MODULE 2: In Born Errors of Metabolism Flashcards
A public health program for the early identification of disorders (inborn errors of metabolism) that can lead to mental retardation and death
Newborn Screening
Newborn Screening is an integral part ;
a. routine newborn care
b. BCG
c. Vitamin K injjction
When is Newborn Screening ideally done
after 24 hours to maximum of 48 hours
When is the best time to treat
Critical time of age beyond which if no appropriate treatment is given, signs and symptoms are irreversible
How newborn screening began?
It was first used for the detection of Phenylketonuria
by Dr. Robert Guthrie (1960) in the US
Newborn Screening is guided by the law
RA 9288
RA 9288 Newborn Screening Act of 2004 was enacted
April 7, 2004
Signing of the Implementing Rules and
Regulation of RA 9288
October 5, 2004
Highlights of Newborn Screening Act of 2004
a. Institutionalization of a National Newborn Screening
System
b. Obligation of health workers and professionals to
inform parents about newborn screening and
include such act in the parents record
c. Sample collection may be performed by TRAINED
physicians, medical technologists, nurses and
midwives
d. Monitoring and follow-up of confirmed patients shall
be done regularly for life
e. NS is part of the licensing and accreditation of DOH
f. NBS is a requirement for PHIC accreditation
g. NS is part of the PHIC Newborn Care Package
Disorders tested in ENBS
a. Endocrine disorders
b. Amino Acid disorders
c. Fatty Acid Oxidation disorders
d. Organic Acid disorders
e. Urea Cycle defects
f. Hemoglobinopathies (HGB)
g. Others (G6PD deficiency, Galactosemia, Cystic Fibrosis, and
Biotinidase Deficiency)
The NBS Panel of Disorders
a. local prevalence
b. reversible if treated on time
c. treatment is available
Importance of Newborn Screening
a. One will never know that the baby has the disorder
until the onset of signs and symptoms
b. May already be irreversible such as mental retardation and death
Newborn Screening Fee under what law
AO # 2008 - 0026
Fines of Newborn Screening Fee
a. 1st offense: warning
b. 2nd offense: 50,000 fine
c. 3rd offense: 100,00 fine
Congenital Hypothyroidism: Effect if not screened
Severe growth and mental retardation
Congenital Hypothyroidism: Effect if screened and treated
Normal
Congenital adrenal hyperplasia: Effect if not screened
death
Congenital adrenal hyperplasia: Effect is screened and treated
alive and normal
Galactosemia: Effect is not screened
death or cataracts
Galactosemia: Effect if screened and treated
alive and normal
G6PD Deficiency: Effect if not screened
severe anemia kernicterus
G6PD Deficiency: Effect is screened and treated
normal
Phenylketonuria: Effect if not screened
severe and mental retardation
Phenylketonuria: Effect if screened and treated
normal
Maple Syrup Urine Disease: Effect if not screened
death
Maple Syrup Disease: Effect if screened and treated
alive and normal
Organic Acid Disorders: without NBS and Treatment
a. development delay
b. breathing problems
c. neurologic damage
d. seizures
e. coma
f. early death
Organic Acid Disorders: with NBS and treatment
a. alive
b. most will have normal development with episodes of metabolic crisis
Fatty Acid Oxidation Disorder: with NBS and treatment
a. usually healthy in between episodes of metabolic crises
b. alive
Fatty Acid Oxidation Disorder: without NBS and treatment
a. developmental and physical delays
b. neurologic impairment
c. sudden death
d. coma
e. seizure
f. enlargement of the heart & liver
g. muscle weakness
Hemoglobinopathies: without NBS and treatment
a. painful crises
b. anemia
c. stroke
d. multi organ failure
e. death
Hemoglobinopathies: with NBS and treatment
a. alive
b. reduces the frequency of painful crises
c. may reduce the need for blood transfusions
Amino Acid disorders: with NBS and treatment
a. alive
b. normal growth
c. normal intelligence for some
Amino Acid Disorders: without NBS and treatment
a. mental retardation
b. coma and death from metabolic crisis
Best time to treat for CH
<2 weeks
Best time to treat for CAH
7 days
Best time to treat for PKU
2 weeks
Best time to treat for GAL
7 days
Best time to treat for MSUD
Before 5 days
Best time to treat for G6PD deficiency
Avoid trigger agents of hemolysis
Refer to the sequence of
enzyme catalyzed reactions that lead to the
conversion of a substance into a final product
Metabolic pathways
Inherited diseases caused by interruptions in
the various pathways involved in the metabolism of
proteins, carbohydrates, and lipids
IEMS
IEMS characteristics
Most IEMs produce no symptoms during the first
24 hours of life
What substrate need to product byproduct
enzyme
Diagnosis of IEM’S is challenging
a. the episodic nature of metabolic illness
b. The wide range of clinical symptoms that are
associated with more common conditions like
infection or sepsis
c. The low incidence of these disorders
d. The consequent lack of experience among the
pediatric subspecialties
e. The need for specialty testing
How do we screen for IEM’s
a. Expanded newborn screening uses a new
technology called tandem mass spectrometry
b. Only a few drops of the baby’s blood are needed to
do this expanded newborn screening test
c. MS/MS works by separating and measuring
substances according to their weight
Why Early detection of IEM’s is important
a. Affected babies are identified quickly before
symptoms appear
b. Cases of disease are not missed
c. Number of false-positive results is minimized
d. Early treatment can begin, that prevents the
negative and irreversible health outcomes for
affected newborns
e. Most treatments are inexpensive and may involve
the addition of vitamin to the diet, hormone
supplementation, avoidance of certain foods and
chemicals and dietary change
Condition in which an individual does not produce enough thyroid hormone
Congenital Hypothyroidism
Butterfly shaped organ on the base of the neck
Thyroid gland
Causes of Permanent CH
a. Defective development of thyroid gland
b. Enzymatic defect in thyroxine synthesis
c. Pituitary dysfunction (rare)
Causes of Transient CH
a. maternal intake of anti-thyroid medication, or excess iodine
Thyroid Hormones
a. t3 tri-iodothyronine
b. t4 thyroxine
Which releases TRH
hypothalamus
Which releases TSH
Pituitary Gland
Clinical Manifestations
a. hypotonia
b. prolonged jaundice
c. inactive defecation
d. umbilical hernia
e. pallor, coldness, hypothermia
f. edema, rough facial structures
g. enlarged tongue
h. rough, dry skin
i. open posterior fontanelles
j. delayed overall development
Late Manifestations
a. mental retardation
b. growth retardation
c. delayed skeletal maturation
d. delayed dental development and tooth eruption
e. delayed puberty (no menstrual period)
Additional Test on diagnostic evaluation for Congenital Hypothyroidism
a. T4, T3 resin uptake - decreased
b. Free T4 - decreased
c. Thyroid hormone globulin
d. Thyroid scan
Diagnostic Evaluation for Congenital Hypothyroidism
a. newborn screening
b. initial filter-paper blood spot thyroxine (T4) measurement
c. TSH measurement (if low T4 levels)
Treatment of Congenital Hypothyroidism
Thyroid Hormone Replacement
Management of Congenital Hypothyroidism
a. Thyroid Replacement (before 2 weeks old)
b. Tablets must be crushed and added to food or small amount of formula or breast milk
c. Do not give soy based formulas and iron supplements
Thyroid Replacement (before 2 weeks old) includes oral administration of synthetic thyroid hormone;
a. sodium levothyroxine
b. L-thyroxine
c. synthroid
d. levothyroid
Nursing Management of Congenital Hypothyroidism
a. Nurses should ensure that screening is performed
b. Explain to the parents that the disorder necessitates
lifelong treatment
c. Stress the importance of compliance with the drug
regimen for the child to achieve normal G & D
d. Teach client drug overdosage
Client Overdosage
a. rapid pulse
b. dyspnea
c. irritability
d. insomnia
e. fever
f. sweating
g. weight loss
An endocrine of the adrenal gland that causes
severe salt loss, dehydration and abnormally high
levels of male sex hormones in both boys and girls
Congenital Adrenal Hyperplasia
Enzyme is missing or not working properly in Congenital Adrenal Hyperplasia
21-hydroxylase (21-OH)
Parts of Adrenal Gland
a. adrenal medulla
b. adrenal cortex
Inheritance of Congenital Adrenal Hyperplasia
Autosomal recessive trait
What Adrenal Medulla secretes
a. epinephrine
b. norepinephrine
c. somatostatin nd substance P by peptides
What Adrenal Cortex secrete
a. Cortisol and Cortisone by glucocorticoid
b. Aldosterone and Corticosterone by mineralocorticoids
c. Estrogen and Testosterone by Androgen
Hormone for maintenance of normal blood sugar
Cortisol
Hormone for maintenance of normal serum sodium
Aldosterone
Hormone for male sexual differentiation
Androgen (testosterone)
What causes a release of Cortisol Releasing Hormone form Hypothalamus
Stress
Who secretes ACTH from CRH
Anterior Pituitary Gland
Cortisol released from Adrenal Cortex would lead to
a. increased blood glucose
b. increased blood amino acids
c. increased blood fatty acids
Where is renin secreted
Juxtaglomerular apparatus in kidney
Who secretes angiotensin
Liver
Who secretes ACE
Lungs
Renin secretion would lead to
Aldosterone secretion to increase blood pressure
Absence of 21-OH enzyme would lead to
a. decreased cortisol and aldosterone
Is a protein that serves as a precursor in the synthesis of cortisol, and its elevated levels are commonly used to diagnose congenital adrenal hyperplasia (CAH)
17-OHP (17-hydroxyprogesterone)
An enzyme that converts 17-hydroxyprogesterone and a deficiency of it impairs the production of cortisol and aldosterone
21-hydroxylase
Deficiency of 21-hydroxylase leads to a compensatory increase in adrenocorticotropic hormone (ACTH), which stimulates the adrenal glands to produce more precursors like 17-hydroxyprogesterone (17-OHP). As a result, 17-OHP levels become elevated because it is a precursor in the cortisol synthesis pathway. Since cortisol production is impaired, the excess 17-OHP is shunted toward androgen production, causing
increased androgen levels
In complete 21-hydroxylase deficiency this leads to
a. loss of sodium and chloride
b. elevated potassium
Used to check for ambiguous genitalia
Ultrasonography
Main features of CAH
a. cortisol deficiency
b. aldosterone deficiency
c. testosterone excess
Aldosterone deficiency would lead to
a. low serum sodium
b. high serum potassium
Low level of cortisol and aldosterone stimulates what
Anterior Pituitary gland
Stimulated adrenal gland hyperplasia would lead to
a. increases release of aldosterone, cortisol & androgens
Too much androgen would lead to
a. Girls develop masculine characteristics
b. Boys develop masculine characteristics too rapidly
Clinical Manifestations of Congenital Adrenal Hyperplasia
a. Salt-losing (salt wasting) form of CAH - low cortisol, low aldosterone, no salt retention and fluid retention
b. immediately after birth - vomiting, diarrhea, anorexia, weight loss, extreme dehydration
If symptoms of clinical manifestations remain untreated, it would lead to
a. extreme loss of salt & fluid can lead to shock & death as early as 48-72 hours
Late Manifestations of Congenital Adrenal Hyperplasia
a. precocious puberty
b. pubic hair growth
c. oily skin
d. body odor
e. dark skin color
Precocious puberty
a. early sexual maturity and bone maturation
b. accelerated growth during childhood
c. short adult stature
Hormone Replacement
a. hydrocortisone - pill, synthetic hormone
will be given throughout newborn’s life to
prevent CAH effects
b. Recommended oral dosage is divided to
stimulate the normal diurnal pattern of ACTH secretion
Diagnostic Evaluation of Congenital Adrenal Hyperplasia
a. Congenital abnormalities - difficulty in assigning sex to newborn
b. 17-OHP – increased serum 17-ketosteroid levels -
definitive diagnosis
c. In 21 complete hydroxylase deficiency ; loss of sodium and chloride
elevated potassium
d. ultrasonography - ambiguous genitalia
Lifelong treatment of deficient cortisol
a. hydrocortisone
b. prednisone
Management of Congenital Adrenal Hyperplasia
a. hormone replacement
b. lifelong treatment of deficient cortisol
c. aldosterone
d. reconstructive surgery
Aldosterone
a. Fludrocortisone
Reconstructive Surgery
a. reduce the size of clitoris
b. separate the labia
c. create vaginal orifice
Nursing management
a. Nurse should recognize ambiguous genitalia in
newborn
b. Explain to the parents about child’s condition
c. Refer the infant as “child” or “baby” rather than “he”
or “she”
d. Refer to the external genitalia as sex organs
(penis/clitoris and scrotum/labia)
e. Teach parents signs of dehydration and its
treatment
f. Teach parents how to prepare and administer
hydrocortisone IM
g. Refer parents for genetic counseling
Enzyme that is deficient for a child having Galactosemia
Galactose 1 - Phosphate Uridyltransferase
Metabolic disorder characterized by the body’s
inability to use galactose as a source of energy
Galactosemia
A disorder of carbohydrate metabolism
characterized by abnormal amounts of galactose in
the blood
Galactosemia
what is being converted to glucose through the action of the hepatic enzyme galactose-1-phosphate uridyltransferase, which facilitates its entry into glycolysis or glycogenesis pathways.
Galactose 1 -phosphate
Inheritance of Galactosemia
Autosomal recessive trait
Enzyme that converts galactose to glucose
Galactose 1 - Phosphate Uridyltransferase
Excessive Galactose 1 -phosphate leads to
a. cognitive delay
b. jaundice
c. hepatomegaly
d. cirrhosis
e. cataracts
Buildup of galactose in blood would lead to
a. jaundice
b. cataract
c. brain damage
d. kidney problems
e. death
Diagnostic Evaluation of Galactosemia
a. history taking
b. physical exam
c. galactosuria
d. increased levels of galactose in the blood
e. decreased levels of uridine diphosphate (UDP)
Physical Exam
a. malnutrition
b. dehydration
c. decreased muscle mass and body fat
Clinical Manifestations of Galactosemia
a. normal at birth
b. develop symptoms a few days to 2 weeks after initiation of milk feedings
Develop symptoms a few days to 2 weeks after initiation of milk feedings
a. poor feeding
b. vomiting, and occasionally diarrhea
c. jaundice
d. lethargy, weakness, coma
Can cause hemolytic anemia usually after exposure
to certain medications, food, or even infections
Glucose 6 Phosphate Dehydrogenase Deficiency
An inherited condition in which the body lacks the
enzyme glucose-6-phosphate dehydrogenase
which helps RBCs function normally
Glucose 6 Phosphate Dehydrogenase Deficiency
Inheritance of Glucose 6 Phosphate Dehydrogenase Deficiency
X-linked recessive trait
Trivias about G6Pd deficiency
a. An estimated 400 MILLION people worldwide have
g6pd deficiency
b. Occurs most frequently in certain parts of Africa,
Asia, Mediterranea, and Middle East
A molecule with proteins and iron where oxygen binds
Hemoglobin
Has iron
Heme
Functions of G6PD
a. Enzyme needed for the protection of RBC from
oxidative substances
b. G6PDC gene is located near the telomeric region of
the long arm of the X chromosome (Xq28)
Energy pathway that supplies energy to cells and RBC that are deficient in G6PD enzyme are
susceptible to rupture (haemolysis) when subjected
to oxidative stress
Pentose Phosphate Pathway
G6PD deficiency
Kids with G6PD deficiency typically do not show any
symptoms of the disorder until their RBC are exposed to
certain triggers
Certain triggers
a. Illness, such as bacterial and viral infections
b. Certain painkillers and fever-reducing drugs like
Aspirin
c. Certain antibiotics – esp. Those that have “sulf” in
their names like Sulfamethoxazole-bactrim
d. Certain antimalarial drugs – those that have “quine” and “xacin” in their names like Chloroquine
e. SOYA foods – taho, tokwa, soy sauce
f. Red wine
g. Legumes – munggo, garbanzos, abitsuelas
h. Vitamin K
i. Naphthalene (moth balls)
j. FAVA beans
k. Blueberries
When RBC’s are destroyed it would lead to
Hemolytic Anemia
Hemolytic Anemia would lead to
a. pallor
b. dizziness
c. headache
d. difficulty of breathing
e. palpitations
f. tea-colored urine
Destroyed RBC is broken down by
Liver
Accumulation of excess bilirubin would lead to
a. jaundice in skin
b. MR or death in brain
Liver produces what byproduct
Bilirubin
Tea colored urine is caused by
due to the excessive breakdown of bilirubin
Clinical Manifestations of G6PD deficiency
a. Dark urine
b. Fever
c. Pain in abdomen
d. Enlarged spleen and liver
e. Fatigue
f. Pallor
g. Rapid heart rate
h. Shortness of breath
i. Jaundice
Diagnostic Tests used for G6PD deficiency
a. Check G6PD levels
b. Bilirubin levels
c. CBC (Hgb)
d. Check presence of Hgb in urine
e. Haptoglobin level
f. LDH test
g. Methemoglobin reduction test
h. Reticulocyte count
Management of G6PD deficiency
a. Limit exposure to triggering factors of its symptoms
b. Give folic acid
c. Photheraphy
d. Blood transfusion
Folic acid is give to
Prevent hemolysis and support production of RBC
Drugs with definite risk of hemolysis in most G6PD deficient individuals
a. Dapsone and other sulfones
b. Methylthioninium chloride
c. Niridazole
d. Nitrofurantoin
e. Pamaquine
f. Primaquine
g. Quinolones
h. Rasburicase
i. Sulfonamides
Dapsone and other sulfones
higher doses for dermatitis herpetiformis more likely to cause problems
Quinolones
a. ciprofloxacin
b. moxifloxacin
c. nalidixic acid
d. norfloxacin
e. ofloxacin
Drugs with possible risk of hemolysis in most G6PD deficient individuals
a. Aspirin
b. Chloroquine
c. Menadione, water, soluble derivatives –
menadiol sodium phosphate
d. Quinidine
e. Quinine
f. Sulfonylureas
g. Naphthalene
Molecules that combine to form proteins
Amino Acids
Amino Acid Disorders
a. Phenylketonuria
b. Maple Syrup Urine Disease
Building blocks of
life
Amino Acids and Proteins
Build muscles, cause chemical reactions in the
body, transport nutrients, prevent illness, and carry
out other functions
Amino Acids
Essential Amino Acids
a. 9 Amino Acids
b. Cannot be produced by the body
c. Can only be get from food
Functions of Amino Acids
a. To build and repair the body
b. To regulate and maintain the body
c. To give energy to the body
Non Essential Amino Acids
a. 11
b. Can be produced by the body
Deficiencies of Amino Acids lead to;
a. Decreased immunity
b. Digestive problems
c. Depression
d. Fertility issues
e. Lower mental alertness
f. Slowed growth in children
An absence of the enzyme,
phenylalanine hydroxylase (PAH) needed to
metabolize the essential amino acid phenylalanine which leads to excessive accumulation of phenylalanine is
neurotoxic in the body that causes brain damage
Phenylketonuria
Absence of the enzyme Phenylalanine Hydroxylase leads to
Decreased Tyrosine
What chromosome number is affected in Phenylketonuria
Chromosome 12
Inheritance of Phenylketonuria
Autosomal Recessive
Decreased tyrosine leads to
a. decreased tryptophan
b. decreased levels of serotonin
c. decreased dopa
d. decreased plasma levels of catecholamines
e. decreased melanin
f. fair skin, blue eyes, blond hair
The first effects of phenylketonuria are usually seen around
6 months of age
Untreated infants with phenylketonuria may be
a. late in learning, to sit, crawl, stand
Absence of phenylalanine hydroxylase would lead to
accumulation in the blood and body tissues
Cognitive perception of infants with phenylketonuria
Pay less attention to things around them
Without treatment a child with phenylketonuria will become
Mentally retarded
Excess phenylketonuria would lead to
Preventing normal brain development and result in mental retardation
Diagnostic test used for Phenylketonuria
Guthrie bacterial inhibition assay
Guthrie bacterial inhibition assay
a. check phenylalanine levels in the blood
b. presence of bacillus subtilis
c. normal range (newborn): 0.5-1.0 mg/dl
d. normal value: 1.6 mg/dl
Presence of bacillus subtilis indicates
excessive amounts of phenylalanine
Management of phenylketonuria
a. protein diet restriction for their entire life
b. Frequent monitoring of phenylalanine and
tyrosine levels
Protein diet restriction for their entire life
Should start as soon as possible but not
later than 7–10 days
Nursing Management for Phenylketonuria
a. Teach the family about dietary restrictions
b. Foods low in phenylalanine levels
c. Encourage prenatal testing or genetic counseling
for future pregnancies
Foods low in phenylalanine levels
a. Some vegetables – exp. Legumes
b. Fruits
c. Juices
d. Cereals
e. Breads
f. Starches
Rare genetic metabolic disorder wherein the body can’t break down branched amino acids
Maple Syrup Urine Disease
For future pregnancies
Encourage prenatal testing or genetic counseling
Inability to break down branched amino acids leads to
Buildup of amino acids and toxic metabolic
byproducts
The condition gets its name from
distinctive
sweet odor of affected infants’ urine
This amino acid has characteristic sweet smell which gives the disorder its name
Isoleucine
What enzyme is absent in Maple Syrup Urine Disease
Branched-chain ketoacid dehydrogenase (BCKAD)
What kind of disorder is Maple Syrup Urine Disease
Amino Acid Disorder
Branched-chain amino acids
a. leucine
b. isoleucine
c. valine
What chromosome disrupts BCKAD
Chromosome 19q13
Leucine is converted to 2-ketoisocaproate by
branched chain amino acid aminotransferase
Isoleucine is converted to 2-keto-3methylvalerate by
branched chain amino acid aminotransferase
Valine is converted to 2-ketoisovalerate by
branched chain amino acid aminotransferase
2-ketoisocaproate would be converted into
Acetoacetate and Acetyl-CoA
2-ketoisocaproate, 2-keto-3-methylvalerate, 2-ketoisovalerate would not move forward when their is absence of
Branched chain amino acid dehydrogenase
2-keto-3-methylvalerate would be converted to
Acetyl Coa and Propionyl-CoA
2-ketoisovalerate would be converted into
Propionyl-CoA
Absence of branched chain Amino Acids would lead to
Buildup
If MSUD is not treated, it is life threatening
a. Episodes where muscles tone alternates between
being rigid and floppy
b. Swelling of the brain
c. Seizures
d. High levels of acidic substances in the blood, called
metabolic acidosis
e. Coma, sometimes leading to death
Common in the Philippines
Classic MUD
Classic MUD first symptoms about 3-5 days
a. Poor appetite / feeding
b. Irritability / high pitch
c. Incessant crying
d. Characteristic odor of cerumen and urine
After a few days, they
a. Become limp with episodes of rigidity
b. Have seizures
c. Lose their sucking reflex
d. Have increased sleeping time
e. Become comatose
Diagnosis of MSUD
a. Plasma amino acid test
b. Urine organic acid test
c. Genetic testing
Treatment of MSUD
a. Medical Formula
b. Diet low in branched-chain amino acids
c. Supplements
d. Tracking BCAA levels
e. Liver transplant
f. Low protein – must be carefully measured
g. High protein – must be avoided !!
No enzyme for the substrate would lead to
Deficiency of the existing byproduct before
No enzyme for the substrate would lead to
Buildup and toxicity
Often the first consideration in infants
who present with lethargy and poor feeding
Sepsis
These
symptoms in a full term infant with no specific risk factors
strongly suggest a metabolic disorder
lethargy and poor feeding
Infants with _ may become debilitate and septic rather
quickly, and it is therefore important that the presence of
sepsis not exclude consideration of other possibilities.
Inborn errors of metabolism
Life-threatening condition caused by the inability to process certain nutrients or toxins, leading to metabolic instability
Metabolic Crisis
Signs and symptoms of Metabolic Crisis
a. Extreme sleepiness
b. Sluggishness
c. Irritable mood
d. Vomiting
If not treated, other symptoms follow
a. Muscle rigidity
b. Swelling of the brain
c. Seizures
d. High levels of acidic substances in the blood
e. Coma, sometimes leading to death
Increased enzyme activity would lead to
Increase disposal of toxic metabolites
To prevent accumulation and metabolic crisis
Decrease substrate availability
To improve metabolic flow
Increase enzyme activity
Enhancing the clearance or breakdown of toxic byproducts to prevent harmful effects
Increase disposal of toxic metabolites
