Rare Disease and Cellular Abnormalities I (HKMU 2024) PDF

BIOL 2006SEF Cells in Health and Disease Topic 4 Rare Disease and Cellular Abnormalities I Dr CHEUNG Ka Tik HKMU 2024  WHAT IS RARE Never seen before, Unbelievable, Unrecognized or Unusual or When one comes to know that he or she is suffering from so...

BIOL 2006SEF Cells in Health and Disease Topic 4 Rare Disease and Cellular Abnormalities I Dr CHEUNG Ka Tik HKMU 2024  WHAT IS RARE Never seen before, Unbelievable, Unrecognized or Unusual or When one comes to know that he or she is suffering from something which is different kind of disorder and is rarely seen; say one in 200,000. HKMU 2024 HKMU 2024  I AM RARE- THE QUESTIONS OCCUPIES ONE’S MIND Am I unlucky to be cursed with this disorder? Am I correctly diagnosed? Is this curable? If so, how expensive is the treatment? What will be the success rate of my treatment? HKMU 2024  RARE AND ORPHAN Poorly Diagnosed Heavy cost of treatment Neglected Untreated Abandoned/Orphan People with rare disorders and their families often suffer isolation, frustration, depression, and abandonment. HKMU 2024 Hong Kong Chief Executive Carrie Lam meets 23-year-old Josy Chow Pui-shan, who suffers from spinal muscular atrophy, outside government headquarters on October 8. Photo: Kwong Wing-kin HKMU 2024  Rare Diseases Group of conditions which affect tiny numbers of people 95% of rare diseases are genetic, and the rest may occur as a result of viral or bacterial infections, allergies, and other environmental causes. About 95% of rare diseases do not have a treatment option  greatest challenge for patient care HKMU 2024  FACTS TO KNOW ABOUT RARE DISORDERS (RDs) There are approximately 8,000 different types of RDs, with more being discovered each day. There is currently no uniform definition of RD that has been adopted unanimously around the world. National Health Commission released in June 2018 "The First Catalogue of Rare Diseases in China" comprising 121 rare diseases; and in September 2023 "The Second Catalogue of Rare Diseases in China" including another 86 rare diseases with the relevant list of drugs and producers. HKMU 2024  FACTS TO KNOW ABOUT RARE DISORDERS (RDs) About 95 % of the RDs are genetic in origin, and thus are present throughout a person’s life, even if symptoms do not appear immediately. The age of onset varies from birth to old age, depending on the individual and disease type. About 50% of RDs onset at birth. The vast majority of RD pose a serious and long-term threat to patients’ health, and some can even be disabling and fatal. Most of RDs have no FDA Approved Drug Treatment Lack of awareness, dispersed target population and inefficient reporting limits the pace of drug development for RDs. HKMU 2024  FACTS TO KNOW ABOUT RARE DISORDERS (RDs) At present, ‘rare diseases” are referred to as “uncommon diseases” by the Hong Kong Government, and there is no official definition of “uncommon diseases”. Well-known ones include Mucopolysaccharidoses, Pompe Disease, Angelman Syndrome, Albinism, Marfan Syndrome, Rett Syndrome, Spinocerebellar Ataxia, Tuberous Sclerosis Complex, Spinal Muscular Atrophy, Fabry Disease, Retinitis Pigmentosa. The total number of rare disease patients in Hong Kong is as high as 110, 000. HKMU 2024  Rare Diseases - Cell disorders CELL MEMBRANE - CYSTIC FIBROSIS NUCLEUS - PROGERIA LYZOSOME - MUCOPOLY SACCHARIDOSIS CYTOSKELETON - DUCHENNE MUSCULAR DYSTROPHY MITOCHONDRIA - LEIGH’S DISEASE ENDOPLASMIC RETICULUM - PRION DISEASES HKMU 2024 HKMU 2024  Cystic fibrosis Cystic fibrosis is an autosomal recessive disorder that affects epithelial cells of the respiratory , gastrointestinal and reproductive tracts and leads to abnormal exocrine gland secretions. An individual must inherit a defective copy of the CF gene (one from each parent) to have CF. Although it can affect many organ system, CF is particularly damaging to the lungs, leading to COPD in childhood and early adulthood. Autosomal recessive  Epidemiology The frequency of CF is 1 in 2,000 to 3,000 live births, and there are approximately 30,000 children and adults with this disease in the United States (Cystic Fibrosis Foundation, 2002). Although CF was once considered a fatal childhood disease, approximately 38% of people living with the disease are 18 years of age or older (Cystic Fibrosis Foundation,2002).  Etiology /Pathophysiology CF is due to a mutation in the CF gene on chromosome 7. The CF gene encodes a protein known as the cystic fibrosis transmembrane regulator (CFTR). The abnormal CFTR protein in patients with CF leads to disruption of chloride channels on the cells.  Etiology /Pathophysiology Mutations in the CFTR gene cause cystic fibrosis. Disrupt the function of the chloride channels, preventing them from regulating the flow of chloride ions and water across cell membranes. Produce mucus that is unusually thick and sticky. Damages the lungs and digestive system. HKMU 2024  Etiology /Pathophysiology Defective chloride transport cause more water and sodium reabsorption than normal. Secretion in affected organs becomes thick and viscous obstructing the glands and ducts. Dilatation of the secretory glands damage to the exocrine tissue  GABA receptors are ligand-gated ion HKMU 2024 channels HKMU 2024 HKMU 2024  Non-pulmonary clinical manifestations Gastrointestinal problems (eg, pancreatic insufficiency) Biliary cirrhosis, Vitamin D deficiencies, Recurrent pancreatitis, Weight loss HKMU 2024  Assessment and Diagnostic Findings Sweat chloride concentration test: Sweat test: sweat chloride values of greater than 60 mEq/L Genetic tests to find out what type of CFTR defect is causing CF. Chest x ray: Inflated lung, lungs fibrosis and scaring Guess..? HKMU 2024 HKMU 2024  What Is Progeria? Progeria is an extremely rare, fatal genetic condition that affects children and gives them an appearance of accelerated aging. The word Progeria comes from the Greek rogeros meaning 'prematurely old'. It was first described in an academic journal by Dr. Jonathan Hutchinson in 1886, and Dr. Hastings Gilford in 1897 - both in England. The condition was later named Hutchinson-Gilford Progeria Syndrome (HGPS).  Prevalence Progeria is listed as a "rare disease" by the Office of Rare Diseases (ORD) of the National Institutes of Health (NIH). HGPS prevalence is reported to be 1 in 8 million births. The true prevalence, however, has been suggested to be closer to 1 in 4 million births because many cases likely go undiagnosed or are misdiagnosed.  Prevalence Progeria affects all races with about 97% of the children affected being Caucasian. Also, it affects both sexes almost equally with slight male predilection; the male-to-female ratio is 1.5:1. In the past 15 years, children with Progeria have been reported all over the world.  Fertility In general, people with progeria have such severe failure to thrive (poor growth from the time of childhood) that it prevents fertility. The absence of complete sexual maturation has been considered characteristic of the syndrome. Yet a case described and published at 1989 by endocrinologists in Spain reported that a 32-year-old woman with progeria had delivered a child at age 23 which means that she must have been sexually mature to deliver the child. However sexual maturity is rare in these patients.  Prognosis As there is no known cure, the average life expectancy for a patient with HGPS is 13 years, with an age range of 7-27 years. At least 90% of patients die from complications of atherosclerosis, such as heart attack or stroke. Mental development is not adversely affected; in fact, intelligence tends to be above average.  Symptoms Although they are born looking healthy, children with Progeria begin to display many characteristics of accelerated aging at around 18-24 months of age. The children have a remarkably similar appearance, despite differing ethnic backgrounds. Most of the following features are manifested after the age of three years in children with Hutchinson-Gilford progeria syndrome.  Symptoms Baldness Pinched nose Small, wrinkled face Head large for the size of the face Loss of eyebrows and eyelashes Prominent scalp veins Delayed tooth formation Loss of muscles and body fat Bulging eyes Wrinkled, scaly, dry skin High pitched voice Short stature Stiffness in joints Progressive cardiovascular diseases Progressive atherosclerosis Fig: Dutch Patient at the age of 1 year, 1 year, 2 years, 6 years, 7 years, 8 years, 10 years, and 12 years.  Genetic causes Mutations in the LMNA gene cause Hutchinson-Gilford progeria syndrome. LMNA gene is located on chromosome 1q22 and is composed of 12 exons. Only four causative heterozygous mutations for HGPS in LMNA are recognized.  Mode of inheritance HGPS is not usually passed down in families. The gene change is almost always a chance occurrence that is extremely rare. However, HGPS is considered a “sporadic autosomal dominant” mutation. Fig : Progeria mode of inheritance  Molecular Basis of Disease A key to disease in HGPS is the presumably persistent farnesylation of progerin, which renders it permanently intercalated into the inner nuclear membrane where it can accumulate and exert progressively more damage to cells as they age. The inability to release progerin from the nuclear membrane results in structural stress on the nucleus. This permanently farnesylated mutant form of prelamin A (progerin) leads to the progressive defects in nuclear architecture that are seen in HGPS. HKMU 2024 Fig : Normal cell Vs. progeria cell HKMU 2024 HKMU 2024  Diagnosis The diagnosis is based on recognition of common clinical features and Molecular genetic testing of LMNA, the only gene known to be associated with HGPS.  Molecular genetic testing Molecular genetic testing: Targeted mutation analysis can be used to identify the pathologic variant c.1824C>T (p.Gly608Gly), the common recurrent de novo LMNA mutation in exon 11 that defines classic HGPS. HKMU 2024  Treatments Regular monitoring for cardiovascular disease may help with managing the child's condition. Some children undergo coronary artery bypass surgery or dilation of cardiac arteries (angioplasty) to slow the progression of cardiovascular disease. Low-dose aspirin. A daily dose may help prevent heart attacks and stroke. Other medications. Depending on the child's condition, doctor may prescribe other medications, anticoagulants to help prevent blood clots. The use of growth hormone may help increase height and weight.  MUCO POLY SACCHARIDOSES HKMU 2024  Mucopolysaccharidoses Hereditary, progressive diseases caused by mutations of genes coding for lysosomal enzymes needed to degrade glycosaminoglycans (GAGs) (acid mucopolysaccharides). GAGs accumulate in the lysosomes, resulting in cellular dysfunction and clinical abnormailites HKMU 2024  Mucopolysaccharidoses Mucopolysaccharidoses are autosomal recessive disorders, with the exception of Hunter disease, which is X- linked recessive. Mucopolysaccharidoses 10/24/2024 49 Prof.Dr.Saad S Al Ani Khorfakkan Hospital Classification HKMU 2024 HKMU 2024  Glycosaminoglycan(GAG) A long-chain complex carbohydrate composed of: 1. Uronic acids 2. Amino sugars 3. Neutral sugars. www.mun.ca Mucopolysaccharidoses 10/24/2024 52 Prof.Dr.Saad S Al Ani Khorfakkan Hospital  GAGs are highly polar molecules and attract water; the body uses them as lubricants or shock absorbers. GAGs interact with a wide range of proteins, including proteases, growth factors, cytokines, chemokines and adhesion molecules, enabling them to mediate many physiological processes, such as protein function, cellular adhesion and signaling. HKMU 2024  Proteoglycans degradation Proteoglycans Proteolytic Protein core Stepwise degradation GAG moiety www.glycoforum.gr.jp Mucopolysaccharidoses 10/24/2024 54 Prof.Dr.Saad S Al Ani Khorfakkan Hospital  Proteoglycans degradation disturbance Proteoglycans Absent or grossly reduced activity of mutated lysosomal enzymes Glycosaminoglycans (GAGs) Intralysosomal Mucopolysaccharidoses 10/24/2024 55 Prof.Dr.Saad S Al Ani Khorfakkan Hospital  Proteoglycans degradation disturbance (cont.) Distended lysosomes cell function printablecolouringpages.co.uk Characteristic pattern of clinical, radiologic, and biochemical abnormalities Specific diseases can be recognized that evolve from the intracellular accumulation of different degradation products Mucopolysaccharidoses 10/24/2024 Prof.Dr.Saad S Al Ani Khorfakkan Hospital 56 Pathophysiology HKMU 2024 HKMU 2024 Symptoms HKMU 2024  Symptoms Feature MPS I (Hurler MPS II (Hunter MPS III MPS IV MPS VI MPS VII (Sly Syndrome) Syndrome) (Sanfilippo (Morquio (Maroteaux- Syndrome) Syndrome) Syndrome) Lamy Syndrome) Inheritanc Autosomal X-linked Autosomal Autosomal Autosomal Autosomal e Pattern recessive recessive recessive recessive recessive recessive Deficient α-L- Iduronate-2- Heparan N- Galactosamine N- β- Enzyme iduronidase sulfatase sulfatase -6-sulfatase acetylgalactosam glucuronidase ine-4-sulfatase Key Coarse facial Coarse facial Severe Skeletal Coarse facial Dysmorphic Clinical features, features, neurological abnormalities, features, features, Features symptoms, hepatospl behavioral hepatomegaly, joint short stature, organomegaly, enomegaly issues, joint stiffness abnormalities, skeletal dysmorphic , corneal intellectual short abnormalities, , clouding, limited disability stature organomegaly features cognitive mobility decline Skeletal Yes No Yes Yes Yes Yes Involveme nt Neurologic Cognitive Mild cognitive Severe Absent Mild Severe al Features decline impairment neurological neurological neurological symptoms HKMU 2024 symptoms symptoms Diagnosis HKMU 2024  Treatment of MPS Enzyme replacement Hematopoietic stem cell transplantation HKMU 2024  Enzyme replacement It reduces : Organomegaly Number of episodes of sleep apnea Urinary GAG excretion It ameliorates : rate of growth joint mobility Physical endurance. The enzymes do not : Cross the blood-brain barrier Prevent deterioration of neurocognitive involvement. This therapy is the domain for patients with mild central nervous involvement HKMU 2024 Blood-Brain Barrier HKMU 2024  Hematopoietic stem cell transplantation Hematopoietic stem cell transplantation results in significant clinical improvement of somatic disease in MPS I, II, and VI Enzyme replacement using recombinant enzymes is approved for patients with MPS I, MPS II, and MPS VI. Enzyme activity in serum and urinary GAG excretion is normalized. Transplantation prevents neurocognitive degeneration Transplantation does not correct : Existent cerebral damage Skeletal and ocular anomalies HKMU 2024 HKMU 2024  Prevention Primary prevention – Through genetic counseling Tertiary prevention – To avoid or treat complications remains the mainstay of supportive pediatric care Multidisciplinary attention to: Respiratory and cardiovascular complications Hearing loss Carpal tunnel syndrome Spinal cord compression Hydrocephalus, and other problems – Can greatly improve the quality of life for patients and their families HKMU 2024  WATCH… The progressive nature of clinical involvement in MPS patients dictates the need for specialized and coordinated evaluation HKMU 2024 HKMU 2024