Transcript Genetics and Inborn Errors of Metabolism and Failure to Thrive

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
Chapter 5 Special Section:
Neonatal Intensive Care Nutrition:
Prematurity and Complications
Liesje Nieman, RD, CNSD, LDN
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.
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
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.
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.
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.
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.
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.
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.
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.
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
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.
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.
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.
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.
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.
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
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).
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.
Medical Nutrition Therapy for
Homocystinuria
Treatment includes:
• using vitamin B6 therapy
• protein-restricted and methioninerestricted diets
• betaine treatment
• folate and vitamin B12 supplementation
Urea Cycle Disorders
• Urea cycle disorders are caused by a deficiency of one
the enzymes (carbamyl phosphate synthetase, nacetylglutamate 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.
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.
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.
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
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).
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
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.
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 weightfor-height) falls less than two standard
deviations below the mean (z-score less
than –2.0) for sex- and age-matched.
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.
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.
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.