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An Overview of Enzyme Replacement Therapy for Lysosomal Storage Diseases

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Laurie Bailey, MS, CGC


The lysosomal storage diseases (LSDs) are a group of disorders heralding in a new era in the treatment of genetic diseases. Enzyme replacement therapy (ERT) moves the treatment of these disorders from symptomatic management to therapeutic interventions. ERT is not a cure for these disorders, but it can greatly modify or attenuate the phenotype. Treatment for LSDs is lifelong and the diseases affect multiple organ systems. It is possible that nurses in almost every specialty will encounter a patient with one of these conditions. Therefore knowledge of the conditions, the benefits and limitations of ERT, and its effective management are becoming more important for all nurses. This article will describe several LSDs, namely Gaucher disease, Fabry disease, Pompe disease, and the mucopolysaccharidoses. Each disease pathology, signs and symptoms, and effectiveness of ERT treatment will be discussed, as well as the administration of ERT, common side effects, management of the side effects, and nursing implications. Additionally drug costs and insurance concerns will be highlighted.

Citation: Bailey, L., (January 31, 2008) "An Overview of Enzyme Replacement Therapy for Lysosomal Storage Diseases" OJIN: The Online Journal of Issues in Nursing Vol. 13, No. 1, Manuscript 3.

DOI: 10.3912/OJIN.Vol13No01Man03

Key words: lysosomal storage disease, enzyme replacement therapy, Gaucher disease, Fabry disease, Pompe disease, mucopolysaccharidosis I, Hurler syndrome, Hurler-Scheie syndrome, Scheie syndrome, mucopolysaccharidosis II, Hunter syndrome, mucopolysaccharidosis VI, Maroteaux-Lamy syndrome.

The lysosomal storage diseases (LSDs) are a group of disorders heralding in a new era in the treatment of genetic diseases. Not since the discovery that dietary modifications could alter the outcome of inborn errors of metabolism, such as phenylketonuria (PKU), galactosemia, and medium chain acyl carnitine deficiency (MCAD), has there been such hope for both children and adults diagnosed with these serious and often lethal genetic disorders. Enzyme replacement therapy (ERT) moves the treatment of these disorders from symptomatic management and comfort care to therapeutic interventions that address the underlying metabolic defect. ERT is not a cure for these disorders, but it can greatly modify or attenuate the phenotype (the signs and symptoms and severity of the condition) and disease progression. The success of ERT has proven that development of pharmacologic treatments for the LSDs is economically feasible and that development of better treatment options is worthwhile (Beutler, 2006; Connock et al., 2006).

This article will describe several LSDs, namely Gaucher disease, Fabry disease, Pompe disease, and the mucopolysaccharidoses. Each disease pathology, signs and symptoms, and effectiveness of ERT treatment will be discussed, as well as the administration of ERT, common side effects, management of the side effects, and nursing implications. Additionally drug costs and insurance concerns will be addressed.

Lysosomal Storage Diseases

The disease manifestations result from progressive accumulation of the specific macromolecules that cause the cells containing the lysosomes to become engorged. The lysosome is a membrane-bound organelle (a specialized part of the cell with a specific function) that contains a variety of hydrolytic enzymes that are capable of digesting essentially all types of biologic macromolecules (Kornfeld, 1992). The LSDs are a group of over 40 different disorders characterized by the lack of sufficient enzymatic activity to prevent the accumulation of specific macromolecules, such as glycosphingolipids (a variety of different lipids), mucopolysaccharides, or glycogen, in various tissues. Each unique disorder is caused by deficiency or dysfunction of a different enzyme. The disease manifestations result from progressive accumulation of the specific macromolecules that cause the cells containing the lysosomes to become engorged. Eventually this leads to tissue damage and organ dysfunction and/or failure (Kornfeld, 1992). Although each individual LSD is rare, as a group they have an estimated incidence of 1 in 6,500 to 7,500 live births, which is only slightly less common that cystic fibrosis (CF), one of the most frequently occurring genetic diseases.

Most LSDs are inherited in an autosomal recessive pattern. Two carrier parents have a 25% chance with each pregnancy to have an affected child. When each parent is a carrier, there is a 25% chance that a child will be affected, a 50% chance that a child will be a carrier like the parents, and a 25% chance that a child will have two working copies of the gene and not be a carrier or affected. This means that with each pregnancy there is 25% chance to have a child with the condition, and a 75% chance that the child will not be affected. Since the carrier rate for each LSD is usually on the order of 1 in 100 people in the general population, and there must be two carriers of the same condition to have an affected child, one would not expect a family history of the condition to be present. However, Fabry disease and Hunter syndrome, also known as Mucopolysaccharidosis type II (MPS II), are inherited in an X-linked pattern, and a family history is often present. Heterozygous (carrier) females have a 50% chance of passing the gene to each child. A female child who inherits the mutated gene will be heterozygous just like the mother, and a male child inheriting the mutated gene will be affected. If affected men can have children, then all of their female children will be heterozygous, and none of their male children will be affected. For currently treatable LSDs a variety of mutations in the gene, ranging from single substitutions to whole gene deletions, lead to deficient enzyme or enzyme activity (Grabowski et al., 2006; Kornfeld, 1992; Krivit, 2002; MacDermot, Holmes, & Miners, 2001; Pastores et al., 2004).

Lysosomal enzymes are normally synthesized via the rough endoplasmic reticulum in each cell. They are then processed in the Golgi where a mannose-6-phosphate (Man-6-P) residue is added. This residue identifies it as a lysosomal enzyme and allows it to be targeted to the lysosome of the cell. Lysosomes contain a Man-6-P receptor allowing for the efficient transfer of lysosomal enzymes across the lysosomal membrane. It is important to note that in Gaucher disease a Man-6-P residue is not naturally present on the enzyme, glucocerebrosidase. For the purposes of ERT, the enzyme is modified in the laboratory to expose a Man-6-P residue so that it may be targeted to the lysosome like the other lysosomal enzymes (Beutler & Grabowski, 2001; Kornfeld, 1992).

In the mid-1960’s Roscoe Brady speculated that injection of exogenously purified enzyme (enzyme purified outside of the body) into an affected person might provide therapeutic benefit. Early experiments in patients with Tay-Sachs disease, Fabry disease, and infantile-onset Pompe disease provided proof of this concept in that injections of small amounts of the disease specific enzyme resulted in reduced amounts of the stored substrate as measured in the patient’s blood (Brady, 2006). The first large-scale attempt at ERT occurred in patients with the most common LSD, Gaucher disease, in the 1980’s, using modified human enzyme purified from human placentas. It was approved by the Food and Drug Administration (FDA) for the treatment of patients with type 1 Gaucher disease in 1991. Due to both supply issues and safety concerns, an equally effective recombinant form of the enzyme is now produced in Chinese Hamster Ovary (CHO) cells (Brady, 2006; Pastores et al., 2004).

The following pages will describe several LSDs including Gaucher disease, Fabry disease, Pompe disease, and three mucopolysaccharidoses (MPS I, MPS II, and MPS VI). These conditions were chosen because they are the only LSDs for which there is an enzyme replacement product approved for the treatment of these conditions in both the United States (US) and Europe.

Gaucher Disease

Case study of Gaucher disease: Bryan (not a real patient) is a 28 year old male who had been having significantly more fatigue over the last 3 months. He required 9-10 hours of sleep per night and never felt refreshed upon waking in the morning. When he got home from work he usually took a 30 minute nap and could have probably slept longer if his family would have let him. He had also been having more pain, unlike any pain he had ever had before. It was primarily in his upper legs and upper arms and did not seem to be related to activity or changes in the weather. The pain had been severe enough on several occasions for him to call in sick to work. He looked awful because he was pale, had incredibly skinny arms and legs, and an enormous abdomen despite the many sit ups he did each night. He couldn’t find clothes to fit properly no matter where he shopped. His poor self image, increasing trouble with fatigue, difficulty staying awake at work, chronic pain, and overall feeling of malaise was causing him to feel quite depressed. He felt that he was too young to feel this old.

He went to see his primary care physician and routine bloodwork was consistent with low hemoglobin (10.3 g/dL) and low platelets (98,000). A physical examination revealed an enlarged liver (about 2 times enlarged) and spleen (about 15 times enlarged). Several large bruises were present on his lower legs and arms; Bryan could not recall how they had occurred. The physician referred Bryan to a hematologist to work him up for cancer. A bone marrow aspirate was not consistent with a malignancy, but revealed numerous large macrophages with a crinkled tissue paper appearance. These cells were most likely Gaucher cells, so blood was drawn and Gaucher disease was confirmed by both enzymatic and genetic studies.

Bryan was then referred to a center specializing in the treatment of lysosomal storage diseases, such as Gaucher disease. Although he was quite thankful not to have cancer, he wasn’t sure if Gaucher disease was better or worse than cancer. At the specialist’s office he learned more about the actual condition and the available treatment, namely enzyme replacement therapy. Within a few weeks Bryan became a regular patron at the clinic receiving his two-hour intravenous (IV) infusions of enzyme once every 2 weeks. Six months later he had made remarkable improvement. His liver was barely palpable and his spleen was about six to seven times enlarged and still shrinking. His hemoglobin had normalized and his platelets were about 130,000. He was pain free and his energy had improved dramatically. Special scans of his bones showed no progression of disease. His abdominal girth had decreased because his liver and spleen had gotten smaller. His color had improved and he had gained some muscle mass thereby giving him greater self-confidence related to his appearance. He still bruised easily, but not nearly as badly as before starting therapy. He felt like a new person.

He had been able to work out a schedule with his employer to leave early once every 2 weeks, and was still able to perform some work-related activities via computer while he was being infused. Although he had thought that the therapy would be a huge intrusion in his life, in actuality it was pretty easy especially given how much better he was feeling. Prior to therapy he was quite afraid of needles and thought that this fear may cause him to have to discontinue therapy. Although he still did not enjoy getting the IV catheter inserted, he had grown to trust the nurses and was usually impressed by how easily and quickly the needle was placed. He also thought that he would have had more difficulty getting his health insurance to cover the costs of the drug and related infusion charges. He was really surprised at the helpfulness of his case manager at the drug manufacturer who collected some information and was able to work with his healthcare providers and his insurance company to get all of the approvals in place prior to the start of treatment.

He had really gotten to know and trust the nurses at the infusion center who were so adept at inserting the IV catheter and managing his infusion. Now that he had completed six months of infusions without a reaction, and his Gaucher-related problems had responded so well to therapy, he had been given the opportunity to continue his enzyme replacement therapy through a home infusion company. Although he would miss the people at the clinic he was looking forward to the flexibility and comfort of home therapy especially since he would have to continue infusions for the rest of his life.

Gaucher disease was first described in 1882 by Philippe Gaucher. The disease results from the defective activity of glucocerebrosidase (GCase) and the subsequent storage of glucosylceramide in lysosomes of the macrophages. Classically, three clinical phenotypes have been described; type 1 (non-neuronopathic) with an incidence of 1 in 57,000, and types 2 and 3 (acute and sub-acute neuronopathic, respectively) with an incidence of 1 in 100,000. Type 1 disease has an increased incidence in the Ashkenazi Jewish population of 1 in 855 (Meikle, Hopwood, Clague, & Carey, 1999). The age of onset of Gaucher disease is quite variable ranging from severe manifestations in infancy to asymptomatic/sub-clinical manifestations in the eighth or ninth decade. Gaucher disease type 1 is characterized by hepatosplenomegaly, anemia, thrombocytopenia, and severe bone complications, such as avascular necrosis, bone pain/crises, and osteoporosis. Patients with type 1 disease have no central nervous system (CNS) involvement. Individuals with type 3 disease may have varying degrees of visceral involvement and the presence of CNS manifestations, such as myoclonic seizures and saccadic eye initiation defects. Infants with Gaucher disease type 2 have rapidly progressive CNS disease and pulmonary complications in addition to the visceral complications described in type 1 disease. The disease is usually lethal by 2 years of age (Grabowski et al., 2006; Pastores et al., 2004).

The patient transformation occurring as a result of ERT established a medical model for the successful pharmacologic treatment of not just LSDs, but rare diseases in general. It is not an accident that the first ERT product was for the treatment of Gaucher disease type 1. This condition became the natural choice for the development of ERT because of the relatively large numbers of affected individuals and lack of CNS involvement. Continuous enzyme infusions have been shown to restore health and reverse disease manifestations for most patients, allowing them to lead near-normal lives. Over the last 15 years Genzyme Corporation’s ERT product, imiglucerase (CerezymeTM) has proven to be effective at reducing the size of the liver and spleen to normal or near normal levels with concomitant improvements in anemia and thrombocytopenia over 2 years. Bone crises and bone pain improve or resolve over a period of 1 year (Wenstrup et al., 2007). Osteopenia/osteoporosis, however, takes 6-8 years to resolve (Brady, Murray, Moore, & Schiffmann, 2001). If ERT is initiated in childhood many of the other serious bone complications, such as avascular necrosis, lytic lesions, and pathologic fractures, may be prevented (Charrow, Dulisse, Grabowski, & Weinreb, 2007; Pastores et al., 2004). Pre-existing bone complications do not respond to treatment with ERT (Wraith, 2006). The degree of improvement and the time it takes to achieve therapeutic goals is dependent upon the dose used (Charrow, Dulisse, Grabowski, & Weinreb, 2007). The patient transformation occurring as a result of ERT established a medical model for the successful pharmacologic treatment of not just LSDs, but rare diseases in general. It also demonstrated that pharmaceutical companies could profit from the development of treatments for rare diseases and paved the way for the development of ERT for other LSDs (Beutler, 2006; Connock et al., 2006).

As noted in the Bryan case study, patients with Gaucher disease first receive ERT in the hospital with the expectation that they will be able to transition to home infusions. In the hospital, nurses need to be alert to possible infusion reactions that are described later in this paper. Remembering that therapy is lifelong once it is started, hospital nurses may need to be advocates for patients for whom peripheral IV access is difficult. Such patients may benefit from central line placement, and this possibility should be discussed with the patient’s physician and specialty team. Patient teaching regarding home infusions begins during the first 3 to 6 months of hospital infusions. In some cases, a patient’s parent or significant other may be willing and capable of learning how to establish IV access or access central lines and manage the infusions. Regardless, a home care nurse is usually involved in the transition. In the home, nurses, the patient, and family members need to remain alert for any signs of infusion reactions or worsening of Gaucher symptoms that may indicate the ERT is not working as intended. (Additional information may be found at the following online sites:, .)

Fabry Disease

Fabry disease is caused by the defective function of a-galactosidase A (a-gal A) and the subsequent storage of globotriaosylceramide (GL3) in lysosomes of the vascular endothelium, renal podocytes, and myocardial and neural cells. The incidence of the condition is estimated to be 1 in 50,000 (Desnick, Ioannou, & Eng, 2001). Classic Fabry disease primarily affects males, but many heterozygous females experience some symptoms and complications. Symptoms typically begin in early adolescence with acroparesthesias (burning pain in the hands and/or feet), gastrointestinal complications, such as nausea, diarrhea, and abdominal pain, temperature and exercise intolerance, and generalized pain or malaise. Anhidrosis or hypohidrosis, angiokeratomas (small purple marks on the skin), and corneal abnormalities are also common. Severe complications of Fabry disease, such as kidney failure; cardiac diseases, fsuch as myocardial infarctions, hypertrophic cardiomyopathy, and arrhythmias; and cerebrovascular changes resulting in stroke, do not typically occur until adulthood. The average age of death in untreated males is 41-55 years. Females on average experience a shortened life-span by about 15 years compared to the general population (Desnick, Ioannou, & Eng, 2001; Eng et al., 2007; Eng et al., 2006; Hoffmann & Keshav, 2007; MacDermot, Holmes, & Miners, 2001; Mehta et al., 2004; Ramaswami et al., 2006; Ries et al., 2005; Ries et al., 2003).

In 2003, ERT with Genzyme Corporation’s product, agalsidase beta (FabrazymeTM) received approval from the U.S. FDA. Fabrazyme is also approved for use in Europe and many other countries. Another ERT product made by ShireHGT, ReplagalTM, has also been approved for use in Europe and several other countries outside of the U S. Infusions were shown to reduce the amount of substrate measured in the serum, and serial renal, myocardial, and skin biopsies. Compared to untreated males with Fabry disease, ERT also slowed, and in a few cases prevented, the progression to kidney dialysis or transplant. Other studies showed improvement in some cardiac manifestations, such as left ventricular hypertrophy. There is increasing evidence that gastrointestinal complaints decrease and sweating improves when taking these products  (Banikazemi et al., 2007; Desnick & Brady, 2004; Kishnani, Hwu et al., 2006; Moon et al., 2003; Ramaswami et al., 2007; Ries et al., 2006).

...nurses play a critical role both in monitoring how the patient is coping with the therapy and in referring the patient to available support groups and community resources. After significant tissue or organ damage has occurred, ERT may not be able to reverse the disease process or prevent adverse outcomes, such as kidney failure. Therefore, it has been recommended that ERT be initiated prior to obvious organ dysfunction (Banikazemi et al., 2007). About 50% of heterozygous females (previously thought to be asymptomatic) may actually require ERT (MacDermot, Holmes, & Miners, 2001). There is currently much interest in identifying early signs, symptoms, or markers that correlate with disease activity and could be used to help decide when to initiate ERT and how well an individual is responding to the therapy. Unfortunately some of the more bothersome manifestations for the patient, including pain, have not adequately improved with ERT (Banikazemi et al., 2007; Ramaswami et al., 2007; Ries et al., 2006). This is in stark contrast to individuals with Gaucher disease who may feel significantly better after only a few months on ERT (Pastores et al., 2004). A major goal of early treatment is to reduce the risk for severe, life-threatening complications. Since the patients cannot “feel” this benefit it can be difficult to motivate a patient to remain on ERT.

Infusion reactions are more common with ERT for Fabry disease than Gaucher disease. Therefore, these patients may remain in outpatient care for a longer initial period before being transitioned to home care  These infusions also tend to take longer (4 hours as opposed to 2 hours for Gaucher disease). Considering the greater burden for infusions and the lack of dramatic early changes in how a patient feels, nurses play a critical role both in monitoring how the patient is coping with the therapy and in referring the patient to available support groups and community resources. Some reputable online links to support groups for Fabry disease include, but are not limited to: (United States), (Australia), and (United Kingdom).

Pompe Disease

Case study of Pompe disease: Maddie (not a real patient), a 4 month old baby, was emergently taken to the hospital because of increased work of breathing. Her pediatrician has been concerned about failure to thrive and severe hypotonia for the past few weeks. Her tongue also appeared large. The emergency room team performed a routine chest X-ray that revealed a massively enlarged heart. An ECG was consistent with right atrial enlargement and biventricular hypertrophy. Given the clinical picture and cardiac findings, Pompe disease was highly suspected. A nurse had previously been involved in the care of a baby with Pompe disease and was aware that they were at significant risk to develop life threatening arrhythmias  when exposed to general anesthesia. After sharing her previous experience with the physician, blood was drawn to confirm the diagnosis via genetic mutation analysis.

The blood was obtained and mutation analysis was performed at a specialized laboratory. Infantile-onset Pompe disease was confirmed within one week and enzyme replacement therapy was started within 24 hours of the diagnosis since infantile-onset Pompe disease is lethal by 1 year of age. Infusions had to begin before the disease progressed and irreversible damage had occurred to the heart and skeletal muscles.

Since infusions needed to be given every 2 weeks, a peripherally inserted central catheter (PICC) line was started. When the patient had stabilized after 4 months of therapy, a port was cautiously placed with sedation. The infusions were done in a hospital setting and lasted about 5 hours. Maddie had had some mild infusion reactions after the seventh infusion. She developed a hive-like itchy rash over her trunk in the last hour of the infusion. The nurses were able to quickly get the reaction under control by administering an additional antihistamine and slowing the final rate of infusion. No further reactions occurred once the infusion rates were adjusted.

...enzyme therapy clearly changed [Maddie's] outcome. She was alive with an excellent quality of life. In the family’s eyes the enzyme replacement therapy was nothing short of a miracle. Maddie, now 4 years, had a completely normal heart size and function, no respiratory distress, and had achieved all gross and fine motor skills appropriate for her age, although a little later than typical children. She walked with a bit of an abnormal gait, climbed stairs, used a pencil and crayons, attended preschool, and played with her siblings. She continued to have decreased muscle tone in her facial muscles and therefore had difficulty with speech. Maddie had been expected to die by age 12 months. She was never predicted to roll over let alone sit independently or walk. She was expected to be ventilator dependent. She will probably continue to have some muscle weakness and problems related to that weakness, especially problems with endurance, fatigue, and muscle tightness, but enzyme therapy clearly changed her outcome. She was alive with an excellent quality of life.

Pompe disease (glycogen storage disease type II) is caused by deficiency of acid a-glucosidase (GAA) resulting in lysosomal glycogen accumulation. The infantile form is estimated to affect 1 in 100,000 Caucasian people. The late-onset form is more common affecting an estimated 1 in 50,000 to 1 in 60,000 people (Martiniuk et al., 1998). It is very common in the African American population with an incidence of 1 in 14,000 (Hirschhorn & Reuser, 2001). Pompe disease is a cardioskeletal myopathy with onset ranging from infancy to adulthood. Infantile Pompe disease can present with weakness, hypotonia, poor feeding, respiratory distress, and hypertrophic cardiomyopathy in the first months of life. The disease is rapidly progressive with death occurring around one year. Late-onset Pompe disease can present from childhood to adulthood and patients primarily have skeletal muscle involvement. Although the cardiac and smooth muscle appears to be spared, patients can have significant diaphragmatic weakness and become ventilator (vent) dependent as the disease progresses. The condition can be quite debilitating (Hagemans et al., 2005; Kikuchi et al., 1998; Winkel et al., 2005).

Nurses can help families construct a mobile medical record and fact sheet about the disorder, with Internet addresses to useful resources, if the professional wants further information. In 2006 Genzyme Corporation’s product, alglucosidase alfa (MyozymeTM) received approval from the FDA for the treatment of Pompe disease. The initial studies were conducted in patients with infantile-onset Pompe disease. The drug prolongs the patient’s overall survival, prolongs vent-free survival, and improves cardiomyopathy. Many patients experience gains in gross and fine motor skills, but still lag behind typical children of comparable age. Some patients do not experience any significant functional gains while on enzyme. Those individuals most likely produce no detectable enzyme [cross-reacting immunological material (CRIM) negative]. Patients with late-onset Pompe disease would be expected to produce some enzyme. Although Myozyme has a broad label for use in any patient diagnosed with Pompe disease, specific information about efficacy in patients with late-onset disease is not available. However, this information is currently being collected through on-going clinical trials (Amalfitano et al., 2001; Kikuchi et al., 1998; Kishnani et al., 2007; Kishnani, Nicolino et al., 2006; Reuser et al., 2002; Thurberg et al., 2006; Van den Hout et al., 2004).

As demonstrated in the Maddie case study, infants who survive and later thrive as a result of ERT do have remaining developmental issues. An important role for nurses is to help families access early intervention services in their community. These children may also require occupational, physical, and speech therapies as well as regular monitoring by specialists and their pediatrician. Therefore, nurses can play an important role in assuring coordinated care by initiating care conferences as needed. Parents who have children with complex health needs also become frustrated when they have to teach new health care professionals about their child’s rare condition. Nurses can help families construct a mobile medical record and fact sheet about the disorder, with Internet addresses to useful resources, if the professional wants further information. (Helpful sites include: , , , and .)

Mucopolysaccharidoses (MPS)

The mucopolysaccharidoses are a group of LSDs that result in abnormal tissue accumulations of glycosaminoglycans (GAGs). In general, the incidence for each MPS is 1 in 100,000 (Meikle, Hopwood, Clague, & Carey, 1999). There are six types of MPS disorders. Currently enzyme replacement therapy is available for three MPS disorders. MPS I (Hurler, Hurler-Scheie, or Scheie syndrome) resulting from deficiency of alpha-L-idurnoidase, MPS II (Hunter syndrome) resulting from deficiency of iduronate sulfatase, and MPS VI (Maroteaux-Lamy syndrome) caused by deficiency of arylsulfatase B. The disorders have overlapping symptoms and are most commonly characterized by varying degrees of intellectual disability (except MPS VI), coarse facies, corneal clouding (except MPS II), deafness, cardiac disease, hepatosplenomegaly, skeletal disease including joint contractures and dysostosis multiplex, and growth retardation after several years of normal growth. All of the MPS disorders are inherited in an autosomal recessive pattern except MPS II, which is X-linked (Wraith et al., 2004).

Stem cell or bone marrow transplant (BMT) is the standard of care for patients with severe MPS I (Hurler syndrome) if diagnosed and performed under the age of two years. It typically results in improved coarse facies, cardiac disease, and upper airway obstruction. BMT can slow or even prevent further neurologic complications, but has little to no effect on the skeletal disease. BMT is still associated with high morbidity and mortality despite recent advances in the field (Peters et al., 1998; Sifuentes et al., 2007; Vellodi et al., 1997). An enzyme replacement product, Laronidase (AldurazymeTM) made by Genzyme Corporation was approved by the FDA in 2003. It, too, has been approved for use in Europe and other countries. It has been shown to improve hepatosplenomegaly, respiratory complications, urine GAG levels, growth velocities, and range of motion and endurance. There is not expected to be any effect on the brain or bone disease progression (Gassas, Sung, Doyle, Clarke, & Saunders, 2003; Guffon, Souillet, Maire, Straczek, & Guibaud, 1998; Kakkis et al., 2001).

Some centers are using ERT prior to bone marrow transplant in hopes of decreasing the storage burden and improving the patient’s health prior to BMT. There is no need to continue ERT in a fully engrafted patient with MPS I. ERT is also appropriate for patients who are not candidates for, or who choose not to pursue, BMT. Patients with the attenuated forms of MPS I (Hurler-Scheie or Scheie), which have little to no neurologic involvement, are excellent candidates for ERT because they can get many of the same benefits of BMT without the significant risk for morbidity or mortality (Gassas, Sung, Doyle, Clarke, & Saunders, 2003; Guffon, Souillet, Maire, Straczek, & Guibaud, 1998).

There may be a larger role for ERT in the treatment of MPS II since BMT has not been found to be as beneficial as it is in MPS I (Sifuentes et al., 2007). In 2006, idursulfase (ElapraseTM), made by ShireHGT, received approval in the United States from the FDA and also in Europe. Improvements in hepatosplenomegaly, cardiopulmonary function, urinary GAGs, and endurance were noted in the clinical trials. Elaprase, like Aldurazyme, is not expected to have an impact on CNS progression or significant bone disease (Hughes, Ramaswami, Elliott, Deegan, et al., 2005).

ERT for MPS VI using recombinant arylsulfatase B (NaglazymeTM), made by Biomarin, became available in 2005. It was shown to reduce hepatosplenomegaly, pain, and urinary GAGs. Patients also report being able to walk farther and climb stairs more easily. (Additional patient support information about MPS disorders may by found at the following online sites:,,,

Administration of ERT and Management of Drug Side Effects

Enzyme replacement therapy is a lifelong therapy. All products are administered intravenously either through a peripheral line or central access device, such as a Port-a-Cath. Infusions typically occur once every 2 weeks, except Aldurazyme and Elaprase which are administered weekly. Initially infusions should be performed in an outpatient clinic setting; although for some of the more medically fragile patients, an inpatient setting or short stay infusion unit may be more appropriate. Infusions are usually administered over 2-6 hours depending on the amount of drug that needs to be infused and the patient’s previous adverse event history. Many patients can be transferred to a home infusion setting after a period of successful clinic infusions without infusion-related reactions, typically in 6 months. Patients with Pompe disease or MPS may not be able to transfer to home care because of an increased risk for serious adverse events during an infusion.

Nurses need to become familiar with adverse events specific for each enzyme replacement product. Some of the common adverse infusion-related reactions that nurses need to be aware of include itching and redness at the IV site, edema, hives, and allergic-like symptoms, such as nasal discharge, watery eyes, and generalized itching. Other commonly reported events are chills, rigors, and fatigue. More significant events including chest tightness, respiratory distress, and cardiac arrhythmia could be signs of anaphylaxis.

Infusion reactions can usually be managed by decreasing the rate of the infusion together with antihistamines or occasionally corticosteroids. Infusion reactions can usually be managed by decreasing the rate of the infusion together with antihistamines or occasionally corticosteroids. Pretreatment with antipyretics and/or antihistamines is recommended, especially in subsequent infusions after an infusion reaction has occurred. Administering the infusions using a ramp-up protocol (slowly increasing the rate of the infusion over the course of the infusion) has also proven quite successful at preventing infusion reactions. Even patients with more serious anaphylactic reactions have been able to resume ERT following desensitization in a controlled setting. Since ERT has only been available for a few years, the long-term adverse effects have not been delineated. However, many patients with Gaucher disease have received ERT for 15-20 years without any significant drug-related adverse events.

Patients who have drug-related infusion reactions require blood work to determine if they have developed antibodies to the enzyme. Antibodies are substances made by the body in response to the presence of the foreign ERT drug. Two types of antibodies typically form. IgG antibodies bind to the drug and increase the chance for mild to moderate infusion reactions as described above. The reactions are usually easily controlled with infusion rate reductions and administration of pre-treatment medications. IgE antibodies increase the risk for more serious anaphylactic reactions. If an anaphylactic-like infusion reaction has occurred, it is imperative to know if IgE antibodies are present prior to administering the next infusion. Because alternative treatments do not exist for many of the diseases described in this article, ERT is often continued in patients with IgE antibodies despite the risk for anaphylaxis. In these situations an immunologist should be consulted and the infusion performed in a high risk or intensive-care setting.

Some patients who initially improve during therapy may seem to later regress/redevelop previously resolved symptoms. In Gaucher disease less than 1% of patients on ERT develop inhibitory antibodies that bind to and inactivate the enzyme being infused. This number may be higher for other LSDs. Therefore, nurses need to be alert to this possibility and report any suspicions of such to the treating physician.

...the drug response is somewhat dependent on disease burden, previous damage that occurred prior to the start of ERT, and the patient’s individual disease complications. Except for Gaucher disease the percentage of people receiving ERT who become IgG antibody positive ranges from 50% - 90%. In Gaucher disease about 12% of patients receiving Cerezyme become IgG antibody positive, and reported infusion reactions are typically mild. Fabry patients on Fabrazyme have an IgG antibody conversion rate of 50% - 90%. Infusion reactions are usually more significant than what is observed with Cerezyme, but still very manageable. Pompe patients on Myozyme have an IgG antibody conversion rate of 50%-90%. The conversion rate in MPS I (Aldurazyme) is 59%-90%; MPS II (Elaprase) is 50%, and MPS VI (Naglazyme) is 90%. Patients with Pompe disease or any of the MPS disorders are more medically fragile and may have more significant underlying visceral disease affecting their heart and airway. When any infusion reaction occurs, even if initially mild, there is a greater chance that the complication could be severe and require more significant interventions. For this reason it is highly recommended that these infusions be performed in a unit with easy access to emergency medical interventions should this become necessary.

Drug Costs/Insurance Concerns

In general patients are not denied drug coverage by their third party payers in the United States, but often times must be concerned about lifetime maximums...Some drug companies also have international programs in place to provide ERT free of charge... The majority of patients receive some benefit from ERT, however the drug response is somewhat dependent on disease burden, previous damage that occurred prior to the start of ERT, and the patient’s individual disease complications. On average the drug cost per year for ERT is $200,000-$300,000 in the United States, depending on the individual’s weight, prescribed dose, and the average wholesale price of the drug (Brady, 2006). This does not include markup on the drug from hospitals, private offices, or infusion centers. It does not include supplies, infusion charges, or other medications and therapies needed to treat the condition. In general patients are not denied drug coverage by their third party payers in the United States, but often times must be concerned about lifetime maximums which could be reached in 2-5 years, thereby  increasing premium costs, and pharmacy plans with an annual maximum of $25,000-$50,000 on a subset of drugs. Although it is not actually known how many people have reached their lifetime insurance maximum for a particular insurance plan, it is a constant worry for most patients and affects their decisions about employment in particular. ERT is also available in Canada, Europe, South America, Australia, and many Asian countries. In the United States insurance companies, both private and public, pay for the cost of the drug, infusions, and disease management. Outside of the United States there are numerous mechanisms in place to determine when ERT treatment will be provided. The mechanism to start ERT varies from country to country. However, in countries with socialized health care, therapy is available, but only after certain disease-specific criteria have been met. There may be an individual approval process or a board that must meet to decide who can be treated. In other countries smaller doses of the medication are prescribed in order to decrease some costs. Some drug companies also have international programs in place to provide ERT free of charge to certain patients living in countries where ERT is not currently available because of financial restrictions. Additionally, ERT can put an incredible burden on a patient or family. It is time consuming, often requiring a day off of work or absence from school every 1-2 weeks, and travel of great distances to infusion centers to receive the drug.


For nurses in the primary care setting, being able to recognize the signs and symptoms of the conditions is imperative since early diagnosis and early treatment are necessary to optimize the response from ERT. Treatment for chronic LSDs is lifelong and the diseases affect multiple organ systems. It is possible that nurses in almost every specialty and across the lifespan will encounter a patient  receiving  ERT for one of these conditions. Therefore knowledge of the conditions, the benefits and limitations of ERT, and its effective management are becoming more important for all nurses. For nurses in the primary care setting, being able to recognize the signs and symptoms of the conditions is imperative since early diagnosis and early treatment are necessary to optimize the response from ERT. Helping to make appropriate referrals to genetic specialists and other specialists, such as hematologists, nephrologists, or neurologists is important for disease management. Nurses can also help educate the patients regarding the disease, enzyme therapy, and infusions in general. Currently infusion nurses often care for oncology patients, but they are becoming more likely to encounter patients with a LSD requiring ERT. Knowledge of the condition and an understanding that ERT is different from chemotherapy is imperative. In contrast to oncology patients, LSD patients receiving ERT are not likely to become sick during the infusion; however, their infusions are lifelong. The ERT patients may be uncomfortable if surrounded by cancer patients or may be fearful that similar chemotherapy side effects may be in their future. Nurses are in a unique position to act as a bridge between the patient and other health care providers. They are often the first health care provider to interact with the patient and may be the one to whom the patient first turns to for education and/or support regarding the diagnosis and therapy.

The development of ERT has brought hope to individuals with some rare, inherited LSDs. What has become clear as more enzyme therapies have become available for different LSDs is that the benefits of each product are different for each disorder. ERT is not a cure for any condition; but it does offer a therapy that treats the underlying cause of the disease, namely deficient enzyme activity. It is probably most beneficial for patients with Gaucher disease since ERT can reverse and prevent some complications. It is not effective at treating CNS disease or existing bone disease, so other therapies need to be developed to treat those aspects of the disease. Fabrazyme has been shown to slow the progression of some life-threatening complications. However, it has had a disappointing effect on pain and other manifestations of the disease that the patients find most bothersome. It remains to be determined if Fabrazyme can prevent certain complications if started prior to development of major organ damage. Although Myozyme has the potential to have the greatest impact on infantile-onset Pompe disease by extending the child’s overall and vent-free life and improving muscle tone so that motor milestones can be achieved, it is not equally effective for all patients. Facial muscle weakness, general muscle weakness, and hearing loss remain despite early intervention with the enzyme. The MPS disorders are the group of disorders with the most uncertainty regarding benefit. Although most patients anecdotally report improvements in quality of life, it remains to be determined if both the monetary cost and psychosocial burden of infusions support the benefits derived from ERT.

ERT is safe and effective; however, it is costly and burdensome to the family. As individuals live longer with these conditions and some aspects of the disease are treated, it is likely that new disease complications will emerge as the disease phenotype changes in response to therapy. Since most disease complications do not appear to be completely reversible, if at all, it is of utmost importance to diagnose LSDs early in life and begin ERT prior to the onset of irreversible damage. ERT is safe and effective; however, it is costly and burdensome to the family. Now that it has been demonstrated that the development of therapies for rare diseases is financially feasible, hopefully further development of more convenient, cost-beneficial therapies will continue so that life-changing therapies are available to prevent the devastating complications of LSDs.


Laurie Bailey, MS, CGC

Laurie Bailey is a board certified genetic counselor (CGC) who has coordinated the Cincinnati Support, Treatment, Advocacy, and Research (STAR) Center for Lysosomal Diseases at Cincinnati Children's Hospital in Cincinnati, Ohio, Ohio since 1999. She received a Bachelor of Arts degree in Microbiology from Miami University in Oxford, Ohio, and a Master of Science degree in Medical Genetics from the University of Cincinnati in Ohio. She currently follows over 150 patients and coordinates clinical research and enzyme replacement therapy trials for families affected by various lysosomal diseases including Gaucher disease, Fabry disease, Pompe disease, and the MPS disorders. She is also the genetic counselor associated with the lysosomal testing section of the Molecular Genetics Laboratory and Biochemical Genetics Laboratory. She has spoken at numerous local, regional, and national meetings about various lysosomal storage disorders, management of chronic diseases, and enzyme replacement therapy.


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© 2008 OJIN: The Online Journal of Issues in Nursing
Article published January 31, 2008

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