DEPARTMENT OF MEDICAL TECHNOLOGY

FAR EASTERN UNIVERSITY

CONGENITAL METABOLIC DISORDERS (WEEK 13 to 14)

The Embryo Develops

• Organogenesis is the transformation of the simple three germ layers into distinct organs
• Development of organs (8th week to birth)
• 3 GERM LAYERS formed from Gastrulation
• ECTODERM: outermost layer
• MESODERM: middle layer
• ENDODERM: innermost layer
• During week 3, a band called the primitive streak appears along the back of the embryo
• Followed by the connective tissue progenitor cells, notochord, neural tube, heart,
central nervous system, arms, legs and other organ rudiments
• By week 8, all the organs that will be present in the newborn have begun to develop

• First 2 weeks after conception: GERMINAL STAGE

• 3rd Week to 8th Week: EMBRYONIC PERIOD
• 9th Week to 37th Week: FETAL PERIOD
• FIRST MONTH ( 4 WEEKS) AFTER BIRTH: NEONATAL PERIOD

The Fetus Grows

• During the fetal period, body proportions approach those of a newborn
• Bone replaces softer cartilage
• Nerve and muscle functions become coordinated
• Sex organs become more distinct by week 6
• By week 12, sucks thumb, kicks, makes fists and faces, and has the beginnings of teeth
(UNDER THE GUMS)
• Fingernails and toenails begin to develop and the external ears are also formed
• Vocal cords will be formed by 18 weeks.
• By the end of the second trimester, the woman feels distinct kicks and jabs and may
detect fetal hiccup.
• In the final trimester, fetal brain cells link into networks as organs elaborate and grow,
and fat fills out the skin.
• The digestive and respiratory systems mature last.

WEEK 16
• 2ND TRIMESTER
• Muscle tissue and bone continue to form
• Skin begins to form
• Meconium develops in the baby's intestinal tract
o MECONIUM: baby's first bowel movement.
• sucking motions (sucking reflex)
• length : 4 to 5 inches
• weighs : 3 ounces.

CYTOGENETICS CP TOLENADA/ ctolenada@feu.edu.ph

DEPARTMENT OF MEDICAL TECHNOLOGY
FAR EASTERN UNIVERSITY
Birth Defects
• Minor or severe
• Time when genetic abnormalities, toxic substances, or viruses can alter a specific
structure is critical period
• Most birth defects develop during the embryonic period
• More severe than those that arise during the fetal period
• Some defects can be attributed to an abnormal gene

Newborn Screening
A procedure to detect if a newborn has congenital metabolic disorders that may lead to
mental retardation or death
Part of “Unang Yakap”: Early Essential Newborn care Protocol

Why newborn screening is important?

• Most newborns with metabolic disorders look normal at birth
• Reversed or treated
• Prevent Mental retardation or death

Procedure:
• Testing is done on the 24 to 48 hours after birth.
• heel prick method
• Blood drops on NBS kit
• Air dry for 4 hours
• Send to testing facility
• Blood Collector: Doctor, Nurse, Midwife, Medical technologist

CYTOGENETICS CP TOLENADA/ ctolenada@feu.edu.ph

DEPARTMENT OF MEDICAL TECHNOLOGY
FAR EASTERN UNIVERSITY

Newborn Screening Disorders

Basic (6 disorders)
1. Congenital hypothyroidism (CH)
2. Congenital adrenal hyperplasia (CAH)
3. Phenylketonuria (PKU)
4. Galactosemia (GAL)
5. Glucose 6 phosphate deficiency (G6PD)
6. Maple syrup urine disease (MSUD): added in 2012

EXPANDED NEWBORNS (28 disorders): Current 6 disorders plus 22 more disorders such as
hemoglobinopathies and additional metabolic disorders, namely, organic acid, fatty acid
oxidation, and amino acid disorders.

Prevalence of Disorders as of December 2017

Disorders Screened Confirmed Prevalence

CH 10,415,695 3,979 1:2,618

CAH 10,415,695 576 1:18,083

PKU 10,415,695 84 1:123,996

GAL 10,415,695 128 1:81,373

MSUD 7,031,276 96 1:73,242

G6PD Def 10,208,668 176,510 1:58

Fatty Acid Disorders 402,841 15 1:26,856

Organic Acid Disorders 402,841 10 1:40,284

Hemoglobinopathies

HbH Disease/Alpha Thalassemia 402,841 272 1:1,481

Hemoglobin E Disease or Interacting

402,841 20 1:20,142
Hb E/Beta Thalassemia

Beta Thalassemia 402,841 3 1:134,280

Hemoglobin D Disease 402,841 1 1:402,841

CYTOGENETICS CP TOLENADA/ ctolenada@feu.edu.ph

DEPARTMENT OF MEDICAL TECHNOLOGY
FAR EASTERN UNIVERSITY

Prevalence of Disorders as of December 2018

Disorder Appearance at birth Onset

CH Normal 4 weeks

Hyperpigmentation; Ambiguous genitalia

CAH 7-14 days
in female infants

PKU Normal 3 weeks

GAL Normal 2 weeks

MSUD Normal 7-10 days

G6PD On exposure to specific

Normal
DEF agents causing hemolysis

CYTOGENETICS CP TOLENADA/ ctolenada@feu.edu.ph

DEPARTMENT OF MEDICAL TECHNOLOGY
FAR EASTERN UNIVERSITY
CONGENITAL HYPOTHYROIDISM

Thyroid Gland: butterfly shaped organ that produces thyroid hormones

• makes iodine-containing hormones
FUNCTIONS
Normal brain development
Development of muscles and bones
Regulation of body temperature
Maintain heart rate
- Free thyroid hormone (FT4): determines whether the thyroid is performing properly

Congenital Hypothyroidism
• 1 in 2,000 to 4,000 newborns
• Autosomal recessive
• 15 to 20 % of cases
• Most common – shortage of iodine in the diet of the mother during pregnancy

2 TYPES OF CH
• Thyroid dysgenesis: thyroid gland fails to develop or function properly
2 Genes involved
• Paired box gene 8 (PAX8) in chromosome 15
• Thyroid stimulating hormone receptor (TSHR) in chromosome 14
• Thyroid dyshormonogenesis
• Dual oxidase 2 (DUOX2) – 15
• Solute Carrier Family 5 Member (SLC5A5) – 19
• Thyroglobulin (TG) – 8
• thyroid peroxidase (TPO) – 2
MANIFESTATION
• Early manifestations
• Prolonged jaundice
• Inactive defecation
• Umbilical Hernia
• Hypotonia
• Skin: rough and dry
• Delayed overall development
• Late manifestations:
• Mental retardation
• Growth retardation
• Delayed skeletal maturation
• Delayed dental development and tooth eruption
• Delayed puberty
Treatment
L-thyroxine tablet: provides more thyroid hormone

CYTOGENETICS CP TOLENADA/ ctolenada@feu.edu.ph

DEPARTMENT OF MEDICAL TECHNOLOGY
FAR EASTERN UNIVERSITY
CONGENITAL ADRENAL HYPERPLASIA

Adrenal Gland: located on top of the kidneys

Hormones produced in Adrenal Gland
1. Epinephrine or adrenalin: for vigorous physical activities
2. Cortisol: maintains blood sugar levels, protects the body from stress, and suppress
inflammation
3. Aldosterone (salt-retaining hormone): regulates the amount of salt retained by the
kidneys.

CONGENITAL ADRENAL HYPERPLASIA

• Autosomal recessive
• 21-hydroxylase deficiency : produce excess androgens (MALE SEX HORMONES)
• Mutations in the Cytochrome P450 Family 21 Subfamily A Member 2 (CYP21A2 gene)
found in Chromosome 6 within the human leukocyte antigen histocompatibility (HLA)
complex.
• CYP21A2 gene: provides instructions for making an enzyme called 21-hydroxylase

3 types of 21-hydroxylase deficiency

• Classic form: 1 in 15,000 newborns
1. Salt-wasting: Most severe
CYP21A2 mutations that result in a completely non-functional enzyme
2. Simple virilizing
CYP21A2 gene mutations that allow the production of low levels of
functional enzyme
3. Non-classic / late onset: 1 in 1,000 individuals
CYP21A2 mutations that result in the production of reduced amounts of
the enzyme
More enzyme produced compared to the other types

Manifestations
• Increased pigmentation
• Ambiguous genitalia in female infants
• Poor suck, weak cry
• Vomiting, excessive urination, dehydration
• Irritability and seizures
• Failure to thrive
• Hypotension, shock
• Coma
• Late Manifestations
• Precocious puberty: child's body begins changing into that of an adult
(puberty) too soon
• “Skin Puberty”: pubic hair growth, oily skin, “body odor"
• Dark skin color
• Short adult stature

CYTOGENETICS CP TOLENADA/ ctolenada@feu.edu.ph

DEPARTMENT OF MEDICAL TECHNOLOGY
FAR EASTERN UNIVERSITY

• Treatment
• Hormone replacement
• Surgery

PHENYLKETONURIA

1 in 10,000 to 15,000 newborns

Autosomal recessive
Mutation in phenylalanine hydroxylase (PAH) gene – chromosome 12
missing or lack of phenylalanine hydroxylase
Phenylalanine – neurotoxic
The first effects are usually seen around 6 months of age
Delayed development
Will lead to mental retardation

MANIFESTATION
Vomiting
Hyperactivity
Seizures and hypertonia
Musty or mousy urine odor
Light hair and skin color
Seborrheic or eczematoid rash
Mental retardation

TREATMENT
Complete avoidance of food containing high amounts of phenylalanine
Calculated intake of low protein/phenylalanine natural food
Sufficient intake of fats and carbohydrates

CYTOGENETICS CP TOLENADA/ ctolenada@feu.edu.ph

DEPARTMENT OF MEDICAL TECHNOLOGY
FAR EASTERN UNIVERSITY
GALACTOSEMIA

• disorder that affects how the body processes Galactose

• Component of dietary sugars
• Converted to GLUCOSE for energy storage (glycogen) and energy production
• autosomal recessive
• MUTATIONS IN
1. Galactose-1-phosphate uridyltransferase (GALT)
Chromosome 9
Classic Galactosemia
Type I Galactosemia
2. Galactokinase 1 (GALK1)
Chromosome 17
Type II Galactosemia
3. UDP-Galactose-4-epimerase (GALE)
Chromosome 1
Type III
3 TYPES
Type I
• Classic galactosemia
• Most common
• Most severe
• 1 in 30,000 to 60,000 newborns
Type II
• Galactokinase deficiency
• 1 in 100,000
Type III
• Galactose epimerase deficiency
• Very rare
• Symptoms vary from mild to severe

CYTOGENETICS CP TOLENADA/ ctolenada@feu.edu.ph

DEPARTMENT OF MEDICAL TECHNOLOGY
FAR EASTERN UNIVERSITY

MANIFESTATION
Develop a few days to two weeks after initiation of milk feedings
Poor suck
Vomiting, occasionally diarrhea
Jaundice
Lethargy, weakness, coma
Septicemia (E. coli)
Late due to galactose deposits in tissues
Liver: hepatomegaly, edema, ascites, cirrhosis
Lens: cataracts
Brain: mental retardation
Kidney
Growth failure

TREATMENT: eliminate lactose and galactose from diet

Glucose-6-phosphate dehydrogenase deficiency

Glucose-6-phosphate dehydrogenase
- protect red blood cells from damage and premature destruction
- prevent Hemolysis (destruction of red blood cells)
- responsible for the first step in the Pentose phosphate pathway
o Pentose phosphate pathway: convert glucose to ribose-5-phosphate

G6PD deficiency
• Glucose-6 Phosphate Dehydrogenase (G6PD gene)
• X chromosome (Xq28)
• provides instructions for making an enzyme called glucose-6-phosphate
dehydrogenase
• X-linked recessive
• 400 million people worldwide
• Hemolytic anemia: due to RBC hemolysis, exposed to oxidative stress

CYTOGENETICS CP TOLENADA/ ctolenada@feu.edu.ph

DEPARTMENT OF MEDICAL TECHNOLOGY
FAR EASTERN UNIVERSITY

Triggering factors
• Illness such as viral or bacterial
• Anti-pyretics or analgesics like aspirin
• Some antibiotics
• Some antimalarial drugs
• Soya food
• Red wine
• Legumes (monggo, gabanzos, abitsuelas)
• Napthalene balls
• Fava beans
• Blueberries

MANIFESTATION
• Pallor
• Extreme tiredness
• Rapid heartbeat
• Rapid breathing
• Jaundice
• Splenomegaly
• Tea-colored urine
TREATMENT
• Avoid triggers
• Phototherapy
• Blood transfusion

MAPLE SYRUP URINE DISEASE

Autosomal recessive
1 in 185,000 infants worldwide
Mutations in genes:
Branched-chain alpha-keto acid dehydrogenase (BCKD) enzyme complex
BCKDHA – Chromosome 19
BCKDHB – Chromosome 6
Dihydrolipoamide Branched Chain Transacylase E2
DBT – Chromosome 1
leucine, isoleucine, valine, and their oxoacids accumulate in body fluids

MANIFESTATION
Sweet-smelling urine
Erratic behaviour and moods
Hallucinations
Anorexia
Seizures

TREATMENT: Dietary restriction of branched-chain amino acids

CYTOGENETICS CP TOLENADA/ ctolenada@feu.edu.ph

DEPARTMENT OF MEDICAL TECHNOLOGY
FAR EASTERN UNIVERSITY

NBS is covered by law!

CYTOGENETICS CP TOLENADA/ ctolenada@feu.edu.ph