CYTOGENETICS - CONGENITAL METABOLIC DISORDERS

• Organogenesis


  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
• Stages of embryo and fetal development

  • 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
• Fetal growth


  1. Body proportions approach those of a newborn

  2. Bone replaces softer cartilage

  3. Nerve and muscle functions become coordinated

  4. Sex organs become more distinct by week 6

  5. By week 12: Sucks thumb, kicks, makes fists and faces, and has the beginnings of teeth

  6. Fingernails and toenails begin to develop and the external ears are also formed

  7. Vocal cords will be formed by 18 weeks

  8. By the end of the second trimester: Woman feels distinct kicks and jabs and may detect fetal hiccup

  9. In the final trimester: Fetal brain cells link into networks as organs elaborate and grow, and fat fills out the skin

  10. The digestive and respiratory systems mature last
• Week 16

  • Muscle tissue and bone continue to form
  • Skin begins to form
  • Meconium develops in the baby's intestinal tract
  • Sucking motions (sucking reflex)
  • Length: 4 to 5 inches
  • Weighs: 3 ounces
• Critical period


  Time when genetic abnormalities, toxic substances, or viruses can alter a specific structure
• Most birth defects develop during the embryonic period and are more severe than those that arise during the fetal period
• Some birth 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
• Newborn screening is part of "Unang Yakap": Early Essential Newborn care Protocol

  
• Why newborn screening is important

  Most newborns with metabolic disorders look normal at birth, but can be reversed or treated to prevent mental retardation or death
• Newborn screening procedure


  1. Testing is done 24 to 48 hours after birth

  2. Heel prick method

  3. Blood drops on NBS kit

  4. Air dry for 4 hours

  5. Send to testing facility

  6. Blood Collector: Doctor, Nurse, Midwife, Medical technologist
• Basic newborn screening disorders (6 disorders)

  • Congenital hypothyroidism (CH)
  • Congenital adrenal hyperplasia (CAH)
  • Phenylketonuria (PKU)
  • Galactosemia (GAL)
  • Glucose 6 phosphate deficiency (G6PD)
  • Maple syrup urine disease (MSUD): added in 2012
• Expanded newborn screening disorders (28 disorders)


  • Current 6 basic disorders plus 22 more disorders such as hemoglobinopathies and additional metabolic disorders, namely, organic acid, fatty acid oxidation, and amino acid disorders
• 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 caused by shortage of iodine in mother's diet during pregnancy
• Types of congenital hypothyroidism

  • Thyroid dysgenesis: thyroid gland fails to develop or function properly (Genes involved: PAX8, TSHR)
  • Thyroid dyshormonogenesis (Genes involved: DUOX2, SLC5A5, TG, TPO)
• Early manifestations of congenital hypothyroidism

  • Prolonged jaundice
  • Inactive defecation
  • Umbilical hernia
  • Hypotonia
  • Rough and dry skin
  • Delayed overall development
• Late manifestations of congenital hypothyroidism

  • Mental retardation
  • Growth retardation
  • Delayed skeletal maturation
  • Delayed dental development and tooth eruption
  • Delayed puberty
• Adrenal gland


  Located on top of the kidneys, produces hormones like epinephrine, cortisol, and aldosterone
• Congenital adrenal hyperplasia


  Autosomal recessive disorder caused by 21-hydroxylase deficiency, leading to excess production of male sex hormones (androgens)
• CYP21A2 gene


  Provides instructions for making the 21-hydroxylase enzyme, mutations in this gene cause congenital adrenal hyperplasia
• Adrenal Gland is located on top of the kidneys
• Hormones produced in Adrenal Gland

  • Epinephrine or adrenalin
  • Cortisol
  • Aldosterone (salt-retaining hormone)
• Epinephrine or adrenalin


  For vigorous physical activities
• Cortisol


  Maintains blood sugar levels, protects the body from stress, and suppresses inflammation
• Aldosterone (salt-retaining hormone)


  Regulates the amount of salt retained by the kidneys
• Manifestations of Congenital Adrenal Hyperplasia

  • Increased pigmentation
  • Ambiguous genitalia in female infants
  • Poor suck, weak cry
  • Vomiting, excessive urination, dehydration
  • Irritability and seizures
  • Failure to thrive
  • Hypotension, shock
  • Coma
  • Precocious puberty
  • Skin Puberty
  • Dark skin color
  • Short adult stature
• Treatment for Congenital Adrenal Hyperplasia

  • 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
• Manifestations of Phenylketonuria

  • Vomiting
  • Hyperactivity
  • Seizures and hypertonia
  • Musty or mousy urine odor
  • Light hair and skin color
  • Seborrheic or eczematoid rash
  • Mental retardation
• Treatment for Phenylketonuria


  • Complete avoidance of food containing high amounts of phenylalanine
  • Calculated intake of low protein/phenylalanine natural food
  • Sufficient intake of fats and carbohydrates
• 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
• 3 Types of Galactosemia

  • Type I - Classic galactosemia, Type II - Galactokinase deficiency, Type III - Galactose epimerase deficiency
• 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
• Manifestations of Galactosemia

  • Poor suck
  • Vomiting, occasionally diarrhea
  • Jaundice
  • Lethargy, weakness, coma
  • Septicemia (E. coli)
  • Liver: hepatomegaly, edema, ascites, cirrhosis
  • Lens: cataracts
  • Brain: mental retardation
  • Kidney
  • Growth failure
• Treatment for Galactosemia: eliminate lactose and galactose from diet