Neurodegenerative disorders Flashcards
What is Huntington’s disease?
Autosomal dominant trinucleotide repeat disease characterised by progressive chorea and dementia, typically commending in middle age.
What is chorea?
Involuntary muscle movements
What is the aetiology of Huntington’s disease?
GENETIC: huntingtin gene is located on Chr4p and codes for huntingtin. There is repeat expansion of CAG at N-terminal resulting in a toxic chain of function. This disease is inherited in an autosomal dominant pattern and exhibits ANTICIPATION, meaning earlier age of onset in each successive generation.
What is the role of huntingtin?
Axonal transport
What is the epidemiology of Huntington’s disease: Age? Ethnicity?
Average age of onset is 30-50. Rare in East Asian populations
What are the signs and symptoms of Huntington’s disease? (x4)
- Insidious onset of progressive fidgeting, clumsiness, developing into involuntary, jerky, dyskinetic movements accompanied by grunting and dysarthria (motor speech disorder)
- Late disease: rigidity, akinetic, bed-bound
- EYE: slow voluntary saccades (eyes jump rather than move smoothly e.g., when reading sentence; can be indicated by head turning and blinking), and supranuclear gaze restriction (not able to look in vertical direction)
- Cognitive impairment: lability (rapid changes in mood), dysphoria (unease with life), mental inflexibility, depression, leading to dementia
What are the investigations for Huntington’s disease? (x3)
- Diagnosis is CLINICAL!
- GENETIC ANALYSIS: diagnostic if over 39 CAG repeats in the HD gene
- IMAGING: MRI or CT show symmetrical atrophy of the striatum (where disease mostly affects) and butterfly dilation of lateral ventricles
- BLOODS: exclude other pathology such as ceruloplasmin (high levels can lead to Wilson’s, Alzheimer’s and schizophrenia), ANA (test for acanthocytes (abnormal RBCs) in blood film as acanthocytosis can be a cause of chorea)
What is motor neurone disease?
Progressive neurodegenerative disorder of cortical, brainstem and spinal motor neurones (LMN and UMN)
What are the types of MND? (x5)
- Amyotrophic lateral sclerosis (ALS) aka. Lou Gehrig’s disease: combined degeneration of UMN and LMNs
- Progressive muscular atrophy variant: LMN signs only such as flail arm or flail foot syndrome (complete lack of mobility and sensation)
- Progressive bulbar palsy variant: dysarthria and dysphagia with wasted fasciculating tongue (LMN) and brisk jaw jerk (UMN)
- Pseudobulbar palsy variant: UMN lesion to the lower brainstem, presenting with monotonous speech, dysphagia, raised gag reflex, brisk jaw jerk reflex, shrunk immobile tongue, UMN limb spasticity and weakness
- Primary lateral sclerosis variant: UMN pattern of weakness, brisk reflexes, extensor plantar responses, with no LMN signs
What is bulbar palsy?
Any lesion affecting CNIX-CNXII at nuclear, nerve or muscle level, presenting with nasal speech, nasal regurgitation of food, especially liquids (palatal weakness), reduced gag reflex, absent jaw jerk, and wasted fasciculating tongue.
What is the aetiology of MND?
Family history in 10% of cases with autosomal dominant pattern. Free radical damage and glutamate excitotoxicity have been implicated and caused by mutations in superoxide dismutase (SOD1 gene). SOD1 codes for metalloenzyme for the conversion of free radicals. However, this has only be identified as a cause in 20% of familial cases and 4% of sporadic cases. Aetiology is otherwise unknown.
What is the pathophysiology of MND? (x2 points)
Motor neurone degeneration and death, coupled with gliosis (hypertrophy and proliferation of glial cells such as astrocytes, microglia, and oligodendrocytes) replacing lost neurons. Neurones may exhibit intracellular inclusions (general term for abnormal microscopic collection; neurofilaments or ubiquitin – a degradation protein)
What is the epidemiology of MND: Age?
Mean age of onset is 55
What are the signs and symptoms of MND? (x2 +4 +1)
- Combination of UMN and LMN signs, often affecting several regions asymmetrically
- LMN: wasting, fasciculations, flaccid weakness, depressed or absent reflexes
- UMN: spastic weakness, unsteady gait, brisk reflexes, extensor plantars. Note that UMN relates to raised tone and reflexes; LMN is the opposite
- Speech disturbance (slurring or reduction in volume) from UMN loss of coordination of tongue, and LMN weakness
- Dysphagia (chocking, nasal regurgitation) from UMN loss of coordination of tongue, and LMN weakness of tongue and pharyngeal muscles
- Behaviour changes (disinhibition, emotional liability)
- May have respiratory signs from progressive diaphragmatic weakness
- SENSORY examination is NORMAL
What are the investigations for MND? (x4)
- Diagnosis is clinical, after ruling out differentials
- BLOOD: mildly elevated CK. Consider testing anti-GM1 ganglioside antibodies to exclude multifocal motor neuropathy (not MND but characterised by asymmetrical LMN signs and conduction block)
- EMG: shows denervation with giant motor unit action potentials in more than 1 limb
- NERVE CONDUCTION STUDIES: normal
- MRI: exclude cord or root compression, and brainstem lesion in bulbar palsy variant
