Lecture 14 - Pathophysiology of Genetic Neuronal Diseases PDF

Pathophysiology of Genetic Neuronal Diseases Dr. Kelly C.S.Roballo Learning Objetives • 1. Describe the Pompe Disease Syndrome, identify affected organ systems, and explain possible complications of the disease • 2. Describe the Alzheimer’s disease, identify affected organs, pathophysiology and ma...

Pathophysiology of Genetic Neuronal Diseases Dr. Kelly C.S.Roballo Learning Objetives • 1. Describe the Pompe Disease Syndrome, identify affected organ systems, and explain possible complications of the disease • 2. Describe the Alzheimer’s disease, identify affected organs, pathophysiology and major symptoms • 3. Describe the Parkinson’s disease, identify affected organs, pathophysiology and major symptoms • 4. Describe the Fabry Disease, identify affected organ systems, and explain possible complications of the disease Pompe Disease also known as glycogen storage disease type II (GSD II) General Information • The clinical presentation of Pompe disease ranges from a rapidly progressive infantile (IPD) form which is uniformly lethal to a more slowly progressive late-onset form (LOPD). • As early as 1965, brain autopsies demonstrated abnormal glycogen accumulation in the cerebral cortex, cerebellum, anterior horn cells, and spinal cord in patients with IPD (severe) and in the cerebral cortex and spinal cord in patients with LOPD (mid~) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642933/ Pathophysiology • Pompe disease (PD) is a lysosomal storage disorder caused by deficiency of the lysosomal enzyme acid-alpha glucosidase (GAA). It is now clear that there is a neurological component to the disease Pathophysiology Pathogenic variants in the GAA gene lead to deficient or absent GAA and excessive accumulation of lysosomal glycogen primarily in the heart, skeletal, smooth muscles, and the nervous system https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642933/ Diagnostic • Currently, acid α-glucosidase (GAA) assay performed on skin fibroblasts (preferred tissue) or muscle biopsy, by experienced laboratories is the diagnostic “gold standard” as it can render a definitive diagnosis of Pompe disease, when combined with clinical and laboratory data (muscle histology when available). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3110959/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642933/ Treatment • With the approval of enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA, Alglucosidase alfa) by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in 2006 and the subsequent success of immunomodulation protocols to prevent anti-drug antibody responses Alzheimer’s Disease (AD) Introduction to Alzheimer’s Disease • Named & first documented by Dr. Alois Alzheimer in ~1906 after he did an autopsy on a women who had died with an unusual mental illness. He observed many abnormal clumps (now called amyloid plaques) and tangled bungles of fibers (now called neurofibrillary tangles). Her symptoms included: • Memory loss • Language problems • Labile behavior • Since been observed that individuals develop neurological changes well before symptomology sets in and a diagnosis can be made. • Makes it difficult to treat • 6th most common cause of death National Institutes of Health (NIA Alzheimers Fact sheet) 1. Mild (early) Stages of Alzheimer's Disease • Patient is likely still functioning independently, but has symptoms (can be difficult to discern) • Experiencing memory lapses such as forgetting familiar words or location of everyday objects • Increasing trouble with planning or organization 2. Moderate (middle-stage) • Typically, longest lasting and patients become increasingly dependent. Common symptoms: • Emotional lability, especially in socially or mentally challenging situations • Forgetting personal history • Confusion on location or what day it is • Bowel control • Suspiciousness/delusions 3. Severe (late stage) • Individuals lose ability to respond to environment, carry on conversation and eventually control movement. Will be or become dependent on round the clock assistance for daily activities • Most common complications of brain dysfunction that lead to death of Alzheimer's patients include infections (aspiration pneumonia, sepsis (bedsores), injuries from falls • Cause of death may say pneumonia, but Alzheimer’s did it Patients live an avg of 8 years after diagnosis*, but can vary greatly. Depends on age at diagnosis and presence of other comorbidities Gross Brain Alterations in Alzheimer • Neuropathologic changes that follow a pattern of regional spread throughout the brain, starting at the hippocampus and gradually affecting other parts of the cerebral cortex in later stages • Hippocampus region of the brain Mild Moderate Severe • Important role in learning and consolidation of memory, thinking and planning • Cerebral cortex: • • • • Interpretation of stimuli Generate thoughts, solve problems Form and store memories Control voluntary movement Neurology. 2009 Mar 17; 72(11): 999–1007. Alzheimers, APP and Aβ • Researchers in 1984 isolated and purified the plaques from AD patients and showed that these plaques were primarily composed of a 4.2 kDa peptide, 40 or 42 amino acids in length • Peptide came to be known as Aβ • Speculated this peptide was cleaved from a larger protein • Researchers in 1987 found that Aβ was in fact part of a larger protein, which was named amyloid precursor protein (APP) Annu Rev Neurosci. 2011; 34: 185–204. APP • A ~695 amino acid transmembrane protein with a large extracellular domain • The AB fragment within APP is within the membrane and extracellular • A thorough understanding of the normal biological function of APP has yet to be established (like HTT protein), but some studies point to: • Synaptic formation and repair • Iron export • Anterograde neuronal transport Annu Rev Neurosci. 2011; 34: 185–204. Processing of APP to Get Aβ • APP produced in neurons in large quantities (risk for aggregation already!) and shipped to the axonal terminal • APP is processed (cut into pieces) very rapidly by secretase enzymes in a series of steps • Processing by beta and gamma secretase releases Aβ • Processing by alpha then gamma secretase does not release any pathogenic protein fragments Aβ Mechanisms of Toxicity • Aβ fibrils are toxic to cultured neurons, inducing apoptosis (caspases) by ROS generation • Evidence exists that Aβ monomers and other dimer or oligomers have other mechanisms of toxicity, some causing prolonged gliosis • Aβ monomers stimulate processing and hyperphosphorylation of tau (which form the neurofibrillary tangles, also characteristic of AD) Genetics of AD • Familial Alzheimer’s disease (FAD) occurs between mid 30’s to mid 60’s & accounts for ~10% of all Alzheimer's cases • Is inherited in an autosomal dominant fashion • So far, mutations in four genes have been linked to FAD • • • • Mutations to APP Mutations to presenilin 1 Mutations to presenilin 2 Mutations to APOE4 • Exactly how mutations to these genes leads to AD is still debated APP Mutations in FAD • A number of different missense mutations to APP increase the risk for generating Aβ • General themes: • Cluster around gamma secretase cleavage site • Alter processing to increase abundance of Aβ42, which is more toxic than Aβ40 Aβ and Alzheimer's: Unconnected Dots • Unclear whether the accumulating AB plaques of patients with dementia caused the dementia or simply indicated presence of dying neurons • Studies of head trauma and brain ischemia found transient increases in brain Aβ deposition • However, studies of chronic brain injury and ischemia do not indicate Aβ is a nonspecific marker of neuronal injury • There is no increase in the age-expected prevalence of Aβ pathology in patients with other dementias • Seems to be specific to Alzheimers Case: Patient • Chief Complains/History of Present Illness: • “I got lost in a grocery store and my children think I need those diapers that old people have to wear” Previous Medical History • Probable AD diagnosis 9 years ago when children started noticing: • Constantly misplacing glasses & other heavy use items • Placing items in illogical places (coffee pot in refrigerator) • Got lost in neighborhood she’s lived in for 45 years • Changes to personality – became quite and passive and lost interest in things she’d enjoyed • Full workup revealed no other diseases • 4 years ago • Other features more severe • New features • Problems with numbers • Forgot how to play bridge (playing for 60+ years) • Poor judgement – left house in cold weather without coat or shoes & kitchen fire from forgetting to turn off kitchen stove • Imaging showed cortical atrophy • Full workup again revealed no other diseases Previous Medical History (con’t) • Past 6 weeks • Occasional urinary accidents • Multiple, sudden outbursts of anger • Because lost, confused, angry and violent in grocery store when people tried to help • Violent rage when grapes fell out of bag when checking out • Other General • • • • • • Hypertension Nephrolithiasis episode Gout Hypercholesterolemia Plantar fasciitis Occasional constipation Family History • Parents deceased • Mother developed AD • Brother died from heart disease • Sister developed AD & died at 76 yo Social History • Lives with daughter • Widow for 14 years • Does not smoke or drink alcohol • Mild case of iron-deficient anemia Parkinson's disease (PD) General information • It was first described by James Parkinson in 1817 and further characterized by JeanMartin Charcot. • Parkinson's disease is a progressive nervous system disorder that affects movement. Symptoms start gradually, sometimes starting with a barely noticeable tremor in just one hand. Tremors are common, but the disorder also commonly causes stiffness or slowing of movement. • Parkinson’s disease (PD) is a common neurodegenerative disorder. While a number of non-motor manifestations arise, the typical clinical features involve a movement disorder consisting of bradykinesia, resting tremor, and rigidity, with postural instability occurring at a later stage. The cause of PD is not known, but a number of genetic risk factors have now been characterized, as well as several genes which cause rare familial forms of PD. https://www.ncbi.nlm.nih.gov/books/NBK536722/ Pathophysiology (?) • PD is a multifactorial disease, with both genetic and environmental factors playing a role. • Environmental influences such as: • Smoking • Caffeine consumption • And pesticide exposure • Although PD is generally an idiopathic disorder, there is a minority of cases (10–15%) that report a family history, and about 5% have Mendelian inheritance. • Genes that have been found to potentially cause PD are assigned a “PARK” (autosomal dominant or recessive), and numerically most important genetic risk factors predisposing to PD are mutations in GBA1, a gene encoding β-glucocerebrosidase—a lysosomal enzyme responsible for the hydrolysis of glucocerebrosides Pathophysiology • The movement disorder arises due to the loss of dopaminergic neurons of the substantia nigra pars compacta, with the pathological hallmark being intracellular aggregates of α-synuclein, in the form of Lewy bodies and Lewy neurites. • Several processes have been implicated in PD, including mitochondrial dysfunction, defective protein clearance mechanisms, and neuroinflammation, but the way in which these factors interact remains incompletely understood. https://www.youtube.com/watch?v=Ztwkwqgvoso Diagnosis • Currently, diagnosis is based on clinical symptoms with the criteria for a diagnosis requiring the presence of two of the following clinical features: resting tremor, bradykinesia, rigidity and/or postural instability. • The pre-motor or prodromal phase of PD may start as early as 12–14 years before diagnosis. • There is now a great deal of evidence supporting the fact that the disease may begin in the peripheral autonomic nervous system and/or the olfactory bulb, with the pathology then spreading through the central nervous system affecting the lower brainstem structures before involving the substantia nigra. This may thus explain the presence of hyposmia, constipation, and rapid eye movement sleep disorders in PD patients before motor symptoms begin. Treatment • Treatment predominantly focuses on symptomatic relief with drugs aiming to either restore the level of dopamine in the striatum or to act on striatal post-synaptic dopamine receptors. • However, as dopamine is not the only neurotransmitter involved in PD, many other drugs are also being used to target specific symptoms, such as depression or dementia. • In an advanced disease stage, both motor and non-motor symptoms may become resistant to current medications. Postural instability and freezing of gait may lead to falls and fractures, while dementia and hallucinations can develop in some patients, which sometimes warrant care home placement. Fabry Disease Fabry Disease • Fabry disease is an inherited disorder that results from the buildup of a particular type of fat in the body's cells. • Beginning in childhood, this buildup causes signs and symptoms that affect many parts of the body. • Characteristic features of Fabry disease include: 1.episodes of pain, particularly in the hands and feet (acroparesthesias); 2.clusters of small, dark red spots on the skin called angiokeratomas; 3.a decreased ability to sweat (hypohidrosis); 4.cloudiness of the front part of the eye (corneal opacity); and 5.hearing loss. • Fabry disease also involves potentially life-threatening complications such as progressive kidney damage, heart attack, and stroke. Milder forms of the disorder may appear later in life and affect only the heart or kidneys. Fabry Disease Angiokeratomas: the red-purple maculopapular skin lesions characteristic of the disorder. (a) Skin lesions on buttocks, and (b) lesions on the umbilicus F C Fervenza, et al Kidney International 73, 1193-1199 (May (2) 2008) Angiokeratomas appear as non-blanching red to blue-black lesions from 1 to 5 mm in diameter, they are not always covered by fine white scales as their name would suggest, being also macular (non-elevated spots) or just palpable. www.fabrydisease.org Fabry Disease Ocular Manifestations Note “spoke-like” pattern on cornea, visible through slit lamp ophthalmoscopy (does not affect vision) Sodi et al. Br J Ophthalmol 2007;91:210-214 doi:10.1136/bjo.2006.100602 Eye abnormalities associated with Fabry's disease. (A) Conjunctival vessel tortuosity; (B) retinal vessel tortuosity; (C) cornea verticillata (vortex opacities located in the superficial corneal layers); and (D) Fabry cataract (posterior lens opacities with a radiating appearance). Conjunctival Involvement Conjunctival vessel tortuosity • Note the sausage-like and markedly dilated vessels in the eye. Fabry Disease: Perspectives from 5 Years of FOS. Mehta A, Beck M, Sunder-Plassmann G, editors. Oxford: Oxford PharmaGenesis; 2006. Magnetic resonance image of a lesion caused by a large intracranial vessel occlusion in a patient with Fabry disease. • (a) Left cerebellar hemisphere stroke caused by a vertebral artery occlusion (fluidattenuated inversion recovery magnetic resonance image). • (b) A left middle cerebral stroke in the area of the central sulcus (T1-weighted image). Fabry Disease: Perspectives from 5 Years of FOS. Mehta A, Beck M, SunderPlassmann G, editors. Oxford: Oxford PharmaGenesis; 2006. (a) Serial axial fluid-attenuated inversion recovery (FLAIR) magnetic resonance image, demonstrating the posterior and periventricular predominance of Fabry leukoencephalopathy. (b) Serial axial FLAIR images of a patient with severe Fabry leukoencephalopathy, demonstrating grossly abnormal confluent white matter signal abnormality consistent with advanced disease. Magnetic resonance angiogram, showing occlusion of the left vertebral artery in a patient with Fabry disease. What genes are related to Fabry disease? • Mutations in the GLA gene cause Fabry disease. • The GLA gene provides instructions for making an enzyme called alpha-galactosidase A. • This enzyme is active in lysosomes. Alpha-galactosidase A normally breaks down a fatty substance called globotriaosylceramide. • Mutations in the GLA gene alter the structure and function of the enzyme, preventing it from breaking down this substance effectively. • As a result, globotriaosylceramide builds up in cells throughout the body, particularly cells lining blood vessels in the skin and cells in the kidneys, heart, and nervous system. • The progressive accumulation of this substance damages cells, leading to the varied signs and symptoms of Fabry disease. © The New England Journal of Medicine July 5, 2001 • GLA gene mutations that result in an absence of alpha-galactosidase A activity lead to the classic, severe form of Fabry disease. • Mutations that decrease but do not eliminate the enzyme's activity usually cause the milder, late-onset forms of Fabry disease that affect only the heart or kidneys. How do people inherit Fabry disease? • This condition is inherited in an X-linked pattern. • A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes in each cell. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. • Because females have two copies of the X chromosome, one altered copy of the gene in each cell usually leads to less severe symptoms in females than in males, or may cause no symptoms at all. How do people inherit Fabry disease? • Unlike other X-linked disorders, Fabry disease causes significant medical problems in many females who have one altered copy of the GLA gene. • These women may experience many of the classic features of the disorder, including nervous system abnormalities, kidney problems, chronic pain, and fatigue. • They also have an increased risk of developing high blood pressure, heart disease, stroke, and kidney failure. The signs and symptoms of Fabry disease usually begin later in life and are milder in females than in their affected male relatives. • Some females who carry a mutation in one copy of the GLA gene never have any of the signs and symptoms of Fabry disease.