Down syndrome

Question 1

clinical presentations of DS (invariant features)

Answer 1

1. cognitive impairment
2. hypotonia
3. AD-like pathology
4. Dementia

Question 2

incidence and risk factor for DS

Answer 2

• approx 1 in 750 births world-wide
• 6 million people
• 2% of all spontaneous abortions

risk factor:
- age 30: 1 in 935
- age 40: 1 in 85.

Question 3

clinical presentations of DS (variant features)

Answer 3

1. Spontaneous abortion (2% at least will be foetuses with DS)
2. Heart defects (can usually be corrected by surgery)
3. Autoimmune disorders
4. Leukaemia
5. ADHD.

Question 4

Life expectancy of DS

Answer 4

In the 1940s, life expectancy was around 12 years of age. In 2017 in the UK where medical systems have high standards of care the life expectancy is OVER 60 YEARS.

Question 5

Cause of DS

Answer 5

Trisomy 21 - abnromal gene dosage.
* Hsa21 approx230 protein coding genes, 29 miRNAs, lots of non-coding elements.

Question 6

Cognition in DS

Answer 6

• DS is the most common genetic intellectual disability.
  o 40% IQ 50-60
  o 1% IG 70-80
• Different effects in different domains, e.g.
  o Vocabulary (usually quite good), emotional control (can be almost completely normal)
  o Learning and memory are impaired.
• Cognition over lifespan: decreasing function – highly variable inter-individual.

Question 7

ST and LT explicit memory - DS

Answer 7

• Short term and long-term explicit memory
  o Memory for facts/semantics (declarative) and memory for personal events (episodic). Utilise distinct neural pathways.
  o Visuospatial memory – hippocampal dependent.
  o More complex tasks are more disabling.
• TD for implicit
  o Unconscious memory e.g., tying shoelaces.
  o This is usually pretty good.

Question 8

DS neurodevelopment (brain regions)

Answer 8

IN utero - reduced sized brian regions:
- Hippocampus, prefrontal cortex, cerebellum, brainstem, fontal/temporal lobes

Question 9

DS neurodevelopment (cellular changes)

Answer 9

• Changes to the cellular biology of the brain are also observed, for example there is a gliogenic shift to astrocyte production, with a decrease in neuronal production
• Possible defect cell proliferation – particularly neuronal proliferation (looking likely but is controversial)
• Reduction calbindin and parvalbumin (PV) interneurons?
• GABA and other neurotransmitters affected – if you have a reduction in NTs that affect a particularly

Question 10

DS and AD risk

Answer 10

• Approx. 100% DS AD-like pathology by age 40
• APP lies on Hsa21
• APP triplication ALONE causes early onset.
• APP is massively dosage sensitive - three copies of APP sufficient to cause AD in DS, but likely effects from other hsa21 genes in DS.

HOWEVER – 1/3 of DS individuals do not have AD by the age of 66. Therefore, there must be other mechanisms occurring that affect the onset of AD

Question 11

Homologs in mice of Hsa21

Answer 11

Mmu16, Mmu17, and Mmu10

Question 12

DRYK1A

Answer 12

candidate gene for DS - found in mouse models.

• It’s a serine/threonine kinase.
• Involved in neurogenesis.
• Involved in regulation dendritic tree development.
• May be involved in neurodegeneration mediated by tau.
• Three copies disrupt many pathways – incredibly dosage sensitive gene.
• HAS a large capacity of interactions.

Question 13

Therapies for various DS phenotypes

Answer 13

DRYK1A.
* Small molecules/conventional therapies
o Kinase inhibitors for example – but these tend to be very non-specific – how do we get the dose right. Also an issue of specificity. Could exacerbate disease phenotype rather than rescue it.

Question 14

Hsa21 genes of interest

Answer 14

1. APP
2. DRYK1A