Down Syndrome – Comprehensive Study Notes

Overview of Down syndrome

  • Down syndrome is a neurodevelopmental disorder caused by trisomy of chromosome 21, resulting in mild to moderate learning disabilities and may affect many other systems as well.
  • Named after the British doctor who first described the syndrome in 1866.
  • It is referred to as a “syndrome” because not all people with the syndrome have the same symptoms or to the same degree; there is a group of symptoms that regularly and consistently occur together, but not necessarily all present in every individual.
  • Down syndrome causes slowed or delayed development, usually manifested by mild to moderate intellectual disability.
  • Pathophysiological changes in the brain are widespread and generally accompanied by reduced volume of brain structures.
  • Many other systems can be affected, including:
    • Craniofacial abnormalities
    • Skeletal abnormalities
    • Increased thyroid problems
    • Heart abnormalities
    • Increased risk for hearing problems
    • Increased risk for vision problems
    • Increased risk for Alzheimer’s disease or other dementia (early onset: ~40 years old)
  • Each person with Down syndrome is an individual and may possess these symptoms to different degrees or not at all.
  • Trisomies arise from defects in chromosomal segregation, resulting in an extra copy of a chromosome (2n + 1).
  • Most cells have 23 pairs of chromosomes (one set from each parent).
  • Under certain conditions, chromosomal abnormalities can occur.
  • Aneuploidy is the presence of an abnormal number of chromosomes (i.e. 45 or 47 chromosomes).
  • Usually occurs during meiosis (cell division that reduces the number of chromosomes in the parent cell by half and produces gamete cells).
  • Nondisjunction is the process in which sister chromatids fail to completely separate during cell division, resulting in one daughter cell with extra copies of genomic information.
  • There are three major types of chromosomal changes resulting from non-disjunction:
    • Complete trisomy – occurs in egg or sperm and all cells contain the extra copy of chromosome.
    • Mosaic trisomy – some cells have extra copy, but not all.
    • Translocation trisomy – an extra portion of chromosome is attached to its sister chromosome and is transmitted to other cells during division.
  • Trisomy disorders can, and probably do, occur with any chromosome.
  • It is possible that the number of genes per chromosome can impact survival rates.

Chromosomal changes, missegregation, and affected trisomies

  • Chromosomes 1-12, 14, 17, 19, and 20 generally result in very early miscarriage that occurs before it can be evaluated or treated.
  • Trisomy 16, Trisomy 22, and Trisomy 15 are likely to cause miscarriage.
  • Trisomy 18 (Edwards syndrome) – mental retardation, breathing and feeding difficulties, delayed growth, and malformations of kidneys, intestines, and heart; generally results in very short life span.
  • Trisomy 13 (Patau syndrome) – neurological problems, mental and motor deficiencies, and physical deformities; less than 5% survive into childhood.
  • Trisomy 21 (Down syndrome) – moderate to severe mental retardation and a wide variety of health problems including heart defects, leukemia, and Alzheimer’s disease.
  • Sex chromosome abnormalities: 47, XXY; 47, XYY; and XXX syndromes.
  • Down syndrome is the most commonly occurring trisomy resulting in live birth.
  • Approximately 1700\frac{1}{700} live births in the US have Down syndrome (~6,000 new cases per year; ~250,000 people living with Down syndrome in the US).
  • Down syndrome is the most common genetic cause of intellectual disability. Down syndrome is typically not inherited, but rather arises from parental nondisjunction during meiosis.
  • There is an increased risk of giving birth to children with Down syndrome with increasing maternal age. The majority of cases are caused by nondisjunction of chromosome 21 during maternal meiosis I. Although the risk increases with maternal age, the majority of babies with Down syndrome are still born to mothers under 35 years old due to higher birth numbers in younger women.
  • The exact mechanisms behind the maternal-age–related risk are still under investigation.

Prenatal detection and diagnostic testing

  • There are several different methods for detecting Down syndrome before birth:
    • Prenatal Screening (less invasive; not sufficient for diagnosis):
    • Maternal blood tests to look for protein markers that could suggest increased risk for DS.
    • Ultrasound to detect developmental abnormalities that could suggest increased risk for DS.
    • Prenatal Diagnostic testing (more invasive; can carry risk of miscarriage; sufficient for diagnosis):
    • Samples needed for testing: from amniotic fluid, placenta, or umbilical cord blood.
    • Diagnostic tests for presence of trisomy:
      • G-Banded Karyotype
      • Fluorescence in situ hybridization (FISH) – fluorescently labeled DNA probes to genes on chromosome 21 (and 13 as a control)
      • Quantitative PCR (qPCR) – detects alleles of different sizes on chromosome 21; presence of 3 different sizes indicates trisomy
      • Paralogous Sequence Quantification (PSQ) – detects differences in the percentages of sequences on chromosome 5 and chromosome 21

Gene expression and the chromosome 21 landscape

  • Because Down syndrome is caused by the presence of an extra chromosome, a prevailing hypothesis is that the overexpression of genes present on chromosome 21 causes the developmental problems observed in Down syndrome.
  • HSA 21 description:
    • Approximately 48 Mb48\text{ Mb}, ~1.5%1.5\% of the human genome
    • Approximately 696696 genes
    • At least 235235 protein-coding genes and 142142 pseudogenes
    • A 5.4 Mb5.4\text{ Mb} region on HSA21q22 containing ~50 genes called the Down Syndrome critical region (DSCR) that was once thought to be sufficient to underlie most of the symptoms of DS
  • The expectation that genes expressed on chromosome 21 would be increased by 50% (i.e. a 3:2 expression ratio) is complicated by empirical data:
    • Mouse models of trisomy show:
    • 45%45\% of genes were lower than 1.5×1.5\times
    • 37%37\% of genes were approximately 1.5×1.5\times
    • 18%18\% of genes were expressed at levels greater than 1.5×1.5\times
    • 9%9\% of genes were not overexpressed at all
    • A human study found:
    • 22%22\% of genes expressed at ~1.5×1.5\times
    • 7%7\% were greater than 1.5×1.5\times
    • 56%56\% were lower than 1.5×1.5\times
    • 15%15\% were highly variable between cases and controls
  • A meta-analysis of 4545 heterogeneous publicly available DS data sets identified 7777 up-regulated genes on HSA21, and 247247 non-HSA up-regulated genes. This suggests that up-regulated genes on HSA21 can influence the expression of genes on other chromosomes.
  • Possible mechanisms for cross-chromosome gene up-regulation:
    • Overexpression of HSA21 transcription factors that increase expression of genes on other chromosomes
    • Overexpression of HSA21 gene products involved in feedback regulation of genes on other chromosomes
    • Overexpression of HSA21 gene products that influence DNA methylation or chromosomal organization of genes on other chromosomes
  • Not all gene products’ functions will be changed by overexpression.
  • Allele-specific expression: individuals can have high, medium, or low levels of expression of a particular gene depending on differences in DNA sequences in enhancers, silencers, promoters, and untranslated regions; three copies of high-expressing alleles could cause more severe phenotypes than three copies of low-expressing alleles; the inheritance of allele-specific expression can play a major role in phenotype severity.
  • Duplication of conserved non-genic sequences could also play a role.

Gene-by-gene and pathway implications

  • It is vital to understand which genes are overexpressed and how this overexpression may affect the function of the proteins.
  • Several chromosome 21 genes have been implicated in DS across multiple pathways:
    • Development: the tyrosine kinase DYRK1A can affect many pathways; upregulation can cause neuronal precursor cells to stop dividing and differentiate prematurely, resulting in fewer neurons and reduced cortical volumes.
    • DYRK1A is often considered to have indirect effects because it can change the function of other proteins through phosphorylation.
    • Learning and Memory: DYRK1A and synaptojanin 1 could play significant roles.
    • Early Onset Alzheimer’s Disease: the Amyloid Precursor Protein (APP) is located on chromosome 21 and could lead to AD-like pathology. DYRK1A could increase tau phosphorylation, as could RCAN1. Overexpression of APP is often considered to have a direct effect on phenotypes because it directly contributes to the increase in Alzheimer’s disease senile plaque pathology.
  • It is unlikely that any one gene could account for all DS phenotypes – a multifactorial process is likely:
    • How much is gene expression increased?
    • What effect does increased expression have on function?
    • Are the combinations of alleles sufficient to produce a phenotype?
    • Do the genes expressed interact with other non-Chromosome 21 proteins?
    • Could conserved non-genic DNA sequences play a role?
  • The amount of gene expression (on chromosome 21 and non-Chromosome 21 gene interactions) and how overexpression changes function can result in differences in severity of phenotypes. This has been described as the “Phenotypic Threshold Effect”: phenotypic manifestation of a genetic defect occurs only when a threshold level is exceeded.
  • Allelic differences in gene expression can lead to variable amounts of gene product produced depending on which allele has the extra copy.

Implications for treatment and care

  • Treatments are tailored to the individual:
    • Early intervention & educational therapy – Special education services such as Individualized Education Programs (IEPs) to address developmental delays and intellectual disability.
    • Other therapies:
    • Physical therapy (to assist with skeletal-muscular difficulties)
    • Speech-language therapy (to assist with language development and craniofacial difficulties)
    • Occupational therapy (to assist with daily living and work-related tasks)
    • Emotional and behavioral therapy (to assist with emotional disturbances and social integration)
  • Experimental drugs to help cognition have shown mixed safety and efficacy results.
  • Recent development and pre-clinical testing of experimental DYRK1A inhibitor.
  • Drugs aimed at reducing amyloid plaques and early-onset Alzheimer’s disease are being explored.

Ethical, practical, and societal considerations

  • Prenatal screening and diagnostic testing raise important ethical and practical considerations, including decisions about pregnancy and potential risks of invasive testing.
  • Access to early intervention, therapies, and experimental treatments varies and can influence quality of life and long-term outcomes.
  • Understanding the multifactorial basis of DS phenotypes highlights the importance of individualized care plans and educational supports.

Summary of key data points (for quick reference)

  • DS arises from an extra chromosome 21 (trisomy 21):2n+12n+1; aneuploidy is 45 or 47 chromosomes.
  • Most common trisomy resulting in live birth; incidence ~1700\frac{1}{700} live births in the US; ~6,000 new cases/year; ~250,000 affected individuals in the US.
  • DSCR region: 5.4 Mb5.4\text{ Mb} on HSA21q22HSA21q22 containing ~50 genes; located within the ~48 Mb48\text{ Mb} chromosome 21, which accounts for 1.5%1.5\% of the genome and contains ~696 genes (≈ 235 protein-coding235\text{ protein-coding} and 142 pseudogenes142\text{ pseudogenes}).
  • Expression expectations vs reality: many chr21 genes are not simply tripled in expression; observed ranges include
  • Meta-analysis: 7777 up-regulated HSA21 genes; 247247 non-HSA up-regulated genes, indicating cross-chromosome regulatory effects.
  • Phenotypic Threshold Effect: phenotypes manifest when a threshold of gene expression is exceeded.
  • Key genes/pathways: DYRK1A (development and neuronal proliferation), APP (Alzheimer’s risk), RCAN1 (tau phosphorylation), Synaptojanin-1 (memory/learning).
  • Treatment approaches emphasize individualized, multi-modal strategies: early education, PT/OT/SLP, behavior therapy, plus exploration of DYRK1A inhibitors and anti-amyloid strategies.