PATHOPHYSIOLOGY OF DOWN SYNDROME

Predisposing Factors
Precipitating Factors
>Genetic predisposition
Etiology: Unknown > Low Folic Acid intake
> Advanced Maternal Age
during pregnancy
(>35 y/o)

Gametogenesis Gametogenesis (Meiosis) or Cell Fertilization of euploidic

(Meiosis) division of zygote (Mitosis) sperm and egg

Failure of Chromosome 21 to Portion of Chromosome 21 attaches Normal zygote (46

separate normally (Meiotic to another chromosome chromosomes)
nondisjunction) (Translocation)

Mitotic nondisjunction of
Production Formation of euploidic cells with extra chromosome 21 during
ofaneuploidicsperm/egg cell chromosome 21 attached to one embryonic development or
(24 chromosomes) chromosome cell division

Fertilization of aneuploidic Asymptomatic offspring with normal Mixture of euploidic (46) and aneuploidic
gamete with a normal gamete D phenotype but considered as a “carrier” (47) cells (Partial Trisomy 21)

A B C
 A B C

Formation of embryo Normal gametogenesis and disjunction Overexpression of genes in chromosome

with 47 chromosomes of carrier still results to gametes with 21 to aneuploidic cells
and extra chromosome extra chromosome 21
21 (Trisomy 21)

D
Overexpression of genes
in chromosome 21

Multi-system manifestations

Amyloid beta A4 Superoxide dismutase Dual-specificity Tyrosine Interferon, Alpha, Beta, Avian Erythroblastosis Crystallin, Alpha-A TransientAbnormal
precursor protein (SOD1) Phosphorylation- and Omega, Receptor Virus E26 Oncogene (CRYA1) Myelopoiesis (TAM)
(APP) Regulated Kinase 1A (IFNAR) Homolog 2 (ETS2)
(DYRK)
Alzheimer’s disease Cataracts Leukemia
Cognitive defects and immune problems Immune system Neurocranial,
Abnormal neurogenesis Problems viscerocranial and cervical
skeletal abnormalities
Impulsive behaviour,
Poor judgment, Delayed mental and
Short attention span, motor development Small head, flattened facial
Slow learning features, short neck, small
nose, delayed teeth eruption
E

Cysteine-rich with EGF-like domains Cystathione Beta

1(CRELD1) and Zinc Finger Protein 295 Synthase (CBS)
(ZNF295)

Disruption in
Atrioventricular septal metabolism
heart defects

Obesity
Decreased perfusion
to body tissues

Hypoxia

Multi-organ failure

Death