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VOLUME 29 C O R A M ’ S C O N T I N U I N G E D U C AT I O N P R O G R A M Lysosomal Storage Diseases and Enzyme Replacement Therapy Enzymes are proteins that play critical roles in the body. Made from amino acids, an enzyme is a catalyst — it makes a specific action happen in the body. There are three categories of enzymes: food enzymes, which are derived from raw foods and initiate the digestive process; digestive enzymes, which digest food; and metabolic enzymes, which catalyze cellular function. Each cell in the body requires a specific enzyme to initiate a chemical reaction that the cell needs to work properly. Each enzyme works on one specific chemical reaction rapidly and efficiently. Enzymes can generally be recognized by their name; most are named by adding “-ase” to the root name of the molecule the enzyme is acting upon. For example, lipase catalyzes the breakdown of a lipid; sucrase is the enzyme that starts the process of breaking down sucrose into the usable sugars glucose and fructose. If an enzyme is either missing or dysfunctional, whatever function that enzyme was supposed to initiate does not happen; thus, the patient has a related disease. Lysosomal storage diseases (LSDs) are caused by problems with lysosomal enzymes. Inside each cell, lysosomal enzymes are held within sacs (or organelles) called lysosomes. Lysosomal enzymes break down large molecules, such as glycolipids and glycogen, into functional units. When any lysosomal enzyme is not functioning properly, whatever substrate was to be broken down accumulates in the cells of various tissues and organs, eventually leading to cellular degeneration and progressive tissue and organ dysfunction. Lysosomal storage diseases (LSDs) are characterized by the deficiency of a lysosomal enzyme. For patients with LSDs, successful cellular function requires replacement of the enzyme that is not functioning properly. Intravenous enzyme replacement therapy (ERT) refers to the infusion of a specific enzyme directly into a vein to replace the patient’s missing, deficient, or ineffective enzyme. Mucopolysaccharidoses – A Group of LSDs One group of inherited LSDs is the mucopolysaccharidoses (MPSs). Lysosomal enzymes help digest foods such as certain carbohydrates and fats (lipids). In people with MPS disorders, missing or malfunctioning lysosomal enzymes cause an accumulation throughout the body of certain complex carbohydrates known as mucopolysaccharides or glycosaminoglycans, ultimately resulting in damage. The MPSs are inherited diseases, some of which have prevalence Figure 1. Inheritance Pattern for MPSs Autosomal recessive Carrier father Affected child Affected Carrier mother Carrier child Carrier child Unaffected child Unaffected Image source: http://kintalk.org/files/2012/07/recessive-inheritance.jpg A leading national provider of home infusion services, including alternate site of care and specialty pharmacy distribution. 12600 E Arapahoe Road, Suite A, Centennial, CO 80112 | 720.568.3401 | coramhc.com Carrier within certain ethnicities. Most are autosomally recessive. (See Figure 1.) This means that two defective genes are necessary to get the disease, and therefore, a person must have inherited the defective gene from both parents. If a person inherits a defective gene from one or the other parent only, he or she is a carrier (more commonly known as a heterozygote). Types of MPSs More than 50 disorders in the MPS category have been identified, and while each individual disease is rare, as a group they have an estimated incidence of 1 in 6,500–7,700 live births.1 While there are some similarities between the diseases, there are also unique effects depending on the specific enzyme affected. And while the treatment is the same in that the enzyme needs to be replaced, the drug with which it is replaced is unique to the specific disease. See Table 1 for a list of the MPSs for which ERT is currently available. Fabry Disease Fabry disease is caused by a lack or deficiency of the enzyme alpha galactosidase A (a-GAL A). A genetic mutation in the gene that controls a-GAL A production causes a poor breakdown of lipids, leading to a harmful accumulation of lipids in the cardiovascular system, autonomic nervous system, kidneys, and eyes. This accumulation of lipids— particularly one lipid called globotriaosylceramide (GL-3)— can lead to circulatory problems and increase the risk of stroke or heart attack. Fabry is an x-linked recessive disorder, which means that if a male inherits a defective x gene, he will have the disorder. If a female inherits a defective x gene, she will be a heterozygote. With most diseases, 2 | Table 1. Mucopolysaccharidoses Treated with ERT Disease Missing/Deficient Enzyme Enzyme Replacement Therapy Fabry disease Alpha-galactosidase A — agalsidase beta Fabrazyme® Gaucher disease Glucocerebrosidase — alglucerase Ceredase® Cerezyme® VPRIV® Hunter syndrome Iduronate-2 sulfatase-idursulfase Elaprase® Hurler-Scheie syndromes Alpha-iduronidase-laronidase Aldurazyme® Maroteaux-Lamy syndrome Arylsulfatase B-galsulfase Naglazyme® Pompe disease Alglucosidase alpha Myozyme® a heterozygote is unaffected by the disorder and is symptom-free. This is not always true in the case of Fabry disease. Symptoms of Fabry disease vary, and are typically more significant in males than females. They may include episodes of pain in the hands and feet, skin rash, decreased ability to sweat, and clouding of the corneas (does not affect vision). Since the fat accumulates gradually over years, symptoms also develop over time. After about age 30, patients may also experience nausea, vomiting, and diarrhea; cardiac problems including heart failure, arrhythmias, heart attack, and valvular disease; central nervous system symptoms such as stroke, headaches, dizziness, and numbness and tingling; gradual hearing loss or ringing in the ear; and renal dysfunction or failure. In fact, Fabry disease is often first diagnosed when the patient presents with renal insufficiency. Treatment of Fabry disease includes the replacement of the missing a-GAL A enzyme with the recombinant (man-made) preparation agalsidase beta (Fabrazyme). Fabrazyme is dosed at 1 mg/kg IV every two weeks over four to five hours. The infusion rate can be increased as tolerated. Infusion reactions can happen, and pre-treatment with an antipyretic and an antihistamine is common. C O R A M ’ S C O N T I N U I N G E D U C AT I O N P R O G R A M The life expectancy of patients with Fabry disease is often 20 years less than normal in men, and 15 years less in women. Death is often secondary to renal failure or a cardiac or cerebrovascular event, and typically occurs in the late fifties or sixties.2 Gaucher Disease Gaucher (pronounced “go-SHAY”) disease is the most common of the MPSs. People with Gaucher disease do not have enough of the enzyme glucocerebrosidase, which helps the body break down glucocerebroside, a type of fat molecule. As a result, glucocerebroside is not broken down or digested, and dangerous levels of undigested fat build up in the patient’s spleen, liver, bone marrow, and sometimes the brain, resulting in a number of potential symptoms. As described in Table 2 below, there are three types of Gaucher disease, with key differences between the types. It is important to recognize, too, that the signs and symptoms vary between individuals, even with the same type of disease. There is currently no available treatment for type 2 Gaucher disease. Patients with type I disease who present with mild symptoms may not require treatment. However, for symptomatic patients with type 1 or type 3 Gaucher disease, replacement of the missing enzyme (glucocerebrosidase) is the standard VOLUME 29 of care. The three current ERT drugs for Gaucher disease are: yy Alglucerase – injection (Ceredase®) yy Imiglucerase (Cerezyme®) yy Velaglucerase alfa (VPRIV®) ERT is administered intravenously every two weeks, over one to two hours. ERT can alleviate and, in some cases, even reverse the effects of Gaucher disease. With ERT, there is a risk of hypersensitivity reaction, and premedication is common. Patients also have the potential to develop Ig (immunoglobulin) antibodies, usually within the first six months of therapy. This results in the need for intermittent monitoring throughout the first year. In addition to ERT, there are two available oral medications for the treatment of Gaucher disease. Miglustate (Zavesca®) may be indicated for the treatment of adult patients with mild to moderate type 1 Gaucher disease for whom ERT is not a therapeutic option (for instance, because of allergy, hypersensitivity, or poor venous access). As opposed to ERT, which replaces the missing enzyme, miglustate functions as substrate reduction therapy, reducing the production of fatty substances. One important potential adverse effect is the development of peripheral neuropathy. Neurological evaluations at baseline and every six months are recommended. Eliglustat (Cerdelga®) is another oral agent. Similar to miglustate, Eliglustat — a glucosylceramide synthase inhibitor — reduces production of the lipid glucosylceramide. Thus, there is less to accumulate. Hunter Syndrome The normal function of the enzyme iduronate-2-sulfatase is to cause lysosomes to break down complex sugars called glycosaminoglycans. The body requires these sugars to build structures such as bone, cartilage, tendons, corneas, skin, and connective tissue, and to lubricate joints. With Hunter syndrome, the enzyme does not work properly. Undigested glycosaminoglycans collect in the cells, blood, and connective tissues, leading to progressive and permanent damage. There are two distinct forms of Hunter syndrome — early onset and late onset. Early onset disease presents with severe symptoms, and physical and mental development peaks at two to four years of age. Symptoms of late onset disease are milder, typically presenting after age 10 and often not until adulthood. Symptoms for both types of Hunter syndrome vary in terms of both incidence and severity. For early onset disease, symptoms can include: yy Delayed development and short stature Table 2. Symptoms of the Three Types of Gaucher Disease Type 1 Incidence /Age of Onset yy Most common type (~90%) /Can appear at any age, average around age 30 Possible Symptoms yy Easy bruising yy Nose bleeds yy Fatigue yy Enlarged liver and spleen yy Skeletal abnormalities (bone thinning, pain, fractures) Primary Treatment Complications / Prognosis yy In mild cases, may require no treatment yy Bleeding disorders yy Enzyme replacement therapy yy Bone pain yy Increased risk of certain cancers, such as multiple myeloma yy Near-normal life expectancy yy Lung and kidney injury yy Delayed puberty yy Yellow spots in eyes (pingueculae) yy No brain involvement 2 yy Rare/Appears in infancy yy Liver and spleen enlargement by three months of age yy None available yy Bone pain yy Bleeding disorders yy Widespread and rapidly progressive brain damage yy Increased risk of certain cancers, such as multiple myeloma yy Cognitive deterioration (such as mental retardations, dementia) yy Seizures yy Rigidity yy Abnormal gait yy Seizures yy Swallowing difficulties yy Death by age two years 3 yy Rare/Appears in childhood, early teens yy Chronic, more slowly progressive yy Liver and spleen enlargement yy Milder, gradually progressive brain involvement yy Enzyme replacement therapy yy Bone pain yy Bleeding disorders yy Skeletal abnormalities yy Increased risk of certain cancers, such as multiple myeloma yy Cognitive deterioration yy Heart valve calcifications yy Abnormal eye movement disorders yy If survival to the teens, numerous additional years likely yy Loss of muscle coordination yy Blood disorders VOLUME 29 C O R A M ’ S C O N T I N U I N G E D U C AT I O N P R O G R A M | 3 yy Intellectual disability yy Aggressive behavior yy Changing facial features such as thickening of the lips, tongue, and nostrils, broadening of the nose, protrusion of the tongue yy Skeletal abnormalities such as claw-like hands, abnormal bone size or shape, joint stiffness yy Spasticity yy Carpal tunnel syndrome yy Enlarged liver and spleen yy Sleep apnea yy High blood pressure yy Visual changes yy Progressive hearing loss In late onset disease, symptoms may include varying degrees of: yy Abnormal bone size or shape and other skeletal irregularities, but less severe than in early onset yy Shorter stature, but to a lesser degree than in early onset yy Poor peripheral vision yy Joint stiffness yy Hearing loss yy Carpal tunnel syndrome yy Sleep apnea Enzyme replacement for Hunter syndrome is done using iduronate-2 sulfatase-idursulfase (Elaprase), administered weekly by IV over about three hours. The infusion time may be gradually decreased if the patient remains free of signs of hypersensitivity. It may also need to be longer depending on patient tolerance, but cannot exceed eight hours. This therapy comes with a black box warning for risk of anaphylaxis, as life-threatening anaphylactic reactions have been observed. About 50% of patients develop anti-idursulfase IgG antibodies, 4 | which increase the risk of infusionrelated reactions. expectancy with Sheie syndrome is close to normal. Hurler-Scheie Syndromes Treatment for all three syndromes is recombinant alpha-iduronidaselaronidase (Aldurazyme) ERT and is aimed at slowing disease progression. Weekly infusions typically require premedication, and monitoring is required. The Hurler-Scheie (pronounced “shay”) syndromes are three variations of another MPS. In order of severity, they are Hurler syndrome, Hurler-Sheie syndrome, and Sheie syndrome. The genetic abnormality in this set of diseases causes a deficiency of the alpha-L-iduronidase enzyme. Patients with these diseases present with varying degrees of many of the same symptoms described for Hunter syndrome. In the severe form, symptoms include short stature and coarse facial features such as a broad flat nose, flat face, long head with a bulging forehead, thick lips, an enlarged tongue, and poorly formed, widely spaced teeth. Noisy breathing, chronic runny nose, and ear infections are common due to the flattened nose and thickened soft tissues in the nasal passages. Weakening of the heart muscle and valves commonly leads to heart disease. Hydrocephalus commonly presents, and corneal clouding may develop. Importantly, with Hurler syndrome, progressive mental retardation occurs, with peak intelligence achieved at about age two, after which there is a progressive regression of skills until death. Patients rarely live beyond 10 years. Patients with Hurler-Scheie typically present with normal intelligence but also have progressive physical involvement, short stature, and a significantly decreased life expectancy. Patients with Scheie syndrome typically have normal intelligence, stature, and life expectancy, but other physical symptoms occur, such as stiff joints and corneal clouding. These symptoms usually start after five years of age. Life C O R A M ’ S C O N T I N U I N G E D U C AT I O N P R O G R A M Maroteaux-Lamy Syndrome Maroteaux-Lamy syndrome, also known as mucopolysaccharidosis type VI or MPS VI, is characterized by complete or partial lack of activity of the enzyme arylsulfatase B (also called N-acetylgalactosamine-4-sulfatase). This causes the accumulation of complex carbohydrates called glycosaminoglycans. The symptoms and severity of Maroteaux-Lamy syndrome can vary dramatically from one person to another, and range from mild to severe and life-threatening. Symptoms are progressive and can include coarse facial features; impaired bone formation and growth; dwarfism; enlarged tongue and thick lips; corneal clouding, which, if severe enough, can impair vision; hearing loss; an abnormally enlarged liver and/or spleen; cardiac disease; and restrictive pulmonary disease. Symptoms usually begin around age two to three years. Intelligence is usually not affected. Treatment for Maroteaux-Lamy syndrome is weekly infusions, over four hours, of the ERT galsulfase (Naglazyme). Pre-medication is usually required. Sleep apnea is not an uncommon adverse effect, and requires monitoring. Pompe Disease Pompe disease results from a defective gene that causes a deficiency of the enzyme acid alpha-glucosidase (GAA). Glycogen, a form of sugar that is stored in the VOLUME 29 muscle cells, builds up in the body. As excess glycogen accumulates, it interferes with normal cell function and causes continuous damage to cells, resulting in worsening muscle weakness that can affect movement, breathing, and in infants, heart function. Pompe disease affects people of all ages, from infancy through adulthood, although there are two forms of the disease with distinct differences. With infantile onset, patients have a complete GAA deficiency, and the primary site of glycogen accumulation is in the heart muscle. With adult-onset Pompe disease, GAA activity is between 1% and 40% of normal levels, with glycogen accumulation occurring primarily in the skeletal and respiratory muscles. Patients with infantile onset may present with: yy Cardiac hypertrophy yy Severe muscle weakness »» Floppiness due to loss of muscle tone »» Head lag yy Respiratory difficulties yy Enlarged liver and tongue yy Feeding problems yy Cardiac failure yy Frequent pulmonary infections yy Failure to meet motor milestones yy Poor weight gain and failure to thrive Patients with adult onset disease may present with: yy Progressive muscle weakness »» Trunk and proximal lower limbs yy Delayed motor milestones and progressive loss yy Gait abnormalities; difficulty walking or climbing stairs; frequent falls; arthralgia VOLUME 29 yy Lordosis, kyphosis, or scoliosis yy Respiratory difficulties; exertional dyspnea yy Morning headache and daytime sleepiness yy Nocturnal hypoventilation yy Poor weight gain and maintenance yy Eventual loss of ambulation and mechanical ventilation, and premature death Pompe disease is treated with the enzyme alglucosidase alfa (Myozyme). Myozyme infusion is typically given via one dose every two weeks. It is administered over about four hours, depending on how the patient tolerates the infusion. This agent also has a black box warning for life-threatening anaphylactic reaction. Severe allergic and immune-mediated reactions have been observed. In addition, patients with compromised cardiac or respiratory function may be at risk for serious acute exacerbation of this compromised function due to infusion reactions, and require additional monitoring. Enzyme Replacement Therapy Administration While not a cure for LSDs, ERT can impact both symptoms and disease progression. Most disease-related complications of LSDs cannot be reversed by ERT, so early diagnosis and treatment is critical in order to prevent their development. Patients who require ERT need lifetime treatment. ERT is given by IV through either a peripheral line or a central line. Most patients require an infusion every two weeks, although patients with Hunter or the Hurler-Scheie syndromes typically require weekly infusions. Treatment is usually infused over two to six hours, depending on the specific therapy, the patient’s weight, and whether or not the patient has or has had a reaction to the infusion. Since patients often develop antibodies to their ERT, there is potential for infusion reactions, including anaphylaxis. Most of the time, infusion reactions can be managed by decreasing the rate of the infusion, as well as providing an anti-fever medication and an antihistamine prior to the infusion. This treatment is called pre-medication, and it is usually required. Because there are no other medications to treat these diseases, the risk of infusion reaction is cautiously accepted. Infusions are often given in a controlled setting, such as an outpatient clinic or ambulatory infusion suite. After a period of infusions without infusion-related reactions, some patients may be able to infuse in their homes. However, due to the therapyspecific complexity and potential adverse effect profile, the majority of ERTs require a nursing presence for the entire length of drug administration. Other Treatment Options Blood cell transplantation (bone marrow or umbilical cord) may be an option, with or without ERT, especially when performed early in the course of disease.3 In addition to the ERT available for the above-mentioned diseases, enzyme replacement options continue to be developed for other enzyme disorders as well. Route of administration is also being evaluated, with particular focus on intrathecal enzyme delivery. Current therapy has limited impact on improving central nervous system manifestations related to the neuronopathic forms of the diseases.t *Do not use the information in this article to diagnose or treat a health problem or disease without consulting a qualified physician. Patients should consult their C O R A M ’ S C O N T I N U I N G E D U C AT I O N P R O G R A M | 5 physician before starting any course of treatment or supplementation, particularly if they are currently under medical care, and should never disregard medical advice or delay in seeking it because of something set forth in this publication. References 1. American Society of Gene and Cell Therapy. www.asgct.org/general-public/educationalresources/gene-therapy-and-cell-therapyfor-diseases/lysosomal-storage-diseases. Accessed March 19, 2015. 2. Golfomitsos C, Sengupta A, Prasad U, Gray S. Fabry disease. Br J Cardiol. 2012;19(1):41-45. 3. Martino S. Therapy for lysosomal storage disorders: a matter for stem cells. Int J Stem Cell Res Transplant. 2015;3(1e) 1-2. Bibliography • Alroy J, Lyons JA. Lysosomal storage diseases. Jl Inborn Errors Metab & Screening. March 28, 2014. doi:10.1177/2326409813517663. http://iem. sagepub.com/content/2/2326409813517663. full. Accessed June 10, 2015. •Fong CT. Lysosomal storage disorders. www.merckmanuals.com/professional/ pediatrics/inherited-disorders-of-metabolism/ lysosomal-storage-disorders. Updated February 2010. Accessed June 10, 2015. •Kruer MC. Lysosomal storage disease. Medscape reference. http://emedicine. medscape.com/article/1182830. Updated October 18, 2013. Accessed June 10, 2015. •Nagueh SF. Contemporary reviews in cardiovascular medicine: Anderson-Fabry disease and other lysosomal storage disorders. Circulation. 2014; 130:1081-1090. •Ortolano S, Vieitez I, Navarro C, Spuch C. Treatment of lysosomal storage diseases: recent patents and future strategies. Recent Pat Endocr Metab Immune Drug Discov. 2014;8(1):9-25. 6 | C O R A M ’ S C O N T I N U I N G E D U C AT I O N P R O G R A M VOLUME 29 Self-Assessment Quiz: Lysosomal Storage Diseases and Enzyme Replacement Therapy LEARNING GOAL LEARNING OBJECTIVES To gain knowledge of lysosomal storage diseases, including signs, symptoms, and outcomes, as well as therapy considerations, with a focus on enzyme replacement therapies. At the end of this program, the reader will be able to: 1. Identify the primary role of enzymes. 2. Describe the impact of missing or ineffective enzymes. 3. Identify and discuss enzyme replacement therapies for lysosomal storage diseases. SELF-ASSESSMENT QUESTIONS In the Quiz Answers section on the next page, circle the correct answer for each question. To obtain two (2.0) contact hours toward CE credit, the passing score is 100%. Return your Self-Assesment Quiz to Coram via email, fax or mail. See the next page for details on how to return to your quiz. Please allow approximately seven days to process your test and receive your certificate upon achieving a passing score. 1. Enzymes are essential catalysts for specific activities in the body. a.True b.False 2. More than __ disorders in the MPS category have been identified so far, with treatments available for only a few. a.20 b.40 c.50 3. Lysosomal storage disorders are: a.Inherited via an autosomal dominant pathway. b.Inherited via an autosomal recessive pathway. c.Neither A nor B. 4. In people with MPS disorders, missing or malfunctioning lysosomal enzymes cause: a.An accumulation of certain complex carbohydrates. b.A deficiency of certain complex carbohydrates. c.A and B. 5. Each lysosomal storage disorder requires its own specific enzyme replacement therapy. a.True b.False VOLUME 29 6. Unlike most carriers of inherited diseases, a carrier of Fabry disease: a.Will remain free of symptoms of the disease. b.May present with symptoms of the disease. 7. Enzyme replacement therapy (ERT) is primarily administered to: a.Replace the missing or deficient enzyme. b.Cure the disease. c.Reverse most complications of disease. d.A and C. e.B and C. 8. ERT is administered: a.Intravenously for a lifetime. b.Orally for a lifetime. c.A or B. 9. Patients often develop antibodies to their ERT, creating potential for infusion reactions, including anaphylaxis. a.True b.False 10.Infusion reactions can often be managed by: a.Decreasing the rate of the infusion. b.Pre-medicating with an antipyretic and an antihistamine. c.A and B. C O R A M ’ S C O N T I N U I N G E D U C AT I O N P R O G R A M | 7 VOLUME 29 C O R A M ’ S C O N T I N U I N G E D U C AT I O N P R O G R A M Lysosomal Storage Diseases and Enzyme Replacement Therapy QUIZ ANSWERS Circle the correct answers below to receive 2.0 Continuing Education credits.* To obtain Continuing Education credits, please complete this information in full. Please print clearly. 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