Nervous System Disorders PDF

Nervous System Disorders This document provides an overview of major nervous system disorders, including cerebellar ataxia, motor neuron disease, Parkinson's disease, myasthenia gravis, epilepsy, Alzheimer's disease, and stroke. It covers the clinical presentations, pathophysiology, and current unde...

Nervous System Disorders This document provides an overview of major nervous system disorders, including cerebellar ataxia, motor neuron disease, Parkinson's disease, myasthenia gravis, epilepsy, Alzheimer's disease, and stroke. It covers the clinical presentations, pathophysiology, and current understanding of the molecular mechanisms underlying these conditions. The text explores how advances in genetics and neuroscience are shedding light on disease processes and potential therapeutic targets. by pharmaqz pharmacist Cerebellar Ataxia Cerebellar ataxia refers to a group of disorders affecting the cerebellum and its connections. Clinical features include ataxic gait, truncal ataxia, dysmetria, limb ataxia, vertigo, tremor, dysarthria, and abnormal eye movements. Causes range from vascular insults and toxins to infections, autoimmune disorders, vitamin deficiencies, and degenerative conditions. The prevalence of inherited ataxias may be as high as 25-30 per 100,000 persons. Multiple system atrophy of the cerebellar type (MSA-C) is the most common sporadic form. 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, including SCA types 1, 2, 3, 6, 7, and 17. The expanded polyglutamine repeats in the respective disease proteins are thought to cause a toxic gain-of-function. Although the affected proteins have diverse roles, the clinical features of polyglutamine SCAs are remarkably similar. Proposed mechanisms include 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. They are crucial 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. The neurological symptoms may indicate the presence of a previously unidentified tumor, making the ataxia a paraneoplastic syndrome. Understanding these autoimmune ataxias can provide insights into disease pathogenesis and guide treatment approaches. Gluten Ataxia Cerebellar ataxia can be a neurological manifestation of celiac disease, a disorder associated with gluten sensitivity. Patients may experience gastrointestinal symptoms like diarrhea and bloating along with ataxia following gluten ingestion. Antibodies against tissue transglutaminase 6 serve as a serologic marker. Interestingly, mutations in the gene encoding transglutaminase 6 (TGM6) can cause a rare genetic form of cerebellar ataxia. A gluten-free diet can reduce antibody levels over time, potentially resolving gastrointestinal symptoms and improving neurological symptoms. Cerebellar Ataxias from Ion-Channel Antibodies Some patients with cerebellar ataxia have elevated levels of antibodies directed against calcium channels (P/Q- and N-type) and voltage-gated potassium channels. P/Q-type calcium channels are highly expressed in cerebellar Purkinje neurons, and reduced channel activity is associated with ataxia in mouse models. In humans, mutations in CACNA1A, the gene encoding the P/Q calcium channel, result in episodic spinocerebellar ataxia type 2 (SCA2) and spinocerebellar ataxia type 6 (SCA6). These findings highlight the importance of ion channel function in cerebellar physiology and ataxia pathogenesis. Motor Neuron Disease: Clinical Presentation Motor neuron diseases predominantly affect the anterior horn cells of the spinal cord, causing wasting and skeletal muscle weakness. Patients may experience fasciculations (muscle twitches) due to spontaneous discharges of degenerating motor nerve fibers. Electromyography typically shows features of denervation, including increased spontaneous discharges (fibrillations) in resting muscle and reduced motor units during voluntary contraction. Reinnervation by sprouting of remaining healthy motor fibers can lead to large, polyphasic motor unit potentials. Spinal Muscular Atrophy Spinal muscular atrophies (SMAs) are a heterogeneous group of genetic diseases characterized by selective degeneration of lower motor neurons. The most common form is autosomal recessive with childhood onset, occurring in 1:6000 to 1:10,000 individuals. Childhood SMA is divided into three types based on age of onset and clinical progression. SMA I (Werdnig-Hoffmann disease) manifests within the first 3 months of life, causing difficulty with sucking, swallowing, and breathing. It progresses rapidly, often leading to death by age 3. SMA II begins in the latter half of the first year and progresses more slowly. SMA III (Kugelberg-Welander disease) develops after age 2, causing proximal limb weakness that progresses gradually into adulthood. Genetics of Spinal Muscular Atrophy All three forms of childhood SMA result from deletions or 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. Loss of SMN function promotes apoptosis of lower motor neurons, though the reason for selective motor neuron vulnerability remains unknown. Clinical trials have explored modulating SMN protein levels using drugs like hydroxyurea and valproic acid, but these have not shown improvement. Recent research has focused on antisense oligonucleotides and stem cell therapies to slow disease progression. Adult-Onset Motor Neuron Disease In adults, 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. Like other triplet repeat disorders, it is characterized by neuronal inclusions. Testosterone promotes inclusion formation, and female homozygotes develop only mild symptoms. Amyotrophic Lateral Sclerosis (ALS) Amyotrophic lateral sclerosis (ALS) is the most common form of adult motor neuron disease. It involves mixed upper and lower motor neuron deficits in limb and bulbar muscles. In 80% of patients, initial symptoms result from limb muscle weakness, often bilateral but asymmetric. Bulbar muscle involvement causes difficulty with swallowing, chewing, speaking, breathing, and coughing. Neurologic examination reveals a mixture of upper and lower motor neuron signs. Extraocular muscles and sphincters are usually spared. The disease is progressive and generally fatal within 3-5 years, with death typically resulting from pulmonary infection and respiratory failure. Pathology of ALS In ALS, there is 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. While the exact cause is unknown, biochemical and genetic studies have provided several clues about potential mechanisms involved in the disease process. 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. Inhibition of glutamate transport in cultured spinal cord slices induces motor neuron degeneration, suggesting that loss of glutamate transporters may cause excitotoxicity in ALS by increasing extracellular glutamate levels. Additionally, 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. Transgenic mice expressing mutant SOD1 develop motor neuron disease analogous to human familial ALS. One hypothesis suggests that mutant SOD1 has altered substrate specificity, catalyzing reactions that produce hydroxyl radicals and nitration of tyrosine residues in proteins. This is consistent with findings of elevated carbonyl proteins in the brain and free nitrotyrosine in the spinal cord of ALS patients. Cytoskeletal Proteins in ALS Motor neurons are very large cells with extremely long axons, making cytoskeletal proteins critical for maintaining axonal structure. 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. Peripherin expression increases in response to cell injury, and its overexpression causes late-onset motor neuron disease in mice. Inclusions containing peripherin and neurofilaments may interfere with axonal transport, disrupting the maintenance of axonal structure and transport of macromolecules like neurotrophic factors required for motor neuron survival. TDP-43 in ALS and Frontotemporal Dementia The discovery of transactive response DNA-binding protein 43 (TDP-43) has provided new insights into ALS pathogenesis. TDP-43 is the major component of ubiquitinated, tau-negative inclusions that are the pathological hallmark of sporadic and familial ALS and frontotemporal dementia (FTD). It is also found in some cases of Alzheimer's and Parkinson's diseases. Mutations in the TDP-43 gene co-segregate with disease in familial forms of ALS and FTD. FTD and ALS overlap in approximately 15-25% of cases, leading to the term "TDP-43 proteinopathies" for these disorders. Several other genes have been identified that can cause both FTD and ALS, including TARDBP, MAPT, and DCTN1. C9ORF72 in ALS and FTD The major genetic cause of ALS and/or FTD was recently discovered to be hexanucleotide repeats in an intron of C9ORF72 on chromosome 9. These repeats are found in 34% of familial ALS cases, 6% of sporadic ALS cases, 26% of familial FTD cases, and 5% of sporadic FTD cases. The protein encoded by C9ORF72 is of unknown function. These mutations likely induce a gain-of-function similar to other noncoding repeat expansion disorders. This discovery of another disorder caused by nucleotide repeats may provide additional rationale for developing new drugs focused on decreasing expression of these toxic repeats. Parkinson Disease: Clinical Presentation Parkinsonism is a clinical syndrome characterized by rigidity, bradykinesia, tremor, and postural instability. Most cases are due to Parkinson disease, an idiopathic disorder affecting 1-2 per 1000 people. Parkinsonism can also result from exposure to certain toxins, drugs, repeated head trauma, or as a feature of other basal ganglia diseases. In Parkinson disease, there is selective degeneration of monoamine-containing cell populations in the brainstem and basal ganglia, particularly dopaminergic neurons of the substantia nigra. Scattered neurons contain eosinophilic, cytoplasmic Lewy bodies composed of α-synuclein aggregates along with other proteins. MPTP and Parkinson Disease Pathogenesis Important clues about Parkinson disease pathogenesis have come from studying the neurotoxin MPTP. MPTP selectively injures dopaminergic neurons and produces a syndrome very similar to Parkinson disease. It enters the brain and is converted by monoamine oxidase B to MPP+, which is taken up by dopaminergic neurons. MPP+ inhibits mitochondrial complex I, reducing ATP production and increasing formation of reactive oxygen species. This supports a role for mitochondrial dysfunction and oxidative damage in Parkinson disease pathogenesis. Impaired complex I activity has been observed in cell lines from Parkinson disease patients, and a genetic variant of complex I is associated with reduced disease risk in Caucasians. Dopamine and Oxidative Stress in Parkinson Disease Dopaminergic neurons appear selectively vulnerable to complex I inhibition, possibly due to dopamine's potential to promote neurotoxicity. Dopamine can undergo auto-oxidation to generate superoxide radicals or be metabolized by monoamine oxidase to produce hydrogen peroxide. While superoxide dismutase converts superoxide to H2O2, which is normally detoxified by glutathione peroxidase and catalase, H2O2 can also react with ferrous iron to form highly reactive hydroxyl radicals. Thus, dopamine within dopaminergic neurons may provide a source of reactive oxygen species that, when coupled with reduced complex I function, promotes cell death. Genetics of Parkinson Disease Approximately 5% of Parkinson disease cases are familial. Genetic studies have identified causative mutations in several genes, providing important information about molecular pathways involved in the disease. These genes include α-synuclein (PARK1), parkin (PARK2), DJ-1 (PARK7), ubiquitin- C-hydrolase-L1 (PARK5), PTEN-induced kinase 1 (PINK1), and leucine-rich repeat kinase 2 (LRRK2). Mutations in α-synuclein cause autosomal dominant Parkinson disease. Overexpression of normal α-synuclein in transgenic mice results in Lewy body formation and motor impairment. Genomic triplication of α-synuclein leading to overexpression has been documented in a human family with autosomal dominant Parkinson disease, suggesting that α-synuclein aggregation contributes to dopaminergic neuron degeneration. Protein Degradation and Parkinson Disease Misfolded or damaged proteins are normally degraded through the ubiquitin-proteasome system. Mutations in components of this system have been found in some familial Parkinson disease cases. For example, 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. However, most patients with parkin mutations lack Lewy bodies, suggesting other mechanisms like increased oxidative stress may cause neurodegeneration in these cases. Glucocerebrosidase in Parkinson Disease The most common known genetic form of Parkinson disease involves mutations in the glucocerebrosidase (GCase) enzyme. These account for 3% of sporadic Parkinson disease cases and 25% of juvenile-onset cases. 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: Clinical Presentation Myasthenia gravis is 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. In severe cases, all muscles including the diaphragm and intercostals can be affected, potentially leading to respiratory failure. Myasthenia gravis is associated with other autoimmune disorders, suggesting a shared genetic predisposition. Pathophysiology of Myasthenia Gravis The major structural abnormality in myasthenia gravis is simplification of the postsynaptic region of the neuromuscular junction. The muscle end plate shows sparse, shallow, and abnormally wide or absent synaptic clefts. 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. During repetitive nerve stimulation, the reduced number of functional receptors leads to neuromuscular transmission failure at lower levels of quantal release, manifesting as muscle fatigue. Treatment of Myasthenia Gravis Treatment strategies for myasthenia gravis 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 but must be carefully dosed to avoid cholinergic crisis. 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 with generalized myasthenia without thymoma. For MuSK antibody-positive patients, cholinesterase inhibitors are often ineffective, but plasma exchange and immunosuppressive therapy can be very beneficial. Some double seronegative patients have antibodies to lipoprotein-related protein 4 (LRP4), which disrupt AChR clustering. Epilepsy: Overview and Classification Epilepsy refers to a group of disorders characterized by recurrent seizures, which are paroxysmal disturbances in cerebral function caused by abnormal synchronous discharge of cortical neurons. Approximately 0.6% of people in the United States suffer from recurrent seizures, with idiopathic epilepsy accounting for over 75% of cases. Seizures are classified based on behavioral and electrophysiologic data. Types include generalized tonic-clonic seizures, absence seizures, focal seizures, and various other forms. The specific type of seizure depends on the location of abnormal activity and its pattern of spread in the brain. 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. Normally, inhibitory mechanisms involving GABA and potassium currents suppress neuronal excitability. Disruption of these inhibitory mechanisms 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. In secondary epilepsy, loss of inhibitory circuits and sprouting of excitatory fibers contribute to seizure focus generation. Genetics of Epilepsy Several idiopathic epilepsies have been linked to mutations in ion channels. Severe myoclonic epilepsy of infancy often involves mutations in SCN1A, a sodium channel subunit. Benign familial neonatal convulsions are linked to mutations in voltage-gated potassium channels KCNQ2 and KCNQ3. Generalized epilepsy with febrile seizures has been associated with mutations in sodium channel subunits SCN1A and SCN1B, and the GABAA receptor subunit GABRG2. Autosomal dominant nocturnal frontal lobe epilepsy is linked to mutations in the α4 subunit of neuronal nicotinic cholinergic receptors. Recent genome-wide association studies have identified common genetic risk variants in genes like CHRM3, VRK2, and ZEB2. These genetic findings provide insights into the molecular mechanisms underlying different forms of epilepsy. Anticonvulsant Mechanisms The main targets for current anticonvulsants are voltage-gated sodium and calcium channels involved in action potential generation and neurotransmitter release, and ligand-gated channels that modulate synaptic excitation and inhibition. Many agents act through multiple mechanisms. For example, phenytoin and carbamazepine primarily block voltage-gated sodium channels, while valproic acid affects GABA levels and may block voltage-gated sodium channels. Ethosuximide blocks T- type calcium channels, which are important in absence seizures. Gabapentin and pregabalin modulate calcium channels, while levetiracetam acts on synaptic vesicle protein 2A. Understanding these mechanisms helps guide the development of new antiepileptic drugs and the selection of appropriate treatments for different seizure types.