Alternative genetic mechanisms of disease causation Flashcards
Define triplet repeat disorders
Triplet repeat disorders are characterised by an abnormal number of triplet repeat sequences either in the coding or non-coding regions
Define the phenomenon of anticipation
Phenomenon of decreasing age of onset or increasing disease severity through successive generations
- Occurs more commonly in paternal transmission
- Sperm precursors constantly replicating - More opportunities for errors
- Ova begin meiosis in uterone, the pause in prophase 1
- Only one round of DNA replication in oogenesis
What are the clinical features of Huntington’s disease?
Neurological:
- Chorea (>90% individuals)
- Impaired voluntary movements
- Gait disturbance
- Dysphagia/Dysarthria
Psychiatric:
- Change in personality
- Increased incidence of suicide (possibly up to 12% affected)
Cognitive decline
What is the clinical managment of Huntington’s disease?
- No cure
- Medications to help chorea
- Antidepressents and antipsychotics
- Therapies - OT, SLT, physio
Describe the genotype of Huntington’s disease?
- Expansion of a CAG trinucleotide repeat in exon 1 of huntington gene (HTT)
- CAG repeat → Polyglutamine tract
- Number of CAG repeats = Significant
Describe genetic counselling
Genetic counselling is the process of investigating patients who are affected by or at risk of genetic disorders
- Autosomal dominant disorder
- Diagnoistic vs predictive testing
- Reasons for predictive testing:
- Reduce uncertainity
- Reproductive decision making
- Hope for future treatments
- Reasons against predictive testing:
- Absence of disease-modifying treatments
- Anxiety about an abnormal result - prefer living with uncertainty
- Already had children
Describe the features of fragile X syndrome
Characterised by:
- Developmental delay
- Learning disability
- Behavioral difficulties
- Autism spectru disorder (50-70%)
Physical features:
- Long face
- Prominent forehead
- Large ears
- Macroorchidism always seen post-pubertally
Medical problems in childhood:
- Reflux
- Hypotonia
- Strabismus
- Seizures
- Sleep disorders
- Joint laxity
- Pes planus
- Scoliosis
- Recurrent otitis media
What causes fragile X syndrome?
- Caused by an expanded CGG trinucleotide repeat (>200 repeats) in the 5’-UTR of FMR1 on the X-chromosome
- X linked dominant inheritance
- Females can be affected due to skewed X inactivation
- Aberrant hypermethylation of the expanded repeat leads to decrease in or silencing of FMR1 so no FMR protein is produced
Describe fragile X associated premature ovarian insufficiency
- Hypergonadotropic hypogonadism before age 40
- Observed in 20% of women who carry a premutation allele compared to 1% of general population
Describe fragile X associated tremor/ataxia syndrome (FXTAS)
- Late onset, progressive cerebellar ataxia and intention tremor followed by cognitive impairment
- Typical age of onset 60-65 y/o
- More common in males
What is the function of epigenetics?
Epigenetic is the study of changes in organisms caused by modification of gene expression rather than alteration of the genetic code itself
- Controls how genome is regulated w/o altering DNA sequence:
- DNA methylation
- Non-coding RNA (ncRNA) associated gene silencing
- Histone modification
- Acquired, transient, adaptive vs permanently from formation of the zygote
Define imprinting and the meaning of imprinting disorders
Imprinting disorders result from changes in the expression of imprinted genes themselves, or epigenetic changes in their control
Imprinting:
- Process by which only one copy of a gene in an individual (either from mum or dad) is expressed, while the other copy is suppressed
- Variety of mechanisms, predominantly methylation imprinting which occurs during development of male and female germ cells
- Imprinted gene expression is controlled by imprinting control regions (ICRs)
- Maintained throughout life
- Many of the genes are involved in embryonic growth, placental development, metabolism and tumour sepression
What is imprinted gene expression controlled by?
Imprinting control regions (ICR, also known as imprinting centres) that demonstrate differential DNA methylation
Describe Prader Willi syndrome and its cause
Caused by an absence of expression of imprinted genes in the paternally derived Prader Willi critical region of chromosome 15
Infancy:
- Hypotonia with history of poor suck
- Poor feeding
- Global developmental delay
Childhood:
- History of hypotonia
- Global developmental delay
- Excessive eating with central obesity if uncontrolled
- Short stature
Adulthood:
- Cognitive impairment, usally mild intellectual disability
- Excessive eating with central obesity if uncontrolled
- Hypogonadism
- Typical behavioural phenotype
Describe Angelman syndrome and its cause
Caused by loss of maternal expression of UBE3A in 15q11-q13
- Severe developmental delay or intellectual disability
- Severe speech impairment
- Gait ataxia and/or tremulousness of limbs
- Typical behavioural profile - Happy demeanor that includes frequent laughing, smiling and excitability
- Microcephaly
- Seizures are common
- Scoliosis
Compare Prader Willi to Angelman
Prader Willi:
Abnormal methylation at 15q11-q13 due to:
- Deletion of 15q11-q13 on paternal chromosome 15 (includes SNRPN) - Loss of paternal expression of genes on chromosme 15q11-q13
- Uniparental disomy of maternal chromosome 15
- Imprinting defect on paternal chromosome 15 e.g. abnormalities of the imprinting control region (ICR)
Angelman:
Abnormal methylation at 15q11-q13 due to:
- Deletion of 15q11-q13 on maternal chromosome 15 (including UBE3A) - Loss of maternal expression of genes in chromosome 15q11-q13
- Uniparental disomy of paternal chromosome 15
- Imprinting defect on maternal chromosome 15 e.g. abnormalities of the imprinting control region (ICR) → loss of expression of UBE3A
- Pathogenic variant in maternal UBE3A e.g. point mutation
Compare the features of Beckwith-Wiedemann Syndrome to Silver Russel Syndrome
Both are imprinting disorders
Beckwith- Wiedemann:
- Neonatal hypoglycaemia
- Macrosomia
- Macroglossia
- Hemihypertrophy
- Exomphalos
- Embryonal tumours (e.g. Wilms tumour, hepatoblastoma)
- Renal abnormalities
- Ear creases/pits
Silver Russell:
- Asymmetric IUGR with relative macrocephaly
- Triangular face
- Frontal bossing
- Body asymmetry
- Growth failure
Compare the causes of Beckwith-Wiedemann Syndrome to Silver Russel Syndrome
BWS - Abnormal methylation at 11q15.5 due to:
- Loss of methylation on the maternal chromosome at IC2 (50%)
- Paternal UPD (20%)
- Gain of methylation on the maternal chromosome at IC1 (5%)
- Pathogenic variant in maternally inherited CDKN1C (5%)
- Cytogenetic abnormalities
SRS - Abnormal methylation at 11q15.5 due to:
- Loss of paternal methylation of IC1 11p15.5 (35-50%_
- Rarely - Cytogenetic abnormalities involving the imprinting centers at 11p15.5
- Rare - Pathogenic LOF variants in IGF2
- Unknown (40%)
Describe mitochondrial DNA
- Each mitochondrion contains one copy of circular mitochondrial DNA (mtDNA)
- 37 genes are encoded my mtDNA, all of which are involved in oxidative phosphorylation
- 100,000-600,000 mitochondria per egg cell
- 50-75 mitochondria per sperm cell
- Sperm mitochondria do not enter the egg and are marked for destruction following fertilisation. Therefore, mitochondrial DNA and variations are always maternally inherited
Describe mitochondrial inheritance
Maternally inherited
Define mitochondrial disorders
Pathogenic variation with mitochondrial genome leading to mitochondrial disorders. They are maternally inherited
Mitochondrial diseases are usually severe, resulting from defects in the production of energy
What are the common clinical symptoms of mitochondrial disorders?
- Deafness
- Blindness
- Diabetes
- Seizures
- Loss of skills
- Heart and liver failure
Describe the features of LHON
LHON = Leber Hereditary Optic Neuropathy
Optic features:
- Bilateral, painless, subacute visual failure
- Optic disc atrophy and optic nerve dysfunction
- Severely reduced visual acuity - majority cases registered legally blind
Extraocular features:
- Neurologic abnormalities
- Postural tremor
- Peripheral neuropathy
- Movement disorders
- Multiple sclerosis-like illness
- Nonspecific myopathy
- Cardiac arrhythmias
Describe MERRF
MERRF = Myoclonic Epilepsy Associated with Ragged Red Fibres
- Multisystem disorder charaterised by myoclonus (often 1st symptom) followed by generalised epilepsy, ataxia, weakness, and dementia
- Onset usually in childhood, after normal early development
- Common symptoms:
- Hearing loss
- Lipomas
- Short stature
- Optic atrophy
- Cardiomyopathy with Wolff-Parkinson-White (WPW) syndrome
- Pigmentary retinopathy and lipomatosis are occasionally observed
How is MERRF investigated?
- Biochemical tests (blood, CSF) - Lactic acidosis
- EEG - Generalised spike and wave discharges with background slowing
- ECG - Pre excitation
- EMG - Myopathy
- Brain MRI - Brain atrophy and basal ganglia calcification
- Muscle biopsy - Ragged red fibers (RRF)
Describe Homoplasmy and Heteroplasmy
Homoplasmy:
mtDNA genomes in mitochondria or cells are either uniformly wild-type or uniformly mutant
Heteroplasmy:
mtDNA genomes in mitochondria or cells are a mixture of mutant and wild-type DNA. There is an approximate correlation of symptom severity with increasing mutant mtDNA load
