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Week 10: Developmental Disorders & Fetal Congenital Abnormalities…

- - - - Grafted from a quail embryo to a chick host, which induces a new (additional) axis in the host
      - Hence, reinforces role of node in axis development
  - - - Node cells secrete Nodal and FGF (fibroblast growth factor)
        
        Induce signalling through tyrosine kinase
  - - - Signals to adjacent epiblast to form neural ectoderm
        
        Develops into brain
      - Restricts the primitive streak from forming in anterior
  - - - Induces asymmetric gene expression (i.e. left-right symmetry is broken)
      - Cells are transient population
      - Evidence
        
        When flow is forced to the right, left-right axis is reversed
        
        Dynein mutant mice do not form cilia, and subsequently exhibit randomised left-right organ location
    - - Left
        
        Nodal (signalling molecule)
        
        Pitx2 (TF)
        
        Gut-looping and heart on left
        
        Cascade of gene expression and morphogenic changes
      - Right
        
        Lack of Nodal
        
        Snail
      - Loss of asymmetry
        
        Loss of Pitx2
        
        Rieger Syndrome
        
        Situs inversus
        
        Due to loss of dynein
        
        Asymmetry diseases
        
        Dyslexia, schizophrenia (increased prevalence of LH)
      - Proteins
        
        BMP (bone morphogenetic protein)
        
        FGF (fibroblast growth factor)
        
        Shh (sonic hedgehog)
        
        Lefty2
    - - 85% right-handedness for tool use
        
        Suggests left-hemisphere dominance for hand preference
      - 93% of RH show left hemisphere language dominance
        
        Compared to 73% for left hand
        
        Hence, link between handiness and language
      - Heritable, as with cerebral asymmetry
      - Genes
        
        Localise candidate genes, e.g. X-linked androgen receptor (AR) gene has opposing impact of LH probability in males/females
        
        GWAS located relative hand skill to an intron of pro protein convertase subtilisin/kexin type 6 (PCSK6)
- - - - Leftward flow of fluid across the cilia in the midline sets up a cascade for Nodal expression on the left of the embryo
        
        Amplified via positive feedback (as Nodal signalling activates Nodal gene transcription)
        
        Calcium ion release from left-side cells also increases Nodal at this time
    - - High Nodal on the left induces expression of Pitx2 transcription factor
        
        Left-side determinant
        
        E.g. heart forms from the left lateral plate mesoderm in response to Nodal and Pitx2
        
        Forced symmetrical Nodal/Pitx2 expression = randomised organ location
  - - - Expressed in the left half of the notochord
        
        Forms a midline barrier
        
        Prevents Nodal from crossing to the right
  - - - Mice with pcsk6 mutation have heterotaxia, i.e. abnormal organ distribution
  - - - Concentration determines cell responses in development
        
        Adults: controls division of stem cells, is implicated in cancer development, has a role in energy metabolism
        
        Digit formation
        
        Anterior has lowest [Shh], posterior has highest; observe increasing number of descendants of SHH-expressing cells
        
        Programmed cell death occurs in between digits, and Msx1/Sp8 concentrated at digit tips
      - Growth of digits, brain organisation, sex organ differentiation
    - - Cause holoprosencephaly due to loss of the ventral midline
    - - Inhibits patched
        
        Ci protein is made an activator, and transcription of hedgehog-response genes occurs
        
        Patched normally inhibits smoothened
      - Right
        
        FGF8 inhibits Caronte
        
        Hence BMP inhibits Nodal/Lefty2
        
        This induces Snail
      - Left
        
        Shh induces Caronte (Cerberus)
        
        Caronte inhibits BMP (which normally inhibits Nodal/Lefty2)
        
        This induces Pitx2
- - - - Drugs, alcohol, tobacco
        
        Born addicted to drugs; withdrawal symptoms; low birth weight
        
        Foetal Alocohol Spectrum Disorder, epilepsy, behavioural problems and impulse control
      - Diseases
        
        Rubella, Herpes simplex, Chickenpox, Zika
        
        Cause serious malformation, mental retardation, and miscarriage or infant mortality
  - - - Spina bifida
      - Congenital cardiac defects
      - Congenital dislocation of hips
    - - Haemophilia
      - Cystic fibrosis
  - - - Collects data on developmental anomalies and cerebral palsy in WA to guide research and investigation into causes, prevention, and management of anomalies
        
        Western Australian incidence of developmental anomalies ~5%
        
        More common in males and multiple pregnancies
        
        In 2014, 12.4% of stillbirths and 28.9% of neonatal deaths had a birth defect present
        
        Musculo-skeletal was the most common category, and developmental dysplasia of the hip was a major contributor
      - Notifications mandatory since 2011
        
        Each defect coded according to the 5-digit British Paediatric Association ICD-9 system
      - Diagnostic categories
        
        Nervous system
        
        Congenital anomalies of the eye
        
        Congenital anomalies of the ear/face/neck
        
        Cardiovascular
        
        Respiratory system
        
        1 more item...
  - - - Closure of the neural tube begins in the cervical area (in the middle of the embryo) and spreads from there in the cranial and caudal directions
      - By day 24, the cranial end closes
        
        By 26, the caudal end closes
      - Neural tube defects
        
        If the closure of the anterior neuropore fails to take place, anencephaly results
        
        If the posterior neuropore does not close, spina bifida occurs
        
        Risk factors
        
        Multifactorial
        
        2-5% recurrence in subsequent pregnancies
        
        Genetic influences (known genetic syndromes e.g. trisomy 18, familial clustering)
        
        Multiple pregnancies
        
        Nutritional deficiencies
        
        Environmental agents (hyperthermia e.g. saunas, maternal pyrexia)
    - - Necessary for production and maintenance of new cells
      - Coenzyme in one-carbon transfer during the methylation cycle (process essential for the synthesis of nucleic acids), which form part of DNA and the neurotransmitters
        
        Methylation of homocysteine to produce methionine uses 5-MTHL as the methyl donor
      - Folate deficiency leads to accumulation of homocysteine, associated with CVD risk
        
        Several gene polymorphisms affect folate metabolism/are associated with reduced folate absorption and hence increased folate needs
        
        THFR (methylene-tetrahydrofolate reductase) gene mutation affects 8-35% population depending upon ethnicity; reduced folate carrier (RFC1) gene
        
        In the absence of a folate-sufficient diet these mutations are associated with an increased risk of NTDs and conotruncal cardiac anomalies
        
        Folate supplementation
        
        Periconceptional folic acid
        
        2 more items...
        
        Pregnancy
        
        2 more items...
        
        In 2009, mandatory folic acid fortification in Australia; 200-300 mcg/100g flour; neural tube defects predicted to fall 40-70%
  - - - Most frequent and recognisable chromosomal anomaly; most common genetic cause of intellectual impairment in our community
        
        Progressive increase in incidence over the past three decades (increasing maternal age, increasing early prenatal detection)
        
        Incidence is 3.2/1000 in WA or 100/year, and accounts for half of chromosomal abnormalities
        
        55% of T21 pregnancies occur in women >= 35 years
        
        Prenatal screening now incorporated into antenatal care
        
        Based on maternal age (amniocentesis/CVS)
        
        Noninvasive prenatal testing (99.5% detection rate)
        
        Trimester screening
        
        Second trimester screening (60-70% detection rate)
        
        Combined first trimester screening (80-90% detection rate)
        
        Ultrasound (nuchal translucency) at 11.3-14 weeks’ gestation; involves free beta-hCG, PAPP-A (maternal biochemistry)
        
        4 more items...
      - Chromosome 21 is the smallest chromosome in humans (48 million base pairs): 1-2% of total DNA
        
        95% of cases are due to nondisjunction, 4% due to unbalanced translocation (typically #14), and 1% due to mosaicism
        
        Nondisjunction: failure of homologous chromosomes to separate in first meiotic division, and failure of sister chromatids to separate in second meiotic division
      - Phenotype
        
        CNS effects
        
        Intellectual disability (IQ 50), Alzheimer’s disease, hypotonia
        
        Gastrointestinal
        
        Duodenal atresia, imperforate anus
        
        Cardiac defects
        
        1 more item...
    - - Trisomy
        
        Trisomy 18 (Edwards Syndrome)
        
        Gives multiple anomalies, typically identified on ultrasound (or FTS or NIPT)
        
        Incidence 1/5000, or 30/year in WA
        
        Trisomy 13 (Patau's Syndrome)
        
        Incidence 1/8-10,000 or 8/year in WA
        
        Typically recognised on ultrasound or FTS/NIPT
      - Monosomy X
        
        Characteristics include short stature, early loss of ovarian function, webbed neck, lymphedema, cardiac abnormalities, and renal abnormalities
        
        Incidence is 1/2500 births (higher if include first trimester losses)
  - - - Often associated with other conditions e.g. Di George syndrome
      - 11/year in WA
    - - 90% of cases are isolated defects; 8-9/year in WA
    - - Often associated with other cardiac conditions e.g. VSD
      - 18/year in WA
- - - - Limb deformation
        
        Abnormalities in forelimb, lower jaw, ear and tail in 100 day Rhesus monkey foetus following treatment of pregnant mother with 30mg/kg thalidomide on Day 26 of the pregnancy
        
        Proposed theory is that induction of apoptosis is transient, but kills distal mesenchymal cells
        
        In vitro thalidomide is metabolised by prostaglandin H, increasing reactive oxygen species
        
        There is less active NF-kappa-B; get de-repression of BMP, no block of apoptosis, and hence cell death/limb truncations
      - Chemical structure
        
        Racemic mixture of glutamic acid derivative
        
        1:1 mix of enantiomers (R,S)
        
        R+ acts as sedative, probably mediated by sleep receptors in the forebrain
        
        S- potently inhibits the release of tumour necrosis factor alpha
        
        TNF-alpha
        
        TNF-alpha gene located 6p21.3 and encodes for synthesise of cytokine TNF-alpha
        
        Induces transcription factor NF-kappa-B
        
        Activating expression of genes for cell growth, suppression of apoptosis, metastasis, and immune/inflammatory response
        
        Thalidomide decreases TNF-alpha protein production by accelerating mRNA degradation
      - Use in cancer
        
        Inhibits angiogenesis; anti-inflammatory
        
        Stimulates the immune system (tuberculosis in AIDS patients)
        
        In 1998, the drug was licensed for treatment of ENL (Erythema Nodosum Leprosum), a form of leprosy; it was amazingly effective and WHO showed 99% of patients improved significantly
      - Critical exposure periods
        
        35-37 days
        
        No ears
        
        Extent of foetal damage depends on time/duration of exposure and genetic susceptibility (mother metabolism of certain drugs)
        
        39-41 days
        
        No arms
        
        41-43 days
        
        No uterus
        
        45-47 days
        
        No tibia
        
        47-49 days
        
        Triphalangeal thumbs
    - - Ineffective as anti-convulsant and anti-histamine; finally used as a sedative
        
        Then, phocomelia (severe limb abnormalities), plus deafness/blindness/cleft palate/internal abnormalities, were noticed in children of mothers taking thalidomide
        
        40% dead within first year; drug finally withdrawn in 1961
- - - - BMP4 knockouts are embryonic lethal
        
        Mutants fail to properly to form mesoderm
        
        Implicated in limb development
- - - - Human data lacking or inadequate for drugs in B1, B2, and B3 categories; subcategorisation of B category based on animal data
        
        Allocation of B category does not imply greater safety than C category
        
        Medicines in Category D are not absolutely contraindicated during pregnancy e.g. anticonvulsants