Down syndrome pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Overview[edit | edit source]

Down Syndrome (DS) is the consequence of trisomy of human chromosome 21 (Hsa21) and is the most common genetic form of intellectual disability. Additional copy of chromosome 21 results in elevated expression of many of the genes encoded on this chromosome, leading to variying expression of genes associated with this chromosome. Mechanisms leading to trisomy 21 include meiotic non-disjunction during meiosis I (majority) and meiosis II, Robertsonian translocation and mosaicism (rare). In addition, increased maternal age leads to rapid degradation of cellular proteins involved in spindle formation, sister chromatid cohesion and anaphase separation of sister chromatids in oocytes during cell cycle. Absence of chiasmata and suboptimally placed chiasmata are the major mechanisms involved in non-disjunction of chromosome 21.Immaturity of the feto-placental unit has been proposed as an explanation for the reduced maternal serum alpha fetoprotein (AFP) and unconjugated oestriol (UE3) levels and increased hCG levels in Down’s syndrome pregnancies. Reduced synthesis of AFP by the fetal liver is also thought to contribute to low AFP in Down’s syndrome pregnancies. Robertsonian translocation occurrs when the long arms of 2 acrocentric chromosomes (chromosomes with centromeres near their ends) fuse at the centromeres and the 2 short arms are lost. Mosaicism does not have any maternal association and it is a post-fertilization mitotic error. Disbilities found in Down syndrome patients are thought to arise secondary to varied genetic expression associated with the presence an extra 21st chromosome.

Pathophysiology[edit | edit source]

• Down Syndrome (DS) is the consequence of trisomy of human chromosome 21 (Hsa21) and is the most common genetic form of intellectual disability.
• Additional copy of chromosome 21 results in elevated expression of many of the genes encoded on this chromosome, leading to variying expression of genes associated with this chromosome.^[1][2][3]
• Recent data points towards a number of ‘susceptibility regions’ located on Hsa21, which are modified by other loci on Hsa21 and other genomic regions, increase the risk of developing specific DS associated phenotypes.^[4][5]

Mechanisms of trisomy 21[edit | edit source]

Meiotic non-disjunction[edit | edit source]

•  In trisomy 21 the extra chromosome 21 is maternal in origin in about 95 percent of the cases, and paternal in only about 5 percent.
• In approximately 95% cases, the extra chromosome occurs as a result of meiotic nondisjunction (NDJ) or abnormal segregation of chromosomes. Of these, in the majority of cases the error occurs during maternal oogenesis, specially during meiosis I.^[6][7]
• The process of oogenesis is lengthy and involves meiotic arrest, which makes predisposes the process to inappropriate segregation of chromosomes than spermatogenesis.^[8]
• In addition, increased maternal age leads to rapid degradation of cellular proteins involved in spindle formation, sister chromatid cohesion and anaphase separation of sister chromatids in oocytes during cell cycle.^[9][10][11]
• Nondisjoined chromosomes often show recombination in various patterns and for trisomy 21, achiasmate meioses contribute about 45% of maternal meiotic error cases.^[12][13]
• Absence of chiasmata and suboptimally placed chiasmata are the major mechanisms involved in non-disjunction of chromosome 21.^[14]
• Exchange of telomeric segments increase the risk for MI error, whereas exchanges in the pericentromeric regions predispose to MII error. A distally placed chiasma probably links the homologue less efficiently to the spindle and leads to suboptimal orientation of the kinetochore towards opposite pole.^[15]
• Achiasmate meioses and mono-telomeric exchanges lead to an increased risk of NDJ regardless of maternal age.^[16]
• On the other hand, pericentromeric exchange pedispose older mothers to NDJ during meiosis II.^[17][18]
• Immaturity of the feto-placental unit has been proposed as an explanation for the reduced maternal serum alpha fetoprotein (AFP) and unconjugated oestriol (UE3) levels and increased hCG levels in Down’s syndrome pregnancies. Reduced synthesis of AFP by the fetal liver is also thought to contribute to low AFP in Down’s syndrome pregnancies.
• In Down’s syndrome pregnancies the normal proportion of syncytiotrophoblasts to cytotrophoblasts is disturbed leading to increased hCG levels.

Robertsonian translocation[edit | edit source]

• Approximately 4 percent cases of DS arise from Robertsonian translocation.
• This involves non-reciprocal chromosomal translocation that commonly involves chromosome pairs 13, 14, 15, 21 and 22.
• The event occurrs when the long arms of 2 acrocentric chromosomes (chromosomes with centromeres near their ends) fuse at the centromeres and the 2 short arms are lost
• Unbalanced translocations result in miscarriage, stillbirth and chromosomal imbalance (Down's syndrome, Patau syndrome)

Mosaicism[edit | edit source]

• Down syndrome resulting from mosaicism is very rare and accounts for around 1 percent of cases of DS.
• Mosaicism does not have any maternal association and it is a post-fertilization mitotic error.

Effects on increased gene dosage[edit | edit source]

• The phenotypical characrteristics produced in DS may be attributed to the disturbed gene expression due to trisomy 21.

Learning and memory[edit | edit source]

• Patients with DS have learning and memory problems and exhibit differences in brain structure compared to the euploid population.^[19][20][21]
• Impaired synaptic plasticity in the interstriatal cholinergic system has been though to play a key role in DS-associated motor and cognitive defects.^[22]
• Murine models have allowed to identify genes thought to affect memory and learning in DS patients. The main genes involved are:^{[23][24][25][26][27][28][29]}
  • DYRK1A
  • Synaptojanin 1(SYNJ1)
  • SIM2
  • DOPEY2
  • DSCAM

Neurodevelopment[edit | edit source]

• DS patients have increased rates of neuronal apoptosis related to oxidative stress.^[30]
• Brain size of fetuses carrying trisomy 21 is smaller than euploid fetuses.
• Murine models have suggested that disruption in expression of the following genes may play key roles in affecting neurodevelopment in DS patients:
  • PREP1^[31]
  • Tetratricopeptide repeat domain 3 (TTC3)^[32]
  • DYRK1A^[33][34] 
  • MECP2^[35]

Alzheimer's disease[edit | edit source]

• Trisomy 21 leads to increased expression of amyloid precursor protein (APP), which is suspected to predispose individuals with DS to early-onset Alzheimer's disease (dementia by the age of 60).^[36][37]
• Patients with Alzheimer's disease exhibit brain atrophy, extracellular β-amyloid (Aβ) deposits and the accumulation of neurofibrillary tangles (NFTs) that are composed of hyperphosphorylated Tau. The amyloid precursor protein, (APP), from which Aβ is produced, is encoded on Hsa21.
• Trisomy 21 leads to loss of basal forebrain cholinergic neurons and enlargement of early endosomes.^[38][39]
• DYRK1A gene (found on chromosome 21) encodes a kinase which may contribute to phosphorylation of Tau found in patients suffering from Alzheimer's disease.^[40]

Cancer and leukemias[edit | edit source]

• DS predisposes individuals to developing myeloproliferative dosorders, as well as acute megakaryocytic leukemia (AMKL) and acute lymphoblastic leukemia (ALL).^[41][42][43]
• Trisomy 21 lies at the heart of these abnormal cell proliferations.
• Varied expression of the following genes may lead to the development of disorders of cellular proliferation:
  • GATA binding protein 1 (GATA1) gene- Transient myeloproliferative disorder^[41][44][45]
  • Janus kinase 3 (JAK3)- Acute megakaryocytic leukemia (AMKL)^[43][46][47]
  • Janus kinase 2 (JAK2) point mutation- Acute lymphoblastic leukemia (ALL)^[48][49]

Genetics[edit | edit source]

Expression of the following genes may be disturbed in trisomy 21:

Associated Conditions[edit | edit source]

The following conditions may be associated with Down's syndrome:

• Early onset Alzheimer's disease
• Hypothyroidism
• Hyperthyroidism
• Mental retardation
• Leukemias
• Infertility
• Delayed puberty
• Autoimmune diseases:
  • Diabetes
  • Celiac disease
• Short stature
• Congenital heart defects (atrioventricular canal defect, ventricular septal defect, atrial septal defect, patent ductus arteriosus, tetralogy of Fallot)
• Hearing loss (related to otitis media with effusion or sensorineural)
• Ophthalmic disorders (congenital cataracts, glaucoma, strabismus)
• Gastrointestinal malformations (duodenal atresia, Hirschsprung disease)

Gross Pathology[edit | edit source]

There are no gross pathological findings associated with Down syndrome.

Microscopic Pathology[edit | edit source]

There are no microscopic findings associated with Down syndrome.

References[edit | edit source]

Template:WH Template:WS