose/galactose free feed until results of Beutler Test is known. High incidence amongst travellers (1:450) Dr Suja Somanadhan 2024 continued At risk infants – high risk siblings and known traveller infants tested on day 1 Beutler Test – tests for enzyme activity in red blood cells and is independent of food intake. Need to mark the card that it is for Beutler test. Galactacaemia in travellers (1: 700) in other Irish pop 1:19,000. At risk infants put on a lactose free formula until condition diagnosed (O’Connor, 2004). Screening for this condition started in 1972. Dr Suja Somanadhan 2024  Nursing care General observations Neurological Status TPR Intake output (Strict) Calorie count Diet (well/unwell calories) Discontinue all natural protein containing products (i.e. all food and food products which contain protein). Continue synthetic protein mixture) either orally or via nasogastric tube if possible. Extra calories are required to prevent catabolism. Calories are given as protein-free foods, carbohydrate and fat, or, if administered intravenously, as dextrose and intralipid. On-going education Multidisciplinary management and support Dr Suja Somanadhan 2024  Metabolic clinic for medical, dietetic and nursing support Psychology Multidisciplinary Social Work Support Other e.g. Neurology, Speech and Language therapy Dr Suja Somanadhan 2024 Mucopolysaccharide diseases Mucopolysaccharides are long chains of sugar molecule used in the building of connective tissues in the body (Glycosaminoglycan (GAGs) "muco" refers to the thick jelly- like consistency of the molecules "poly" means many "saccharide" is a general term for a sugar molecule Dr Suja Somanadhan 2024 Dr Suja Somanadhan 2024  Lysosomal storage disorders Sandoff 2% GM1 Gangliosidosis 2% Gaucher 14% Mucolipidosis II/III 2% Niemann Pick A/B 3% Maroteaux-Lamy Hurler-Scheie 3% 9% Niemann Pick C 4% Sanfilippo B 4% MLD 8% Tay-Sachs 4% Cystinosis 4% Sanfilippo A 7% Morquio 5% Pompe Fabry 5% 7% Krabbe Hunter 5% 6% Meikle et al., 1999: Australia 1980-1996 Dr Suja Somanadhan 2024  Signs & Symptoms General: Short stature Coarse/distinctive facies Enlarged adenoids/tonsils Hepatosplenomegaly Cardiopulmonary: Umbilical/inguinal hernia Obstructive airway disease Sleep apnea Cardiac valve Bone & Joints: regurgitation/stenosis Dysostosis multiplex Odontoid hypoplasia Dysplastic teeth Joint stiffness & contractures Dr Suja Somanadhan 2024 Wraith JE, Clarke JTR. In: Physician’s Guide to the Treatment and Follow-up of Metabolic Diseases. 195, 2006 Spectrum of Disease in MPS Severe Attenuated Hydrops fetalis common presentation of MPS VII MPS I, MPS II & MPS VII can have multi-systemic somatic and CNS involvement, but never only CNS disease MPS III - primarily a neurological disorder; mild slowly progressive forms are most likely not detected MPS IV - the skeleton in the major organ of involvement with normal intelligence MPS VI – multi-systemic somatic involvement, but with normal intelligence Dr Suja Somanadhan 2024  Assessment of Disease severity Pulmonary function tests Nerve conduction tests EKG/Echocardiog ram Sleep apnea Cervical spine X-rays study Ophthalmological exam Brain/C-spine MRI Range of motion measurements Hearing tests 6 minute walk tests 3-stair climb Dr Suja Somanadhan 2024  Multidisciplinary care Geneticist Genetic Counselor Neurologist Orthopedic Surgeon Pulmonary Specialist Rehabilitation Respiratory therapist Medicine Cardiologist Physical/Occupati onal therapist Nurse Dentist Social worker Dr Suja Somanadhan 2024  Title: Parents’ Experiences of Living with and Caring for Children, Adolescents and Young Adults with Mucopolysaccharidosis (MPS) Research Question Research “What is the experience of a parent living and caring for a child, adolescent, or young adult with MPS?” Research Aim To explore and interpret parents’ experiences of living and caring for their child, adolescent, or young adult with MPS. Dr Suja Somanadhan 2024  Defined Inborn Errors of Metabolic Disorders (IEMs) Demonstrated an understanding of the abnormality contributing to metabolic disorders. Summary Discussed the classification of Metabolic Disorders. Discussed the management of a child with Metabolic Disorders. Reference Hendriksz C. & Gissan P. (2014) Glycogen storage disease. Paediatrics and Child Health 25(3), 139-144. Agana, M., Frueh, J., Kamboj, M., Patel, D. R., & Kanungo, S. (2018). Common metabolic disorder (inborn errors of metabolism) concerns in primary care practice. Annals of translational medicine, 6(24), 469. https://doi.org/10.21037/atm.2018.12.34 Saudubray JM, Garcia-Cazorla À. Inborn Errors of Metabolism Overview: Pathophysiology, Manifestations, Evaluation, and Management. Pediatr Clin North Am 2018;65:179-208. 10.1016/j.pcl.2017.11.002 HSE (2023) Heel prick screening, https://www2.hse.ie/heel-prick-screening/ Ford S, O'Driscoll M, MacDonald A. Reproductive experience of women living with phenylketonuria. Mol Genet Metab Rep. 2018 Nov 2;17:64-68. doi: 10.1016/j.ymgmr.2018.09.008. PMID: 30416967; PMCID: PMC6218656. Jameson E. & Walter J. (2014) Medium-chain acyl-CoA dehydrogenase deficiency. 25(3), 145-148. Stuart G., & Ahmad, N. (2010) Perioperative care of children with inherited metabolic disorders. Continuing Education in Anaesthesia Critical Care & Pain 11(2), 62-66. Vockley, J. et al. (2014) ‘Phenylalanine hydroxylase deficiency: Diagnosis and management guideline’, Genetics in Medicine, 16(2), pp. 188–200. doi:10.1038/gim.2013.157. Gaustadnes M., Rudiger N., Rasmussen K., Ingerslev J. Familial thrombophilia associated with homozygosity for the cystathionine beta-synthase 833T—>C mutation. Arterioscler Thromb Vasc Biol. 2000;20:1392–1395. Gaustadnes M., Wilcken B., Oliveriusova J., McGill J., Fletcher J., Kraus J.P. The molecular basis of cystathionine beta-synthase deficiency in Australian patients: genotype- phenotype correlations and response to treatment. Hum Mutat. 2002;20:117–126. Linnebank M., Junker R., Nabavi D.G., Linnebank A., Koch H.G. Isolated thrombosis due to the cystathionine beta-synthase mutation c.833T>C (1278T) J Inherit Metab Dis. 2003;26:509–511. Dr Suja Somanadhan 2024  Reference Scriver, C.R., Watters, P.J., Sarkissian, C, Ryan, S., Prevost, L., Côté, D., Novak, J., Teebi, S. Nowacki, P.M. (2000) PAHdb: A locus-specific knowledgebase. Human Mutation 15(1), 99-104. Acosta, P.B. (2010) Nutrition Management of Patients with Inherited Metabolic Disorders. Jones & Bartlett Publishers, Sudbury, MA. Clarke, J.T.R. (2006) A Clinical Guide to Inherited Metabolic Diseases. 3rd Edition. Cambridge Press, Cambridge. HSE, (2022) A Practical Guide to Newborn Bloodspot Screening in Ireland, 09th Edition, National Newborn Bloodspot Screening Laboratory Temple Street Children’s University Hospital, Dublin. CHI (2020) Children’s Health Ireland at Temple Street, available at : http://metabolic.ie/healthcare-professionals/nursing/ Maclean K.N., Gaustadnes M., Oliveriusova J., Janosik M., Kraus E., Kozich V. High homocysteine and thrombosis without connective tissue disorders are associated with a novel class of cystathionine beta-synthase (CBS) mutations. Hum Mutat. 2002;19:641–655. Mazaheri A, Mostofizadeh N, Hashemipour M. Homocystinuria with Stroke and Positive Familial History. Adv Biomed Res. 2017 Oct 25;6:132. doi: 10.4103/2277-9175.217215. PMID: 29279830; PMCID: PMC5674651. Janošík et al.(20009) Birth Prevalence of Homocystinuria in Central Europe: Frequency and Pathogenicity of Mutation c.1105C>T (p.R369C) in the Cystathionine Beta-Synthase Gene, Journal of Pediatrics, 154(3): 431–437 Hoytema van Konijnenburg, E.M. et al. (2021) “Treatable inherited metabolic disorders causing intellectual disability: 2021 review and Digital app,” Orphanet Journal of Rare Diseases, 16(1). Available at: https://doi.org/10.1186/s13023-021-01727-2. Dr Suja Somanadhan 2024  Reference Somanadhan, S, Brinkley, A, Larkin, PJ. (2021) Living through liminality? Situating the transitional experience of parents of children with mucopolysaccharidoses. Scand J Caring Sci. 00: 1– 11. https://doi.org/10.1111/scs.13026 Somanadhan S, Bristow H, Crushell E, et al (2021). IMPACT study: measuring the impact of caregiving on families and healthcare professionals of children and adults living with mucopolysaccharidoses in Ireland. Therapeutic Advances in Rare Disease. 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