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investigation of human disease > channelopathies 1 > Flashcards

channelopathies 1 Flashcards

1
Q

Describe channelopathies in the context of ion channels.

A

Channelopathies refer to human and animal diseases caused by defects in ion channel function, leading to mutations that result in cardiovascular, neurological, and muscular disorders.

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2
Q

What distinguishes nociceptors within dorsal root ganglia based on histochemical characteristics?

A

Nociceptors within dorsal root ganglia differ in histochemical characteristics, ion-channel expression, connectivity, and functional properties, with two main populations: neuropeptide-expressing nociceptors (CGRP-positive, red) and isolectin B4-binding nociceptors (green).

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3
Q

How have channelopathies impacted medical terminologies and treatments since the 1990s?

A

Channelopathies, a relatively new term in medicine since the 1990s, have led to a better understanding of ion channels, mutations, and defects, paving the way for tailored pharmacotherapy and gene therapy as new treatment strategies.

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4
Q

Define tailored pharmacotherapy in the context of channelopathies.

A

Tailored pharmacotherapy in channelopathies involves customizing drug treatments based on the specific ion channel defects present in an individual, aiming to address the underlying cause of the disorder.

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5
Q

What potential treatment strategies have emerged from recognizing fundamental defects in channelopathies?

A

Recognizing fundamental defects in channelopathies has led to the development of new treatment strategies such as tailored pharmacotherapy and gene therapy to address the specific ion channel mutations causing cardiovascular, neurological, and muscular disorders.

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6
Q

Describe the two main populations of nociceptors within dorsal root ganglia based on their characteristics.

A

Nociceptors within dorsal root ganglia can be divided into two main populations: neuropeptide-expressing nociceptors labeled with CGRP (red) and isolectin B4-binding nociceptors (green), each with distinct histochemical characteristics and functional properties.

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7
Q

How do mutations in ion channels contribute to channelopathies?

A

Mutations in ion channels can lead to channelopathies, causing defects in ion channel function that result in various human and animal diseases, including cardiovascular, neurological, and muscular disorders.

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8
Q

What are the implications of recognizing fundamental defects in channelopathies for treatment strategies?

A

Recognizing fundamental defects in channelopathies provides the basis for new treatment strategies such as tailored pharmacotherapy and gene therapy, aiming to address the specific ion channel mutations underlying cardiovascular, neurological, and muscular disorders.

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9
Q

Describe the difference in projection of nociceptors and-threshold myelinated afferent fibers in the dorsal horn.

A

Nociceptors project to superficial laminae of the dorsal horn, while low-threshold myelinated afferent fibers project to deeper laminae.

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10
Q

What distinguishes painful and painless channelopathies?

A

Painful and painless channelopathies are distinguished based on the presence or absence of pain.

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11
Q

Define channelopathies.

A

Channelopathies are diseases caused by dysfunction of ion channels in cell membranes.

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12
Q

How common are inherited channelopathies typically?

A

Inherited channelopathies are usually very rare.

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13
Q

What is the prevalence of cystic fibrosis in Northern Europe and the United States?

A

Cystic fibrosis affects around 1 in 2,000 people in Northern Europe and the United States.

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14
Q

How is cystic fibrosis inherited?

A

Cystic fibrosis is a recessive disease.

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15
Q

What proportion of people are carriers of cystic fibrosis?

A

As many as 1 in 20 people are carriers of cystic fibrosis.

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16
Q

Describe the characteristics of channelopathies mentioned in the content.

A

Channelopathies are disorders caused by mutations in ion channel genes, affecting the flow of ions across cell membranes.

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17
Q

What is the difference between inherited erythromelalgia and small-fibre neuropathy in terms of sensory nerve-fibre degeneration?

A

Inherited erythromelalgia is not associated with sensory nerve-fibre degeneration, unlike small-fibre neuropathy.

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18
Q

How are epidermalervations detected in a healthy individual according to the content?

A

Epidermal innervations in a healthy individual are detected by immunostaining with the pan-neuronal marker PGP9.5 (red).

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19
Q

What are the two categories of channelopathies based on the nature of the disease progression mentioned in the content?

A

Channelopathies can be either episodic (e.g., periodic paralysis) or progressive (e.g., spinocerebellar ataxia).

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20
Q

Explain the relationship between mutations and disease states in channelopathies according to the content.

A

Different mutations on the same channel can lead to different disease states.

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21
Q

Provide examples of mutations on specific channels and the resulting diseases mentioned in the content.

A

Examples include SCN4A mutations causing periodic paralysis and paramyotonia congenita, and CACNA1A mutations leading to episodic ataxia and hemiplegic migraine.

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22
Q

Describe channelopathies.

A

Channelopathies are a group of disorders caused by abnormal ion channel function in cell membranes, leading to various diseases and conditions.

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23
Q

What is significance of immunost hiPSC-ventricular and atrial CMs for α-actinin and MLC2v?

A

Immunostaining helps visualize the distribution and expression of specific proteins in human induced pluripotent stem cell-derived ventricular and atrial cardiomyocytes.

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24
Q

How are human induced pluripotent stem cells utilized in studying atrial arrhythmias in the short QT syndrome?

A

They are used to model and investigate the mechanisms underlying atrial arrhythmias associated with the short QT syndrome.

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25
Q

Define short QT syndrome.

A

Short QT syndrome is a rare genetic heart condition characterized by an abnormally short QT interval on an electrocardiogram, potentially leading to life-threatening arrhythmias.

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26
Q

What can mutations in different channels lead to in terms of diseases?

A

Mutations in different ion channels can result in the same disease phenotype, highlighting the complex interplay of ion channel function in various disorders.

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27
Q

Describe KVLQT1, SCNA5A, and CACNA1A in relation to Long QT Syndrome.

A

These genes are associated with Long QT Syndrome, a heart condition characterized by a delayed repolarization of the heart following a heartbeat, which can lead to arrhythmias and sudden cardiac death.

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28
Q

How can channelopathies be studied?

A

Channelopathies can be studied using techniques like site-directed mutagenesis and overexpression of ion channel genes in host cells.

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29
Q

What is the significance of site-directed mutagenesis in studying channelopathies?

A

Site-directed mutagenesis is useful for mimicking disease-related polymorphisms in ion channel genes to understand their impact on channel function.

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30
Q

What is the role of recombinant wild-type or mutant ion channel genes in studying channelopathies?

A

Recombinant wild-type or mutant ion channel genes can be overexpressed in host cells for experimental studies on channelopathies.

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31
Q

Describe channelopathies

A

Channelopathies are a group of disorders caused by abnormal ion channel function in cells, leading to various diseases.

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32
Q

How can channelopathies like long QT syndrome be studied?

A

Channelopathies like long QT syndrome can be studied by modeling them in vitro using iPSC technology.

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33
Q

What is iPSC technology used for in studying channelopathies?

A

iPSC technology is used to model the abnormal functional phenotype of inherited cardiac disorders and identify potential new therapeutic agents.

34
Q

What are the benefits of using iPSC technology in studying channelopathies?

A

iPSC technology represents a promising paradigm to study disease mechanisms, optimize patient care (personalized medicine), and aid in the development of new therapies.

35
Q

Define personalized medicine in the context of channelopathies

A

Personalized medicine in the context of channelopathies refers to tailoring medical treatment to the individual characteristics of each patient based on their genetic makeup and other factors.

36
Q

How can induced pluripotent stem cells be utilized in modeling long QT syndrome?

A

Induced pluripotent stem cells can be used to model long QT syndrome, allowing researchers to study the disease and test potential therapeutic interventions.

37
Q

What was the focus of the study by Illanit Itzhaki et al. published in Nature in 2011?

A

The study focused on modeling the long QT syndrome using induced pluripotent stem cells as a method to understand the disease and explore new treatment options.

38
Q

Describe myotonia congenita in terms of symptoms and genetic mutation.

A

Myotonia congenita is characterized by delayed relaxation or maintained contraction of skeletal muscle following sudden forceful contraction. It is caused by a mutation in either Na+ or Cl- channels.

39
Q

Define channelopathies and provide an example related to skeletal muscle.

A

Channelopathies are disorders caused by dysfunction of ion channels. An example related to skeletal muscle is myotonia congenita.

40
Q

How does myotonia congenita affect muscle function?

A

Myotonia congenita results in muscle stiffness, making it difficult to release the grip on objects or rise from a sitting position.

41
Q

What are some key characteristics of myotonia congenita?

A

Some key characteristics include membrane hyper-excitability, repetitive muscle action potential, and continued muscle activity after cessation of voluntary effort or stimulation.

42
Q

Describe the muscle fiber morphology seen in H&E staining of a patient with myotonia congenita.

A

In H&E staining of a patient with myotonia congenita, muscle fiber morphology shows small, irregular-shaped fibers with clear regions in the cytoplasm and mildly varied fiber sizes.

43
Q

Describe skeletal muscle channelopathies related to Na+ mutation.

A

Missense mutation in SCN4A gene affecting voltage-gated sodium channels, leading to impaired inactivation and continuous Na+ currents during repolarization.

44
Q

What is the impact of Na+ mutation in skeletal muscle channelopathies?

A

It reduces the refractory time of channels, contributing to the generation of repetitive action potentials and causing increased Na+ in muscle fibers.

45
Q

What histopathological findings are observed in patients with skeletal muscle channelopathies related to Na+ mutation?

A

Variation in fiber size, atrophic fibers, central nuclei, pycnotic nuclear clumps, and fast myosin positivity in biceps brachii biopsy.

46
Q

Define the role of SCN4A gene in patients with myotonic dystrophy type 2.

A

It acts as a modifier gene, contributing to the manifestation of the disease.

47
Q

How do skeletal muscle channelopathies with Na+ mutation affect muscle function?

A

They cause repetitive discharges beyond the stimulus due to increased Na+ in muscle fibers.

48
Q

Do skeletal muscle channelopathies with Na+ mutation have any specific impact on muscle fibers?

A

Yes, they lead to atrophic fibers, central nuclei, and pycnotic nuclear clumps as observed in histopathological analysis.

49
Q

Describe the immunostaining results in patients with skeletal muscle channelopathies related to Na+ mutation.

A

Fast myosin positivity is observed in atrophic fibers and nuclear clumps.

50
Q

What was the source and year of the study mentioned in the content regarding SCN4A as a modifier gene?

A

The study was conducted by Anna Bindas et al and published in Nature in 2018.

51
Q

Describe the function of the CLCN1 gene in skeletal muscle channelopathies.

A

CLCN1 gene encodes for the skeletal muscle voltage-gated Chloride channel, which helps dampen membrane excitability and stabilize resting potential.

52
Q

What are the consequences of a loss of function mutation in the CLCN1 gene?

A

Muscle stiffness and hampered muscle relaxation.

53
Q

Do you know who first discovered the cause of myotonia congenita and how?

A

Shirley Bryant discovered it by studying a hereditary condition in a herd of goats in 1969. The goats were startled by nearby trains but could not run after a period of rest.

54
Q

Define Becker-type myotonia and mention its inheritance pattern.

A

Becker-type myotonia is the most common form and is inherited in an autosomal recessive manner.

55
Q

Describe Thomsen disease in terms of rarity and inheritance pattern.

A

Thomsen disease is a very rare, relatively milder form that manifests from childhood and is inherited in an autosomal dominant pattern.

56
Q

What is the significance of histochemical staining of muscle sections in patients affected by myotonia?

A

It helps in identifying specific changes or abnormalities in muscle tissues that can be indicative of myotonia.

57
Q

How can a missense mutation in the CLCN1 gene contribute to congenital myotonia?

A

It can serve as a candidate causal mutation for congenital myotonia, affecting the function of the chloride channel in skeletal muscle.

58
Q

Describe the role of the skeletal muscle chloride channel 1 (CLCN1) in the context of congenital myotonia.

A

It is involved in regulating chloride ion flow in skeletal muscle, impacting muscle excitability and relaxation.

59
Q

Describe Acquired Myasthenia Gr (MG)

A

Acquired Myasthenia Gravis is a rare autoimmune disease that the neuromuscular junction by targeting nicotinic acetylcholine receptors, leading to muscle weakness and fatigue.

60
Q

What are the initial symptoms seen in 2/3 of patients with Acquiredasthenia Gravis?

A

Initial symptoms in 2/3 of patients include extrinsic ocular muscle symptoms that affect the eyes and eyelids.

61
Q

How does Acquired Myasthenia Gravis affect facial muscles and jaw?

A

It can cause weakness in facial muscles and jaw, resulting in the inability to smile.

62
Q

Define the progression of symptoms in Acquired Myasthenia Gravis.

A

Symptoms usually progress from affecting muscles involved in talking, swallowing, and holding up the head to general muscle weakness in the upper limbs.

63
Q

What is shown in the electron micrographs of endplate regions from mice with experimental MG?

A

The electron micrographs show lysis and altered morphology of the postsynaptic membrane, with a loss of normal endplate morphology due to complement-mediated lysis in myasthenic mice.

64
Q

What type of receptors are targeted in Acquired Myasthenia Gravis?

A

Nicotinic acetylcholine receptors, which are ligand-gated ion channels at the neuromuscular junction, are targeted in this autoimmune disease.

65
Q

How do the affected receptors in Acquired Myasthenia Gravis impact muscle function?

A

The receptors do not respond properly, leading to the inability of muscles to contract effectively.

66
Q

Describe the impact of Acquired Myasthenia Gravis on muscle function in the upper limbs.

A

It results in generalized muscle weakness in the upper limb muscles.

67
Q

What is the source of the electron micrographs showing endplate regions in mice with experimental MG?

A

The electron micrographs are from a study published in The Lancet Neurology in 2009, titled ‘Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity’.

68
Q

Describe the function of nAChRs in skeletal muscle channelopathies.

A

nAChRs are ligand-gated ion channels that depolar the muscle cell membrane potential when activated.

69
Q

What ions can permeate through non-selective cation channels in skeletal muscle channelopathies?

A

Na+, K+, and Ca2+ can permeate through non-selective cation channels.

70
Q

How does depolarization the muscle cell membrane potential affect muscle contraction in skeletal muscle channelopathies?

A

Depolarization activates voltage-gated Ca2+ channels, leading to an increase in cellular Ca2+ levels and muscle contraction.

71
Q

Define Acquired Myasthenia Gravis (MG) in the context of skeletal muscle channelopathies.

A

Acquired Myasthenia Gravis is a condition where autoantibodies target nAChRs, affecting neuromuscular transmission.

72
Q

What was discussed in the paper by Karlin et al in Nature Reviews Neuroscience, 2002, related to skeletal muscle channelopathies?

A

The paper discussed the emerging structure of the Nicotinic Acetylcholine receptors.

73
Q

Describe the role of B cells in Acquired Myasthenia Gravis (MG).

A

B cells in MG produce autoantibodies specific to proteins or cells, such as nAChRs.

74
Q

What happens when autoantibodies by B cells bind to nAChRs in Myasthenia Gravis?

A

When autoantibodies bind to nAChRs, acetylcholine (ACh) cannot bind anymore, leading to a lack of muscle contraction signal from the central nervous system.

75
Q

How do autoantibodies in Myasthenia Gravis contribute to inflammation and muscle cell destruction?

A

Autoantibodies in MG can activate the classical complement pathway, leading to inflammation and destruction of muscle cells, affecting their morphology.

76
Q

Define Acquired Myasthenia Gravis (MG).

A

Acquired Myasthenia Gravis is an autoimmune disorder where B cells produce autoantibodies that target nicotinic acetylcholine receptors (nAChRs), leading to muscle weakness and fatigue.

77
Q

What is the impact of autoantibodies binding to receptors in Myasthenia Gravis?

A

When autoantibodies bind to receptors, they prevent acetylcholine from binding, disrupting the muscle contraction signal from the CNS.

78
Q

Do autoantibodies in Myasthenia Gravis only affect muscle cell function?

A

No, in addition to affecting muscle cell function, autoantibodies can also trigger inflammation and lead to the destruction of muscle cells.

79
Q

How do autoantibodies in Myasthenia Gravis interfere with muscle contraction?

A

Autoantibodies in MG bind to nicotinic acetylcholine receptors, preventing acetylcholine from binding and transmitting the signal for muscle contraction.

80
Q

Describe the mechanism by which autoantibodies in Myasthenia Gravis cause muscle cell destruction.

A

Autoantibodies in MG can activate the classical complement pathway, resulting in inflammation and destruction of muscle cells, impacting their morphology.

investigation of human disease (19 decks)

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