Cells in Health and Disease: Topic 4 Rare Disease and Cellular Abnormalities II PDF

BIOL 2006SEF Cells in Health and Disease Topic 4 Rare Disease and Cellular Abnormalities II Dr CHEUNG Ka Tik HKMU BIOL2006SEF 2024 1 Rare Diseases - Cell disorders CELL MEMBRANE - CYSTIC FIBROSIS NUCLEUS - PROGERIA LYZOSOME - MUCOPOLY SACCHARIDOSIS CYTOS...

BIOL 2006SEF Cells in Health and Disease Topic 4 Rare Disease and Cellular Abnormalities II Dr CHEUNG Ka Tik HKMU BIOL2006SEF 2024 1 Rare Diseases - Cell disorders CELL MEMBRANE - CYSTIC FIBROSIS NUCLEUS - PROGERIA LYZOSOME - MUCOPOLY SACCHARIDOSIS CYTOSKELETON - DUCHENNE MUSCULAR DYSTROPHY MITOCHONDRIA - LEIGH’S DISEASE ENDOPLASMIC RETICULUM - Wolcott-Rallison syndrome HKMU BIOL2006SEF 2024 2 HKMU BIOL2006SEF 2024 3  DUCHENNE MUSCULAR DYSTROPHY The muscular dystrophies are a group of genetically determined, progressive diseases of skeletal muscle They are non-inflammatory and have no neurological cause Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy affecting 1 in 3500 boys born worldwide. Seen in males only (expect in females with TURNER’S SYNDROME) HKMU BIOL2006SEF 2024 4  Genetics DMD is inherited in an X-linked recessive pattern (defect at Xp21 locus) Females will typically be carriers for the disease while males will be affected The son of a carrier mother has a 50% chance of inheriting the defective gene from his mother. The daughter of a carrier mother has a 50% chance of being a carrier or having two normal copies of the gene. HKMU BIOL2006SEF 2024 5  Pathogenesis The disorder is caused by a mutation in the dystrophin gene, the largest gene located on the human X chromosome which codes for the protein dystrophin Without dystrophin, muscles are susceptible to mechanical injury and undergo repeated cycles of necrosis and regeneration. Ultimately, regenerative capabilities are exhausted or inactivated HKMU BIOL2006SEF 2024 6 HKMU BIOL2006SEF 2024 7  Forms in healthy muscle involving dystrophin and binding partners. Plays crucial signaling and structural roles. Links cytoskeleton internally with the sarcolemma and extracellular matrix via laminin. HKMU BIOL2006SEF 2024 8 Healthy Muscle (Left Side): Depicts the intact dystrophin-associated protein complex. Shows a highly organized transmembrane protein complex. Illustrates the functional connection between the cytoskeleton, sarcolemma, and extracellular matrix. Duchenne Muscular Dystrophy (DMD) Muscle (Right Side): Highlights the absence of dystrophin. Indicates disassembly of the protein complex. Notes delocalization and reduced expression of complex components. The loss of interaction between F-actin and the extracellular matrix. Consequences: Resulting effects include severe tissue integrity and functional compromises. Loss of F-actin and extracellular matrix interaction. Implications on the structural and signaling roles previously fulfilled by the dystrophin-associated protein complex. HKMU BIOL2006SEF 2024 9 HKMU BIOL2006SEF 2024 10 Efficient Muscle Regeneration: Loss of dystrophin impacts the ability for efficient muscle regeneration. Healthy Muscle (Left Side): Regenerative myogenesis begins with activated satellite cells. Satellite cells undergo symmetric division to maintain the stem cell pool. Asymmetric division yields myogenic progenitor cells for muscle repair. DMD Context (Right Side): Dystrophin loss in activated satellite cells disrupts cell polarity cues. Impaired polarity leads to mitotic defects and reduced asymmetric divisions. Without dystrophin, symmetric stem cell expansion prevails Satellite cell hyperplasia occurs due to the imbalance Impaired muscle regeneration due to reduced cell diversity Muscle degeneration and wasting occur in the absence of efficient regeneration HKMU BIOL2006SEF 2024 11 Dystrophin is responsible for connecting the cytoskeleton of each muscle fiber to the underlying basal lamina The absence of dystrophin permits excess calcium to penetrate the sarcolemma leading to mitochondrial dysfunction Mitochondrial dysfunction gives rise to an amplification of stress-induced cytosolic calcium signals and an amplification of stress-induced reactive- oxygen species (ROS) production. HKMU BIOL2006SEF 2024 12 Increased oxidative stress within the cell damages the sarcolemma and eventually results in the death of the cell. Muscle fibers undergo necrosis and are ultimately replaced with adipose and connective tissue HKMU BIOL2006SEF 2024 13 HKMU BIOL2006SEF 2024 14 HKMU BIOL2006SEF 2024 15 HKMU BIOL2006SEF 2024 16  Prognosis most are unable to ambulate independently by age 10 most are wheelchair dependent by age 15 most die of cardio respiratory problems by age 25-30 HKMU BIOL2006SEF 2024 17 HKMU BIOL2006SEF 2024 18 Diagnosis Serum Creatine phosphokinase Electromyography Nerve Conduction Velocity Study Molecular diagnosis Muscle biopsy Imaging Studies Electrocardiogram and echocardiogram HKMU BIOL2006SEF 2024 19 Serum Creatine phosphokinase It is elevated in patients with muscle disease and is not specific to the muscular dystrophies As the muscle cell degenerates, CK is released and levels can be elevated 20 to 200 times above normal It is elevated in the Presymptomatic phase, falls as the disease worsens, and approaches near-normal levels in end-stage disease useful for carrier screening Muscle provocation test - After strenuous exercise, CPK levels rise more in carrier females than non carriers. HKMU BIOL2006SEF 2024 20 Electromyography not diagnostic but excludes primarily neurogenic processes. Myopathic pattern decreased amplitude, short duration, polyphasic motor HKMU BIOL2006SEF 2024 21  Molecular diagnosis PCR amplification to examine deletion "hotspots Absence of a DNA abnormality does not exclude them as carriers HKMU BIOL2006SEF 2024 22  Carrier detection Carrier detection is an important aspect of the care and evaluation of patients with DMD and their family members For many years, CPK testing was the best method for carrier detection; however, it is elevated in only two thirds of female carriers If affected male in family has a known deletion or duplication of the dystrophin gene, testing for carrier status is performed accurately by testing possible carriers for the same deletion or duplication HKMU BIOL2006SEF 2024 23  Carrier detection Absence of clinical signs does not exclude them as carriers In families in which the affected male has no detectable deletion or duplication, muscle immunofluorescence for dystrophin used Carrier females should exhibit a mosaic pattern, with some myofibers being normal and some being abnormal HKMU BIOL2006SEF 2024 24  Muscle biopsy increased fibrosis in and between muscle spindles with necrosis of the fibers deposition of fat within the fibers accompanied by hyaline and granular degeneration of the fibers Special histochemical stains that can show muscle fiber type show a preponderance of type I fibers will show absent dystrophin with immunostaining HKMU BIOL2006SEF 2024 25 Treatment Corticosteroid therapy (prednisone 0.75 mg/kg/day) acutely improves strength, slows progressive weakening, prevents scoliosis formation, and prolongs ambulation delays deterioration of pulmonary function side effects osteonecrosis weight gain cushingoid appearance GI symptoms short stature pulmonary care with nightly ventilation HKMU BIOL2006SEF 2024 26 HKMU BIOL2006SEF 2024 27 HKMU BIOL2006SEF 2024 28 Leigh’s Disease Leigh’s Disease, also known as subacute necrotizing encephalomyelopathy is a rare inherited disease that effects the central nervous system. Classic (early-onset) Leigh syndrome affects approximately 1 in 40,000 newborns worldwide. It is neurometabolic, which means it deals with the nerves and metabolism. Begins normally in infants between the age of three months and two years. Very rarely occurs in teenagers and adults, but is possible. HKMU BIOL2006SEF 2024 29 HKMU BIOL2006SEF 2024 30 Causes Can be caused by two things: Mutations within the mitochondrial DNA Deficiencies in pyruvate dehydrogenase, an enzyme. HKMU BIOL2006SEF 2024 31 Types of Leigh syndrome (Leigh’s disease) The types of Leigh syndrome include: Early-onset (infantile): The most common form of Leigh syndrome appears before age 2. Providers also call it classical Leigh syndrome or infantile necrotizing encephalopathy. The condition affects boys and girls equally. Late-onset (adult-onset): Symptoms appear after age 2 and may not occur until adolescence or early adulthood. Adult-onset Leigh syndrome is rare. The condition affects more males than females. The disease progresses slower than the infantile type. Leigh-like syndrome: A person has some symptoms of Leigh syndrome but imaging scans don’t detect signs of the disease. HKMU BIOL2006SEF 2024 32  Symptoms Early symptoms: loss of sucking ability, control of the head, and motor skills. Those three may be accompanied by a lesser appetite, vomiting, crying, and seizures. Progressed symptoms: weakness, loss of muscle, and lactic acidosis which can later affect the kidneys and lungs. Lactic acidosis - a condition characterized by the accumulation of lactic acid in bodily tissues HKMU BIOL2006SEF 2024 33  Evolution of Leigh Disease The association between febrile illness, acute brainstem damage, and respiratory failure also became more clear Acute Respiratory Febrile Illness Brainstem Death Failure Damage Genetic Causes It has now become clear that Leigh’s disease is not a single entity caused by a single genetic condition As the concept of a heterogenous disorder became more accepted, the terminology shifted from Leigh’s disease (implying a single disorder) to Leigh syndrome (implying a set of symptoms with multiple potential etiologies)  Experts have identified mutations in more than 75 different genes that can cause Leigh syndrome. The gene mutations affect your body’s ability to make ATP. Leigh syndrome inherit the gene change that causes the condition through one of two ways: Autosomal recessive disorder X-linked recessive genetic disorder HKMU BIOL2006SEF 2024 36  Mitochondrial diseases Mitochondria are your body’s energy factories. These tiny cellular structures convert the energy in fatty acids and glucose into adenosine triphosphate (ATP). This substance energizes cells. All cells (except red blood cells) have mitochondria. Mitochondrial diseases occur when mitochondria don’t function as they should. As the energy output of cells diminishes, cell damage or death occurs. Your nervous system requires a lot of energy to function. Leigh syndrome damages or destroys cells in your child’s nervous system that provide energy to their brain, nerves and spinal cord. HKMU BIOL2006SEF 2024 38 Cellular respiration HKMU BIOL2006SEF 2024 39 Mitochondrial diseases Anaerobic glycolysis HKMU BIOL2006SEF 2024 40  Prognosis The outcome of Leigh syndrome remains poor The majority of affected individuals die from sudden respiratory failure With the onset of early diagnosis and careful watching during febrile illness, more and more children with Leigh syndrome are surviving longer As of yet we do not know what adulthood holds for these complicated kids  In 2000, Arii et.al. investigated 8 patients with Leigh syndrome (3 months to 12 years of age) to determine if respiratory failure could be predicted on the basis of clinical characteristics or findings on longitudinal MR images of the brain They found that fatal respiratory failure was unpredictable from clinical or neuroradiologic findings brain stem lesions are associated with the loss of respiratory control however the time at which these lesions develop is unpredictable Treatment To date there exist no good treatment options for patients with Leigh syndrome A multitude of oxidative phosphorylation cofactors and antioxidants are prescribed secondary to their potential benefits however, no definitive trials have been published demonstrated clear evidence for clinical improvement in patients CoQ10 L-carnitine Alpha-lipoiic acid Creatine Biotin Thiamine Riboflavin Treatment Newly diagnosed patients should all receive a trial of high dose biotin (10-20 mg/kg) and thiamine (100-300 mg) in case they have biotin responsive basal ganglia disease (BBGD) Malnutrition should be corrected Ketogenic diet in PDH deficiency Wolcott-Rallison syndrome rare disease associated with endoplasmic reticulum (ER) dysfunction characterized by early-onset diabetes mellitus, multiple epiphyseal dysplasia (a skeletal disorder affecting the growth of the ends of long bones), and liver dysfunction. HKMU BIOL2006SEF 2024 45 Genetic Basis Mutation in the EIF2AK3 gene (Eukaryotic translation initiation factor 2-alpha kinase 3) also known as PERK (PKR-like endoplasmic reticulum kinase) Role of EIF2AK3 in regulating protein production in response to ER stress HKMU BIOL2006SEF 2024 46 HKMU BIOL2006SEF 2024 47 How mutations lead to ER dysfunction Impaired Unfolded Protein Response (UPR) Activation  accumulation of misfolded proteins, leading to ER stress Protein Folding Defects  impair the cell's ability to properly fold proteins, leading to an accumulation of misfolded proteins in the ER lumen. ER Stress Response Dysregulation  disrupt the balance between protein synthesis and protein folding capacity in the ER  prolonged or severe ER stress, impacting essential cellular processes and ultimately leading to cell dysfunction or death HKMU BIOL2006SEF 2024 48  Apoptosis Induction  Excessive cell death due to ER stress-induced apoptosis Impaired Lipid Homeostasis  disrupt lipid metabolism regulation, affecting insulin signaling and glucose homeostasis Cellular Toxiciity  ccumulation of misfolded proteins and the failure to properly manage ER stress HKMU BIOL2006SEF 2024 49 Clinical Features Early-onset diabetes mellitus Multiple epiphyseal dysplasia Liver dysfunction Other associated symptoms (if applicable) HKMU BIOL2006SEF 2024 50 Diagnosis Challenges in diagnosing Wolcott-Rallison syndrome Genetic testing for EIF2AK3 mutations Importance of early detection HKMU BIOL2006SEF 2024 51 Treatment and Management Supportive care to manage symptoms Potential future treatment strategies Multidisciplinary approach for comprehensive care HKMU BIOL2006SEF 2024 52 Prognosis Impact of Wolcott-Rallison syndrome on quality of life Prognosis and long-term outlook Research on improving outcomes HKMU BIOL2006SEF 2024 53 HKMU BIOL2006SEF 2024 54