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Questions and Answers
What is the genetic cause of SMA III (Kugelberg-Welander disease)?
At what age does SMA III typically develop?
What is a common initial symptom observed in patients with ALS?
In which demographic does adult-onset motor neuron disease typically begin?
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What characterizes the pathology of ALS?
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Which of the following treatment approaches has shown improvement for SMA?
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What typically results from the degeneration of motor neurons in ALS?
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What is the average age of onset for adult motor neuron disease?
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What is the most common form of sporadic cerebellar ataxia?
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Which of the following is NOT a clinical feature of cerebellar ataxia?
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Autoimmune cerebellar syndromes are significant because they can be:
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What is the proposed mechanism leading to symptoms in polyglutamine ataxias?
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What might autoimmune cerebellar ataxia indicate?
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In which inheritance pattern are spinocerebellar ataxias commonly found?
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Which of the following disorders primarily affects the cerebellum and its connections?
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Which of the following is a key feature of polyglutamine ataxias?
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What percentage of sporadic ALS patients shows a significant decrease in glutamate transport activity?
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Which protein is associated with glutamate transport in ALS?
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What is the typical inheritance pattern of familial ALS cases due to SOD1 mutations?
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Which of the following hypotheses is supported by findings of elevated carbonyl proteins in ALS patients' brains?
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Which intermediate filament protein is found alongside neurofilaments in ALS neuronal inclusions?
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What cellular event is induced by inhibition of glutamate transport in cultured spinal cord slices?
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Which of the following roles does the protein SOD1 play in the body?
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What makes cytoskeletal proteins particularly critical for motor neuron function?
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What disease is characterized by missense mutations in the ubiquitin carboxyl terminal hydrolase L1?
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What is the primarily affected enzyme in the most common genetic form of Parkinson disease?
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In myasthenia gravis, which muscle group is most commonly affected?
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What happens to the activity of glucocerebrosidase in patients with sporadic Parkinson disease?
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What are the primary antibodies found in 90% of myasthenia gravis patients?
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Which mechanism is suggested to contribute to neurodegeneration in patients with parkin mutations who lack Lewy bodies?
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What structural abnormality is major in myasthenia gravis at the neuromuscular junction?
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What is the consequence of inhibiting glucocerebrosidase in Parkinson disease patients?
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What is the primary aim of treatment strategies for myasthenia gravis?
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Which treatment is particularly indicated if a thymoma is suspected in a myasthenia gravis patient?
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What common condition is characterized by recurrent seizures resulting from abnormal synchronous discharge of cortical neurons?
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Which type of seizure is characterized by a loss of consciousness and rhythmic contractions of the body?
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What is often ineffective for MuSK antibody-positive patients with myasthenia gravis?
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What can disrupt AChR clustering in double seronegative myasthenia gravis patients?
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What reflects the synchronous depolarization of neuron groups in epilepsy?
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What typically suppresses neuronal excitability under normal conditions?
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Study Notes
Cerebellar Ataxia
- A group of disorders affecting the cerebellum and its connections
- Clinical features: ataxic gait, truncal ataxia, dysmetria, limb ataxia, vertigo, tremor, dysarthria, and abnormal eye movements
- Prevalence of inherited ataxias: 25-30 per 100,000 persons
- Common causes: vascular insults, toxins, infections, autoimmune disorders, vitamin deficiencies, and degenerative conditions
- Most common sporadic form: Multiple system atrophy of the cerebellar type (MSA-C)
- Heritable ataxias can be inherited in dominant (spinocerebellar ataxias) or recessive patterns
Polyglutamine Ataxia
- The largest group of dominantly inherited ataxias
- Result from glutamine-encoding CAG repeats in various disease genes (SCA types 1, 2, 3, 6, 7, and 17)
- Expanded polyglutamine repeats in the respective disease proteins are thought to cause a toxic gain-of-function
- Proposed mechanisms: altered protein function, formation of toxic oligomeric complexes, transcriptional dysregulation, aberrant neuronal signaling, mitochondrial dysfunction, impaired axonal transport, impairment in cellular protein homeostasis, and RNA toxicity
Autoimmune and Paraneoplastic Ataxia
- Autoimmune cerebellar syndromes represent a small but important subset of ataxias
- Important to recognize because some are treatable, particularly when identified early
- A subset is associated with underlying malignancy, where the ataxia results from immune cross-reactivity between tumor and cerebellar antigens
- Neurological symptoms may indicate the presence of a previously unidentified tumor, making the ataxia a paraneoplastic syndrome
Spinal Muscular Atrophy (SMA)
- A group of autosomal recessive disorders characterized by progressive degeneration of alpha motor neurons
- Result from mutations in the survival motor neuron 1 (SMN1) gene on chromosome 5q13
- The SMN protein is expressed in all tissues and appears to be involved in RNA metabolism
- Three forms:
- SMA I (Werdnig-Hoffmann disease): onset before 6 months, severe weakness and death within 2 years
- SMA II (intermediate form): onset between 6-18 months, progresses more slowly
- SMA III (Kugelberg-Welander disease): develops after age 2, proximal limb weakness that progresses gradually into adulthood
- Loss of SMN function promotes apoptosis of lower motor neurons
- Recent research has focused on antisense oligonucleotides and stem cell therapies to slow disease progression
Adult-Onset Motor Neuron Disease
- Typically begins between ages 20 and 80, with an average onset at 56 years
- While usually sporadic, up to 10% of cases are familial
- Several varieties exist, depending on the relative involvement of upper or lower motor neurons and bulbar or spinal anterior horn cells
- X-linked spinobulbar atrophy is an X-linked recessive disorder typically manifesting in the fourth or fifth decade, associated with an expanded CAG repeat in the androgen receptor gene
Amyotrophic Lateral Sclerosis (ALS)
- The most common form of adult motor neuron disease
- Involves mixed upper and lower motor neuron deficits in limb and bulbar muscles
- Initial symptoms often result from limb muscle weakness, often bilateral but asymmetric
- Bulbar muscle involvement causes difficulty with swallowing, chewing, speaking, breathing, and coughing
- The disease is progressive and generally fatal within 3-5 years, with death typically resulting from pulmonary infection and respiratory failure
Pathology of ALS
- Selective degeneration of motor neurons in the primary motor cortex and the anterolateral horns of the spinal cord
- Many affected neurons show cytoskeletal disease with accumulations of intermediate filaments in the cell body and axons
- The glial cell response is subtle, and there is little evidence of inflammation
Glutamate Signaling and RNA Processing in ALS
- Glutamate is the most abundant excitatory neurotransmitter in the CNS
- In 60% of patients with sporadic ALS, there is a large decrease in glutamate transport activity in the motor cortex and spinal cord
- This has been associated with a loss of the astrocytic glutamate transporter protein EAAT2, possibly due to defective mRNA splicing
- Defective RNA editing of the GluR2 receptor subunit has been found in spinal motor neurons from some ALS patients, potentially increasing calcium permeability of glutamate receptors
Free Radicals in ALS
- About 10% of ALS cases are familial, and 20% of these result from missense mutations in the cytosolic copper-zinc superoxide dismutase (SOD1) gene on chromosome 21q
- SOD1 catalyzes the formation of hydrogen peroxide from superoxide anions
- The disorder is typically inherited as an autosomal dominant trait, suggesting a gain-of-function mutation
- One hypothesis suggests that mutant SOD1 has altered substrate specificity, catalyzing reactions that produce hydroxyl radicals and nitration of tyrosine residues in proteins
Cytoskeletal Proteins in ALS
- Neurofilamentous inclusions in cell bodies and proximal axons are an early feature of ALS pathology
- Mutations in the heavy chain neurofilament subunit (NF-H) have been detected in some patients with sporadic ALS
- Peripherin, another intermediate filament protein, is found with neurofilaments in neuronal inclusions in ALS and in mice with SOD1 mutations
Parkinson's Disease
- A progressive neurodegenerative disorder characterized by resting tremor, bradykinesia, rigidity, and postural instability
- Caused by the loss of dopaminergic neurons in the substantia nigra pars compacta
- Lewy bodies, protein aggregates containing α-synuclein, are a hallmark of the disease
- Several potential causes include mutations in specific genes, exposure to toxins, and oxidative stress
Genetics of Parkinson's Disease
- A missense mutation in ubiquitin carboxyl terminal hydrolase L1 has been identified in one family with autosomal dominant Parkinson disease
- Mutations in parkin, an E3 ubiquitin ligase, cause autosomal recessive juvenile parkinsonism
- These parkin mutations lead to loss of function, presumably disturbing protein degradation
Glucocerebrosidase in Parkinson Disease
- The most common known genetic form of Parkinson disease involves mutations in the glucocerebrosidase (GCase) enzyme
- GCase is involved in lysosomal processing
- Enzyme activity is reduced by 58% in the substantia nigra of heterozygous patients and by 33% in patients with sporadic Parkinson disease
- Inhibiting this enzyme leads to accumulation of α-synuclein, which further inhibits the enzyme, creating a vicious cycle that may contribute to disease progression
Myasthenia Gravis
- An autoimmune disorder of neuromuscular transmission characterized by fluctuating fatigue and weakness that improve with rest and acetylcholinesterase inhibitors
- Muscles with small motor units, like ocular muscles, are most often affected
- Oropharyngeal muscles, neck flexors and extensors, proximal limb muscles, and erector spinae muscles may also be involved
- Severe cases can affect all muscles including the diaphragm and intercostals, potentially leading to respiratory failure
Pathophysiology of Myasthenia Gravis
- The major structural abnormality is simplification of the postsynaptic region of the neuromuscular junction
- Circulating antibodies to the acetylcholine receptor (AChR) are present in 90% of patients
- These antibodies block acetylcholine binding and receptor activation, cross-link receptor molecules increasing internalization and degradation, and activate complement-mediated destruction of the postsynaptic region
- Some AChR antibody-negative patients have autoantibodies against muscle-specific receptor tyrosine kinase (MuSK), which inhibits AChR clustering
Treatment of Myasthenia Gravis
- Treatment strategies aim to increase acetylcholine at the neuromuscular junction and inhibit immune-mediated destruction of AChRs
- Cholinesterase inhibitors can compensate for the decline in neurotransmitter release during repeated stimulation
- Plasmapheresis, corticosteroids, and immunosuppressants effectively reduce autoantibody levels
- Thymectomy is indicated if a thymoma is suspected and can induce remission or improve symptoms in many patients
- For MuSK antibody-positive patients, cholinesterase inhibitors are often ineffective, but plasma exchange and immunosuppressive therapy can be very beneficial
Epilepsy
- A group of disorders characterized by recurrent seizures, which are paroxysmal disturbances in cerebral function caused by abnormal synchronous discharge of cortical neurons
- Seizures are classified based on behavioral and electrophysiologic data
- Types include: generalized tonic-clonic seizures, absence seizures, focal seizures, and various other forms
Pathogenesis of Epilepsy
- Seizures occur when neurons are activated synchronously
- Interictal spike discharges on EEG reflect synchronous depolarization of neuron groups in abnormally excitable brain areas
- This paroxysmal depolarizing shift is followed by a hyperpolarizing afterpotential
- Disruption of inhibitory mechanisms involving GABA and potassium currents may allow for the development of a seizure focus
- Spread of local discharges occurs through accumulation of extracellular potassium, enhanced neurotransmitter release at excitatory synapses, and decreased efficacy of inhibitory synapses during high-frequency stimulation
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Description
This quiz covers the disorders affecting the cerebellum, including clinical features, prevalence, and common causes of cerebellar ataxia. It also focuses on polyglutamine ataxias, the largest group of dominantly inherited ataxias caused by expanded CAG repeats. Test your knowledge on these neurological conditions and their genetic implications.
