Genetics Flashcards
Inheritance of duchenne muscular dystrophy?
X-linked recessive - Boys only
Delay in motor development
Onset of weakness around 3-4 years
Die from resp depression in 20s
How do you diagnose Duchenne muscular dystrophy?
- Developmental delay in boys
- Muscle weakness (Gower’s sign, toe walking)
- Raised CK
- EMG
DDx for duchennes is autosomal recessive limb girdle muscular dystrophies (some caused by sarcoglycan deficiencies)
Inheritance pattern of Huntington’s disease?
Autosomal dominant,
- involuntary movements
- dementia
- progression to severe disability and dependence within 15-20years
- age dependent penetrance
CAUDATE atrophy
Late clinical signs of Huntington’s disease?
Bradykinesia (difficulty initiating and continuing movements)
Rigidity
Severe chorea (less common)
What is the molecular genetic defect in Huntington’s disease?
It is in the Huntingtin gene, CAG codes for glutamine and it is the CAG42 that is mutated.
What is the pathology seen in Alzheimers disease?
- Loss of cortical neurones
- Neurofibrillary tangles (intracellular)
- Senile plaques (extracellular)
Senile plaques are extracellular protein deposits containing amyloid beta protein.
Genetic aetiology of Alzheimers disease?
Autosomal dominant in 10% Down syndrome (onset in 3rd or 4th decade)
Name a primary cause of demyelination?
Multiple Sclerosis
Name a few secondary causes of demyelination?
Central pontine myelinosis.
Progressive multifocal leucoencephalopathy.
Common clinical manifestations of multiple sclerosis?
- Visual disturbance
- Parasthesia
- Spasticity of one or more of the extremities.
- Gait abnormalities.
Multiple sclerosis morphology?
External appearance of the brain and spinal cord is usually normal.
Cut surface - multiple areas of demyelination termed “plaques”
MS is a white matter disease and it is grey matter that covers most of the surface of the hemispheres.
How do acute multiple scelerosis appear?
Demyelinated plaques that are yellow/brown with an ill defined edge that blends into the surrounding white matter.
How do chronic multiple sclerosis plaques appear?
Well demarcated grey / brown lesions in the white matter that are classically situated around the lateral ventricles.
Main histological features of MS? (3)
- Inflammation
- Demyelination
- Gliosis
Dementia is a neurodegenerative disorder of which there are two groups:
Primary dementias (organic dementias) - Alzheimer’s disease, diffuse Lewy body disease, Huntington’s disease, Pick’s disease
Secondary dementias – other disorders resulting in secondary changes in the CNS resulting in dementia such as; vascular, metabolic, infection and trauma
Describe Alzheimer’s disease
Insidious impairment of of higher intellectual function, with alterations in mood and behaviour
Later – progressive disorientation, memory loss and aphasia indicate severe cortical dysfunction
What genes are involved in Alzheimers disease?
It is usually a sporadic disease however certain genes can play a role:
Amyloid precursor protein (APP) - Chromosome 21
Presenelin 1 - Chromosome 14
Presenelin 2 - Chromosome 1
Apolipoprotein E - Allele E4
What macroscopic pathology can be seen in Alzheimers disease?
- Decreased size and weight of brain (cortical atrophy), particularly in the frontal and temporal lobes. Parietal lobe can also be affected.
- Widening of sulci
- Narrowing of gyri
- Compensatory dilatation of ventricles, 2* hydrocephalus
- Brainstem and cerebellum normal
Microscopic / Histological features of Alzheimers disease?
- intracytoplasmic neurofibrillary tangles (TAU Protein)
- Aß amyloid plaques (extracellular senile or neuritic plaques)
- amyloid angiopathy
- extensive neuronal loss with astrocytosis
Pathological features of dementia with levy bodies?
- Degeneration of the substantia nigra (as seen in Parkinson’s disease)
- Remaining nerve cells contain abnormal structures called lewy bodies.
Lewy bodies can be detected how?
By immunochemical staining for the protein ubiquitin.
What is the inheritance pattern of Huntington’s disease?
Autosomal dominant (huntingtin gene on chromosome 4p)
List some of the symptoms of Huntington’s disease?
Chorea (dance like movements), myoclonus, clumsiness, slurred speech, depression, apathy (lack of interest or enthusiasm)
Microscopic / Histological appearance of Huntington’s disease?
Loss of neurones in the caudate nucleus and cerebral cortex accompanied by a reactive fibrillary gliosis.
What is Pick’s disease?
A progressive dementia commencing in middle life (usually between 50 and 60 years) characterised by slowly progressing changes in character and social deterioration leading to impairment of intellect, memory and language
What are picks cells?
What are pick bodies?
Pick cells = swollen neurones
pick bodies = intracytoplasmic filamentous inclusions
What are the main symptoms of Pick’s disease?
- Progressive changes related to frontal and temporal lobes. Personality and behavioural change Speech and communication problems Changes in eating habits Reduced attention span
Rapidly progressive, mean length of illness = 7 years.
How many repeats need to be present for Huntington’s to present?
Disease definitely seen in > 40 repeats and not seen if <35 repeats.
CAG42 on Chromosome 4p results in production of a neurotoxin.
What is Sydenham’s chorea?
Self limiting chorea that occurs in children after a strep throat infection.
What is the average lifespan after diagnosis of Huntington’s?
15years.
