1. Chapter 5: Special Topics in Prenatal and Infant Nutrition; Genetics and Inborn Errors of Metabolism and Failure to Thrive Laura Harkness PhD, RD, Sara Snow MS, RD, Claire Blais, RD, LDN, CNSD

2. Chapter 5 Special Section: Neonatal Intensive Care Nutrition: Prematurity and Complications Liesje Nieman, RD, CNSD, LDN

3. Reader Objectives: 1. Define and describe the biochemistry of some of the more prevalent inborn errors of metabolism. 2. Describe the prevalence, diagnosis, clinical symptoms, and long term complications of these diseases.

4. Reader Objectives, cont. 3. Discuss medical nutrition therapy for these diseases: Branched Chain Amino Acids Maple syrup urine disease Isovaleric academia Aromatic amino acids Phenylketonuria Sulfur containing amino acids Tyrosinemia Homocystinuria Urea cycle enzyme deficiencies Disorders of carbohydrate metabolism Galactosemia Fructose intolerance

5. Reader Objectives, cont. 4. Identify and classify failure to thrive. 5. Evaluate the diet of the patient with failure to thrive and describe techniques to treat failure to thrive in the outpatient and inpatient settings.

6. Genetics & Inborn Errors of Metabolism The inheritance of a genetic disease is determined by whether the gene is dominant or recessive as well as the type of chromosome that carries the gene. For a child to inherit a recessive disease both parents must carry at least one gene for the disease and the child must inherit 2 abnormal alleles or in other words the individual is homozygous for the trait. If both parents are carriers (heterozygous for the trait), there is a 25% chance that a child will inherit 2 abnormal genes and inherit the disease and a 50 % chance that a child will inherit 1 abnormal gene and be a carrier for the disease.

7. Branched Chain Amino Acids and Inborn Errors of Metabolism The branched-chain amino acids are (BCAAs): leucine, valine, and isoleucine. The BCAAs share common first steps in catabolism to tricarboxylic acid cycle intermediates. This irreversible oxidative decarboxylation of the keto-acids yields intermediates for energy metabolism. The primary role of BCAAs is incorporation into body proteins.

8. Maple Syrup Urine Disease Maple syrup urine disease (MSUD) is a defect in the metabolism of the branched chain amino acids (BCAAs): isoleucine, leucine, and valine. The clinical symptoms that occur in MSUD are the result of neurotoxicity from the accumulation of leucine, valine, and isoleucine, and their  keto acids. Elevated urine concentrations result in a maple syrup odor. Infants will exhibit a sharp cry, lethargy, vomiting, loss of normal tendon reflexes, poor sucking ability, respiratory failure, metabolic acidosis, alternating flaccidity and rigidity, leading to spasms of the body with the back fully arched and the heels and head bent back, and seizures.

9. Nutrition Therapy for MSUD Long-term nutrition therapy is required to provide a restricted, yet appropriate dietary BCAA intake to support optimal growth and development while maintaining plasma concentrations of BCAA at nontoxic levels. Timely initiation of nutrition therapy is key to preventing impaired physical and mental development. The aim of the therapeutic regime in MSUD is to keep the concentration of toxic metabolites within individual tolerance limits. BCAAs are essential amino acids and therefore cannot be eliminated from the diet.

10. Disorders of Leucine Catabolism: Isovaleric Acidemia Isovaleric acidemia (IVA) is the result of impairment of isovaleryl-coenzyme A dehydrogenase, which leads to toxic accumulation of free isovaleric acid and its precursors. Symptoms include vomiting, diarrhea, tachypnea, poor feeding, lethargy, hypotonia, tremors, and a “sweaty feet” odor of the urine and blood.

11. Medical Nutrition Therapy for Isovaleric Acidemia Therapy, consisting of leucine restriction with supplemental glycine and carnitine, should be started as soon as possible after birth. During acute ketosis, metabolic acidosis must be corrected immediately with glycine and L-carnitine therapy to prevent serious complications such as mental retardation and intraventricular hemorrhage. For long-term therapy, dietary restriction of leucine, combined with supplemental glycine and L-carnitine, are used as the cornerstones of treatment.

12. Aromatic Amino Acids and Inborn Errors of Metabolism Phenylalanine Metabolism Phenylalanine is an essential amino acid used for tissue protein synthesis and hydroxylation reactions that result in the formation of tyrosine. Hyperphenylalaninemia primarily affects the brain tissue. The high concentration of phenylalanine interferes with the transport of the amino acids tyrosine and tryptophan into the brain. Tyrosine is needed to provide energy and to synthesize protein, catecholemines, melanin, and thyroid hormones

13. Phenylketonuria (PKU) A form of hyperphenylalaninemia, defined as plasma phenylalanine value above 120 uM (2 mg/dl). Untreated, PKU can result in severe to profound mental retardation and behavioral difficulties. The severity of the disease can vary with each affected person. Mild or moderate PKU are less severe forms and carry less of a risk for brain damage, however most patients with the disorder will need to follow a life-long restricted diet.

14. Medical Nutrition Therapy for PKU Treatment of PKU involves the immediate and lifelong avoidance of excess dietary phenylalanine. It was once thought that the diet could be discontinued in adolescence but today it is recommended the diet be followed for life. The diet provides supplemental tyrosine and small amounts of PHE for essential functions.

15. Maternal Phenylketonuria Women with PKU, who have elevated levels of phenylalanine during pregnancy, are at an increased risk of giving birth to offspring with intrauterine growth retardation, psychomotor retardation, microencephaly, and congenital heart defects. The best fetal outcomes are seen when strict control of blood phenylalanine 10 weeks before pregnancy and maintained throughout the entire pregnancy.

16. Tyrosinemias Tyrosinemia is a group of inherited inborn errors of metabolism characterized by disordered tyrosine metabolism. Tyrosine is used to synthesize protein and is a precursor for thyroxine, melanin, dopamine, norepinephrine, and epinephrine. Characterized by symptoms of acute liver failure, renal tubular dysfunction and coagulopathy, jaundice, vomiting, diarrhea, and hypoglycemia. A cabbagelike odor may be present possibly due to methionine metabolites.

17. Medical Nutrition Therapy for Tyrosinemias Restrict dietary phenylalanine and tyrosine to amounts that will maintain postprandial plasma amino acid concentration goals and support normal growth and development and good health.

18. Sulfur Containing Amino Acids and Disorders of Sulfur Containing Amino Acids Involves Methionine: an essential amino acid present in dietary proteins is metabolized via the transsulfuration pathway to homocysteine in the transsulfuration pathway, methionine is converted to S-adenosylmethionine, which is subsequently hydrolyzed to homocysteine

19. Methionine, cont : homocysteine can be remethylated to form methionine (via 2 different pathways), metabolized to cystathionine, and oxidized to homocystine. Oxidation to homocytine only happens when homocysteine accumulates to abnormal levels Most homocysteine is metabolized to cystathionine via cystathionine  -synthase (vitamin B6 dependent enzyme).

20. Homocystinuria The most common form of homocystinuria is caused by a lack of cystathionine  -synthase. Clinical Symptoms and Diagnosis of Homocystinuria Cystathionine  -synthase deficient homocystinuria is characterized by developmental delay/mental retardation, ectopia lentis (dislocation of the ocular lens) and/or severe myopia, skeletal abnormalities (excessive height and length of the limbs), osteoporosis, and thromboembolism.

21. Medical Nutrition Therapy for Homocystinuria Treatment includes: using vitamin B6 therapy protein-restricted and methionine- restricted diets betaine treatment folate and vitamin B12 supplementation

22. Urea Cycle Disorders Urea cycle disorders are caused by a deficiency of one the enzymes (carbamyl phosphate synthetase, n- acetylglutamate synthetase, ornithine transcarbamylase, argininosuccinic acid synthetase, argininosuccinate lyase, arginase) in the urea cycle. There are six enzyme disorders of the urea cycle, collectively known as inborn errors of urea synthesis, or urea cycle enzyme defects. Urea, formed to remove nitrogen as ammonia during protein metabolism, is excreted in the urine. In urea cycle disorders, ammonia accumulates causing hyperammonemia.

23. Clinical Symptoms and Diagnosis of Urea Cycle Disorders Symptoms, including irritability, poor feeding, vomiting, and lethargy, usually occur after the first 24 hours of life. If untreated, symptoms will progress to seizures, hypotonia, respiratory distress and alkalosis, coma, and death.

24. Medical Nutrition Therapy for Urea Cycle Disorders The primary objectives of medical nutrition therapy are to limit ammonia production and to maximize alternative pathways for removal of ammonia. Careful provision of dietary protein is needed to minimize ammonia production without adversely affecting growth and development. Optimization of calories from carbohydrate and fat are necessary to ensure that energy needs are met, since poor growth is often reported in patients who are prescribed lower protein diets.

25. Disorders of Carbohydrate Metabolism: Galactosemia Clinical Symptoms and Diagnosis of Galactosemia Vomiting, liver enlargement, and jaundice are often the earliest signs of the disease, but bacterial infections (often severe), irritability, failure to gain weight, and diarrhea may also occur

26. Medical Nutrition Therapy for Galactosemia Nutrition therapy is to provide a galactose-free diet by using galactose-free foods. Galactose is found mainly in milk and dairy products as part of lactose, but is also contained in galactoproteins and galactolipids in others foods (meat, dairy, cereals, peas, lentils, some legumes, organ meats, cereals, and some fruits and vegetables).

27. Disorders of Carbohydrate Metabolism: Fructose Intolerance Fructose intolerance, also called fructosemia, hereditary fructose intolerance (HFI), and fructose aldolase B-deficiency, is caused by the lack of the enzyme fructose-1-phosphate aldolase (aldolase B). Consumption of fructose, sucrose, or sorbitol leads to severe symptoms of vomiting, poor feeding, irritability, jaundice, profound hypoglycemia, enlarged spleen and liver, and progressive liver damage

28. Medical Nutrition Therapy for Fructose Intolerance Medical nutrition therapy includes removal of fructose, sorbitol, and sucrose from the diet (less than 40 mg/kg per day) and results in complete alleviation of most symptoms and a normal life span.

29. Failure to Thrive The American Academy of Pediatrics (AAP) utilizes two criteria for diagnosing failure to thrive (FTT). First of these is when weight (or weight- for-height) falls less than two standard deviations below the mean (z-score less than –2.0) for sex- and age-matched.

30. Failure to Thrive, cont. The second relates to weight-for-age having declined across more than two major percentile lines after having achieved a previously stable growth pattern. The three factors that lead to energy imbalance in the FTT population are inadequate energy intake, inefficient energy utilization, and increased energy expenditure.

31. Organic and Non-organic Failure to Thrive Organic FTT (OFTT) is lack of growth associated with an identifiable disease or disorder. Almost all chronic illnesses in childhood can result in poor weight gain related to any of the factors. Non-organic FTT (NOFTT) is present in the majority of all diagnosed cases of FTT. Children have non-organic failure to thrive when their lack of growth cannot be attributed to an identifiable disease. The cause of NOFTT is psychosocial in origin.

32. Nutritional Interventions Breastfed infant: add infant formula powder or other modular kilocalorie supplements to pumped breast Formula fed infant: concentrate the formula to a higher caloric density. This can be done by concentration up to 24 kcals/oz and by modular kilocalorie supplements as needed up to 30 kcals/oz. For the child who is taking additional solid foods, adding kilocalories to food without adding volume becomes imperative to maximize their intake.