Congenital analgesia disease in which patients do not sense pain Multiple sclerosis (MS) disease in which myelin within the central nervous system is damaged Charcot-Marie Tooth Disease (CMTD) disease in which myelin within the peripheral nervous system is damaged Hereditary spastic paraplegia (HSP) group of inherited disorders that are characterized by progressive weakness and stiffness of the legs, can be caused by defects in axonal transport Diabetic neuropathy disorder in which nerves of the body are damaged due to high blood sugar levels resulting from diabetes Alzheimer s disease (AD) major cause of dementia in old age, characterized by neurofibrillary tangles, amyloid plagues and neuron loss LESSON 2.5 WORKBOOK What can go wrong? Throughout this unit, we ve discussed the basic structures and functions of the major cells that make our nervous systems: neurons and glia. In this lesson, we ll investigate what happens when these functions are compromised by disease or injury. What if there are problems conducting action potentials? We can make several predictions about when and how problems in conducting action potentials might occur. For example, action potential conduction will be affected if: The voltage-gated Na+ channels don t function properly. Myelination is abnormal. If any of the above happens, we can predict what effect it will have on the neuron: If the voltage-gated Na+ channels don t function properly, the axon will be unable to generate an action potentials properly. If myelination is abnormal, then the axon will be unable to synchronize conduction of the action potential and it may fail completely. Diseases of axonal conduction Let s now investigate three diseases of action potential conduction in more depth: Congenital analgesia Multiple Sclerosis (MS) Charcot-Marie Tooth Disease (CMTD) Lesson 2.5 27
Congenital Analgesia Case study of Gabby Gabby is 5 years old (Figure 27). Her parents have consulted with many specialists throughout their daughter s life in hopes of finding an explanation for why their daughter behaves so strangely. Gabby s parents first knew that something was wrong when Gabby was only a few months old. Like other babies her age, she was teething. But unlike other babies, who would cry in pain, Gabby never cried. One morning, her father noticed that she had been chewing on her fingers so much that they were bleeding, but again, she never cried. Figure 27: Five year old Gabby. Her mother described Gabby s hand as mangled and nasty, like raw hamburger. After consulting with several doctors, Gabby s parents had all of her baby teeth removed so that she could not further harm herself. When Gabby was a year old, her mother noticed a white spot on her left eye. She thought it was just something floating in Gabby s eye, but in fact Gabby had somehow scratched her cornea. The doctor who treated Gabby told her mother that In most patients, this type of wound would be so painful, they would not be able to open their eye. To prevent Gabby from scratching her eye any more, the doctor stitched that eye closed. But, unable to feel pain, Gabby ripped out the stitches. These are just two of the incidents that brought Gabby s parents into see a neurologist for further examination. The doctor diagnosed Gabby with congenital analgesia. Congenital analgesia is a very rare inherited disease in which children, usually from birth, cannot sense pain even though their other senses are normal. Like Gabby, children with this disease often suffer from oral damage, like biting off the tip of their tongue, and scratches to the cornea. Researchers have learned that the disease can be caused by a mutation in the gene that codes for a voltage-gated Na + channel. This voltage-gated Na + channel (called SCN9A) is found specifically in the specialized receptors that detect pain called nociceptors. In a normal person, when nociceptor dendrites detect a pain sensation, the SCN9A Na + channel will amplify the signal so it reaches threshold and allows an action potential to fire. However, in patients with congenital analgesia this voltage-gated sodium channel doesn t work and thus the input from the dendrites never reaches threshold so an action potential doesn t fire (Figure 28). Congenital analgesia is not fatal, but patients suffering from it will never lead a normal life. Because they can t detect pain, they need to closely monitor their bodies for injuries and infections. Even so, the inability to Normal Pa)ent What are Gabby s symptoms? What did her doctor diagnose her with? What is the neuronal defect in congenital analgesia? What is the treatment for congenital analgesia? feel pain causes complications that mean very few patients with this Lesson 2.5 the nociceptors never detect disease live a normal life expectancy. 28 Congenital Analgesia X X Figure 28: Congenital analgesia. Patients do not feel pain because a mutation in the voltage-gated Na+ channels in their nociceptors means an action potential cannot fire, so any pain.
Multiple sclerosis (MS) Case study of Maria Maria is 37 years old (Figure 29). She has been having reoccurring episodes of muscle weakness in her arms and legs. The weakness lasts for a week or two and then subsides. At other times she noticed numbness in different parts of her body. Since the episodes came and went, she did not think much of it until she started having changes in her vision. First, she noticed that she was experiencing double vision, and then she noticed that she was having problems seeing out of her left eye. It was at this point that Maria called her doctor. Maria s doctor started the appointment by reviewing Maria s family history. Luckily, none of Maria s extended family had ever suffered from a neurological disease. She then gave Maria a thorough examination. First, she checked her eye reflexes and noted that her left eye had a decreased pupillary reflex, which means it didn t respond to a bright light by contracting. Next, she checked Maria s sensitivity to touch sensation and found it was decreased in different parts of her body. The doctor ordered both an MRI to see if there were any abnormalities in Maria s brain, and a spinal tap to see if there were any abnormal proteins in Maria s cerebrospinal fluid. The MRI showed a couple of small areas in Maria s brain where the myelin looked abnormal (called plaques), and the spinal tap detected a high level of antibodies in her. Her doctor gave Maria a preliminary diagnosis of multiple sclerosis, but told her that to confirm the diagnosis; he would need to follow her condition and rule out any other neurological abnormality. Multiple sclerosis (MS) can occur at any age, but is most commonly diagnosed between the ages of 20 and 40. The disease affects more women than men. MS is caused by damage to myelin within the central nervous system (Figure 30). The CNS myelin is damaged because the immune system makes antibodies against it, and the antibodies attack the myelin, causing inflammation. Repeat episodes of inflammation can occur anywhere in the brain, optic nerve and spinal cord. We think that some aspect of myelin s structure must resemble an infectious agent that previously infected the patient. The body first made antibodies against the infection, but those antibodies then become confused and attack the patient s own myelin. This is attack on self, causes an autoimmune disease. Figure 29: Maria, age 37 Lesson 2.5 denser plagues. Regions close to the ventricles 29 A. B. Figure 30: Multiple sclerosis. (A) Multiple sclerosis is an autoimmune disease in which a patient s T cells destroy the glial cells that myelinate CNS neurons. (B) MRI scans of patients brains with multiple sclerosis show areas of damaged myelin, appearing here as are commonly affected. What are Maria s symptoms? What did her doctor diagnose her with? What is the neuronal defect in multiple sclerosis? What does the treatment for multiple sclerosis hope to do?
The symptoms of MS can vary based on the location of inflammation. The most common symptoms include disturbances in vision, weakness, numbness or abnormal sensations in the arms or legs, muscle spasms and loss of balance. The intensity of any episode and how long it lasts depends on the severity of the inflammation in the CNS. However many patients experience even long periods without any symptoms, and during those stages they are said to be in remission. Most patients return near normal function while they are in remission. But over time and with more episodes, function gradually declines. Even so, most patients with MS remain able to walk and can function normally or with minor disability for 20 years or more. Patients at later stages of disease may require a wheelchair to get around. MS is a chronic disease that is currently incurable; treatment aims to slow the disease progression and lessen symptoms. Even so, patients with MS can have normal or almost normal life expectancy. Charcot-Marie Tooth Disease (CMTD) Case study of Allison Allison is sixteen years old (Figure 31). Recently she noticed that she is having a difficult time walking. Her feet and legs do not seem to be as strong as they were even just a year ago. Allison considers herself to be in good shape, but lately on her daily walks, she has been tripping frequently. She has also been having ahard time breathing. During her yearly physical she mentioned these difficulties to her doctor. Allison s doctor asked questions about her family history. Allison knew that her uncle has a disease called Charcot-Marie Tooth Disease (CMTD). Her uncle s disease was diagnosed when he was in his early 20s and it has made it difficult for him to walk and perform fine tasks with his fingers. A. B. Concerned that Allison might be developing CMTD too, her doctor examined Allison s lower legs carefully. He noticed that Allison s legs look a bit like an inverted champagne bottle because she has lost a lot of muscle bulk in the lower legs (Figure 32). Allison s doctor also tested her tendon reflexes and sensory perception. Given Allison s family history and worried by her poor performance on these tests, the doctor also ordered electrodiagnostic tests to see how well Allison s peripheral nerves to conduct an action potential. The tests are done by placing electrodes on the skin. These electrodes produce a small electric shock which stimulates both sensory and motor nerves. A needle, inserted into the skin, measures the ability of Allison s nerves to conduct an action potential in response to the small electric shock. Unfortunately, Al- Lesson 2.5 lison s readings on this test indicate that her axons are not conducting action potentials as quickly as they 30 would in normal people. Figure 32: Charcot-Marie Tooth disease (CMTD). (A) CMTD is caused by damage to myelin in the peripheral nervous system. (B) Stork legs seen in CMTD are due to muscle wasting in the lower part of the leg because innervation of skeletal muscles is defective. Figure 31: Allison, age 37 What are Allisons symptoms? What did her doctor diagnose her with? What is the neuronal defect in CMTD?
Given her family history, and her results on the electrodiagnostic test, Allison s doctor diagnosed her with Charcot-Marie Tooth Disease (CMTD). CMTD is the one of the most common inherited neurological disorders. CMTD is commonly diagnosed when patients are in their teens or early twenties. CMTD is caused by damage to the myelin sheath around peripheral nerves (Figure 32). Usually, the motor nerves in the legs are affected first, causing lower leg weakness and muscle atrophy, as Allison saw. Sensory nerve degeneration causes a reduced ability to sense heat, cold, and feel pain. In later stages of the disease, similar symptoms may appear in the arms and hands as well as the legs. The severity of the symptoms is variable between patients. CMTD is not fatal and patients with most forms of the disease have normal life expectancy. While there currently is no treatment, orthopedic shoes and braces may help patients to walk. Physical and occupational therapy are also helpful for many patients because therapy helps to maintain muscle strength. Watch some patients with CMTD here: http://www.youtube.com/watch?v=rr6goatrpna What if there are problems with axonal transport? We can make several predictions about when and how problems in transport will occur. For example, transport will be affected if: The transport motors don t function properly. The microtubule tracks are disturbed. The supply of ATP to the neuron is compromised or if mitochondria are defective. If any of the above happens, we can predict the effect on the neuron. If transport of organelles and mitochondria is affected, then the axon terminal will be unable to function. If transport of cytoskeleton is affected, then axonal structure and diameter will be abnormal. Diseases of axonal transport Let us now investigate three of these diseases in more depth: Hereditary spastic paraplegia (HSP) Diabetic neuropathy Alzheimer s disease For two of the three (diabetic neuropathy and Alzheimer s disease) the disruptions to axonal transport occur Lesson 2.5 as a result of the disease, but are not its cause. Regardless, when axonal transport doesn t function 31 properly, neurons degenerate in all three diseases. If you were going to design a drug to treat CMTD, what would you have that drug do?
Hereditary spastic paraplegia (HSP) Case study of Mitchell Mitchell is 17 years old and recently noticed that he has begun to trip up frequently (Figure 33). As he paid more attention to why, he noticed that he was having difficulty raising his legs to walk. Since he thought this was odd, he mentioned it to his doctor during his yearly physical. His doctor asked him to stand up, and then lift just his toes. Mitchell had a really difficult time with it. The doctor prescribed physical therapy and asked Mitchell to make another appointment if his symptoms got worse. A year later, Mitchell s problem had not got better. He felt the muscles in his legs were often weak and quite stiff. He also noticed that his sense of balance was not what it once had been. Sometimes his legs even felt numb. He called the doctor and went back for another appointment. After many tests, including an MRI, Mitchell s doctor diagnosed him with hereditary spastic paraplegia (HSP). HSP is characterized by progressive spasticity, defined as stiff or rigid muscles in the lower limbs. Patients can also experience bladder disturbances, and impaired sensations in the feet. HSP can develop at any age. Those patients who develop symptoms before the age of 35 have Type 1, and those patients who develop symptoms after 35 have Type 2. For type 1 cases, spasticity of the lower limbs is greater than weakness of lower limbs so defective walking is not common. In type 2 cases, muscle weakness, urinary symptoms and sensory loss are more severe. Mitchell s doctor referred him to a specialist who was studying the genetic causes of HSP. The specialist completed a genetic screen on Mitchell to determine if he was a carrier of the mutation his lab studied. As it turned out, Mitchell did carry a mutation within the specialist s gene of interest, KIF5A. Figure 34: Hereditary spastic paraplegia can be caused by mutations within the motor domain of kinesin proteins Figure 33: Mitchell, age 17 KIF5A is a member of the kinesin family. Remember that Kinesins are plus-end directed motor proteins that carry cargo from the cell body to the axon terminal. Research has demonstrated that mutations within the motor part of the KIF5A protein can cause HSP because fast anterograde axonal transport is disrupted, and this in turn disrupts axonal function (Figure 34). There are currently no treatments to slow or reverse HSP. However, regular physical therapy is important for muscle strength and to preserve range of motion. What are Mitchell s symptoms? What did her doctor diagnose him with? What is the neuronal defect in hereditary spastic paraplegia? What does the treatment for hereditary spastic paraplegia hope to do? that are responsible for transporting Lesson 2.5 cargo to the axon terminal. 32
Diabetic Neuropathy Case study of Albert Albert is 67 years old (Figure 35). He was diagnosed with type II diabetes almost 17 years ago. Despite going on a diet and exercising, Albert has never been able to successfully manage the levels of glucose in his blood, and get them under control, so they still remain high (hyperglycemia). During the last year, Albert noticed a tingling sensation in his feet. Since he is getting older, he did not think much of it. However, when the tingling sensation developed into an actual pain, he called his doctor. Figure 35: Albert, age 67 His doctor did a complete examination including testing Albert s ability to detect sensations in his feet. When Albert did not perform well on this test, she told him he has likely developed diabetic neuropathy, a condition that commonly occurs in patients who have had diabetes for 10 to 20 years. Diabetic neuropathy is a common complication of diabetes, in which nerves are damaged as a result of hyperglycemia. Diabetic neuropathy can present with any number of symptoms, including tingling or burning sensations in the feet, a deep pain in the arms or legs, muscle cramps, loss of sensitivity to warm or cold, loss of bladder control, and vision changes. The symptoms vary depending on which nerves are affected. Usually feet and legs are affected first, followed by hands and arms. While it is possible to slow diabetic neuropathy by strictly controlling blood glucose levels, diabetes itself is incurable. Researchers have learned that diabetic neuropathy occurs when the blood supply to nerves is reduced (Figure 36). Over an extended period of time, the high levels of glucose in the blood damage blood vessels. These damaged blood vessels are less able to deliver oxygen to peripheral neurons. Lack of oxygen to nerves reduces their ability to generate ATP. Since fast axonal transport is dependent on ATP, it is particularly vulnerable in diabetic neuropathy. When axonal transport is compromised, the terminal degenerates, resulting in decreased sensitivity and motor control. Figure 36: Diabetic neuropathy. Damage to blood vessels in diabetes results in transport defects because While there is no cure for diabetic neuropathy, the goal of treatment is to minimize the symptoms and prevent the disease from getting any worse. It is critically important to control blood glucose levels, and some medications can help reduce the symptoms in the arms and legs. What are Albert s symptoms? What did her doctor diagnose him with? What is the neuronal defect in diabetic neuropathy? Would you expect myelinated or non-myelinated nerves to be more affected? How does that explain the symaptoms What does the treatment for diabetic neuropathy hope to do? Lesson 2.5 ATP supply to the axons is compromised. 33
Alzheimer s disease (AD) Case study of Yumiko Yumiko is 66 years old and incredibly forgetful (Figure 37). Lately her family has become very concerned. At a recent family dinner, Yumiko could not remember the name of her favorite dessert chocolate mousse pie. She also had difficulty remembering how to get home from her son s house. Then, later that week she had to ask for help to balance her checkbook, something she used to do all the time, often without a calculator. When Yumiko saw her doctor, she described her symptoms and asked if her family s worries were reasonable - that her forgetfulness was not normal, but instead something to be concerned about. The doctor asked her a series of questions about her memory, including whether or not she was having difficulty with language, misplacing things, and thinking about abstract topics. He also asked whether or not she had noticed any changes in her mood or behavior. Yumiko didn t want to admit it, but after being pressed by her daughter she reluctantly answered that yes in fact she had been experiencing all of those things to some degree. The doctor told Yumiko that yes, in fact these symptoms, together with her age were cause for further testing. He did a complete physical exam and ordered a thorough neurological exam. The test results ruled out a brain tumor, stroke, and thyroid disease, which all could also cause the symptoms Yumiko was experiencing, so the doctor gave the diagnosis of Alzheimer s disease (AD). Alzheimer s disease is the leading cause of dementia in the elderly. It is estimated that ten percent of people over 65 have AD, and that fifty percent of those over 85 have the disease. AD affects memory, thinking and behavior. Problems with memory, as well as impairments with language, decision-making ability, judgment and personality must be present for the diagnosis to be made. AD is caused by an increased buildup of tangles of neurofilaments within the cell bodies of neurons as well as increased numbers of protein clumps called amyloid plaques at the synapse (Figure 38). Researchers have discovered that when the plaques develop mitochondria are affected, neurons are not able to communicate with each other. Perhaps due to the accumulation of tangles within the neural cell body, or perhaps due to defects in neuronal signaling, neurons start to die. Figure 37: Alzheimer s disease. Alzheimer s disease results in an Figure 37: Yumiko, age 67 Patients with AD often die earlier than normal, although a patient may live anywhere from 3 to 20 years after the diagnosis. The final phase of the disease, in which patients no longer understand language, recognize family members, and are unable to perform basic activities of daily living, may last from a few months to several years. Death usually occurs from an infection or failure of other body systems. While there is no cure for AD, treatment focuses on slowing the progression of the disease. Watch a short video about the changes to neurons that buildup of neurofibrillary tangles within we see in Alzheimer s disease Lesson 2.5 f neurons as well as amyloid plaques 34 within the synapse. http://www.youtube.com/watch?v=njgbnx1jviu&feature=related What are Yumiko s symptoms? What did her doctor diagnose him with? What are the neuronal defects in Alzheimer s disease? If you were designing a drug to treat Alzheimer s disease, what would you have it do? When would you start giving the drug?
STUDENT RESPONSES Remember to identify your sources In the figure below, label the parts of the neuron and list a function for each part. Describe what could possibly go wrong within the different parts of a neuron. What symptoms might a patient display should these problems arise? Lesson 2.5 35