BIOMED 8 Flashcards
Genetic disorders affecting speech and language
What is another word for a region of coding DNA (a gene)?
Exon
What is another word for a region of non-coding DNA (between genes)?
Intron
What is sequencing?
Reading the order of bases in a stretch of DNA (a sequence)
What does sequencing allow us to do?
Find the DNA sequence of the whole genome
Can use this as reference point to identify variations (variants) in an individual’s genes, this forms basis of genetic testing as can compare + diagnose
What is a genetic disorder?
Health problem caused by one or more abnormalities in the genome
What is a ‘rare’ disease?
Occuring in < 1:2000 in a population
How many in the UK are affected by a rare disease?
Collectively common: 3.5 mil
How many rare conditions have been identified? What % of these are caused by a genetic change?
> 7000
80% caused by genetic change
How have we learned about many new genetic rare diseases?
100,000 genomes project
Made new diagnoses + names, used to screen others with similar symptoms
What is a developmental disorder?
Neurologically based condition that can interfere with acquisition, retention, or application of specific skills/information
Begins at an early age and significantly affects psychological functioning
Many have a genetic basis
What % of children born with a disorder do not have a diagnosis?
60%
What are the 4 different types of genetic disorders?
Single gene disorders
Chromosomal disorder
Mitochondrial disorders
Complex, multifactorial disorders
How do mitochondrial genetic disorders occur?
Errors in mitochondrial DNA
Only carried by maternal side, sperm stays outside just genetic material goes in egg (but: research potentially small amount of paternal?)
Why do single gene disorders occur?
Changes in DNA sequence of a single gene at a single location
Describe single gene disorders
Hereditary
Affect every cell in body, but only where gene is expressed as a protein
Can be…
- autosomal dominant
- autosomal recessive
- sex-linked
For an autosomal dominant disorder, how is the disease expressed in the phenotype?
Only 1 copy of dominant allele needed in genotype
For an autosomal recessive disorder, how is the disease expressed in the phenotype?
Both copies of recessive allele needed in genotype
For X-linked dominant inheritance, who is protected with an affected father?
Sons
For X-linked recessive inheritance, who is protected with an affected father?
All children (may be carriers)
What are the 3 types of chromosomal disorders?
Chromosomal duplication
Aneuploidy (gain/loss of one)
- monosomy (45)
- trisomy (47)
Chromosomal fusion (note: may be implicated in cancers)
What is a syndrome?
Disease/disorder that has numerous symptoms / identifying features
What are 3 genetic disorders affecting speech and language?
Fragile X Syndrome (FXS)
Down’s syndrome
Muscular Dystrophy
What is Fragile X Syndrome?
Due to changes in a gene on X chromosome (single gene disorder)
Gene is called FMR1 (Fragile X Messenger Ribonucleoprotein 1)
Dominant trait
How common is FXS?
Most common inherited cause of learning disability in UK
What is the difference between genders for prevalence of FXS?
1:4000 males (also more severely affected)
1:6000 females
What protein does the FMR1 gene code for?
FMRP: Fragile X Mental Retardation Protein
FMRP attaches directly to ribosomes to assist in translation of mRNA
How is the FMR1 gene ‘switched on’?
Region of DNA called the promoter
How is the promoter for FMR1 made?
15-50 CGG repeats in the DNA
How does Fragile X occur?
Mutation in promoter region
- 70-200 = premutation (FMRP is normal)
- 200+ = full mutation (abnormal/no FMRP)
How did FXS get its name?
Area with full mutation and extended promoter region affects shape of chromosome
What is the difference between genders for prevalence of pre-mutation for FXS?
Females 1 : 130-260
Males 1 : 250-810
What happens for FXS premutation in women?
Repeats tend to lengthen during final stage of egg gamete just before fertilisation, increased risk of child with FXS
20% have primary ovarian insufficiency (FX-POI) over reproductive life span
What happens for FXS premutation in men?
Repeats do not lengthen during fertilisation (less risk to pass on)
Increased risk for ataxia (tremors/balance problems), (FXTAS, FX tremor ataxia syndrome)
What is the inheritance pattern of FXS?
X-linked dominant
- usually mother has pre-mutation
- repeats lengthen in fertilisation
- daughters protected by other normal X chromosome
- sons always express FXS, symptoms worse as no FMR1 gene on Y chromosome
Which cells are affected by FXS?
Neurons in CNS
Cells that synthesise connective tissue
What is the presentation like in FXS due to neurons in CNS affected?
Slower S&L development
Intellectual disability
1/3 males = ASD
What is the presentation like in FXS due to cells that synthesise connective tissue affected?
Elongation of craniofacial bones
Hyper-reflexion of joints
What is the IQ presentation of FXS?
Learning difficulties
Wide range of IQ, dependent on length of abnormal CGG repeats
What is the emotional + behavioural presentation of FXS?
ASD, poor eye contact
ADD, hyperactivity, impulsivity
Anxiety
Mood disorders
Mild seizures
What is the physical presentation of FXS?
Longer face: large ears, high forehead, large jaws
Flat feet
Large testicles
Extremely flexible joints
Hypotonia (low muscle tone)
How does fragile X affect speech and language?
Boys develop language at half the normal rate
Hypotonia in oral-facial muscles
Expressive lang delayed
Excessive self-repetition
Difficulties turn-taking in conversation
Unpredictable speaking (slow-fast)
As there is no cure for fragile X, what are some interventions?
SLT
Behavioural therapy
SSRIs for anxiety
What is life expectancy for fragile X?
Normal
What is Down’s syndrome?
Neurodevelopmental syndrome named after John Langdon Down in 1962
Genetic, chromosomal disorder
Not typically inherited
Why does Down’s syndrome occur?
Extra chromosome 21 in body cells (95% of cases), trisomy 21
What is the prevalence of Down’s syndrome in UK and England?
1 : 1000 UK
1 : 854 England
Can people with Down’s syndrome have a good QOL?
Yes, can lead active, healthy, independent lives in 60s/70s/beyond
How does trisomy 21 occur in Down’s syndrome?
During meiosis, 2 chromosome 21s don’t separate
Which gametes does trisomy 21 dysfunction occur in?
Usually egg
Occasionally sperm
Can also occur randomly post-fertilisation
How is 5% of Down’s syndrome caused?
Translocation, segment of one chromosome transferred to another
Segament of chromosome 21 transferred to 14 / 15
In Robertson’s, entire chromosome 21 moves
Can be inherited (familial DS)
Which cells are affected in Down’s syndrome?
Proteins encoded by chromosome 21 genes
Also overexpression of many genes…
- excess red blood cells
- smaller frontal + parietal lobe + cerebellum
- delayed myelination
- changes in astrocytes + glial cells
- changes in mitochondria
What is the physical presentation of Down’s syndrome in the face + head + neck?
Brachycephaly (wide + flat head)
Flat facial profile + nasal bridge
Short neck, excessive skin at nape of neck
What is the physical presentation of Down’s syndrome in the ears?
Small simple ears, low set (ear infections + glue ear common)
What is the physical presentation of Down’s syndrome in the eyes?
Inward down slant
Epicanthic folds on medial aspect of eyes
Almond shaped
Brushfield spots
What is the physical presentation of Down’s syndrome in the mouth?
Protruding tongue (due to relatively smaller jaw aka macroglossia)
Mouth hanging open
Narrow palate
Abnormal teeth
What is the physical presentation of Down’s syndrome in the hands and feet?
Clinodactyly (bend-curvature of 5th fingers)
Deep plantar crease (sole of foot)
Sandal gap (space between first + second toes)
What is the physical presentation of Down’s syndrome regarding height?
Short stature
What is the physical presentation of Down’s syndrome in the joints?
Low muscle tone
Hyperflexibility
Double jointed
What is the IQ presentation of Down’s syndrome?
Mild-moderate cognitive impairment
Short attention span
Slow learning abilities
Mental retardation, majority have IQ <50
How does Down syndrome affect speech and language?
Difficulty remembering sounds + putting them into words
Hearing problems (ie: difference between speech sounds) delays speech
Low muscle tone in muscles of mouth
Changes in jaw/tongue/teeth affects articulation
What is Duchenne’s muscular dystrophy (DMD)?
Severe, progressive, muscle wasting disease that leads to difficulties with movement (progressive muscle weakness)
Which areas in particular does Duchenne’s muscular dystrophy affect?
Upper leg
Upper arm
Chest
Why does Duchenne’s muscular dystrophy occur?
Mutation on X chromosome (largest known human gene!)
Recessive trait
What is the prevalence of Duchenne’s muscular dystrophy in the UK?
8 : 100,000
More common in male assigned at birth
What protein does the DMD gene code for?
Dystrophin
Where is the dystrophin protein found?
Skeletal muscle cells
Cardiac muscle cells
Small amounts in nerve cells in brain
What does the dystrophin protein do?
Part of protein complex
Strengthens muscle fibres
Protects fibres from injury during contraction/relaxation
What does a mutation of the DMD gene result in? What are these mutations?
Lack of dystrophin protein
Thousands of different mutations have been found…
- 60-70% deletions
- 5-15% duplications
- 20% point mutations, small deletions, or insertions
Why do males always express DMD even with one allele of the gene, when it is a recessive condition?
Males only have one X chromosome
No dominant healthy gene on Y chromosome to compensate
What are some of the earlier symptoms of Duchenne’s muscular dystrophy, seen at around 2-3y?
Difficulty climbing stairs
Waddling gait
Frequent falls
Learning chair disability
When are those with DMD wheelchair dependent?
10-12y
When do those with DMD require assisted ventilation?
20y
When may death occur for those with DMD?
Premature, 20-40y from cardiac and/or respiratory failure (but lifespan now extended?)
How does DMD affect speech and language?
Slower language development
Delay in being able to comprehend complex verbal info
Poor phonological processing/comprehension
Dysarthria in muscles of tongue + mouth
EDS difficulties
